Multifunctional Two-Dimensional Bi2Se3 Nanodiscs for Anti-Inflammatory Therapy of Inflammatory Bowel Diseases

AlexandrosSfakianakis shared this article with you from Inoreader Multifunctional Two-Dimensional Bi<sub>2</sub>Se<sub>3</sub> Nanodiscs for Anti-Inflammatory Therapy of Inflammatory Bowel Diseases via ScienceDirect Publication Acta Biomaterialia Publication date: Available online 17 February 2023 Source: Acta Biomaterialia Author(s): Cong Zhang, Qingrong Li, Jie Shan, Jianghao Xing, Xiaoyan Liu, Yan Ma, Haisheng Qian, Xulin Chen, Xianwen Wang, Lian-Ming Wu, Yue Yu View on Web

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Monitoring of SARS‐CoV‐2 concentration and circulation of variants of concern in wastewater of Leuven, Belgium.

AlexandrosSfakianakis shared this article with you from Inoreader Monitoring of SARS‐CoV‐2 concentration and circulation of variants of concern in wastewater of Leuven, Belgium. via Journal of Medical Virology Abstract Background Wastewater surveillance plays an important role in the management of the COVID-19 pandemic all over the world. Using different wastewater collection points in Leuven, we wanted to investigate the use of wastewater surveillance as an early warning system for an uprise of infections, and as a tool to follow the circulation of specific variants of concern (VOC) in particular geographic areas. Methods Wastewater samples were collected from local neighborhood sewers and from a large regional wastewater treatment plant (WWTP) in the area of Leuven, Belgium. After virus concentration, SARS-CoV-2 RNA was quantified by RT-qPCR and normalized with the human fecal indicator pepper mild mottle virus (PMMoV). A combination of multiplex RT-qPCR assays was used to detect signature mutations of circulating VOCs. Fecal virus shedding of SARS-CoV-2 variants was measured in feces samples of hospitalized patients. Results In two residential sampling sites, a rise in wastewater SARS-CoV-2 concentration preceded peaks in positive cases. In the WWTP, viral load peaks were seen concomitant with the consecutive waves of positive cases caused by the original Wuhan SARS-CoV-2 strain and subsequent VOCs. During the Omicron BA.1 wave, the wastewater viral load increased to a lesser degree, even after normalization of SARS-CoV-2 concentration using PMMoV. This might be attributable to a lower level of fecal excretion of this variant. Circulation of SARS-CoV-2 VOCs Alpha, Delta, Omicron BA1/BA.2 and BA.4/BA.5 could be detected based on the presence of specific key mutations. The shift in variants was noticeable in the wastewater, with key mutations of two different variants being present simultaneously during the transition period. Conclusions Wastewater-based surveillance is a sensitive tool to monitor SARS-CoV-2 circulation levels and VOCs in larger regions. In times of reduced test capacity this can prove to be highly valuable. Differences in excretion levels of various SARS-CoV-2 variants should however be taken into account when using wastewater surveillance to monitor SARS-CoV-2 circulation levels in the population. This article is protected by copyright. All rights reserved. View on Web

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Nuclear membrane irregularity in high‐grade urothelial carcinoma cells can be measured by using circularity and solidity as morphometric shape definitions in digital image analysis of urinary tract cytology specimens

AlexandrosSfakianakis shared this article with you from Inoreader Nuclear membrane irregularity in high‐grade urothelial carcinoma cells can be measured by using circularity and solidity as morphometric shape definitions in digital image analysis of urinary tract cytology specimens via Cancer Cytopathology Abstract Background The Paris System for Reporting Urine Cytology defines objective (elevated nuclear/cytoplasmic ratio ≥0.7) and subjective (nuclear membrane irregularity, hyperchromicity, and coarse chromatin) cytomorphologic criteria to identify conventional high-grade urothelial carcinoma (HGUC) cells. Digital image analysis allows quantitative and objective measurement of these subjective criteria. In this study, digital image analysis was used to quantitate nuclear membrane irregularity in HGUC cells. Methods Whole-slide images of HGUC urine specimens were acquired, and HGUC nuclei were manually annotated using the open-source bioimage analysis software QuPath. Custom scripts were used to calculate nuclear morphometrics and perform downstream analysis. Results In total, 1395 HGUC cell nuclei were annotated across 24 HGUC specimens (48.1 ± 6.0 nuclei per case) using both pixel-level and smooth annotation approaches. Nuclear membrane irregularity was estimated by calculating nuclear circularity and solidity. Annotating at pixel-level resolution artifactually increases nuclear membrane perimeter, thus smoothing is necessary to better approximate a pathologist's assessment of nuclear membrane irregularity. After smoothing, nuclear circularity and solidity discriminate between HGUC cell nuclei with visually apparent differences in nuclear membrane irregularity. Conclusions Nuclear membrane irregularity defined by The Paris System for Reporting Urine Cytology is inherently subjective. This study identifies nuclear morphometrics that visually correlate with nuclear membrane irregularity. HGUC specimens show intercase variation in nuclear morphometrics, with some nuclei appearing remarkably regular while others show marked irregularity. A small population of irregular nuclei generates most of the intracase variation in nuclear morphometrics. These results highlight nuclear membrane irregularity as an important, but not definitive, cytomorphologic criterion in HGUC diagnosis. View on Web

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Risk and incidence of breast cancer in transgender individuals: a systematic review and meta-analysis

AlexandrosSfakianakis shared this article with you from Inoreader Risk and incidence of breast cancer in transgender individuals: a systematic review and meta-analysis via European Journal of Cancer Prevention - Published Ahead-of-Print Background and aims The risk of developing breast cancer in transgender individuals [male-to-female (MtF) or female-to-male (FtM)] is still inadequately quantified. We aimed to evaluate the impact of breast cancer in this population. Methods We conducted a systematic literature search and review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines through the PUBMED and SCOPUS databases. We identified six cohort studies (for both populations) plus 35 case reports. Incidence and breast cancer risk quantification were the main outcomes considered. Results FtM individuals had a higher risk of developing breast cancer in comparison to cisgender men [standardized incidence ratio (SIR) = 63.4; 95% confidence interval (CI), 32.2–124.9] but a lower risk than cisgender women (SIR = 0.42; 95% CI, 0.07–2.41). Similarly, MtF individuals were at higher risk of developing breast cancer in comparison to cisgender men (SIR = 22.5; 95% CI, 5.54–91.8) and at lower risk than cisgender women (SIR = 0.30; 95% CI, 0.22–0.42). Conclusion In this systematic study and meta-analysis, we identified that FtM and MtF individuals are at substantially higher risk of developing breast cancer in comparison to cisgender men, though at lower risk than cisgender women. These individuals, in the absence of defined guidelines for breast cancer prevention, should periodically undergo breast or chest examinations. View on Web

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Impact of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty

AlexandrosSfakianakis shared this article with you from Inoreader Impact of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty via Medicine & Science in Sports & Exercise - Published Ahead-of-Print Purpose We examined the effects of aerobic exercise and detraining on adiponectin, resistin, tumor necrosis factor alpha (TNF-α), white blood cell, and pubertal signs (uterine length, ovarian volume, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)) in girls with central precocious puberty (CPP). Methods Thirty girls with CPP (aged 7-9) were randomly divided into CPP and CPP + Exercise (EX) groups. 15 Healthy age-matched girls without precocious puberty participated for comparison with CPP. Subjects in the CPP + Ex group attended 12 weeks of aerobic exercise protocol three sessions a week. In the baseline, after completing the exercise protocol and after 4 weeks of detraining, all the parameters were measured. In the CPP and healthy groups, all the parameters were measured in all three stages. To measure adiponectin, resistin, and TNF-α, the ELISA method was used. LH and FSH were measured by electrochemiluminescence immunoassay. WBC counts were analyzed by an automated blood cell counter. Analysis of Variance with repeated measures test was used to analyze the results. Results CPP girls have lower adiponectin (P = 0.01) and higher TNF-α levels (P = 0.001) than healthy girls. In the CPP + EX group, after 12 weeks, body weight and fat mass decreased, adiponectin increased significantly (P = 0.02). Resistin (P = 0.02), TNF-α (P = 0.02), neutrophils (P = 0.01), and signs of puberty significantly (P View on Web

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Complex Ataxia‐Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia

AlexandrosSfakianakis shared this article with you from Inoreader Complex Ataxia‐Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia via Movement Disorders Digenic SCA TBP/STUB1 is caused by the concomitant inheritance of an intermediate expansion in TBP gene and a deleterious mutation in STUB1 gene. SCA TBP/STUB1 patients present a complex phenotype including ataxia, chorea, dementia, and diffuse cerebellar and cerebral brain atrophy. Genetic counseling is essential for all family members. ABSTRACT Background and Objectives Spinocerebellar ataxias (SCAs) are autosomal dominant disorders with extensive clinical and genetic heterogeneity. We recently identified a form of SCA transmitted with a digenic pattern of inheritance caused by the concomitant presence of an intermediate-length expansion in TATA-box binding protein gene (TBP 40–46) and a heterozygous pathogenic variant in the Stip1-homologous and U-Box containing protein 1 gene (STUB1). This SCA TBP/STUB1 represents the first example of a cerebellar disorder in which digenic inheritance has been identified. Objectives We studied a large cohort of patients with SCA TBP/STUB1 with the aim of describing specific clinical and neuroimaging features of this distinctive genotype. Methods In this observational study, we recruited 65 affected and unaffected family members from 21 SCA TBP/STUB1 families and from eight families with monogenic SCA17. Their characteristics and phenotypes were compared with those of 33 age-matched controls. Results SCA TBP/STUB1 patients had multi-domain dementia with a more severe impairment in respect to patient carrying only fully expanded SCA17 alleles. Cerebellar volume and thickness of cerebellar cortex were reduced in SCA TBP/STUB1 compared with SCA17 patients (P = 0.03; P = 0.008). Basal ganglia volumes were reduced in both patient groups, as compared with controls, whereas brainstem volumes were significantly reduced in SCA TBP/STUB1 , but not in SCA17 patients. Conclusions The identification of the complex SCA TBP/STUB1 phenotype may impact on diagnosis and genetic counseling in the families with both hereditary and sporadic ataxia. The independent segregation of TBP and STUB1 alleles needs to be considered for recurrence risk and predictive genetic tests. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. View on Web

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LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease

AlexandrosSfakianakis shared this article with you from Inoreader LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease via Movement Disorders Abstract Background Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). Objective The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. Methods Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. Results A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7–1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). Conclusions At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. View on Web

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Spermidine reduced neuropathic pain in chronic constriction injury‐induced peripheral neuropathy in rats

AlexandrosSfakianakis shared this article with you from Inoreader Spermidine reduced neuropathic pain in chronic constriction injury‐induced peripheral neuropathy in rats via Fundamental & Clinical Pharmacology Abstract Neuropathic pain is one of the most critical types of chronic pain despite the increasing advances in medical science. Spermidine (SPD) is a natural polyamine that has wide roles in several cellular processes inducing autophagy and reducing oxidative stress. This study aimed to investigate the effects of SPD on oxidative stress markers and pain threshold in the neuropathic rat model of chronic constriction injury (CCI) model. Eighteen adult male rats were divided into 3 groups: sham, CCI and CCI+ SPD. After induction of neuropathy via CCI model in the CCI and CCI+SPD groups, SPD (1 mg/kg/day, orally) was administered to the CCI+SPD group for 3 weeks. The behavioral tests (von Frey, hot plate) were done 4 times during the experiment. At the end of the study, electrophysiological tests, the H & E staining, and oxidative stress assay of the prefrontal cortex (PFC), spinal cord, and sciatic nerve were performed. The threshold of pain in hot plate and von Frey tests was significant ly lower in the CCI group than the sham group, which was reversed by SPD treatment in the CCI+ SPD group. In addition, nerve conduction was considerably lower in the CCI group than in the sham and CCI+SPD groups (P<0.01, P< 0.05, respectively). The CCI group showed neuronal degeneration and fibrosis in the different tissues in the H & E assay; elevated tissues level of nitrite, decreased levels of SOD, GPx, and catalase were also observed. However, SPD treatment modulated the pathological changes and oxidative stress biomarkers. In conclusion, SPD showed beneficial effects in decreasing neuropathic pains. SPD treatment reduced oxidative stress, improved histopathological changes and behavioral tests in the CCI-induced neuropathic pain in in vivo model. View on Web

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Frequent EGFR exon 20 insertion in the so‐called peripheral‐type squamous cell neoplasm of uncertain malignant potential: a variant of bronchiolar adenoma or underrecognized entity?

AlexandrosSfakianakis shared this article with you from Inoreader Frequent EGFR exon 20 insertion in the so‐called peripheral‐type squamous cell neoplasm of uncertain malignant potential: a variant of bronchiolar adenoma or underrecognized entity? via Histopathology Introduction Herein we describe a series of rare peripheral pulmonary neoplasms temporarily termed "peripheral type squamous cell neoplasm of uncertain malignant potential(PSCN-UMP)" and investigate their relationship to bronchiolar adenoma (BA) and squamous cell carcinoma (SCC). Materials and methods The histologic and immunohistochemical features of ten PSCN-UMPs and six BAs were compared. Whole exome sequencing (WES) and bioinformatics analysis were performed to further compare the genetic features of PSCN-UMPs, BAs, and NSCLCs. Results All PSCN-UMPs were peripherally located and histologically characterized by the lepidic, nested, and papillary proliferation of relatively bland squamous cells, accompanied by entrapped hyperplastic reactive pneumocytes. The basal squamous cells co-expressed TTF1 and squamous markers. Both cellular components exhibited bland morphology and a low proliferative activity. The six BAs met the morphologic and immunophenotypic features of proximal-type BA. Genetically, driver mutations, including frequent EGFR exon 20 insertions, were found in PSCN-UMPs, while the KRAS mutation, BRAF mutation, and ERC1::RET fusion were detected in BAs. PSCN-UMPs also shared some alterations with BAs in mutational signatures, while copy number variants (CNV) were enriched in MET and NKX2-1 in PSCN-UMP and MCL1, MECOM, SGK1, and PRKAR1A in BA. Conclusion PSCN-UMPs exhibited the proliferation of bland squamous cells accompanied by entrapped pneumocytes and frequent EGFR exon 20 insertions, which showed distinct features from BAs and SCCs. Recognition of this specific entity will help to expand the morphologic and molecular spectrum of peripheral lung squamous neoplasms. View on Web

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Central odontogenic fibroma with amyloid: a diagnostically challenging case

AlexandrosSfakianakis shared this article with you from Inoreader Central odontogenic fibroma with amyloid: a diagnostically challenging case via International Journal of Oral and Maxillofacial Surgery via MedWorm.com Odontogenic fibroma is a rare benign mesenchymal odontogenic tumor, with its histological diversity possibly posing diagnostic challenges. A case of the amyloid variant of central odontogenic fibroma, with epithelial cells in perineural and intraneural locations, is reported herein. The 46-year-old female patient had experienced discomfort related to her anterior right hard palate for approximately 25 years. Clinical examination revealed a depression in the anterior hard palate, and radiographic examination showed a well-defined radiolucent lesion with root resorption of the adjacent teeth. (Source: International Journal of Oral and Maxillofacial Surgery) View on Web

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