A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.

AIMS: GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995). METHODS: Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts. RESULTS: In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization. CONCLUSIONS: Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Music festival drug checking: evaluation of an Australian pilot program.

BACKGROUND: This paper explores the feasibility of delivering a music festival-based drug checking service in Australia, evaluating service design and stakeholder acceptability. METHODS: Questionnaire and interview data were collected from adult service users and key stakeholders. A mixed methods approach was used to analyse the data on implementation, impact and acceptability. RESULTS: The trial service tested 170 substances with more than 230 patrons (including individuals who attended in groups). Adult service users had an average age of 21 years. Voluntary participation in the evaluation resulted in 158 participants completing the pre-service questionnaire, most of whom also completed the post-service (147 participants). Eleven in-depth qualitative interviews were conducted with patrons in the weeks following the drug checking. Concordance between what the patron expected the drug to be and drug checking results occurred in 88 per cent (n = 139) of the sample. Evaluation results show that the experience of testing and the accompanying harm reduction brief interventions positively impacted on patrons' self-reported drug harm reduction knowledge, trust of health providers and stated drug use intentions. The service was received positively by service users. CONCLUSION: This is the first independent evaluation of a pilot drug checking service in Australia. Consideration of operational feasibility and self-reported behavioural change suggests that the program was successful, although communication about the interpretation of drug checking results could be improved. Future studies should develop strategies for follow-up and consider the applicability of behavioural change theory.

Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas.

WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERT promoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFR amplification, combined +7/-10, and TERT promoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRX mutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMT promoter methylation were independent good prognosticators for OS (p = 0.022 and p = 0.002, respectively) and TP53 mutation was an independent poor prognosticator (p = 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/B was not correlated with OS (p = 0.197) and PFS (p = 0.278). PDGFRA amplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p = 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRX involvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMT promoter methylation, and TP53 mutation are useful prognostic adjuncts.

Hepatocellular carcinoma and other complications of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: A structured review of published works.

AIMS: Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality in Japan. As the treatment of viral hepatitis improves, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are rapidly becoming leading causes of HCC in Japan. This structured review aims to characterize the morbidity and mortality of HCC and other malignant and non-malignant complications among Japanese NAFLD and NASH patients. METHODS: An English and Japanese structured search of published works was undertaken in PubMed, Embase, and Ichushi Web databases, identifying 6553 studies, 34 of which met predefined inclusion criteria. RESULTS: Hepatocellular carcinoma was the most common incident malignancy among NAFLD/NASH patients, with higher incidence in patients with advanced/severe fibrosis (F3/F4) of 10.5%-20.0%. Although NASH results in a lower HCC cumulative incidence than hepatitis C virus (HCV) (11.3% vs. 30.5%), they have similar impacts on health outcomes, including overall mortality. Among Japanese NASH patients, HCC was found to be the main driver of mortality (40.0% in 2.7 years in NASH-HCC). With longer follow-up, higher mortality rates are observed in F3/4 patients: 25.0% in NASH F3/F4 versus 0.0% in NASH F0/2 over 7.7 years. The NASH-HCC patients also have a higher post-operative mortality than HCV-HCC patients. Additionally, NAFLD/NASH patients had higher rates of cardiovascular disease than non-NAFLD/NASH controls, and slightly higher rates of gastric cancer than HCV patients. CONCLUSION: Hepatocellular carcinoma is the most common malignancy and cause of death among NAFLD/NASH patients in Japan, with higher mortality observed among those with advanced disease and complications. Early identification and effective treatments are needed.

CARD14-associated papulosquamous eruption (CAPE) in a toddler responding to treatment with acitretin.

CARD14-associated papulosquamous eruption (CAPE) is a rare autosomal dominant dermatosis that presents classically in early childhood with clinical features of both psoriasis and pityriasis rubra pilaris (PRP). The disease is known to be refractory to topical and systemic therapies classically used for psoriasis, with the majority of reported cases requiring treatment with biologics, such as ustekinumab and secukinumab. We present a toddler with a clinical presentation consistent with CAPE and found to have a novel heterozygous variant of the CARD14 gene. She was refractory to treatment with topical emollients and topical corticosteroids, but responsive to oral acitretin.

Non-invasive diagnosis of non-alcoholic steatohepatitis and advanced fibrosis in Japan: A targeted literature review.

Despite the invasive nature of liver biopsy, it remains the current standard for diagnosing non-alcoholic steatohepatitis (NASH) and fibrosis staging. Given the rising prevalence of non-alcoholic fatty liver disease (NAFLD) in Japan, there is a need for reliable non-invasive tests to accurately and efficiently identify NASH and advanced (F3/F4) fibrosis. A review of published works from English and Japanese sources was undertaken in PubMed, Embase, and Ichushi Web to identify studies reporting diagnostic characteristics of NITs in biopsy-proven Japanese NAFLD/NASH patients including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve. The performance of non-invasive tests for two diagnostic questions were assessed, namely: (i) identifying NASH cases among NAFLD; and (ii) distinguishing advanced fibrosis (F3-4) from milder fibrosis (F0-2). Twenty-five studies reported outcomes for serum biomarkers, imaging, scoring systems, and novel complex techniques (based on multivariable regression models) for both diagnostic questions. Serum biomarkers were the most commonly assessed method for NASH identification, whereas scoring systems and imaging techniques were most commonly studied for fibrosis staging. In general, tests for NASH identification showed higher PPVs than NPVs, suggesting their usefulness in identifying probable NASH cases. The reverse was observed for fibrosis staging, with higher NPVs than PPVs, suggesting their use in excluding patients at low risk of F3/F4 disease rather than identifying definite F3/F4 fibrosis. In Japanese studies, simple scoring systems and imaging techniques showed particular usefulness in prediction of fibrosis staging, and combinations of serum biomarkers showed diagnostic potential for NASH screening.

Estimation of respiratory rate using infrared video in an inpatient population: an observational study.

Respiratory rate (RR) is one of the most sensitive markers of a deteriorating patient. Despite this, there is significant inter-observer discrepancy when measured by clinical staff, and modalities used in clinical practice such as ECG bioimpedance are prone to error. This study utilized infrared thermography (IRT) to measure RR in a critically ill population in the Intensive Care Unit. This study was carried out in a Single Hospital Centre. Respiratory rate in 27 extubated ICU patients was counted by two observers and compared to ECG Bioimpedance and IRT-derived RR at distances of 0.4-0.6 m and > 1 m respectively. IRT-derived RR using two separate computer vision algorithms outperformed ECG derived RR at distances of 0.4-0.6 m. Using an Autocorrelation estimator, mean bias was - 0.667 breaths/min. Using a Fast Fourier Transform estimator, mean bias was - 1.000 breaths/min. At distances greater than 1 m no statistically significant signal could be obtained. Over all frequencies, there was a significant relationship between the RR estimated using IRT and via manual counting, with Pearson correlation coefficients between 0.796 and 0.943 (p < 0.001). Correlation between counting and ECG-derived RR demonstrated significance only at > 19 bpm (r = 0.562, p = 0.029). Overall agreement between IRT-derived RR at distances of 0.4-0.6 m and gold standard counting was satisfactory, and outperformed ECG derived bioimpedance. Contactless IRT derived RR may be feasible as a routine monitoring modality in wards and subacute inpatient settings.

The association between nutritional adequacy and 28-day mortality in the critically ill is not modified by their baseline nutritional status and disease severity.

BACKGROUND: During the initial phase of critical illness, the association between the dose of nutrition support and mortality risk may vary among patients in the intensive care unit (ICU) because the prevalence of malnutrition varies widely (28 to 78%), and not all ICU patients are severely ill. Therefore, we hypothesized that a prognostic model that integrates nutritional status and disease severity could accurately predict mortality risk and classify critically ill patients into low- and high-risk groups. Additionally, in critically ill patients placed on exclusive nutritional support (ENS), we hypothesized that their risk categories could modify the association between dose of nutrition support and mortality risk. METHODS: A prognostic model that predicts 28-day mortality was built from a prospective cohort study of 440 patients. The association between dose of nutrition support and mortality risk was evaluated in a subgroup of 252 mechanically ventilated patients via logistic regressions, stratified by low- and high-risk groups, and days of exclusive nutritional support (ENS) [short-term (≤ 6 days) vs. longer-term (≥ 7 days)]. Only the first 6 days of ENS was evaluated for a fair comparison. RESULTS: The prognostic model demonstrated good discrimination [AUC 0.78 (95% CI 0.73-0.82), and a bias-corrected calibration curve suggested fair accuracy. In high-risk patients with short-term ENS (≤ 6 days), each 10% increase in goal energy and protein intake was associated with an increased adjusted odds (95% CI) of 28-day mortality [1.60 (1.19-2.15) and 1.47 (1.12-1.86), respectively]. In contrast, each 10% increase in goal protein intake during the first 6 days of ENS in high-risk patients with longer-term ENS (≥ 7 days) was associated with a lower adjusted odds of 28-day mortality [0.75 (0.57-0.99)]. Despite the opposing associations, the mean predicted mortality risks and prevalence of malnutrition between short- and longer-term ENS patients were similar. CONCLUSIONS: Combining baseline nutritional status and disease severity in a prognostic model could accurately predict 28-day mortality. However, the association between the dose of nutrition support during the first 6 days of ENS and 28-day mortality was independent of baseline disease severity and nutritional status.

Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency.

Although common variable immunodeficiency (CVID) has long been considered as a group of primary Ab deficiencies, growing experimental data now suggest a global disruption of the entire adaptive immune response in a segment of patients. Oligoclonality of the TCR repertoire was previously demonstrated; however, the manner in which it relates to other B cell and T cell findings reported in CVID remains unclear. Using a combination approach of high-throughput TCRß sequencing and multiparametric flow cytometry, we compared the TCR repertoire diversity between various subgroups of CVID patients according to their B cell immunophenotypes. Our data suggest that the reduction in repertoire diversity is predominantly restricted to those patients with severely reduced class-switched memory B cells and an elevated level of CD21(lo) B cells (Freiburg 1a), and may be driven by a reduced number of naive T cells unmasking underlying memory clonality. Moreover, our data indicate that this loss in repertoire diversity progresses with advancing age far exceeding the expected physiological rate. Radiological evidence supports the loss in thymic volume, correlating with the decrease in repertoire diversity. Evidence now suggests that primary thymic failure along with other well-described B cell abnormalities play an important role in the pathophysiology in Freiburg group 1a patients. Clinically, our findings emphasize the integration of combined B and T cell testing to identify those patients at the greatest risk for infection. Future work should focus on investigating the link between thymic failure and the severe reduction in class-switched memory B cells, while gathering longitudinal laboratory data to examine the progressive nature of the disease.

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma.

Human head and neck squamous cell carcinoma is a solid tumor malignancy associated with major morbidity and mortality. In this study, we determined that human head and neck squamous cell carcinoma-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by a high level of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. Importantly, matrix hyaluronan (HA) induces the up-regulation of stem cell markers that display the hallmark CSC properties. Histone methyltransferase, DOT1L, is also up-regulated by HA in CSCs (isolated from HSC-3 cells). Further analyses indicate that the stimulation of microRNA-10b (miR-10b) expression is DOT1L-specific and HA/CD44-dependent in CSCs. This process subsequently results in the overexpression of RhoGTPases and survival proteins leading to tumor cell invasion and cisplatin resistance. Treatment of CSCs with DOT1L-specific small interfering RNAs (siRNAs) effectively blocks HA/CD44-mediated expression of DOT1L, miR-10b production, and RhoGTPase/survival protein up-regulation as well as reduces tumor cell invasion and enhances chemosensitivity. CSCs were also transfected with a specific anti-miR-10b inhibitor to silence miR-10b expression and block its target functions. Our results demonstrate that the anti-miR-10 inhibitor not only decreases RhoGTPase/survival protein expression and tumor cell invasion, but also increases chemosensitivity in HA-treated CSCs. Taken together, these findings strongly support the contention that histone methyltransferase, DOT1L-associated epigenetic changes induced by HA play pivotal roles in miR-10 production leading to up-regulation of RhoGTPase and survival proteins. All of these events are critically important for the acquisition of cancer stem cell properties, including self-renewal, tumor cell invasion, and chemotherapy resistance in HA/CD44-activated head and neck cancer.

Immune dysregulation in immunodeficiency disorders: The role of T-cell receptor sequencing.

Immune dysregulation is a prominent feature of primary immunodeficiency disorders, which commonly manifested as autoimmunity, cytopenias and inflammatory bowel disease. In partial T-cell immunodeficiency disorders, it has been proposed that the imbalance between effector and regulatory T-cells drives the breakdown of peripheral tolerance. While there is no robust test for immune dysregulation, the T-cell receptor repertoire is used as a surrogate marker, and has been shown to be perturbed in a number of immunodeficiency disorders featuring immune dysregulation including Omenn's Syndrome, Wiskott-Aldrich Syndrome, and common variable immunodeficiency. This review discusses how recent advances in TCR next-generation sequencing and bioinformatics have led to the in-depth characterization of CDR3 sequences and an exponential growth in examinable parameters. Specifically, we highlight the use of junctional diversity as a means to differentiate intrinsic T-cell defects from secondary causes of repertoire perturbation in primary immunodeficiency disorders. However, key questions, such as the identity of antigenic targets for large, expanded T-cell clonotypes, remain unanswered despite the fact that such clones are likely to play a pathogenic role in driving immune dysregulation and autoimmunity. Finally, we discuss a number of emerging technologies such as in silico reconstruction, high-throughput pairwise αß sequencing and single-cell RNAseq that offer the potential to define the antigenic epitope and function of a given T-cell, thereby enhancing our understanding in this field.

Entanglement Hamiltonians for Chiral Fermions with Zero Modes.

In this Letter, we study the effect of topological zero modes on entanglement Hamiltonians and the entropy of free chiral fermions in (1+1)D. We show how Riemann-Hilbert solutions combined with finite rank perturbation theory allow us to obtain exact expressions for entanglement Hamiltonians. In the absence of the zero mode, the resulting entanglement Hamiltonians consist of local and bilocal terms. In the periodic sector, the presence of a zero mode leads to an additional nonlocal contribution to the entanglement Hamiltonian. We derive an exact expression for this term and for the resulting change in the entanglement entropy.

Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p.

BACKGROUND: Pulmonary arterial hypertension is a chronic lung disease associated with severe pulmonary vascular changes. A pathogenic role of oxidized lipids such as hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids is well established in vascular disease. Apolipoprotein A-I mimetic peptides, including 4F, have been reported to reduce levels of these oxidized lipids and improve vascular disease. However, the role of oxidized lipids in the progression of pulmonary arterial hypertension and the therapeutic action of 4F in pulmonary arterial hypertension are not well established. METHODS AND RESULTS: We studied 2 different rodent models of pulmonary hypertension (PH): a monocrotaline rat model and a hypoxia mouse model. Plasma levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids were significantly elevated in PH. 4F treatment reduced these levels and rescued preexisting PH in both models. MicroRNA analysis revealed that microRNA-193-3p (miR193) was significantly downregulated in the lung tissue and serum from both patients with pulmonary arterial hypertension and rodents with PH. In vivo miR193 overexpression in the lungs rescued preexisting PH and resulted in downregulation of lipoxygenases and insulin-like growth factor-1 receptor. 4F restored PH-induced miR193 expression via transcription factor retinoid X receptor α. CONCLUSIONS: These studies establish the importance of microRNAs as downstream effectors of an apolipoprotein A-I mimetic peptide in the rescue of PH and suggest that treatment with apolipoprotein A-I mimetic peptides or miR193 may have therapeutic value.

The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer.

BACKGROUND: MicroRNAs have been implicated in tumorigenesis, drug resistance, and prognosis in cancer. We investigated the role of microRNA-21 (miR-21) in regulating ovarian cancer drug resistance. METHODS: We used parental and cisplatin resistant ovarian cell lines to demonstrate the role of miR-21 in drug resistance and investigated the gene targets of miR-21. Fresh tumor specimens were used to validate our in vitro findings. RESULTS: Cisplatin resistant ovarian cells were four-fold more resistant compared to the parental cell line. MiR-21 was overexpressed in the resistant cell line on microRNA microarray, which was subsequently validated with qRT-PCR. Using anti-microRNA inhibitors, we demonstrated that miR-21 attenuation reversed the drug resistant phenotype in both the resistant and parental cell lines. The inhibition of miR-21 induced apoptosis based on annexin V-FITC immunostaining. Using Western blot analysis, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, and attenuated apoptosis inhibitor c-IAP2. Using 101 specimens from advanced ovarian cancer patients enrolled in The Cancer Genome Atlas, we found that women with tumors that overexpressed miR-21 were associated with a shorter progression-free survival. CONCLUSION: Our data suggest that miR-21 regulates drug resistance via apoptosis and cellular survival pathways. Targeting miR-21 may have clinical utility in the treatment of resistant ovarian cancer.

Ageism and Dementia-ism in Health Care: A Proposed Framework to Guide Treatment Decisions in Frail Older Persons.

Global population ageing underscores the imperative of ageism and dementia-ism in the heath care setting as there is both anecdotal and published evidence that older persons are liable to receive less than optimum evidence-based treatments on account of their age and apparent frailty. This article explores the reasons for this phenomenon and limitations of current approaches of clinical decision making. We propose a framework to guide decision making to optimize care, with a paradigm shift in redefining a default toward clinical practice guideline-recommended treatments, guided by evidence-based medicine within an ethical means-end proportionality framework, and regularly reviewed advance care plans and goals of care conversations to secure the best interests of older persons.

Triad influence on the detection of crime in Hong Kong.

We use bootstrap data envelopment analysis, adjusting for endogeneity, to examine police efficiency in detecting crime in Hong Kong. We address the following: (i) is there a correlation between the detection of crime and triad influence? (ii) does the level of triad influence affect the efficiency in translating inputs (police strength) into outputs (crime detection)? and (iii) how can the allocation of policing resources be adjusted to improve crime detection? We find that nighty-eight percent of Hong Kong police districts in our sample were found to be inefficient in the detection of crime. Variation was found across districts regarding the detection of violent, property and other crimes. Most inefficiencies and potential improvements in the detection of crime were found in the categories violent and other crimes. We demonstrate how less efficient police districts can modify police resourcing decisions to better detect certain crime types while maintaining current levels of resourcing. Finally, we highlight how the method we outline improves efficiency estimation by adjusting for endogeneity and measuring the conditional efficiency of each district (i.e. the efficiency of crime detection taking the instrumental variables (e.g. influence of triads) into consideration). The use of frontier models to assist in evaluating policing performance can lead to improved efficiency, transparency, and accountability in law enforcement, ultimately resulting in better public safety outcomes and publicly funded resource allocation.

Adulteration and substitution of drugs purchased in Australia from cryptomarkets: An analysis of Test4Pay.

INTRODUCTION: Prohibited drugs in unregulated markets may be adulterated, resulting in increased risks for people who use drugs. This study investigated levels of drug adulteration and substitution of drugs purchased in Australia from cryptomarkets. METHODS: Data were collected from a darknet forum called Test4Pay from 1 September 2022 to 23 August 2023. Posts were included if they reported the results of drug samples submitted by post to the Vancouver-based Get Your Drugs Tested service, which uses Fourier-transform infrared spectroscopy with immunoassay strip tests (fentanyl and benzodiazepines). RESULTS: Of 103 samples, 65% contained only the advertised substance, 14% contained the advertised substance in combination with other psychoactive and/or potentially harmful substances and for 21%, the advertised substance was absent. Substances sold as MDMA, methamphetamine or heroin were consistently found to contain only the advertised substance, while substances sold as 2C-B, alprazolam or ketamine were the most likely to be completely substituted. Only 4 samples sold as cocaine contained solely the advertised substance, with 13 containing cocaine with adulterants like lidocaine, creatine, levamisole and boric acid (n = 19). No fentanyl contamination was detected. Novel dissociatives and novel benzodiazepines were detected, as well as a nitazene compound. DISCUSSION AND CONCLUSIONS: Drug markets under prohibition continue to contain numerous unexpected substances, some of which can elevate risk of harm. Cryptomarkets are not immune to this problem, despite review systems, which should, in theory, make vendors more accountable for the quality of their stock. These findings demonstrate a need for expansion of local drug checking services in Australia.

Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma.

Human head and neck squamous cell carcinoma (HNSCC) is a highly malignant cancer associated with major morbidity and mortality. In this study, we determined that human HNSCC-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by high levels of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. These tumor cells also express several stem cell markers (the transcription factors Oct4, Sox2, and Nanog) and display the hallmark CSC properties of self-renewal/clonal formation and the ability to generate heterogeneous cell populations. Importantly, hyaluronan (HA) stimulates the CD44v3 (an HA receptor) interaction with Oct4-Sox2-Nanog leading to both a complex formation and the nuclear translocation of three CSC transcription factors. Further analysis reveals that microRNA-302 (miR-302) is controlled by an upstream promoter containing Oct4-Sox2-Nanog-binding sites, whereas chromatin immunoprecipitation (ChIP) assays demonstrate that stimulation of miR-302 expression by HA-CD44 is Oct4-Sox2-Nanog-dependent in HNSCC-specific CSCs. This process results in suppression of several epigenetic regulators (AOF1/AOF2 and DNMT1) and the up-regulation of several survival proteins (cIAP-1, cIAP-2, and XIAP) leading to self-renewal, clonal formation, and cisplatin resistance. These CSCs were transfected with a specific anti-miR-302 inhibitor to silence miR-302 expression and block its target functions. Our results demonstrate that the anti-miR-302 inhibitor not only enhances the expression of AOF1/AOF2 and DNMT1 but also abrogates the production of cIAP-1, cIAP-2, and XIAP and HA-CD44v3-mediated cancer stem cell functions. Taken together, these findings strongly support the contention that the HA-induced CD44v3 interaction with Oct4-Sox2-Nanog signaling plays a pivotal role in miR-302 production leading to AOF1/AOF2/DNMT1 down-regulation and survival of protein activation. All of these events are critically important for the acquisition of cancer stem cell properties, including self-renewal, clonal formation, and chemotherapy resistance in HA-CD44v3-activated head and neck cancer.

Food-dependent exercise-induced anaphylaxis: is wheat unique?

This review draws comparisons between wheat-dependent exercise-induced anaphylaxis (WDEIA) and other food-dependent exercise-induced anaphylaxis (FDEIAs) and discusses the importance of co-factors in its pathophysiology. FDEIA remains an enigmatic condition since it was first described 30 years ago. The sporadic and unpredictable nature of its reactions has puzzled clinicians and scientists for decades, but recent studies on WDEIA have enlightened us about the pathophysiology of this condition. The identification of defined allergic epitopes such as Tri a 19, α-gliadin, ß-gliadin and γ-gliadin in WDEIA enables it to become the perfect model for studying FDEIA, but WDEIA is by no means a unique condition. On a larger scale, FDEIA represents a crucial link between IgE-mediated and anaphylactoid reactions and provides supportive evidence for the concept of 'summation anaphylaxis' and the need to overcome the 'allergen threshold'. Future work should focus on identifying more of the FDEIA epitopes and understanding their distinct molecular properties. The development of a biomarker in order to identify patients susceptible to co-factor influences would be invaluable.