Τετάρτη 31 Ιανουαρίου 2018
Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study
Abstract
Background
Lifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent anti-mitotic agent, monomethyl auristatin E (MMAE), which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody-drug-conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients. Patients and Methods
Platinum-resistant OC patients were randomized to receive LIFA (2.4 mg/kg, intravenously, every 3 weeks [Q3W]), or pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary endpoint was progression-free survival (PFS) in intent to treat (ITT) and NaPi2b-high patients. Results
Ninety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 (95% CI, 0.46–1.31; p=0.34) with a median PFS of 5.3 vs. 3.1 months (LIFA vs. PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40–1.26; p=0.24) with a median PFS of 5.3 vs. 3.4 months (LIFA vs. PLD arm, respectively) in NaPi2b-high patients. The objective response rate (ORR) was 34% (95% CI, 22–49%, LIFA) vs. 15% (95% CI, 7–28%, PLD) in the ITT population (p=0.03), and 36% (95% CI, 22–52%, LIFA) vs.14% (95% CI, 6–27%, PLD) in NaPi2b-high patients (p=0.02). Toxicities included grade ≥3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA vs. 2 (4%) PLD patients had grade ≥ 2 neuropathy. Conclusion
Lifastuzumab vedotin Q3W was well-tolerated and improved ORR with a modest, non-statistically significant improvement of PFS compared to PLD in platinum-resistant OC. While the response rate for the MMAE-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADC's in OC. Clinical trials.gov
NCT01991210Results of a multi-institutional, randomized, non-inferiority, phase 3 trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group study (JCOG0701)
Background
We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and Methods
In this multi-institutional, randomized, phase 3 trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1 − 2N0M0, age 20 − 80, Eastern Cooperative Oncology Group (ECOG) performance status of 0 − 1, and adequate organ function. Patients were randomly assigned to receive either SF of 66 − 70 Gy (33 − 35 fractions), or AF of 60 − 64.8 Gy (25 − 27 fractions). The primary endpoint was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results
Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4 − 85.4) for SF and 81.7% (95% CI 75.4 − 87.0) for AF (difference 1.8%, 91% CI 5.1%−8.8%; one-sidedP = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year OS between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1(0.5%)) in the SF/AF arms. Conclusion
Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared to SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. UMIN000000819Real world data on the efficacy and safety of apremilast in patients with moderate to severe plaque psoriasis
Abstract
Background
Psoriasis is a chronic inflammatory skin disease, which requires long term, safe and effective treatment. Apremilast, a small-molecule PDE4 inhibitor, has been introduced as psoriasis (and psoriatic arthritis) treatment in Europe in 2015.
Objective
We analysed and report the efficacy and safety of apremilast in the first 51 patients with psoriasis that have undergone treatment with this novel small molecule in our outpatient clinic.
Method
Our primary endpoint was the evaluation of clinical response to apremilast according to the percentage of PASI reduction (ΔPASI) at 16 weeks after treatment initiation. Secondary endpoints were the evaluation at week 16 of: (i) Psoriasis Area Severity Index (PASI); (ii) Dermatology Life Quality Index (DLQI); (iii) Physician Global Assessment (PGA); (iv) Psoriasis Scalp Severity Index (PSSI); and (v) the percentage of patients who achieved ΔPASI50, ΔPASI75, ΔPASI90 and ΔPASI100; (vi) adverse events (AE); (vii) reasons for drug discontinuation; and (viii) drug survival.
Results
59.3% of the patients who remained on apremilast achieved at least ΔPASI75 at week 16, while 11.1% achieved combined 50%≤PASI<75% and DLQI≤5 (satisfactory response) adequate enough to maintain treatment. Five patients (18.5%) also achieved ΔPASI100. Patients discontinued apremilast (28%), mostly during the first four weeks due to adverse events (12%) with gastrointestinal symptoms being the most common, and later due to lack of efficacy (16%). A statistically significant improvement of PASI, DLQI, PGA and PSSI scores was observed after 4 and 16 weeks of treatment relative to pre-treatment measurements.
Conclusion
Apremilast is a safe and efficacious treatment for psoriasis patients as it produces ΔPASI75 and ΔPASI50 responses combined with DLQI≤5 in 16 weeks in 70.4% of the patients. These results, from a real-world setting, confirm the efficacy and safety of apremilast which has been demonstrated in large phase III clinical trials.
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Inequalities in zoster disease burden: a population-based cohort study to identify social determinants using linked data from the UK Clinical Practice Research Datalink
Abstract
Background
Zoster vaccination was introduced in England in 2013, where tackling health inequalities is a statutory requirement. However, specific population groups with higher zoster burden remain largely unidentified.
Objective
To evaluate health inequalities in zoster disease burden prior to zoster vaccine introduction in England.
Methods
This population-based cohort study utilised anonymised UK primary care data linked to hospitalisation and deprivation data. Individuals aged ≥65 years without prior zoster history (N=862,470) were followed from 01/09/2003-31/08/2013. Poisson regression was used to obtain adjusted rate ratios (ARR) for the association of socio-demographic factors (ethnicity, immigration status, individuals' area-level deprivation, care home residence, living arrangements) with first zoster episode. Possible mediation by co-morbidities and immunosuppressive medications was also assessed.
Results
There were 37,014 first zoster episodes, with incidence of 8.79 (95% confidence interval (CI):8.70-8.88) per 1,000 person-years at risk. In multivariable analyses, factors associated with higher zoster rates included care home residence (10% higher versus those not in care homes), being female (16% higher versus males), non-immigrants (~30% higher than immigrants) and White ethnicity (for example, twice the rate compared to those of Black ethnicity). Zoster incidence decreased slightly with increasing deprivation (ARR most versus least deprived=0.96 (95%CI:0.92-0.99) and among those living alone (ARR 0.96 (95%CI:0.94-0.98). Mediating variables made little difference to the ARR of social factors but were themselves associated with increased zoster burden (ARR varied from 1.11-3.84).
Conclusions
The burden of zoster was higher in specific socio-demographic groups. Further study is needed to ascertain whether these individuals are attending for zoster vaccination.
This article is protected by copyright. All rights reserved.
The PARACELSUS score: A novel diagnostic tool for pyoderma gangrenosum
Abstract
Background
The lack of objective diagnostic criteria renders pyoderma gangrenosum (PG) a diagnosis of exclusion. The diagnostic approaches proposed to date have not been systematically evaluated. Thus, PG remains a challenging and frequently misdiagnosed disorder.
Objectives
To develop and assess a comprehensive yet clinically practicable as well as sensitive diagnostic scoring system for PG.
Methods
Clinical history and images of a total of 60 subjects with previously confirmed PG located on the lower extremity as well as a control cohort of 50 patients with venous leg ulcers were retrospectively evaluated by expert teams at two tertiary dermatological centres specializing in wound care using a newly developed diagnostic scoring system composed of ten criteria.
Results
The three major diagnostic criteria are rapidly progressing disease, assessment (absence) of relevant differential diagnoses and reddish-violaceous wound border (prevalent in 98.3% of PG patients, respectively). Minor criteria (evident in 61-95% of PG cases) include amelioration (alleviation) by immunosuppressant drugs, characteristically irregular shape of ulceration, extreme pain >4/10 on visual analogue scale, and localization of lesion at site of trauma. Three additional criteria (observed in up to 60% of PG subjects) encompass suppurative inflammation in histopathology, undermined wound margins as well as concomitant systemic disease. A total score value of ten points or higher indicates a high likelihood of PG and differentiates PG from venous leg ulcers. The initial letters of the above-listed criteria form the acronym PARACELSUS.
Conclusion
The PARACELSUS score represents a novel, easily implementable, effective and sensitive diagnostic tool for PG.
This article is protected by copyright. All rights reserved.
Sirolimus for treatment of Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon: A retrospective cohort study
Abstract
Kaposiform hemangioendothelima (KHE) is a locally aggressive vascular tumor that mainly occurs during childhood and invades adjacent tissue and organ. It is commonly complicated by Kasabach-Merritt phenomenon (KMP) in about 50%-70% of the cases. KMP is most often associated with a rapidly growing, large solitary tumor that may result in severe hemorrhage and directly responsible for high mortality and morbidity.
This article is protected by copyright. All rights reserved.
“Cleaved Lymphocytes” Could Be Induced by Pertussis Toxin Injection in Mice, and Are Actually Not Lymphocytes
To the Editor—With great interest we read the most recent contribution of Zhang et al reporting that a simple blood smear may provide a diagnostic clue for Bordetella pertussis infection [1]. Zhang et al described a case of pertussis with peripheral blood smear showing mature lymphocytes with cleaved nuclei, characteristic of B. pertussis lymphocytosis. As the authors state, this finding provides a possibly easy and new way to determine pertussis, because current laboratory tests, such as isolation of B. pertussis and detection of its bacterial DNA, are not widely available. Their results were also supported by other 2 previous reports published in Blood [2] and The Lancet Infectious Diseases [3]. However, there were several questions about these "cleaved lymphocytes." Can these cells occur in the blood after the pertussis toxin (PT) injection? PT is a specific toxin of B. pertussis and is the cause of lymphocytosis [4]. If true, cleaved lymphocytes could be a clue to suspect pertussis. In addition, do the cleaved lymphocytes belong to lymphocytes? After all, their morphologic characteristics are obviously different from normal lymphocytes.
Discharge Criteria for Patient With Lassa Fever Infection
To the Editor—We read with interest the report on 2 epidemiologically linked patients with Lassa fever (LF) secondarily acquired from the same index case in Togo and medically evacuated to Cologne, Germany (patient E) and to Atlanta, Georgia (patient F), respectively [1].
Reply to Nicastri et al
To The Editor— We appreciate the comments of Nicastri, Vairo, and Ippolito regarding the need to identify parameters for safe hospital discharge of Lassa fever patients in nonendemic settings.
Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial
Abstract
Background
Vaccination of human immunodeficiency virus (HIV)-infected infants with bacille Calmette-Guérin (BCG) is contraindicated. HIV-exposed newborns need a new tuberculosis vaccination strategy that protects against tuberculosis early in life and avoids the potential risk of BCG disease until after HIV infection has been excluded. Methods
This double-blind, randomized, controlled trial compared newborn MVA85A prime vaccination (1 × 108 PFU) vs Candin® control, followed by selective, deferred BCG vaccination at age 8 weeks for HIV-uninfected infants and 12 months follow-up for safety and immunogenicity. Results
A total of 248 HIV-exposed infants were enrolled. More frequent mild–moderate reactogenicity events were seen after newborn MVA85A vaccination. However, no significant difference was observed in the rate of severe or serious adverse events, HIV acquisition (n = 1 per arm), or incident tuberculosis disease (n = 5 MVA85A; n = 3 control) compared to the control arm. MVA85A vaccination induced modest but significantly higher Ag85A-specific interferon gamma (IFNγ)+ CD4+ T cells compared to control at weeks 4 and 8 (P < .0001). BCG did not further boost this response in MVA85A vaccinees. The BCG-induced Ag85A-specific IFNγ+ CD4+ T-cell response at weeks 16 and 52 was of similar magnitude in the control arm compared to the MVA85A arm at all time points. Proliferative capacity, functional profiles, and memory phenotype of BCG-specific CD4 responses were similar across study arms. Conclusions
MVA85A prime vaccination of HIV-exposed newborns was safe and induced an early modest antigen-specific immune response that did not interfere with, or enhance, immunogenicity of subsequent BCG vaccination. New protein-subunit and viral-vectored tuberculosis vaccine candidates should be tested in HIV-exposed newborns. Clinical Trials Registration
NCT01650389.Trichomonas vaginalis Brain Abscess in a Neonate
Abstract
We describe a case of cerebral trichomoniasis in a neonate in whom seizures and multiorgan failure developed during treatment for staphylococcal sepsis. Brain abscesses were identified with cranial sonography, and Trichomonas vaginalis was isolated from cerebrospinal fluid samples. The patient died despite metronidazole therapy.Dengvaxia Efficacy Dependency on Serostatus: A Closer Look at More Recent Data
To the Editor—We read with concern the recent article by Yang and colleagues, "Dependency of Vaccine Efficacy on Pre-Exposure and Age: A Closer Look at a Tetravalent Dengue Vaccine" [1]. We agree that Dengvaxia was efficacious among children who were dengue seropositive at baseline, but it is important to mention that it is not known how long vaccinated seropositive individuals will be protected. More studies are necessary as this vaccine could be giving only a temporary boost to their immunity.
Reply to Aguiar and Stollenwerk
To the Editor—Aguiar and Stollenwerk [1] analyzed the safety data provided in Martínez-Vega et al [2] for 2 phase 3 clinical trials of Dengvaxia during up to 6 years of follow-up. The authors reported negative vaccine efficacy (VE) against hospitalization, –76% among baseline seronegative individuals 2–8 years old and –40% among 2–16 years old and expressed their concerns, although neither estimate is statistically significant. Martínez-Vega et al presented similar results but challenged the concept of vaccine-induced antibody-dependent enhancement among seronegative young children [2]. Despite the safety concerns, Dengvaxia remains important in the current portfolio for controlling dengue [3]. The ongoing debate on the utility of Dengvaxia justifies our focus on a thorough quantification of the impact of preexposure and age on VE against general dengue disease during the 25-month active phase [4]. A deep understanding of major determinants of the VE against general clinical outcomes would greatly benefit the assessment of the overall public health impact of Dengvaxia in the long run, for example, using the approach of mathematical modeling [3, 5].
Reply to Gilchrist et al. and to Musher
To the Editor—We read with interest Gilchrist and colleagues' report of an adult case of recurrent bacterial meningitis, presenting with both an immunodeficiency and a local promoting factor. The patient first presented with a history of 2 episodes of pneumococcal meningitis in 3 years and then an episode of meningococcal meningitis 6 years later, despite antibiotic prophylaxis (the details of which were not provided) and protein-conjugate vaccination (probably against Streptococcus pneumoniae). After the first 2 episodes, immunological evaluation detected an IgG2 subclass deficiency and associated poor anti-pneumococcal antibody responses. Surprisingly, an initial computed tomography (CT) scan did not find any skull base abnormalities after the 2 episodes of pneumococcal meningitis. However, dehiscence of the right tegmen tympani was observed after the episode of meningococcal meningitis—suggesting a cerebrospinal fluid leak. When directly questioned in this respect, the patient reported watery rhinorrhea.
Polysaccharide Antibody Deficiency: Specific or General?
To the Editor—Lopez et al [1] studied responses to pneumococcal capsular polysaccharides (PPSs) in 9 patients who had recovered from infection caused by an encapsulated bacterium. They showed that these individuals failed to mount appropriate antibody responses to ≥3 of 7 PPSs tested, and called this phenomenon "specific polysaccharide antibody deficiency."
Adult-Onset Recurrent Bacterial Meningitis: Immunological Red Herrings
To the Editor—In their recent article, Lopez et al report the identification of specific polysaccharide antibody deficiencies (SPADs) in adults presenting with invasive infection caused by encapsulated bacteria [1]. The identification of SPAD is important as it may permit intervention with strategies to mitigate the risk of subsequent infection, for example, protein-conjugate vaccination, antibiotic prophylaxis, and immunoglobulin replacement. Not all patients, however, with SPAD will require intervention. Up to 11% of healthy individuals meet the immunological criteria for SPAD [2]. More importantly, the identification of an immunological abnormality, which may be incidental to a patient's infection susceptibility, has the potential to distract from consideration of other causes of infection susceptibility. To illustrate this, we present a case of adult-onset, recurrent bacterial meningitis, in which identification of an immunoglobulin G2 (IgG2) subclass deficiency, with associated SPAD, was incidental to his infection susceptibility.
Genetics and Evolution of Infectious Diseases
Genetics and Evolution of Infectious Diseases2nd ed. Edited by TibayrencMichel. Elsevier, 2017. 667 pp. $190 (hardcover).
The Politics of Fear: Médecins Sans Frontières and the West African Ebola Epidemic
The Politics of Fear: Médecins Sans Frontières and the West African Ebola EpidemicEdited by HofmanMichielAuSokhieng. Oxford University Press, New York, NY, USA, 2017. 304 pp. Hardcover: $24.95. ISBN: 9780190624477.
Collagen-derived peptides modulate CD4+ T-cell differentiation and suppress allergic responses in mice
Abstract
Introduction
Collagen peptides have been widely used as a food supplement. After ingestion of collagen peptides, oligopeptides containing hydroxyproline (Hyp), which are known to have some physiological activities, are detected in peripheral blood. However, the effects of collagen-peptide administration on immune response are unclear. In the present study, we tested the effects of collagen-peptide ingestion on allergic response and the effects of collagen-derived oligopeptides on CD4+ T-cell differentiation.
Methods
BALB/c mice fed a collagen-peptide diet were immunized with ovalbumin (OVA), and their serum IgE and IgG levels, active cutaneous anaphylaxis, and cytokine secretion by splenocytes were examined. Naive CD4+ T cells were stimulated with anti-CD3 and anti-CD28 in the presence of collagen-derived oligopeptides, and the expression of IFN-γ, IL-4, and Foxp3 was analyzed.
Results
In an active anaphylaxis model, oral administration of collagen peptides suppressed serum OVA-specific immunoglobulin E (IgE) production and diminished anaphylaxis responses. In this model, the ingestion of collagen peptides skewed the pattern of cytokine production by splenocytes toward T-helper (Th) type 1 and regulatory T (Treg) cells. In vitro T-helper cell differentiation assays showed that Hyp-containing oligopeptides promoted Th1 differentiation by upregulating IFN-γ-induced signal transducer and activator of transcription 1 (STAT1) signaling. These oligopeptides also promoted the development of Foxp3+ Treg cells in response to antigen stimulation in the presence of TGF-β.
Conclusions
Collagen-peptide ingestion suppresses allergic responses by skewing the balance of CD4+ T cells toward Th1 and Treg cells and seems to be a promising agent for preventing allergies and inflammatory diseases.
Collagen-peptide feeding enhanced IFN-γ and IL-10 secretion by splenocytes. Mice fed a collagen peptide or control diet were immunized with OVA. Splenocytes from the immunized mice were cultured in the presence of OVA for 3 days and cytokine levels in the supernatant were measured.
New findings in non-invasive imaging of cutaneous endometriosis: Dermoscopy, high-frequency ultrasound and reflectance confocal microscopy
Abstract
Background
Cutaneous endometriosis (CE) is rare and its dermoscopic features were reported only in 3 patients. The aim of this study was to examine a case of pigmented CE with multiple non-invasive imaging techniques, to compare the obtained images with histopathology and to define their utility in an early diagnosis of the disease.
Case report
We performed dermoscopy, high-frequency ultrasound (HFUS), in vivo and ex vivo reflectance confocal microscopy (RCM) of a pigmented CE arising on the caesarean scar of a phototype IV patient, along with histologic studies. Dermoscopy showed a greyish background and a brownish pigmentation. HFUS shows well-demarcated anechoic areas corresponding to ectopic endometrial tissue at histopathologic examination. RCM and OCT only showed the alterations of the epidermis.
Conclusion
High-frequency ultrasound could represent a very useful tool for an early diagnosis of CE and its usefulness could be tested in patients with unusual cyclical pain, even before skin lesion appearance. RCM allowed the visualization of skin surface modification due to underlying endometriosic tissue. Dermoscopy showed a new aspect that was probably related to the mix of blood extravasation (ie, greyish background) and epidermal pigmentation (ie, brown pigmentation).
Benign and malignant collision tumors of melanocytic skin lesions with hemangioma: Dermoscopic and reflectance confocal microscopy features
Abstract
Background
Though the combination/collision of nevi or lentigo simplex and hemangiomas is frequent, the malignant collision tumor melanoma-hemangioma is exceptional and can sometime clinically simulate a benign collision. To date, a series of collision tumors of hemangiomas associated with either benign or malignant melanocytic skin lesions (MSL) has yet to be studied by non-invasive imaging and clinico-pathologic correlates.
Methods
We present 10 cases of patients with collision tumors of hemangioma with different MSL including: 2 in situ lentigo-maligna melanoma, 1 invasive melanoma, 5 melanocytic nevi, and 2 lentigo simplex. The clinical aspect along with the dermoscopic and reflectance confocal microscopy (RCM) features is described and compared with histopathologic findings.
Results
Dermoscopic examination allows to recognize a dark ring in malignant collision melanoma-hemangioma and a jelly ring sign in benign collision of nevi/lentigo simplex-hemangioma. These peculiar features were confirmed by RCM and histopathologic findings.
Conclusion
Two simple dermoscopic clues confirmed by RCM features can be proposed to help distinguish between benign and malignant collisions tumors.
Liponeurofibroma: Clinicopathological features and histogenesis
Abstract
A neurofibroma is a common cutaneous benign tumor of neural origin. Various histological variants have been reported. Recently, sporadic reports of fatty variants have been reported but their clinicopathological features have not been well studied. The purpose of this study was to examine liponeurofibroma, and to report the distinctive clinicopathological features and histogenesis in comparison with the classic form. A retrospective study was performed on 130 cases. Immunohistochemical staining was performed for S100, factor VIIIa, perilipin and vascular endothelial growth factor. Masson's trichrome stain was also used. Intratumoral adipocytes were examined with transmission electron microscopy. Thirty-two (24.6%) cases were classified as liponeurofibroma on microscopic examination. This variant was more common in patients with neurofibromatosis type 1, older age and female sex. The most prevalent location was the head and neck. Intratumoral fat deposits showed differences in morphology and size compared with subcutaneous fat on light microscopy. Neurofibromatosis type 1 had the highest odds of fatty change in liponeurofibroma. In sporadic cases, fatty change can be caused by senescence, chronic injury, or tissue hypoxia secondary to internal or external stimuli. Further investigation is needed to identify the pathomechanism of fatty change in various cutaneous neoplasms, including neurofibroma.
Steroid allergy: Clinical features and the importance of excipient testing in a diagnostic algorithm
Publication date: Available online 31 January 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Philip H. Li, Annette Wagner, Iason Thomas, Timothy J. Watts, Ryszard Rutkowski, Krzysztof Rutkowski
BackgroundTrue corticosteroid (CS) allergy is rare. Instead, many patients may be allergic to excipients found in various CS preparations. Excipient testing is frequently overlooked. It might lead to unnecessary CS avoidance or dangerous re-exposure.ObjectiveTo evaluate the clinical characteristics and frequency of excipient allergy in patients with confirmed type I hypersensitivity to systemic CS preparations.MethodsPatients with a confirmed diagnosis of allergy (positive skin test or drug provocation test (DPT)) or tolerance (negative DPT to CS) over the past 10 years were studied. Patient characteristics, index CS, route of administration, clinical indications, symptoms of index reaction, and outcomes of CS/excipient allergy testing were analysed.ResultsSixty-four patients underwent CS allergy testing. True CS allergy was confirmed in 9/64 (14%) patients. The majority (5/9, 56%) with positive skin tests or DPT were actually allergic to the excipients (2 to carboxymethylcellulose and 3 to polyethylene glycol) rather than the CS. Respiratory manifestations were significantly associated with confirmed allergy (OR=6.79 [95% CI=1.36-34.03], p=0.02).ConclusionPatients with respiratory manifestations were significantly more likely to be truly allergic. CS allergies are rare and may be over-diagnosed without excipient testing. We suggest the use of Carmellose eye drops as a readily available source of carboxymethylcellulose for testing and propose a comprehensive diagnostic algorithm for suspected CS allergy.
Health-Related Quality-of-Life with Subcutaneous C1-inhibitor for Prevention of Attacks of Hereditary Angioedema
Publication date: Available online 31 January 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): William R. Lumry, Timothy Craig, Bruce Zuraw, Hilary Longhurst, James Baker, H.Henry Li, Jonathan A. Bernstein, John Anderson, Marc A. Riedl, Michael E. Manning, Paul K. Keith, Donald S. Levy, Teresa Caballero, Aleena Banerji, Richard G. Gower, Henriette Farkas, John-Philip Lawo, Ingo Pragst, Thomas Machnig, Douglas J. Watson
BackgroundHereditary angioedema with C1-INH deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL).ObjectiveTo assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA®) for routine prevention of HAE attacks.MethodsPost-hoc analysis of data from a placebo-controlled, crossover phase III study (COMPACT). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 IU/kg or 60 IU/kg twice-weekly for 16 weeks, preceded or followed by 16 weeks of twice-weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM).ResultsCompared with placebo (on-demand treatment alone), treatment with twice-weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo.ConclusionsIn patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice-weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).
DRESS Syndrome due to benzylpenicillin with cross-reactivity to amoxicillin
Publication date: Available online 31 January 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Timothy J. Watts, Philip H. Li, Rubaiyat Haque
Burden of atopic dermatitis in Japanese adults: Analysis of data from the 2013 National Health and Wellness Survey
Abstract
Atopic dermatitis is a chronic inflammatory skin disease. The objective of this study was to characterize the burden of atopic dermatitis in Japanese adult patients relative to the general population. Japanese adults (≥18 years) with a self-reported diagnosis of atopic dermatitis and adult controls without atopic dermatitis/eczema/dermatitis were identified from the 2013 Japan National Health and Wellness Survey. Atopic dermatitis patients were propensity-score matched with non-atopic dermatitis controls (1:2 ratio) on demographic variables. Patient-reported outcome data on comorbidities, mood and sleep disorders, health-related quality of life, work productivity and activity impairment, and health-care resource utilization were analyzed in atopic dermatitis patients and matched controls. A total of 638 Japanese adult patients with atopic dermatitis were identified, of whom 290 (45.5%) rated their disease as "moderate/severe" and 348 (54.5%) as "mild". The analysis cohort comprised 634 atopic dermatitis patients and 1268 matched controls. Atopic dermatitis patients reported a significantly higher prevalence of arthritis, asthma, nasal allergies/hay fever, anxiety, depression and sleep disorders compared with controls (all P < 0.001). Atopic dermatitis patients also reported a significantly poorer health-related quality of life, higher overall work and activity impairment, and higher health-care resource utilization (all P < 0.001). Self-rated disease severity was not associated with disease burden, except for a significantly higher overall work and activity impairment. In conclusion, Japanese adult patients with atopic dermatitis reported a substantial disease burden relative to adults without atopic dermatitis, suggesting an unmet need for effective strategies targeting disease management.
Evaluating the effect of rain on the fate of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) accumulated in polluted trees in Amman, Jordan
Abstract
Open combustion of solid waste is one of the main sources of the emission of dioxin and dioxin-like compounds (DLCs). Ambient dioxin will eventually undergo depositions on soils and tree leaves. Pine trees have shown an ability to store dioxin in their needles allowing biomonitoring of dioxin atmospheric concentrations. Infiltration can transport dioxin to greater depths into the ground, on one hand, while vaporization can allow dioxin to return back to the atmosphere on the other. Several studies evaluated the migration of dioxin between two compartments; however, few studies have attempted to understand the fate of non-conservative PCDDs and PCDFs in an unsteady state system of more than two mediums. This study focused on the transportation of dioxin between polluted trees and the underlying soil through the effect of rain water. For approximately 10 years, pine trees in this study have been exposed to emissions generated by the open combustion of municipal solid waste (MSW) from a fixed location. Soil samples located further from the point source had generally lower dioxin concentrations. Dioxin concentrations were correlated to distance from the source using least square regression. Soil samples below contaminated trees had dioxin concentrations 10–35% greater than the calculated measurements for the same spots using the regression model. By detecting these spikes in concentrations, it was possible to identify pools of dioxin found directly under the contaminated trees—indicating a rinsing effect of rain water on the stored dioxin on the trees' needles.
Unexpected potential protective associations between outdoor air pollution and cataracts
Abstract
Air pollution is one of the biggest public health issues, and the eye is continuously exposed to multiple outdoor air pollution. However, to date, no large-scale study has assessed the relationship between air pollutants and cataracts. We investigated associations between outdoor air pollution and cataracts in the Korean population. A population-based cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey, including 18,622 adults more than 40 years of age. The presence of cataracts and their subtypes were evaluated by ophthalmologists. Air pollution data (levels of particulate matter, ozone, nitrogen dioxide, and sulfur dioxide) for the 2 years prior to the ocular examinations were collected from national monitoring stations. The associations of multiple air pollutants with cataracts were assessed by multivariate logistic regression analyses. Sociodemographic factors and previously known risk factors for cataracts were controlled as covariates (model 1 included sociodemographic factors, sun exposure, and behavioral factors, while model 2 further included clinical factors). Higher ozone concentrations were protectively associated with overall cataract which included all subtypes [single pollutant model: 0.003 ppm increase—model 1 (OR 0.89, p = 0.014), model 2 (OR 0.87, p = 0.011); multi-pollutant model: 0.003 ppm increase—model 1 (OR 0.80, p = 0.002), model 2 (OR 0.87, p = 0.002)]. Especially, higher ozone concentrations showed deeply protective association with nuclear cataract subtype [0.003 ppm increase—single pollutant model: model 2 (OR 0.84, p = 0.006), multi-pollutant model: model 2 (OR 0.73, p < 0.001)]. Higher tropospheric ozone concentrations showed protective associations with overall cataract and nuclear cataract subtype in the Korean population.
T-type calcium channels drive migration/invasion in BRAFV600E melanoma cells through Snail1
Abstract
Melanoma is a malignant tumor derived from melanocytes. Once disseminated, it is usually highly resistant to chemotherapy and is associated with poor prognosis. We have recently reported that T-type calcium channels (TTCCs) are overexpressed in melanoma cells and play an important role in melanoma progression. Importantly, TTCC pharmacological blockers reduce proliferation and deregulate autophagy leading to apoptosis. Here, we analyze the role of autophagy during migration/invasion of melanoma cells.
TTCC Cav3.1 and LC3-II protein are highly expressed in BRAFV600E compared to NRAS mutant melanomas, both in cell lines and biopsies. Chloroquine, pharmacological blockade or gene silencing of TTCCs inhibits the autophagic flux and impairs the migration and invasion capabilities, specifically in BRAFV600E melanoma cells.
Snail1 plays an important role in motility and invasion of melanoma cells. We show that Snail1
is strongly expressed in BRAFV600E melanoma cells and patient biopsies, and its expression decreases when autophagy is blocked. These results demonstrate a role of Snail1 during BRAFV600E melanoma progression and strongly suggest that targeting macroautophagy and, particularly TTCCs, might be a good therapeutic strategy to inhibit metastasis of the most common melanoma type (BRAFV600E).
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Fate of Lu(III) sorbed on 2-line ferrihydrite at pH 5.7 and aged for 12 years at room temperature. I: insights from ICP-OES, XRD, ESEM, AsFlFFF/ICP-MS, and EXAFS spectroscopy
Abstract
Two-line ferrihydrite (2LFh) was aged for 12 years under ambient conditions and sheltered from light in the presence of Lu(III) used as surrogate for trivalent actinides. 2LFh aging produced hematite rhombohedra with overgrown acicular goethite particles. Analysis of the homogeneous suspension by asymmetrical flow field-flow fractionation (AsFlFFF) coupled to ICP-MS indicated that particles have a mean hydrodynamic diameter of about 140 nm and the strong correlation of the Fe and Lu fractograms hinted at a structural association of the lanthanide with the solid phase(s). Unfortunately, recoveries were low and thus results cannot be considered representative of the whole sample. The suspension was centrifuged and X-ray absorption spectroscopy (XAS) at the Lu L3 -edge on the settled particles indicated that Lu(III) is sixfold coordinated by oxygen atoms, pointing to a retention by structural incorporation within particles. This result is consistent with AsFlFFF results on the same suspension without centrifugation. The detection of next nearest Fe and O atoms were consistent with the structure of goethite, ruling out incorporation within hematite. After centrifugation of the suspension, only nanoparticulate needle-like particles, very likely goethite, could be detected in the supernatant by ESEM. AsFlFFF data of the supernatant were comparable to that obtained for the homogeneous suspension, whereas XAS indicated that Lu(III) is predominantly present as dissolved species in the supernatant. Results from both techniques can be interpreted as a major fraction of Lu present as aqueous ions and a minor fraction as structurally incorporated. Findings from this study are corroborated by STEM-HAADF data and results from DFT calculations in a companion paper.
Blaschkoid Acute Graft-vs-Host Disease
This case report describes a patient who developed acute graft-vs-host disease along the lines of Blaschko.
Trends in Melanoma Incidence Among Non-Hispanic Whites
This analysis examines data from 2 major databases on melanoma incidence trends among the non-Hispanic white population in the United States by 10-year age groups.
Rapid Repigmentation of Vitiligo-Affected Skin After Tofacitinib Plus UV-B
This case report describes 2 patients who experienced rapid repigmentation of vitiligo-affected skin after tofacitinib plus low-dose, narrowband UV-B therapy.
Follicular and Epidermal Cell Suspension for Vitiligo Treatment
This randomized clinical trial compares the effects of combined epidermal cell suspension and follicular cell suspension with those of epidermal cell suspension alone in treatment of vitiligo.
Prevalence and Types of Genital Lesions in Organ Transplant Recipients
This medical record review assesses the prevalence and types of genital lesions observed in organ transplant recipients.
Attention Shifts Recruit the Monkey Default Mode Network
A unifying function associated with the default mode network (DMN), which is more active during rest than under active task conditions, has been difficult to define. The DMN is activated during monitoring the external world for unexpected events, as a sentinel, and when humans are engaged in high-level internally focused tasks. The existence of DMN correlates in other species, such as mice, challenge the idea that internally focused, high-level cognitive operations, such as introspection, autobiographical memory retrieval, planning the future, and predicting someone else's thoughts, are evolutionarily preserved defining properties of the DMN. A recent human study demonstrated that demanding cognitive shifts could recruit the DMN, yet it is unknown whether this holds for nonhuman species. Therefore, we tested whether large changes in cognitive context would recruit DMN regions in female and male nonhuman primates. Such changes were measured as displacements of spatial attentional weights based on internal rules of relevance (spatial shifts) compared with maintaining attentional weights at the same location (stay events). Using fMRI in macaques, we detected that a cortical network, activated during shifts, largely overlapped with the DMN. Moreover, fMRI time courses sampled from independently defined DMN foci showed significant shift selectivity during the demanding attention task. Finally, functional clustering based on independent resting state data revealed that DMN and shift regions clustered conjointly, whereas regions activated during the stay events clustered apart. We therefore propose that cognitive shifting in primates generally recruits DMN regions. This might explain a breakdown of the DMN in many neurological diseases characterized by declined cognitive flexibility.
SIGNIFICANCE STATEMENT Activation of the human default mode network (DMN) can be measured with fMRI when subjects shift thoughts between high-level internally directed cognitive states, when thinking about the self, the perspective of others, when imagining future and past events, and during mind wandering. Furthermore, the DMN is activated as a sentinel, monitoring the environment for unexpected events. Arguably, these cognitive processes have in common fast and substantial changes in cognitive context. As DMN activity has also been reported in nonhuman species, we tested whether shifts in spatial attention activated the monkey DMN. Core monkey DMN and shift-selective regions shared several functional properties, indicating that cognitive shifting, in general, might constitute one of the evolutionarily preserved functions of the DMN.
Selective Suppression of Local Interneuron Circuits in Human Motor Cortex Contributes to Movement Preparation
Changes in neural activity occur in the motor cortex before movement, but the nature and purpose of this preparatory activity is unclear. To investigate this in the human (male and female) brain noninvasively, we used transcranial magnetic stimulation (TMS) to probe the excitability of distinct sets of excitatory inputs to corticospinal neurons during the warning period of various reaction time tasks. Using two separate methods (H-reflex conditioning and directional effects of TMS), we show that a specific set of excitatory inputs to corticospinal neurons are suppressed during motor preparation, while another set of inputs remain unaffected. To probe the behavioral relevance of this suppression, we examined whether the strength of the selective preparatory inhibition in each trial was related to reaction time. Surprisingly, the greater the amount of selective preparatory inhibition, the faster the reaction time was. This suggests that the inhibition of inputs to corticospinal neurons is not involved in preventing the release of movement but may in fact facilitate rapid reactions. Thus, selective suppression of a specific set of motor cortical neurons may be a key aspect of successful movement preparation.
SIGNIFICANCE STATEMENT Movement preparation evokes substantial activity in the motor cortex despite no apparent movement. One explanation for the lack of movement is that motor cortical output in this period is gated by an inhibitory mechanism. This notion was supported by previous noninvasive TMS studies of human motor cortex indicating a reduction of corticospinal excitability. On the contrary, our data support the idea that there is a coordinated balance of activity upstream of the corticospinal output neurons. This includes a suppression of specific local circuits that supports, rather than inhibits, the rapid generation of prepared movements. Thus, the selective suppression of local circuits appears to be an essential part of successful movement preparation instead of an external control mechanism.
Attention Is Required for Knowledge-Based Sequential Grouping: Insights from the Integration of Syllables into Words
How the brain groups sequential sensory events into chunks is a fundamental question in cognitive neuroscience. This study investigates whether top–down attention or specific tasks are required for the brain to apply lexical knowledge to group syllables into words. Neural responses tracking the syllabic and word rhythms of a rhythmic speech sequence were concurrently monitored using electroencephalography (EEG). The participants performed different tasks, attending to either the rhythmic speech sequence or a distractor, which was another speech stream or a nonlinguistic auditory/visual stimulus. Attention to speech, but not a lexical-meaning-related task, was required for reliable neural tracking of words, even when the distractor was a nonlinguistic stimulus presented cross-modally. Neural tracking of syllables, however, was reliably observed in all tested conditions. These results strongly suggest that neural encoding of individual auditory events (i.e., syllables) is automatic, while knowledge-based construction of temporal chunks (i.e., words) crucially relies on top–down attention.
SIGNIFICANCE STATEMENT Why we cannot understand speech when not paying attention is an old question in psychology and cognitive neuroscience. Speech processing is a complex process that involves multiple stages, e.g., hearing and analyzing the speech sound, recognizing words, and combining words into phrases and sentences. The current study investigates which speech-processing stage is blocked when we do not listen carefully. We show that the brain can reliably encode syllables, basic units of speech sounds, even when we do not pay attention. Nevertheless, when distracted, the brain cannot group syllables into multisyllabic words, which are basic units for speech meaning. Therefore, the process of converting speech sound into meaning crucially relies on attention.
Glutamatergic Transmission to Hypothalamic Kisspeptin Neurons Is Differentially Regulated by Estradiol through Estrogen Receptor {alpha} in Adult Female Mice
Estradiol feedback regulates gonadotropin-releasing hormone (GnRH) neurons and subsequent luteinizing hormone (LH) release. Estradiol acts via estrogen receptor α (ERα)-expressing afferents of GnRH neurons, including kisspeptin neurons in the anteroventral periventricular (AVPV) and arcuate nuclei, providing homeostatic feedback on episodic GnRH/LH release as well as positive feedback to control ovulation. Ionotropic glutamate receptors are important for estradiol feedback, but it is not known where they fit in the circuitry. Estradiol-negative feedback decreased glutamatergic transmission to AVPV and increased it to arcuate kisspeptin neurons; positive feedback had the opposite effect. Deletion of ERα in kisspeptin cells decreased glutamate transmission to AVPV neurons and markedly increased it to arcuate kisspeptin neurons, which also exhibited increased spontaneous firing rate. KERKO mice had increased LH pulse frequency, indicating loss of negative feedback. These observations indicate that ERα in kisspeptin cells is required for appropriate differential regulation of these neurons and neuroendocrine output by estradiol.
SIGNIFICANCE STATEMENT The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates the pattern of GnRH (negative feedback) and initiates a surge of release that triggers ovulation (positive feedback). GnRH neurons do not express the estrogen receptor needed for feedback (estrogen receptor α [ERα]); kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to mediate negative and positive feedback, respectively. Here we extend the network through which feedback is mediated by demonstrating that glutamatergic transmission to these kisspeptin populations is differentially regulated during the reproductive cycle and by estradiol. Electrophysiological and in vivo hormone profile experiments on kisspeptin-specific ERα knock-out mice demonstrate that ERα in kisspeptin cells is required for appropriate differential regulation of these neurons and for neuroendocrine output.
Tenuous Inhibitory GABAergic Signaling in the Reticular Thalamus
Maintenance of a low intracellular Cl– concentration ([Cl–]i) is critical for enabling inhibitory neuronal responses to GABAA receptor-mediated signaling. Cl– transporters, including KCC2, and extracellular impermeant anions ([A]o) of the extracellular matrix are both proposed to be important regulators of [Cl–]i. Neurons of the reticular thalamic (RT) nucleus express reduced levels of KCC2, indicating that GABAergic signaling may produce excitation in RT neurons. However, by performing perforated patch recordings and calcium imaging experiments in rats (male and female), we find that [Cl–]i remains relatively low in RT neurons. Although we identify a small contribution of [A]o to a low [Cl–]i in RT neurons, our results also demonstrate that reduced levels of KCC2 remain sufficient to maintain low levels of Cl–. Reduced KCC2 levels, however, restrict the capacity of RT neurons to rapidly extrude Cl– following periods of elevated GABAergic signaling. In a computational model of a local RT network featuring slow Cl– extrusion kinetics, similar to those we found experimentally, model RT neurons are predisposed to an activity-dependent switch from GABA-mediated inhibition to excitation. By decreasing the activity threshold required to produce excitatory GABAergic signaling, weaker stimuli are able to propagate activity within the model RT nucleus. Our results indicate the importance of even diminished levels of KCC2 in maintaining inhibitory signaling within the RT nucleus and suggest how this important activity choke point may be easily overcome in disorders such as epilepsy.
SIGNIFICANCE STATEMENT Precise regulation of intracellular Cl– levels ([Cl–]i) preserves appropriate, often inhibitory, GABAergic signaling within the brain. However, there is disagreement over the relative contribution of various mechanisms that maintain low [Cl–]i. We found that the Cl– transporter KCC2 is an important Cl– extruder in the reticular thalamic (RT) nucleus, despite this nucleus having remarkably low KCC2 immunoreactivity relative to other regions of the adult brain. We also identified a smaller contribution of fixed, impermeant anions ([A]o) to lowering [Cl–]i in RT neurons. Inhibitory signaling among RT neurons is important for preventing excessive activation of RT neurons, which can be responsible for generating seizures. Our work suggests that KCC2 critically restricts the spread of activity within the RT nucleus.
HRPU-2, a Homolog of Mammalian hnRNP U, Regulates Synaptic Transmission by Controlling the Expression of SLO-2 Potassium Channel in Caenorhabditis elegans
Slo2 channels are large-conductance potassium channels abundantly expressed in the nervous system. However, it is unclear how their expression level in neurons is regulated. Here we report that HRPU-2, an RNA-binding protein homologous to mammalian heterogeneous nuclear ribonucleoprotein U (hnRNP U), plays an important role in regulating the expression of SLO-2 (a homolog of mammalian Slo2) in Caenorhabditis elegans. Loss-of-function (lf) mutants of hrpu-2 were isolated in a genetic screen for suppressors of a sluggish phenotype caused by a hyperactive SLO-2. In hrpu-2(lf) mutants, SLO-2-mediated delayed outward currents in neurons are greatly decreased, and neuromuscular synaptic transmission is enhanced. These mutant phenotypes can be rescued by expressing wild-type HRPU-2 in neurons. HRPU-2 binds to slo-2 mRNA, and hrpu-2(lf) mutants show decreased SLO-2 protein expression. In contrast, hrpu-2(lf) does not alter the expression of either the BK channel SLO-1 or the Shaker type potassium channel SHK-1. hrpu-2(lf) mutants are indistinguishable from wild type in gross motor neuron morphology and locomotion behavior. Together, these observations suggest that HRPU-2 plays important roles in SLO-2 function by regulating SLO-2 protein expression, and that SLO-2 is likely among a restricted set of proteins regulated by HRPU-2. Mutations of human Slo2 channel and hnRNP U are strongly linked to epileptic disorders and intellectual disability. The findings of this study suggest a potential link between these two molecules in human patients.
SIGNIFICANCE STATEMENT Heterogeneous nuclear ribonucleoprotein U (hnRNP U) belongs to a family of RNA-binding proteins that play important roles in controlling gene expression. Recent studies have established a strong link between mutations of hnRNP U and human epilepsies and intellectual disability. However, it is unclear how mutations of hnRNP U may cause such disorders. This study shows that mutations of HRPU-2, a worm homolog of mammalian hnRNP U, result in dysfunction of a Slo2 potassium channel, which is critical to neuronal function. Because mutations of Slo2 channels are also strongly associated with epileptic encephalopathies and intellectual disability in humans, the findings of this study point to a potential mechanism underlying neurological disorders caused by hnRNP U mutations.
Visually-Driven Maps in Area 3b
Sensory perception relies on the precise neuronal encoding of modality-specific environmental features in primary sensory cortices. Some studies have reported the penetration of signals from other modalities even into early sensory areas. So far, no comprehensive account of maps induced by "foreign sources" exists. We addressed this question using surface-based topographic mapping techniques applied to ultra-high resolution fMRI neuroimaging data, measured in female participants. We show that fine-grained finger maps in human primary somatosensory cortex, area 3b, are somatotopically activated not only during tactile mechanical stimulation, but also when viewing the same fingers being touched. Visually-induced maps were weak in amplitude, but overlapped with the stronger tactile maps tangential to the cortical sheet when finger touches were observed in both first- and third-person perspectives. However, visually-induced maps did not overlap tactile maps when the observed fingers were only approached by an object but not actually touched. Our data provide evidence that "foreign source maps" in early sensory cortices are present in the healthy human brain, that their arrangement is precise, and that their induction is feature-selective. The computations required to generate such specific responses suggest that counterflow (feedback) processing may be much more spatially specific than has been often assumed.
SIGNIFICANCE STATEMENT Using ultra-high field fMRI, we provide empirical evidence that viewing touches activates topographically aligned single finger maps in human primary somatosensory cortical area 3b. This shows that "foreign source maps" in early sensory cortices are topographic, precise, and feature-selective in healthy human participants with intact sensory pathways.
A{beta} mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease
Dendritic spine loss is recognized as an early feature of Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased globular-actin (G-actin) at as early as 1 month of age in a mouse model of AD (APPswe/PS1E9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1E9 male mice, which could be reversed by the actin-polymerizing agent jasplakinolide. Further, the F-actin-depolymerizing agent latrunculin induced recall deficit after cFC in WT mice, indicating the importance of maintaining F-/G-actin equilibrium for optimal behavioral response. Using direct stochastic optical reconstruction microscopy (dSTORM), we show that F-actin depolymerization in spines leads to a breakdown of the nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1E9 mice. Our results demonstrate that synaptic dysfunction seen as F-actin disassembly occurs very early, before onset of pathological hallmarks in AD mice, and contributes to behavioral dysfunction, indicating that depolymerization of F-actin is causal and not consequent to decreased spine density. Further, we observed decreased synaptosomal F-actin levels in postmortem brain from mild cognitive impairment and AD patients compared with subjects with normal cognition. F-actin decrease correlated inversely with increasing AD pathology (Braak score, Aβ load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression.
SIGNIFICANCE STATEMENT Synaptic dysfunction underlies cognitive deficits in Alzheimer's disease (AD). The cytoskeletal protein actin plays a critical role in maintaining structure and function of synapses. Using cultured neurons and an AD mouse model, we show for the first time that filamentous actin (F-actin) is lost selectively from synapses early in the disease process, long before the onset of classical AD pathology. We also demonstrate that loss of synaptic F-actin contributes directly to memory deficits. Loss of synaptosomal F-actin in human postmortem tissue correlates directly with decreased performance in memory test and inversely with AD pathology. Our data highlight that synaptic cytoarchitectural changes occur early in AD and they may be targeted for the development of therapeutics.
Loss of Intercalated Cells (ITCs) in the Mouse Amygdala of Tshz1 Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes
The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence.
SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.
Disruption of Interneuron Neurogenesis in Premature Newborns and Reversal with Estrogen Treatment
Many Preterm-born children suffer from neurobehavioral disorders. Premature birth terminates the hypoxic in utero environment and supply of maternal hormones. As the production of interneurons continues until the end of pregnancy, we hypothesized that premature birth would disrupt interneuron production and that restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we compared interneuronal progenitors in the medial ganglionic eminences (MGEs), lateral ganglionic eminences (LGEs), and caudal ganglionic eminences (CGEs) between preterm-born [born on embryonic day (E) 29; examined on postnatal day (D) 3 and D7] and term-born (born on E32; examined on D0 and D4) rabbits at equivalent postconceptional ages. We found that both total and cycling Nkx2.1+, Dlx2+, and Sox2+ cells were more abundant in the MGEs of preterm rabbits at D3 compared with term rabbits at D0, but not in D7 preterm relative to D4 term pups. Total Nkx2.1+ progenitors were also more numerous in the LGEs of preterm pups at D3 compared with term rabbits at D0. Dlx2+ cells in CGEs were comparable between preterm and term pups. Simulation of hypoxia by dimethyloxalylglycine treatment did not affect the number of interneuronal progenitors. However, estrogen treatment reduced the density of total and proliferating Nkx2.1+ and Dlx2+ cells in the MGEs and enhanced Ascl1 transcription factor. Estrogen treatment also reduced Ki67, c-Myc, and phosphorylation of retinoblastoma protein, suggesting inhibition of the G1-to-S phase transition. Hence, preterm birth disrupts interneuron neurogenesis in the MGE and estrogen treatment reverses interneuron neurogenesis in preterm newborns by cell-cycle inhibition and elevation of Ascl1. We speculate that estrogen replacement might partially restore neurogenesis in human premature infants.
SIGNIFICANCE STATEMENT Prematurity results in developmental delays and neurobehavioral disorders, which might be ascribed to disturbances in the development of cortical interneurons. Here, we show that preterm birth disrupts interneuron neurogenesis in the medial ganglionic eminence (MGE) and, more importantly, that estrogen treatment reverses this perturbation in the population of interneuron progenitors in the MGE. The estrogen seems to restore neurogenesis by inhibiting the cell cycle and elevating Ascl1 expression. As preterm birth causes plasma estrogen level to drop 100-fold, the estrogen replacement in preterm infants is physiological. We speculate that estrogen replacement might ameliorate disruption in production of interneurons in human premature infants.
Prismatic Adaptation Modulates Oscillatory EEG Correlates of Motor Preparation but Not Visual Attention in Healthy Participants
Prismatic adaption (PA) has been proposed as a tool to induce neural plasticity and is used to help neglect rehabilitation. It leads to a recalibration of visuomotor coordination during pointing as well as to aftereffects on a number of sensorimotor and attention tasks, but whether these effects originate at a motor or attentional level remains a matter of debate. Our aim was to further characterize PA aftereffects by using an approach that allows distinguishing between effects on attentional and motor processes. We recorded EEG in healthy human participants (9 females and 7 males) while performing a new double step, anticipatory attention/motor preparation paradigm before and after adaptation to rightward-shifting prisms, with neutral lenses as a control. We then examined PA aftereffects through changes in known oscillatory EEG signatures of spatial attention orienting and motor preparation in the alpha and beta frequency bands. Our results were twofold. First, we found PA to rightward-shifting prisms to selectively affect EEG signatures of motor but not attentional processes. More specifically, PA modulated preparatory motor EEG activity over central electrodes in the right hemisphere, contralateral to the PA-induced, compensatory leftward shift in pointing movements. No effects were found on EEG signatures of spatial attention orienting over occipitoparietal sites. Second, we found the PA effect on preparatory motor EEG activity to dominate in the beta frequency band. We conclude that changes to intentional visuomotor, rather than attentional visuospatial, processes underlie the PA aftereffect of rightward-deviating prisms in healthy participants.
SIGNIFICANCE STATEMENT Prismatic adaptation (PA) has been proposed as a tool to induce neural plasticity in both healthy participants and patients, due to its aftereffect impacting on a number of visuospatial and visuomotor functions. However, the neural mechanisms underlying PA aftereffects are poorly understood as only little neuroimaging evidence is available. Here, we examined, for the first time, the origin of PA aftereffects studying oscillatory brain activity. Our results show a selective modulation of preparatory motor activity following PA in healthy participants but no effect on attention-related activity. This provides novel insight into the PA aftereffect in the healthy brain and may help to inform interventions in neglect patients.
Decoding Trans-Saccadic Memory
We examine whether peripheral information at a planned saccade target affects immediate postsaccadic processing at the fovea on saccade landing. Current neuroimaging research suggests that presaccadic stimulation has a late effect on postsaccadic processing, in contrast to the early effect seen in behavioral studies. Human participants (both male and female) were instructed to saccade toward a face or a house that, on different trials, remained the same, changed, or disappeared during the saccade. We used a multivariate pattern analysis of electroencephalography data to decode face versus house processing directly after the saccade. The classifier was trained on separate trials without a saccade, where a house or face was presented at the fovea. When the saccade target remained the same across the saccade, we could reliably decode the target 123 ms after saccade offset. In contrast, when the target was changed during the saccade, the new target was decoded at a later time-point, 151 ms after saccade offset. The "same" condition advantage suggests that congruent presaccadic information facilitates processing of the postsaccadic stimulus compared with incongruent information. Finally, the saccade target could be decoded above chance even when it had been removed during the saccade, albeit with a slower time course (162 ms) and poorer signal strength. These findings indicate that information about the (peripheral) presaccadic stimulus is transferred across the saccade so that it becomes quickly available and influences processing at its expected new retinal position (the fovea).
SIGNIFICANCE STATEMENT Here we provide neural evidence for early information transfer across saccades. Specifically, we examined the effect of presaccadic sensory information on the initial neuronal processing of a postsaccadic stimuli. Using electroencephalography and multivariate pattern analysis, we found the following: (1) that the identity of the presaccadic stimulus modulated the postsaccadic latency of stimulus relevant information; and (2) that a saccadic neural marker for a saccade target stimulus could be detected even when the stimulus had been removed during saccade. These results demonstrate that information about the peripheral presaccadic stimulus was transferred across the saccade and influenced processing at a new retinal position (the fovea) directly after the saccade landed.
Conditional Deletion of Hippocampal CA2/CA3a Oxytocin Receptors Impairs the Persistence of Long-Term Social Recognition Memory in Mice
Oxytocin (OXT) receptors (OXTRs) are prominently expressed in hippocampal CA2 and CA3 pyramidal neurons, but little is known about its physiological function. As the functional necessity of hippocampal CA2 for social memory processing, we tested whether CA2 OXTRs may contribute to long-term social recognition memory (SRM) formation. Here, we found that conditional deletion of Oxtr from forebrain (Oxtr–/–) or CA2/CA3a-restricted excitatory neurons in adult male mice impaired the persistence of long-term SRM but had no effect on sociability and preference for social novelty. Conditional deletion of CA2/CA3a Oxtr showed no changes in anxiety-like behavior assessed using the open-field, elevated plus maze and novelty-suppressed feeding tests. Application of a highly selective OXTR agonist [Thr4,Gly7]-OXT to hippocampal slices resulted in an acute and lasting potentiation of excitatory synaptic responses in CA2 pyramidal neurons that relied on N-methyl-d-aspartate receptor activation and calcium/calmodulin-dependent protein kinase II activity. In addition, Oxtr–/– mice displayed a defect in the induction of long-term potentiation, but not long-term depression, at the synapses between the entorhinal cortex and CA2 pyramidal neurons. Furthermore, Oxtr deletion led to a reduced complexity of basal dendritic arbors of CA2 pyramidal neurons, but caused no alteration in the density of apical dendritic spines. Considering that the methodologies we have used to delete Oxtr do not rule out targeting the neighboring CA3a region, these findings suggest that OXTR signaling in the CA2/CA3a is crucial for the persistence of long-term SRM.
SIGNIFICANCE STATEMENT Oxytocin receptors (OXTRs) are abundantly expressed in hippocampal CA2 and CA3 regions, but there are little known about their physiological function. Taking advantage of the conditional Oxtr knock-out mice, the present study highlights the importance of OXTR signaling in the induction of long-term potentiation at the synapses between the entorhinal cortex and CA2 pyramidal neurons and the persistence of long-term social recognition memory. Thus, OXTRs in the CA2/CA3a may provide a new target for therapeutic approaches to the treatment of social cognition deficits, which are often observed in patients with neuropsychiatric disorders.
DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Nav1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Nav1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Nav1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Nav1.7 associated with spontaneous activity. Nav1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.
SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage-gated sodium channel Nav1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Nav1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class.
Gonadotropin-Releasing Hormone (GnRH) Neuron Excitability Is Regulated by Estradiol Feedback and Kisspeptin
Gonadotropin-releasing hormone (GnRH) neurons produce the central output controlling fertility and are regulated by steroid feedback. A switch from estradiol negative to positive feedback initiates the GnRH surge, ultimately triggering ovulation. This occurs on a daily basis in ovariectomized, estradiol-treated (OVX+E) mice; GnRH neurons are suppressed in the morning and activated in the afternoon. To test the hypotheses that estradiol and time of day signals alter GnRH neuron responsiveness to stimuli, GFP-identified GnRH neurons in brain slices from OVX+E or OVX female mice were recorded during the morning or afternoon. No differences were observed in baseline membrane potential. Current-clamp revealed GnRH neurons fired more action potentials in response to current injection during positive feedback relative to all other groups, which were not different from each other despite reports of differing ionic conductances. Kisspeptin increased GnRH neuron response in cells from OVX and OVX+E mice in the morning but not afternoon. Paradoxically, excitability in kisspeptin knock-out mice was similar to the maximum observed in control mice but was unchanged by time of day or estradiol. A mathematical model applying a Markov Chain Monte Carlo method to estimate probability distributions for estradiol- and time of day–dependent parameters was used to predict intrinsic properties underlying excitability changes. A single identifiable distribution of solutions accounted for similar GnRH neuron excitability in all groups other than positive feedback despite different underlying conductance properties; this was attributable to interdependence of voltage-gated potassium channel properties. In contrast, redundant solutions may explain positive feedback, perhaps indicative of the importance of this state for species survival.
SIGNIFICANCE STATEMENT Infertility affects 15%–20% of couples; failure to ovulate is a common cause. Understanding how the brain controls ovulation is critical for new developments in both infertility treatment and contraception. Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway for central neural control of ovulation. We studied how estradiol feedback regulates GnRH excitability, a key determinant of neural firing rate using laboratory and computational approaches. GnRH excitability is upregulated during positive feedback, perhaps driving increased neural firing rate at this time. Kisspeptin increased GnRH excitability and was essential for estradiol regulation of excitability. Modeling predicts that multiple combinations of changes to GnRH intrinsic conductances can produce the firing response in positive feedback, suggesting the brain has many ways to induce ovulation.
Cholinergic Overstimulation Attenuates Rule Selectivity in Macaque Prefrontal Cortex
Acetylcholine is released in the prefrontal cortex (PFC) and is a key modulator of cognitive performance in primates. Cholinergic stimulation has been shown to have beneficial effects on performance of cognitive tasks, and cholinergic receptors are being actively explored as promising targets for ameliorating cognitive deficits in Alzheimer's disease. We hypothesized that cholinergic stimulation of PFC during performance of a cognitive task would augment neuronal activity and neuronal coding of task attributes. We iontophoretically applied the general cholinergic receptor agonist carbachol onto neurons in dorsolateral PFC (DLPFC) of male rhesus macaques performing rule-guided prosaccades and antisaccades, a well established oculomotor task for testing cognitive control. Carbachol application had heterogeneous effects on neuronal excitability, with both excitation and suppression observed in significant proportions. Contrary to our prediction, neurons with rule-selective activity exhibited a reduction in selectivity during carbachol application. Cholinergic stimulation disrupted rule selectivity regardless of whether it had suppressive or excitatory effects on these neurons. In addition, cholinergic stimulation excited putative pyramidal neurons, whereas the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to nonspecific increases in activity. Our results suggest excessive cholinergic stimulation has detrimental effects on DLPFC representations of task attributes. These findings delineate the complexity and heterogeneity of neuromodulation of cerebral cortex by cholinergic stimulation, an area of active exploration with respect to the development of cognitive enhancers.
SIGNIFICANCE STATEMENT The neurotransmitter acetylcholine is known to be important for cognitive processes in the prefrontal cortex. Removal of acetylcholine from prefrontal cortex can disrupt short-term memory performance and is reminiscent of Alzheimer's disease, which is characterized by degeneration of acetylcholine-producing neurons. Stimulation of cholinergic receptors is being explored to create cognitive enhancers for the treatment of Alzheimer's disease and other psychiatric diseases. Here, we stimulated cholinergic receptors in prefrontal cortex and examined its effects on neurons that are engaged in cognitive behavior. Surprisingly, cholinergic stimulation decreased neurons' ability to discriminate between rules. This work suggests that overstimulation of acetylcholine receptors could disrupt neuronal processing during cognition and is relevant to the design of cognitive enhancers based on stimulating the cholinergic system.
Meis1 Coordinates Cerebellar Granule Cell Development by Regulating Pax6 Transcription, BMP Signaling and Atoh1 Degradation
Cerebellar granule cell precursors (GCPs) and granule cells (GCs) represent good models to study neuronal development. Here, we report that the transcription factor myeloid ectopic viral integration site 1 homolog (Meis1) plays pivotal roles in the regulation of mouse GC development. We found that Meis1 is expressed in GC lineage cells and astrocytes in the cerebellum during development. Targeted disruption of the Meis1 gene specifically in the GC lineage resulted in smaller cerebella with disorganized lobules. Knock-down/knock-out (KO) experiments for Meis1 and in vitro assays showed that Meis1 binds to an upstream sequence of Pax6 to enhance its transcription in GCPs/GCs and also suggested that the Meis1–Pax6 cascade regulates morphology of GCPs/GCs during development. In the conditional KO (cKO) cerebella, many Atoh1-positive GCPs were observed ectopically in the inner external granule layer (EGL) and a similar phenomenon was observed in cultured cerebellar slices treated with a bone morphogenic protein (BMP) inhibitor. Furthermore, expression of Smad proteins and Smad phosphorylation were severely reduced in the cKO cerebella and Meis1-knock-down GCPs cerebella. Reduction of phosphorylated Smad was also observed in cerebellar slices electroporated with a Pax6 knock-down vector. Because it is known that BMP signaling induces Atoh1 degradation in GCPs, these findings suggest that the Meis1–Pax6 pathway increases the expression of Smad proteins to upregulate BMP signaling, leading to degradation of Atoh1 in the inner EGL, which contributes to differentiation from GCPs to GCs. Therefore, this work reveals crucial functions of Meis1 in GC development and gives insights into the general understanding of the molecular machinery underlying neural differentiation from neural progenitors.
SIGNIFICANCE STATEMENT We report that myeloid ectopic viral integration site 1 homolog (Meis1) plays pivotal roles in the regulation of mouse granule cell (GC) development. Here, we show Meis1 is expressed in GC precursors (GCPs) and GCs during development. Our knock-down and conditional knock-out (cKO) experiments and in vitro assays revealed that Meis1 is required for proper cerebellar structure formation and for Pax6 transcription in GCPs and GCs. The Meis1–Pax6 cascade regulates the morphology of GCs. In the cKO cerebella, Smad proteins and bone morphogenic protein (BMP) signaling are severely reduced and Atoh1-expressing GCPs are ectopically detected in the inner external granule layer. These findings suggest that Meis1 regulates degradation of Atoh1 via BMP signaling, contributing to GC differentiation in the inner EGL, and should provide understanding into GC development.
Itraconazole Induced Hypertension and Hypokalemia: Mechanistic Evaluation
Abstract
We describe a case of apparent mineralocorticoid excess (hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity) secondary to itraconazole therapy. Inhibition of 11β-hydroxysteroid dehydrogenase 2 was demonstrated, and withholding itraconazole led to resolution of adverse effects that did not recur with voriconazole. This report adds to a growing body of evidence linking apparent mineralocorticoid excess with certain triazoles.
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Exposure to the antifouling chemical medetomidine slows development, reduces body mass, and delays metamorphosis in wood frog ( Lithobates sylvaticus ) tadpoles
Abstract
Antifouling chemicals have a long history of causing toxicity to aquatic organisms. We measured growth and developmental timing in wood frog tadpoles exposed to the antifouling chemical medetomidine (10 nM–10 μM) starting at two different developmental stages in static renewal experiments. For tadpoles hatched from egg masses and exposed for 3 weeks to 100 nM and 1 μM, head width/total body length ratio was significantly shorter compared to control. For field-collected tadpoles at Gosner stage 24–25 and exposed for 2 weeks, 1 and 10 μM medetomidine significantly slowed development as measured by Gosner stage. Medetomidine (1 and 10 μM) significantly increased the time to metamorphosis by over 16 days on average, and at 100 nM and 1 μM, it significantly decreased mass at metamorphosis. We discuss the possible effects of antifouling chemicals containing medetomidine on globally threatened groups such as amphibians.
Finding the brake: dissecting the RhoA pathway regulating glioma cell migration
Abstract
Cell migration is one of the hallmarks of cancer. Cancer cells can adopt two main migratory strategies displaying either a mesenchymal or amoeboid phenotype. Targeting cell migration presents an opportunity in improving treatment of invasive and migratory tumours, however the cellular mechanisms that control the cell migration phenotypes in high-grade gliomas, such as Glioblastoma multiforme, are still not fully understood. In previous work we used 2D and 3D migration assays to screen a panel of inhibitors targeting the actin polymerisation pathway, a key regulator of cell migration in glioma. Amongst RhoA pathway inhibitors, which are key negative regulators of migration, we have identified one compound, CCG-1423, that uniquely failed to inhibit migration. CCG-1423 induces a reduced expression of the adhesion protein CCN1 by blocking nuclear import of MKL-1, a transcriptional co-activator. We suggest that CCG-1423 induces a mesenchymal transition, which permits continued migration. To confirm the effect of CCG-1423 on CCN1 levels we used ELISA to detect secreted CCN1 levels in culture supernatants in treated and non-treated U251 and U87 cells. CCG-1423 significantly reduced CCN1 levels in supernatant of both cell lines compared to untreated controls. Further biochemical analysis was performed to establish levels of MKL-1 in treated versus untreated cells and to elucidate its association with other proteins. Preliminary data indicate an increase in MKL-1 concentration in treated cells, consistent with a build-up of MKL-1 in the cytosol due to lack of nuclear import, as previously reported. Further detailed characterisation of the RhoA signalling pathway in glioma will provide an understanding of the role of MKL-1 in mesenchymal migration and the effect of CCG-1423 on mesenchymal switching. We will next characterise the interactions between CCG-1423 and MKL-1, and use pharmacological and/or genetic manipulation to refine combination treatments to target both mesenchymal and amoeboid cell migration.IDH1 mutations drive an oxygen-sparing metabolic phenotype to permit tumour growth
Abstract
Since the description of mutations in isocitrate dehydrogenase 1 (IDH1) in adult glial tumours in 2008, many studies have focused on the role of the oncometabolite 2-hydroxyglutarate in determining the pheontype of affected gliomas. However, another aspect of IDH1 activity - its redox-dependency - may also represent an important determinant of IDH1-mutant glioma phenotype. To examine the effect of IDH1 mutations on redox homeostasis, we traced their use of redox-active metabolic pathways using nutrients enriched in the stable isotope, 13C. We found that cells expressing the IDH1 R132H mutant demonstrated enhanced proline synthesis, but that unexpectedly the proline produced was excreted rather than used for biosynthetic processes. As proline synthesis is a highly redox-dependent pathway, we hypothesised that this represented a metabolic response to altered isocitrate metabolism by the IDH1 mutant enzyme. We furthermore showed that metabolic response was dependent on pyrroline 5-carboxylate reductase 1 (PYCR1), and was important for the oxidation of mitochondrial NADH. Consistent with this, knockdown of PYCR1 resulted in a compensatory increase in cell respiration. We therefore show that cells with IDH1 mutations require proline synthesis in order to retain normal TCA cycle activity while using less oxygen. This may mean that IDH1 mutant tumours are in general less hypoxic, and therefore more responsive to treatment.High-resolution RNA-seq profiling of glioblastoma residual invasive cells isolated by a novel 5-ALA fluorescence based method
Abstract
INTRODUCTION
Malignant brain cancer Glioblastoma (GBM) kills 3500 people per year in the UK with an average survival of 6 months. The intra-tumour heterogeneity of GBM has meant tailored therapies based on the genetic mutations within the cancer cells have so far failed to replicate in vitro promise in clinical trials. Previous research has focused on the core of the tumour; however this is removed by surgery and doesn't reflect the residual cancer cells left in the patient's brain. The aim of this study is to generate new potential targets from looking at the expression of those residual cancer cells left behind after surgery that ultimately lead to tumour recurrence. METHOD
5-aminolevulinic acid (5-ALA) is a clinically used drug that makes cancer cells glow (fluoresce) pink, allowing more complete removal of brain tumours. 10 Tumour samples were dissociated and fluorescent activated cell sorting (FACS) was used to separate the residual fluorescent cancer cells (1%) from normal brain at the tumour's edge. Samples from 3 distinct tumour regions, core, rim and invasive margin without FACS sorting from the same patients were also included for comparison to the FACS samples. Gene expression was analysed by RNA-seq and validated by qPCR. RESULTS
High-resolution RNA-seq profiles were generated for distinct tumour regions and the fluorescently isolated invasive cell population, allowing potential targetable abnormalities to be identified and validated. CONCLUSION
This study shows that pure tumour cells can be separated from normal cells using fluorescence generated from tumour metabolism of 5-ALA. Further optimisation of FACS is required to increase RNA yield from FACS sorted samples. Our approach gives hope that we can interrogate the true residual disease, and for the first time gain insight into the source of tumour recurrence.The identification and validation of novel aptamers for the diagnosis of oligodendroglioma
Abstract
Oligodendroglioma account for nearly 12% of brain tumours (Jain et al., 2017). In the United Kingdom, 0.4 people per 100 000 per year are newly diagnosed with oligodendroglioma (Crocetti et al., 2012). Early diagnosis and treatment of oligodendroglioma is essential as patients given the appropriate chemotherapy survive on average nearly 8 years longer than patients given radiotherapy alone (Cairncross et al., 2014). Aptamers are short, single-stranded nucleotide sequences (DNA or RNA) that uniquely fold to form specific recognition molecules that selectively bind to a molecular target. Aptamers against targets are generated using a process called systematic evolution of ligands by exponential enrichment (SELEX). Since 2002, a number of aptamers have been identified that can selectively identify cancerous cells. These aptamers have been used both diagnostically and therapeutically against a range of different cancers, however, there are currently no aptamers specific to glioma tissue. This first part of this project was to find aptamers specific to the grade IV glioblastoma cell line U87MG. Previous studies have found aptamers that were able to distinguish U87MG from non-malignant cell lines but showed good binding to most highly tumorigenic cell lines (Cerchia et al., 2009; Aptekar et al., 2015). To ensure that highly specific aptamers were identified, a large number of negative controls were utilised, and two variants of the SELEX process were undertaken to ascertain whether the negative controls had to be selected against individually or if they could be pooled. Patient brain tumour samples will be obtained from the Brain Tumour North West (BTNW) tissue bank and aptamers specific to oligodendroglioma will be selected. These aptamers will be used to screen patient samples to determine if they can identify oligodendroglioma tissue and be of use diagnostically, therapeutically and as a drug delivery tool.Local Delivery Of Irinotecan To Recurrent Glioblastoma At Reoperation Offers A Safe Therapeutic Advantage Over Systemic Delivery
Abstract
Direct drug delivery to a brain tumours offers the surety of access, together with the potential to realise at least therapeutic concentrations. With previously used systemic drugs toxicity and removal mechanisms are avoided. With new formulations drug activation and duration can be explored for low local toxicity, and tumour impact with sequential imaging. In this early study Irinotecan a drug with known efficacy against glioma but with limiting systemic toxicity has been incorporated into biodegradeable hydrogel microspheres and injected into the post-surgical cavity wall in patients with recurrent glioblastoma. 10 patients with focally recurrent GBM were recruited with 9 undergoing injection with up to 3mls of microbeads in alginate suspension in up to 60 ~ 8mm injection tracks after surgical resection (100mg). Patients were assessed for immediate (72hrs) toxicity with clinical assessment and imaging. Pharmacokinetic determination of Irinotecan and SN 38 active metabolite allowed confirmation of activation and comparator with known plasma toxicity profiles. Follow-up was planned for a minimum of 6/12 for SAE but continued to allow overall survival estimation. No overt SAE were determined for this group of patients with imaging and steroid use indicating less local swelling and wound healing issues than have been demonstrated for Carmustine wafers despite early offloading. Phamacokinetic measures (SN38 plasma curves) indicate a much higher activation of Irinotecan (>90%) than expected but shorter period of exposure. Survival curves suggest clinical benefit with 4/9 patient living longer than 8 months warranting further exploration of this safe approachRegulation of DNA double strand break repair by EGF and VEGF signalling reveals Akt to be a critical therapeutic target in glioblastoma
Abstract
Glioblastoma (GBM) is currently incurable. Its radioresistance has been attributed to a subpopulation of cells termed 'GBM stem-like cells' characterised by multipotentiality and tumorigenicity. The discrepancy between pre-clinical and clinical effects of molecular targeted agents on radiosensitivity indicates that 2D in vitro models of GBM do not recapitulate the clinical scenario. In a 3D model developed in our laboratory, EGFR inhibitors failed to enhance radiosensitivity recapitulating their lack of efficacy in the clinic, contrasting with their radiosensitising activity in 2D cultures. Conversely, inhibition of VEGF signalling caused significant radiosensitisation of 3D cultures but had no effect in 2D conditions. The critical role of the DNA damage response in mediating these effects is illustrated by the consistent correlation between radiosensitivity, unrepaired double-strand breaks (γH2AX foci), mitotic catastrophe and micronuclei in both 2D and 3D models. Further investigation revealed unrepaired DSB to be associated with delayed resolution of phosphorylated DNA-PKcs nuclear foci and reduced formation of Rad51 foci. Hence in 2D conditions, EGFR signalling appeared to promote efficient non-homologous end-joining (NHEJ) repair, while in 3D conditions this process was dependent on VEGF signalling. Motivated by previous reports that radiation induced EGFR signalling promotes NHEJ via Akt mediated phosphorylation of DNA-PKcs, we investigated the role of Akt signalling in 2D and 3D systems. Specific inhibition of Akt using the small molecule inhibitor MK-2206 or Akti knockdown increased radiation sensitivity in both 2D and 3D models to a similar extent as EGFR or VEGF inhibition respectively. In keeping with this, phosphorylation of Akt was EGFR dependent in 2D GSC cultures but VEGF dependent in the 3D model. MK-2206 induced radiosensitivity was correlated with increased unrepaired DSBs and extended mouse survival in an U87MGLuc2 orthotopic model compared to radiation only. Our data identify Akt as a promising therapeutic target in combination with radiation for GBM.Risk factors for developing post-operative seizures following meningioma resection
Abstract
BACKGROUND
Meningiomas are benign primary tumours treated by surgical resection. Following surgery patients may develop postoperative seizures. The aim of this study was to investigate the risk factors associated with developing postoperative seizures and determine whether prophylactic antiepileptic drugs (AED) should be prescribed. METHODS
Retrospective analysis of patients undergoing surgical resection of meningioma between 2010–2015. The following clinical factors were assessed: tumour location, grade, Simpson resection, post-operative haemorrhage/infection and use of AED prophylaxis. MRI parameters were assessed including: tumour volume, adjacent parenchymal T2 signal change, midline shift. Logistical regression was performed. RESULTS
285 patients were identified with a median age of 60 years (range: 16–83 years). 68 (24%) had pre-operative seizures of which 62 were on AEDs and post-operatively 48 (17%) had seizures. 217 (76%) were seizure naïve, 19 were given prophylactic AEDs and post-operatively 5 had seizures. Of the 198 patients who did not receive prophylactic AED, 43 had post-operative seizures (22%). Prophylactic AED did not reduce the risk of seizures compared to no use (OR = 1.85, p= 0.260). Clinical risk factors for developing post-operative seizures were non-skull base location (n= 207, OR = 0.35, p= 0.010) and presence of post-operative haemorrhage/infection (n= 25, OR = 1.69, p= 0.002). MRI factors associated with developing post-operative seizures were presence of T2 signal intensity change greater than 66% of tumour volume (n= 81, OR = 4.71, p= 0.000). CONCLUSION
Risk factors associated with postoperative seizure development were the non-skull base tumour location and post-operative haemorrhage/infection. The role of prophylactic AED could not be determined in this study due to insufficient sample size. Randomized control trials are required.
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Publication date: Available online 25 July 2018 Source: Journal of Photochemistry and Photobiology B: Biology Author(s): Marco Ballestr...
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Editorial AJR Reviewers: Heartfelt Thanks From the Editors and Staff Thomas H. Berquist 1 Share + Affiliation: Citation: American Journal...
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Publication date: Available online 28 September 2017 Source: Actas Dermo-Sifiliográficas Author(s): F.J. Navarro-Triviño
