A novel tubulin inhibitor STK899704 induces tumor regression in DMBA/TPA induced skin carcinogenesis model

Abstract

Skin cancer is the most common type of cancer. The incidence rate of skin cancer has continuously increased over the past decades. In an effort to discover novel anticancer agents, we identified a novel tubulin inhibitor STK899704 which is structurally distinct from other microtubule-binding agents such as colchicine, vinca alkaloids, and taxanes. STK899704 inhibited microtubule polymerization leading to mitotic arrest, and suppressed the proliferation of various cancer cell lines as well as multidrug-resistance cancer cell lines. In this study, our investigation is further extended into animal model to evaluate the effect of STK899704 on skin carcinogenesis in vivo. Surprisingly, almost 80% of the tumors treated with STK899704 were regressed with a one fifth reduction in tumor volume. Furthermore, the efficacy of STK899704 was nearly two times higher than that of 5-fluorouracil, a widely used skin cancer therapeutic. Overall, our results suggest that STK899704 is a promising anticancer chemotherapeutic that may replace existing therapies, particularly for skin cancer.

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Eicosapentaenoic acid ethyl ester ameliorates atopic dermatitis-like symptoms in special diet-fed hairless mice, partly by restoring covalently bound ceramides in the stratum corneum

Abstract

Skin barrier dysfunction has a key role in the development of atopic dermatitis (AD). Covalently bound ceramides (Cer), which are essential lipids for permeability barrier homeostasis, are reportedly decreased in the stratum corneum (SC) of AD patients. Hairless mice fed a special diet develop pruritic dermatitis resembling human AD. Our previous study found that oral administration of the n-3 polyunsaturated fatty acid α-linolenic acid ameliorated skin barrier dysfunction in AD mice with concomitant increase in serum eicosapentaenoic acid (EPA). In this study, we examined the effects of EPA ethyl ester (EPA-E) on diet-induced AD in hairless mice. Oral administration of EPA-E ameliorated skin barrier dysfunction and pruritus in AD mice. In the SC of AD mice, covalently bound Cer were markedly diminished. EPA-E administration restored the lack of bound Cer. Our findings imply the possible therapeutic clinical application of EPA-E in the treatment of human AD.

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An efficient method for eccrine gland isolation from human scalp

Abstract

We describe a simple and efficient method to isolate eccrine sweat glands from the human scalp. This method is inspired by the hair graft harvesting method used in hair transplantation. Based on the recently described anatomical relationship between the scalp hair follicle and the eccrine gland, we have found that scalp follicular unit grafts are an excellent eccrine gland isolation source, especially for the coiled component. In order to make the gland visible for stereoscopic microdissection, the follicular units need to be previously stained with a vital dye like Methylene Blue or Neutral Red. The simplicity and efficiency of this isolation method should encourage further research into human eccrine sweat gland function which has always been hindered by the difficulty of gland isolation.

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Effects of UV Irradiation by Light Emitting Diodes on Heterotrophic Bacteria in Tap Water

Abstract

Ultraviolet light emitting diodes (UV-LEDs) are small mercury-free devices that can be installed at the point of use (POU) of water for disinfection. Considering that heterotrophic bacteria are of concern in drinking water systems, we applied a flow-through UV-LED apparatus to dechlorinated tap water, and determined the heterotrophic plate count (HPC) in samples after UV-LED exposure (UV+) compared to samples without UV-LED application (UV-). The UV+ and UV- samples were maintained at 20 °C to track HPC profiles during storage for seven days. It was confirmed that UV+ samples showed negative HPC or lower HPC than UV- for five days of storage after the flow-through test. HPC bacteria formed colonies with different morphological characteristics, and yellow colonies were closest to Novosphingobium sp., with 99% identity, while white and pale pink colonies were closest to Methylobacterium sp., with 99–100% identity, based on 16S rRNA gene sequences. White colonies became dominant in UV+, indicating that UV-LED exposure can select UV-resistant species such as Methylobacterium. This study shows the effects of UV-LED application on HPC bacteria in tap water, and implies that future research is required on the significance and impacts of microbial selection by UV-LED exposure.

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Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02)

Abstract

Background

The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN.

Patients and methods

Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m² on days 1, 8; carboplatin AUC 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m², followed by 250mg/m² weekly until disease progression or unacceptable toxicities. Primary endpoint was overall response rate (ORR). Secondary endpoints were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients.

Results

Forty-seven subjects were accrued from July 2013 to Oct 2014. Of 45 evaluable, 40 were male; median age was 63 years; ECOG PS was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/non-smokers, respectively. ORR, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia.

Conclusions

The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population.

Registered clinical trial numbers

UMIN000010507

Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2-positive gastric cancer patients

Abstract

Background

To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.

Patients and Methods

We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer (AGC). A parallel biomarker study was conducted by simultaneously performing immunohistochemistry (IHC) and next-generation sequencing with tumor and blood samples.

Results

Complete response (CR) was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed CR. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. Next-generation sequencing (NGS) of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2-positive tumors. The relationship between CCNE1 amplification and lack of response to HER2 targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; p = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared to patients with low level ERBB2 amplification (p = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.

Conclusions

The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

Does dietary fluid intake affect skin hydration in healthy humans? A systematic literature review

Abstract

Background

Associations between daily amounts of drinking water and skin hydration and skin physiology receive increasingly attention in the daily life and in clinical practice. However, there is a lack of evidence of dermatological benefits from drinking increased amounts of water.

Materials and methods

Pubmed and Web of Science were searched without any restrictions of publication dates. References of included papers and related reviews were checked. Eligibility criteria were primary intervention and observational studies investigating the effects of fluid intake on skin properties in English, German, Spanish or Portuguese language, including subjects being healthy and 18+ years.

Results

Searches resulted in 216 records, 23 articles were read in full text, and six were included. The mean age of the samples ranged from 24 to 56 years. Overall the evidence is weak in terms of quantity and methodological quality. Disregarding the methodological limitations a slight increase in stratum corneum and "deep" skin hydration was observed after additional water intake, particularly in individuals with lower prior water consumption. Reductions of clinical signs of dryness and roughness were observed. The extensibility and elasticity of the skin increased slightly. Unclear associations were shown between water intake and transepidermal water loss, sebum content, and skin surface pH.

Conclusions

Additional dietary water intake may increase stratum corneum hydration. The underlying biological mechanism for this possible relationship is unknown. Whether this association also exists in aged subjects is unclear. Research is needed to answer the question whether increased fluid intake decreases signs of dry skin.

Ken Hashimoto, M.D., Ph.D. (1931–2017): A tribute

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Asthma and Allergic Disorders in Uganda: A Population-Based Study Across Urban and Rural Settings

Publication date: Available online 1 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Brooks W. Morgan, Trishul Siddharthan, Matthew R. Grigsby, Suzanne L. Pollard, Robert Kalyesubula, Robert A. Wise, Bruce Kirenga, William Checkley
BackgroundAllergic diseases are increasing in sub-Saharan Africa, but few studies have characterized the burden among adults.ObjectiveWe conducted a study to evaluate the prevalence and risk factors of allergic disorders in urban and rural Uganda.MethodsWe present a cross-sectional analysis of enrollment data from a population-based cohort study of adults aged ≥35 years in urban and rural Uganda. Sociodemographic and both lifetime and 12-month respiratory symptoms data were collected and spirometry was conducted following standard guidelines.ResultsIn 1,308 adults (median age 43.8 years and 52.3% female), we found an age-adjusted prevalence of 6.8% for asthma (9.8% urban, 4.3% rural; P < .001), 11.9% for allergic rhinitis (16.4% urban, 7.8% rural; P < .001), and 8.2% for eczema (9.9% urban, 7.8% rural; P = .15). Urbanization was the primary driver of asthma, accounting for 61.4% of cases (95% confidence interval [CI] 22.0% to 83.4%), and was the strongest risk factor for any allergic illness (odds ratio [OR] = 1.87, 95% CI 1.39-2.51). Parental asthma was not associated with allergic illness. Asthma was associated with a lower forced expiratory volume in 1 second (FEV1) by 0.56 z scores (95% CI 0.33-0.80). We found a dose-response association between lower quintiles of the FEV1/forced vital capacity ratio and both hospitalization (OR = 1.77, 95% CI 1.21-2.59) and impairment in daily activities (1.65, 1.20-2.27).ConclusionsAsthma and allergic rhinitis were twice as prevalent in urban settings. Asthma was associated with greater impairment and worse lung function outcomes. We identified a high prevalence of allergic disorders in Uganda, which can be expected to increase due to urbanization and resultant exposures throughout early development.

Allergy and mental health among pregnant women in the Japan Environment and Children's Study

Publication date: Available online 1 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Kiwako Yamamoto-Hanada, Kazue Ishitsuka, Kyongsun Pak, Mayako Saito, Tadayuki Ayabe, Hidetoshi Mezawa, Mizuho Konishi, Limin Yang, Kenji Matsumoto, Hirohisa Saito, Yukihiro Ohya

Should Younger Siblings of Peanut Allergic Children Be Screened for Peanut Allergy?

Publication date: Available online 1 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Elissa M. Abrams, Edmond S. Chan, Scott H. Sicherer
The role of screening younger siblings of peanut allergic children with allergy testing before peanut introduction is controversial. Although certain guidelines note some value in screening this population, it is not a direct indication in the recent National Institute of Allergy and Infectious Diseases guideline. Some studies suggest that siblings of peanut allergic children are at increased risk of peanut allergy, whereas others note that delayed ingestion or mislabeling of allergy in these children may be the main factors accounting for this increased risk. The low risk of severe reaction with first ingestion and risks of pre-emptive testing must be balanced against data suggesting that families are reluctant to introduce peanut in siblings without testing. The goal of this article is to critically appraise the debated issues in this topic, providing a practical approach to this common clinical dilemma.

The Journal of Allergy and Clinical Immunology: In Practice 2017 Year in Review

Publication date: Available online 1 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Michael Schatz, Scott H. Sicherer, Robert S. Zeiger
An impressive number of clinically impactful studies and reviews were published in The Journal of Allergy and Clinical Immunology: In Practice in 2017. As a service to our readers, the editors provide this Year in Review article to highlight and contextualize the advances published over the past year. We include information from articles on asthma, allergic rhinitis, rhinosinusitis, immunotherapy, atopic dermatitis, contact dermatitis, food allergy, anaphylaxis, drug hypersensitivity, urticarial/angioedema, eosinophilic disorders, and immunodeficiency. Within each topic, epidemiologic findings are presented, relevant aspects of prevention are described, and diagnostic and therapeutic advances are enumerated. Treatments discussed include behavioral therapy, allergen avoidance therapy, positive and negative effects of pharmacologic therapy, and various forms of immunologic and desensitization management. We hope this review will help readers consolidate and use this extensive and practical knowledge for the benefit of patients.

Conducting an Integrative Health Interview

Publication date: Available online 1 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Maureen George, Melissa Avila, Thomas Speranger, Heidi K. Bailey, William S. Silvers
Complementary medicine incorporates the use of non–evidence-based complementary modalities into conventional (Western) medicine. Alternative medicines are approaches that are used in place of conventional medicine. Integrative medicine is the synthesis of conventional medical treatments with "evidence-based" complementary medical practices. When complementary approaches are incorporated into mainstream health care, it is called integrative health (IH). Among children and adults, IH is common despite not all therapies being safe and/or effective. Clinicians have suboptimal knowledge of their patients' IH use because, in part, they do not know what questions to ask and/or do not have a standard intake form to collect an IH history, as recently demonstrated by an American Academy of Allergy, Asthma, and Immunology membership survey. To address this unmet need, a group of Complementary and Alternative Practice in Allergy Committee members and interprofessional collaborators reviewed the existing literature to locate IH history forms that could assist in identifying patients' IH use. When none was located, the group created 3 templates for the systematic collection and documentation of IH practices: 2 general screening surveys that could be given to patients to complete before an appointment and a third template that provides the clinician with open-ended questions to help uncover IH practices in culturally diverse patient populations. Specialists, already acknowledged as skillful interviewers, can expand their patient-centered expertise by developing their own IH competencies.

Outcome of 490 Desensitizations to Chemotherapy Drugs with a Rapid One-Solution Protocol

Publication date: Available online 1 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Eva Pérez-Rodríguez, Juan Antonio Martínez-Tadeo, Natalia Pérez-Rodríguez, Guacimara Hernández-Santana, Ariel Callero-Viera, Elena Rodríguez-Plata, José Carlos García-Robaina
BackgroundHypersensitivity reactions to chemotherapy drugs are quite frequent. Desensitization for chemotherapy drugs has become an option to maintain first-line therapy in patients who have suffered such reactions.ObjectiveThe objective of this study was to describe our experience in desensitization with antineoplastic agents using a rapid 1-solution protocol.MethodsWe performed a 3-year prospective observational study recording all patients who were desensitized with this protocol. All patients signed an informed consent. Skin test was performed at concentrations previously described as nonirritant. Desensitization was performed using only 1 solution of the drug prepared following the manufacturer instructions. Most drugs were diluted in a volume of 500 mL. We started infusion at 5 mL/h and increased doses at 15-minute intervals to 10, 25, 50, 75, and 100 mL/h. If no reaction occurred, and if the pharmacokinetics of the drug allowed it, we stepped up to 150, 200, and 250 mL/h.ResultsNinety patients were desensitized to 93 drugs: oxaliplatin (30), carboplatin (16), paclitaxel (19), docetaxel (6), cetuximab (5), rituximab (6), and others (11). A total number of 490 procedures were performed. Sixteen patients (17.77%) presented 26 reactions (5.3%). Most reactions appeared in patients who were desensitized to platins and in patients with severe reactions. All but 3 cycles were completely administrated. No deaths or hospital admissions were recorded.ConclusionsThis 1-solution protocol for desensitization has demonstrated to be safe and useful in our study population, especially for mild-to-moderate reactions and nonplatinum drugs. If our results were reproducible in other centers and larger populations, they could contribute to simplifying protocols and making desensitization available for more patients.

Risk Factors for Food Allergy in Early Adolescence: The SchoolNuts Study

Publication date: Available online 1 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Mari Sasaki, Rachel L. Peters, Jennifer J. Koplin, Michael J. Field, Vicki McWilliam, Susan M. Sawyer, Peter J. Vuillermin, Angela Pezic, Lyle C. Gurrin, Jo A. Douglass, Mimi L.K. Tang, Shyamali C. Dharmage, Katrina J. Allen
BackgroundDespite the rising rates of anaphylaxis in older children and adolescents, risk factors for food allergy among this age group are understudied.ObjectiveThe objective of this study was to investigate the risk factors for current adolescent food allergy using a population-based sample.MethodsThe SchoolNuts study was a questionnaire survey among 10- to 14-year-old adolescents and their parents, followed by clinic evaluation including oral food challenge when food allergy was suspected from questionnaire response. We investigated the association between food allergy and demographic and environmental factors among a total of 4,991 adolescents using multiple logistic regression.ResultsMales and those with early-onset eczema had a higher risk of current food allergy in adolescence (adjusted odds ratio [aOR], 1.55; 95% confidence interval [CI], 1.12-2.15 and aOR, 14.08; 95% CI, 10.25-19.33). Those with Asian parents had increased risk compared with those with Caucasian parents (aOR, 2.82; 95% CI, 1.91-4.16), whereas being born in Asia compared with being born in Australia had decreased risk (aOR, 0.16; 95% CI, 0.04-0.67). Family history risk was higher for those with multiple members versus only 1 member (aOR, 4.62; 95% CI, 2.75-7.74 and aOR, 2.32; 95% CI, 1.36-3.97, respectively). Dog exposure during the first 5 years of life was associated with a decreased risk (aOR, 0.58; 95% CI, 0.38-0.91).ConclusionsEarly-onset eczema, Asian background, and family history of allergic disease were associated with an increased risk of food allergy, whereas dog exposure in early life reduced the risk in 10- to14-year-old adolescents. Factors predicting food allergy risk in an adolescent population-based cohort appear remarkably similar to those predicting early-onset food allergy in infancy.

The Vitamin D3 analogue calcipotriol suppresses CpG-activated TLR9-MyD88 signalling in murine plasmacytoid dendritic cells

Summary

Background

Plasmacytoid dendritic cells (pDCs) are involved in the pathogenesis of psoriasis by secreting interferon-α. Vitamin D3 analogues are widely used to treat psoriasis, and the representative analogue calcipotriol (CAL) uniquely downregulates the cytokine production and chemotactic activity of pDCs. However, the molecular mechanism of action of CAL is not well understood.

Aim

To investigate effects of CAL on the Toll-like receptor 9–myeloid differentiation primary response gene 88 (TLR9-MyD88) signalling pathway, which induces cytokine production, in murine pDCs.

Methods

pDCs were isolated from mouse spleen cells by negative selection or were generated from mouse bone-marrow cells, and were stimulated with CpG-oligodeoxynucleotide (ODN) with or without CAL for 24 h. mRNA expression of TLR9 and MyD88 was assessed by real-time PCR, and the amount of TLR9 was measured by western blotting.

Results

CAL suppressed the CpG-ODN-induced increased expression of MyD88 and TLR9 in pDCs.

Conclusions

CAL may downregulate pDCs by inhibiting TLR9-MyD88 signalling.

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