Search

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion., Competing Interests: Declaration of interests J.W.H. is a co-founder and consultant for Caraway Therapeutics (a subsidiary of Merck Inc) and is a scientific advisory board member for Lyterian Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. We propose that A. baumannii infection impacts the host tryptophan metabolism and promotes AHR- and FOS-mediated cytotoxicity of infected cells., (© 2024. The Author(s).)

For people at risk of HIV infection, pre-exposure prophylaxis (PrEP) can reduce the risk of infection in anticipation of exposure to HIV. The effectiveness of PrEP relies upon a user's adherence to their PrEP regimen. We sought to assess the effect of PrEP adherence interventions compared to usual care or another intervention for people at risk of HIV. We searched electronic databases from 2010 onwards for randomized controlled trials (RCTs) involving persons at risk of HIV randomized to an adherence promoting intervention vs usual care or another intervention. We used network meta-analyses to compare PrEP adherence for all participant populations. Certainty of evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). 21 trials (N = 4917) were included in qualitative analysis (19 in network meta-analyses (N = 4101)). HIV self-testing interventions with adherence feedback elements improved adherence compared to usual care (risk ratio (RR): 1.83, 95%CI 1.19, 2.82). In contrast, HIV self-testing alone was inferior to HIV self-testing with adherence feedback (RR: 0.58, 95%CI 0.37-0.92). Reminders alone also were inferior to HIV self-testing with adherence feedback on adherence (RR: 0.53, 95%CI 0.34-0.84) and had similar effects on adherence as usual care (RR: 0.98, 95%CI: 0.86-1.11). Interventions with only one component were inferior for adherence than those with two components (RR: 0.74, 95%CI 0.62-0.88) and those with three components (RR: 0.78, 95%CI 0.65-0.93). The certainty of evidence was moderate for HIV self-testing plus adherence feedback and interventions with two or three components. When designing future PrEP adherence interventions, we recommend strategies with more than one but no more than three components., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Adequate surveillance of HIV drug resistance prevalence is challenged by heterogenous and inadequate data reporting. To address this issue, we recently published reporting guidance documentation for studies of HIV drug resistance prevalence and incidence., Objectives: In this study, we describe the methods used to develop this reporting guidance., Design: We used a mixed-methods sequential explanatory design involving authors and users of studies of HIV drug resistance prevalence. In the quantitative phase, we conducted a cross-sectional electronic survey (n=51). Survey participants rated various reporting items on whether they are essential to report. Validity ratios were computed to determine the items to discuss in the qualitative phase. In the qualitative phase, two focus group discussions (n=9 in total) discussed this draft item checklist, providing a justification and examples for each item. We conducted a descriptive qualitative analysis of the group discussions to identify emergent themes regarding the qualities of an essential reporting item., Results: We identified 38 potential reporting items that better characterise the study participants, improve the interpretability of study results and clarify the methods used for HIV resistance testing. These items were synthesised to create the reporting item checklist. Qualitative insights formed the basis of the explanation, elaboration, and rationale components of the guidance document., Conclusions: We generated a list of reporting items for studies on the incidence or prevalence of HIV drug resistance along with an explanation of why researchers believe these items are important. Mixed methods allowed for the simultaneous generation and integration of the item list and qualitative insights. The integrated findings were then further developed to become the subsequently published reporting guidance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to evaluate the efficacy, safety, and tolerability of fluvoxamine for the outpatient management of COVID-19. We conducted this review in accordance with the PRISMA 2020 guidelines. Literature searches were conducted in MEDLINE, EMBASE, International Pharmaceutical Abstracts, CINAHL, Web of Science, and CENTRAL up to 14 September 2023. Outcomes included incidence of hospitalisation, healthcare utilization (emergency room visits and/or hospitalisation), mortality, supplemental oxygen and mechanical ventilation requirements, serious adverse events (SAEs) and non-adherence. Fluvoxamine 100 mg twice a day was associated with reductions in the risk of hospitalisation (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.58-0.97; I 2  = 0%) and reductions in the risk of healthcare utilization (RR 0.68, 95% CI 0.53-0.86; I 2  = 0%). While no increased SAEs were observed, fluvoxamine 100 mg twice a day was associated with higher treatment non-adherence compared to placebo (RR 1.61, 95% CI 1.22-2.14; I 2  = 53%). In subgroup analyses, fluvoxamine reduced healthcare utilization in outpatients with BMI ≥30 kg/m 2 , but not in those with lower BMIs. While fluvoxamine offers potential benefits in reducing healthcare utilization, its efficacy may be most pronounced in high-risk patient populations. The observed non-adherence rates highlight the need for better patient education and counselling. Future investigations should reassess trial endpoints to include outcomes relating to post-COVID sequelaes. Registration: This review was prospectively registered on PROSPERO (CRD42023463829)., (© 2023 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. We also show that USP28 binds to mature SREBP2, leading to its deubiquitination and stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP inhibition by statins, which was rescued by the addition of geranyl-geranyl pyrophosphate. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 inhibitor to reduce viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas., (© 2023. The Author(s).)

Introduction: Engagement in the HIV care cascade is required for people living with HIV (PLWH) to achieve an undetectable viral load. However, varying definitions of engagement exist, contributing to heterogeneity in research regarding how many individuals are actively participating and benefitting from care. A standardized definition is needed to enhance comparability and pooling of data from engagement studies., Objectives: The objective of this paper was to describe the various definitions for engagement used in HIV clinical trials., Methods: Articles were retrieved from CASCADE, a database of 298 clinical trials conducted to improve the HIV care cascade (https://hivcarecascade.com/), curated by income level, vulnerable population, who delivered the intervention, the setting in which it was delivered, the intervention type, and the level of pragmatism of the intervention. Studies with engagement listed as an outcome were selected from this database., Results: 13 studies were eligible, of which five did not provide an explicit definition for engagement. The remaining studies used one or more of the following: appointment adherence (n=6), laboratory testing (n=2), adherence to antiretroviral therapy (n=2), time specification (n=5), intervention adherence (n=5), and quality of interaction (n=1)., Conclusion: This paper highlights the existing diversity in definitions for engagement in the HIV care cascade and categorize these definitions into appointment adherence, laboratory testing, adherence to antiretroviral therapy, time specification, intervention adherence, and quality of interaction. We recommend consensus on how to describe and measure engagement., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Jhuti et al.)

Thyrotropin alfa is a heterodimeric glycoprotein containing human thyroid stimulating hormone (TSH). It is used as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy. Inter-lot variability in the Fourier transform near-infrared spectra of 30 samples obtained from four separate lots of Thyrogen ® was detected in the Drug Quality Study (DQS). The vials fell into two distinct groups (r tst = 0.90, r lim = 0.98, p =0.02). In addition, one vial of the 30 (3%) appeared 4.7 multidimensional SDs from all of the other vials, suggesting that it also represents a different material.

MR1 is a highly conserved microbial immune-detection system in mammals. It captures vitamin B-related metabolite antigens from diverse microbes and presents them at the cell surface to stimulate MR1-restricted lymphocytes including mucosal-associated invariant T (MAIT) cells. MR1 presentation and MAIT cell recognition mediate homeostasis through host defense and tissue repair. The cellular mechanisms regulating MR1 cell surface expression are critical to its function and MAIT cell recognition, yet they are poorly defined. Here, we report that human MR1 is equipped with a tyrosine-based motif in its cytoplasmic domain that mediates low affinity binding with the endocytic adaptor protein 2 (AP2) complex. This interaction controls the kinetics of MR1 internalization from the cell surface and minimizes recycling. We propose MR1 uses AP2 endocytosis to define the duration of antigen presentation to MAIT cells and the detection of a microbial metabolic signature by the immune system., (© 2022 Lim et al.)

Background and Objectives: General practitioners (GPs) are ideally placed to have a much larger role in detection and management of familial hypercholesterolaemia (FH) among their patients. The aim of this study was to seek the reflections of practice staff and newly diagnosed patients with FH on the implementation of an FH model of care in the general practice setting., Method: Qualitative descriptive methodology was used. Interviews were conducted with 36 practice staff and 51 patients from 15 practices participating in the study., Results: Data were analysed thematically and coded into themes - efficacy of GP training, screening for FH, model of care, patient awareness and cascade testing., Discussion: Findings reflect the real-world clinical experience of Australian general practice and the acceptability of the model of care for both patients with FH and practice staff. Patient health literacy is a barrier to both management of FH and cascade testing. A systematic approach to cascade testing is required.

Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a 'premalignant' state, and its inhibition synergizes with clinically established compounds used to target EGFR L858R -, BRAF V600E - or PI3K H1047R -driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Skin lesions are not uncommon in children, and most of them are benign. However, they can be a matter of concern. Although in most cases the diagnosis can be suspected based on clinical history and physical examination, in some cases clinical findings are nonspecific. High-frequency color Doppler US is a noninvasive technique that can play a relevant role in these cases and give important anatomical information for final clinical management. US can be helpful to avoid unnecessary surgery, plan a surgical excision and avoid advanced imaging studies such as MRI and CT, which have a lower resolution for the skin. Different lesions can look similar on US, and clinical correlation is always important. The purpose of this article is to show a variety of skin lesions that occur in children, emphasizing clinical-sonographic correlation, and to familiarize pediatric radiologists with the US technique and sonographic appearance of common skin lesions in children., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Familial hypercholesterolaemia (FH) can be effectively detected and managed in primary care, but the health economic evidence for this is scarce. The aim of this study was to examine management pathways and cost implications of FH screening and management in Australian general practice., Method: Cost-effectiveness outcomes were projected using a life table model. Data was used from 133 patients in 15 Australian general practice clinics from an earlier screening and management study. Costing and mortality data were sourced from governmental sources and published literature., Results: Most patients had a regular general practice consultation at baseline (82%), though the proportion seen under a chronic disease management item at follow-up increased to 23%. The median cost of management was $275 per annum in the first year of management. Managing patients with statins up to the age of 60 years yielded an increase of 248,954 life-years at a cost of $759 million, representing a cost per life-year gained of $3047., Discussion: Screening and management of FH in general practice has the potential for substantial health benefits while requiring relatively modest investments from the health system.

Background: HIV drug resistance is a global health problem that limits the effectiveness of antiretroviral therapy. Adequate surveillance of HIV drug resistance is challenged by heterogenous and inadequate data reporting, which compromises the accuracy, interpretation, and usability of prevalence estimates. Previous research has found that the quality of reporting in studies of HIV drug resistance prevalence is low, and thus better guidance is needed to ensure complete and uniform reporting., Objective: This paper contributes to the process of developing reporting guidelines for prevalence studies of HIV drug resistance by reporting the methodology used in creating a reporting item checklist and generating key insights on items that are important to report., Methods: We will conduct a sequential explanatory mixed methods study among authors and users of studies of HIV drug resistance. The two-phase design will include a cross-sectional electronic survey (quantitative phase) followed by a focus group discussion (qualitative phase). Survey participants will rate the essentiality of various reporting items. This data will be analyzed using content validity ratios to determine the items that will be retained for focus group discussions. Participants in these discussions will revise the items and any additionally suggested items and settle on a complete reporting item checklist. We will also conduct a thematic analysis of the group discussions to identify emergent themes regarding the agreement process., Results: As of November 2021, data collection for both phases of the study is complete. In July 2021, 51 participants had provided informed consent and completed the electronic survey. In October 2021, focus group discussions were held. Nine participants in total participated in two virtual focus group discussions. As of May 2022, data are being analyzed., Conclusions: This study supports the development of a reporting checklist for studies of HIV drug resistance by achieving agreement among experts on what items should be reported in these studies. The results of this work will be refined and elaborated on by a writing committee of HIV drug resistance experts and external reviewers to develop finalized reporting guidelines., International Registered Report Identifier (irrid): DERR1-10.2196/35969., (©Cristian Garcia, Nadia Rehman, Daeria O Lawson, Pascal Djiadeu, Lawrence Mbuagbaw. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.05.2022.)

Squamous cell carcinomas (SCC) frequently have an exceptionally high mutational burden. As consequence, they rapidly develop resistance to platinum-based chemotherapy and overall survival is limited. Novel therapeutic strategies are therefore urgently required. SCC express ∆Np63, which regulates the Fanconi Anemia (FA) DNA-damage response in cancer cells, thereby contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity. This phosphorylation event is required to positively regulate the DNA damage repair in SCC by stabilizing ∆Np63. Knock-down or inhibition of USP28 by a specific inhibitor weakens the ability of SCC to cope with DNA damage during platin-based chemotherapy. Hence, our study presents a novel mechanism by which ∆Np63 expressing SCC can be targeted to overcome chemotherapy resistance. Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ∆Np63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-∆Np63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment., (© 2021. The Author(s).)

Strong evidence supports the involvement of sex steroid hormones in the development and progression of dementia. Attention has been largely focused on the association between genetic variants of estrogen receptor alpha (ERα, ESR1) with dementia, although several studies indicate that ERβ is predominantly expressed in the brain. Interestingly, however, a limited number of studies evaluate the role of ERβ (ESR2) in dementia. Therefore, a meta-analysis was conducted to clarify the association between ESR2 genetic polymorphisms and the risk of dementia. All the relevant studies evaluating ESR2 genetic polymorphisms and dementia were identified through online databases. In total, 14 studies including 20,609 subjects were analyzed. Collectively, it was found that a combined data set of ESR2 polymorphisms was not associated with dementia risk. Interestingly, ESR2 rs4986938 polymorphism is significantly associated with dementia in the Asian population (OR = 0.73, 95% CI 0.59-0.91, P = 0.006). The carrier of A allele in rs4986938 exhibits a protective effect against dementia (A vs. G, OR = 0.6633, P = 0.012; AA + GA vs. GG, OR = 0.6499, P = 0.014; GA vs. AA + GG, OR = 0.6672, P = 0.025; GA vs. GG, OR = 0.6617, P = 0.022). In conclusion, our study suggests that ESR2 genetic polymorphisms are not significantly associated with dementia risk. ESR2 rs4986938 may have potential as a genetic marker for dementia in the Asian population. However, further studies need to verify this conclusion., (© 2020. Belgian Neurological Society.)

Background and Objectives: A lack of public and health professional awareness about familial hypercholesterolaemia (FH) leads to an estimated 90,000 Australians remaining undiagnosed. The aim of this study was to establish the level of knowledge and awareness of FH in Australian general practices., Method: A qualitative descriptive methodology was used to explore baseline knowledge and perceptions of practice staff about diagnosing and managing FH. Overall, 63 interviews were conducted with general practice staff at 15 practices taking part in a National Health and Medical Research Council partnership grant study (GNT1142883)., Results: Data were analysed thematically and coded into themes - knowledge/awareness/recall, management, use of guidelines/referrals, and contacting family members. Most general practitioners treated the high cholesterol component as their primary focus. Guidelines and referrals were rarely used., Discussion: This research reflected a lack of knowledge, awareness and use of guidelines similar to that shown in other published studies. Improved primary care infrastructure, knowledge and awareness of FH need to be addressed.

The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome-mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: The purpose of this study was to illustrate the spectrum of sonographic findings in testicular torsion in a large series of neonates and infants. These patterns and their evolution have, to our knowledge, not been described previously., Conclusion: The sonographic appearance of testicular torsion in neonates and infants can be divided into three types. We believe that the findings represent different stages in the evolution of testicular torsion.