'Our culture makes us strong': Understanding and working with community strengths among Aboriginal people in western Sydney.

BACKGROUND: Strengths-based approaches to health care are often seen as an alternative to deficit-based approaches and are common in Aboriginal health settings. Despite this, there is little existing research that describes Aboriginal peoples' perspectives about the strengths of their communities. This paper describes cultural strengths and resources as understood by Aboriginal people living in western Sydney. METHODS: In-depth interviews were used to collect qualitative data from two communities on Dharug and Dharrawal Country in western Sydney Australia. Data come from a larger study, which focused on how cultural strengths supported sexual well-being. Fifty-two interviews were conducted with Aboriginal young people (aged 16-24 years) by trained peer interviewers. Additionally, 16 interviews with Aboriginal adults (25 years and older) were conducted by members of the research team. FINDINGS AND DISCUSSION: While opinions varied, four key areas of cultural strength were identified: (1) strong kinship relationships; (2) knowledge sharing; (3) shared experiences, identities, and values; and (4) knowing Country. Throughout these four themes, the sense of connection and belonging is viewed as an important overarching theme. CONCLUSION: Communities are not homogenous with regard to what they view as cultural strengths. Knowing Country and practising culture meant different things to different individuals while providing a similar sense of belonging, connection, and identity. SO WHAT: Health service providers, policies, and programs can use this information to understand the continuing impacts of past policies and events whilst recognising that each community has strengths that can be drawn upon to improve service engagement, knowledge sharing, and health outcomes.

PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy.

Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid-induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, due to increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase beta-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid-induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy.

Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research.

The serotonin 2A (5-HT2A) receptor is an important target for drug development and the main receptor through which classical psychedelics elucidate their hallucinogenic effects. The 5-HT2A receptor antagonist ketanserin has frequently been used as a tool to block the receptor. Here, we establish the dose-occupancy relation of ketanserin and the cerebral 5-HT2A receptor in healthy participants by conducting a positron emission tomography (PET) study. 120-min PET scans using the 5-HT2A receptor agonist radiotracer [11C]Cimbi-36 were conducted at baseline and after oral doses of either 10, 20, or 40 mg of ketanserin; each participant underwent one or two scans after ketanserin administration. Occupancy was defined as the percent change in neocortex binding potential (BPND), estimated using the simplified reference tissue model (SRTM) with the cerebellum as reference region. Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy with the highest plasma ketanserin concentrations measured after ∼2 h. The relation between mean plasma ketanserin concentrations and 5-HT2A receptor occupancy conformed to a single-site binding model with an estimated EC50 (95 % CI) of 2.52 (0.75; 8.1) ng/mL, which corresponds to a peroral dose of ketanserin of approximately 10 mg. These data elucidate for the first time in humans the cerebral pharmacodynamics of ketanserin, both benefitting its use as a pharmacological tool for probing brain function and adding to its potential for therapeutic use in rescuing a bad psychedelic experience.

Sleep duration irregularity and risk for incident cardiovascular disease in the UK Biobank.

Background: Emerging evidence supports a link between circadian disruption as measured by higher night-to-night variation in sleep duration and increased risk of cardiovascular disease (CVD). It remains unclear whether this association varies by CVD types or may be modified by average sleep duration and genetic risk for CVD. Methods: Our prospective analysis included 86,219 UK Biobank participants who were free from CVD when completing 7 days of accelerometer measurement in 2013-2016. Sleep irregularity was evaluated by the standard deviation (SD) of accelerometer-measured sleep duration over 7 days. Incident major CVD events, defined as fatal or nonfatal myocardial infarction (MI) and stroke, were identified through linkage to Hospital Episode Statistics data until May 31, 2022. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs for associations of sleep duration SD with risk for major CVD events overall and for MI and stroke separately. Results: We documented 2,310 incident cases of major CVD events (MI: 1,183, stroke: 1,175) over 636,258 person-years of follow-up. After adjusting for sociodemographic factors and family history of CVD, the HR (95% CI) associated with a 1-hour increase in sleep duration SD was 1.19 (1.10, 1.27) for CVD (p-trend<0.0001), 1.23 (1.11, 1.35) for MI (p-trend<0.0001), and 1.17 (1.05, 1.29) for stroke (p-trend=0.003). Additional adjustment for lifestyle factors, co-morbidities and sleep-related factors modestly attenuated these associations. Higher sleep irregularity was associated with higher CVD risk irrespective of genetic risk (p-interaction=0.43), but this association was stronger among individuals with longer average sleep duration >8 hours (p-interaction=0.006). Conclusions: Higher night-to-night variation in accelerometer-measured sleep duration was associated with consistently higher risks for major CVD events. The association did not seem to be modified by genetic risk for CVD and was more pronounced in long sleepers.

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Tissue Doppler ultrasound of arm muscles to assess myotonia in myotonic dystrophies: An exploratory study.

INTRODUCTION/AIMS: Myotonia is a key symptom of myotonic dystrophies (DM), and its quantification is challenging. This exploratory study evaluated the utility of tissue Doppler ultrasound (TDU) to assess myotonia in DM. METHODS: Twelve DM patients (seven type-1 DM [DM1] and five type-2 DM [DM2]) and 20 age-matched healthy subjects were included in this cross-sectional study. After measuring cross-sectional areas of the flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC) muscles in a resting state, muscle contraction/relaxation time, time to peak tissue velocity, peak tissue velocity and velocity gradients of these muscles were measured via TDU while performing forced fist unclenching after fist closure. Additionally, grip strength, Medical Research Council Sum score and patient-reported myotonia severity scores were assessed. RESULTS: DM1 and DM2 patients had a lower grip strength than healthy subjects (p = .0001/p = .002). Patient-reported myotonia did not differ between DM1 and DM2 patients. DM1 patients revealed FDS and EDC atrophy compared to DM2 patients and healthy subjects (p = .003/p = .004). TDU revealed prolonged muscle contraction and relaxation times in both DM subtypes, with prolonged time to reach FDS peak relaxation velocity and altered peak FDS relaxation velocity only in DM1 patients (p = .03/p = .003). Peak FDS relaxation velocity correlated inversely with C(C)TG repeat numbers in DM patients. Sensitivity of TDU parameters to detect myotonic dystrophy varied between 50% and 75%, with a specificity of 95%. DISCUSSION: Our exploratory study suggests that TDU could serve as a novel tool to quantify myotonia in DM patients, but larger follow-up studies are warranted to validate its diagnostic accuracy.

A Systematic Approach to the Evaluation of the Coronary Microcirculation Using Bolus Thermodilution: CATH CMD.

Coronary microvascular dysfunction (CMD) can cause myocardial ischemia in patients presenting with angina without obstructive coronary artery disease (ANOCA). Evaluating for CMD by using the thermodilution technique offers a widely accessible means of assessing microvascular resistance. Through this technique, 2 validated indices, namely coronary flow reserve and the index of microcirculatory resistance, can be computed, facilitating investigation of the coronary microcirculation. The index of microcirculatory resistance specifically estimates minimum achievable microvascular resistance within the coronary microcirculation. We aim to review the bolus thermodilution method, outlining the fundamental steps for conducting measurements and introducing an algorithmic approach (CATH CMD) to systematically evaluate the coronary microcirculation. Embracing a standardized approach, exemplified by the CATH CMD algorithm, will facilitate adoption of this technique and streamline the diagnosis of CMD.

Potassium channel TASK-5 forms functional heterodimers with TASK-1 and TASK-3 to break its silence.

TASK-5 (KCNK15) belongs to the acid-sensitive subfamily of two-pore domain potassium (K2P) channels, which includes TASK-1 and TASK-3. TASK-5 stands out as K2P channel for which there is no functional data available, since it was reported in 2001 as non-functional and thus "silent". Here we show that TASK-5 channels are indeed non-functional as homodimers, but are involved in the formation of functional channel complexes with TASK-1 and TASK-3. TASK-5 negatively modulates the surface expression of TASK channels, while the heteromeric TASK-5-containing channel complexes located at the plasma membrane are characterized by changes in single-channel conductance, Gq-coupled receptor-mediated channel inhibition, and sensitivity to TASK modulators. The unique pharmacology of TASK-1/TASK-5 heterodimers, affected by a common polymorphism in KCNK15, needs to be carefully considered in the future development of drugs targeting TASK channels. Our observations provide an access to study TASK-5 at the functional level, particularly in malignant cancers associated with KCNK15.

Effective realization of abatement measures can reduce HFC-23 emissions.

HFC-23 is a potent greenhouse gas, predominantly emitted as an undesired by-product during the synthesis and processing of HCFC-22 (ref. 1). Previously, the Clean Development Mechanism and national efforts called for the implementation of abatement technology for reducing HFC-23 emissions2,3. Nevertheless, between 2015 and 2019, a divergence was found between the global emissions derived from atmospheric observations and those expected from reported abatement1,2. Primarily, this points to insufficient implementation of abatement strategies2,4, calling for independent verification of the emissions at the individual chemical facility level. Here we use regional atmospheric observations and a new, deliberately released tracer to quantify the HFC-23 emissions from an HCFC-22 and fluoropolymer production facility, which is equipped with waste gas destruction technology. We find that our inferred HFC-23/HCFC-22 emission factor of 0.19% (0.13-0.24%) broadly fits within the emission factor considered practicable for abatement projects5,6. Extrapolation to global HCFC-22 production underscores that the operation of appropriate destruction technology has the potential to reduce global HFC-23 emissions by at least 84% (69-100%) (14 (12-16) Gg yr-1). This reduction is equivalent to 17% CO2 emissions from aviation in 2019 (ref. 7). We also demonstrate co-destruction of PFC-318, another by-product and greenhouse gas. Our findings show the importance of the 2016 Kigali Amendment to the Montreal Protocol, which obligates parties to destroy HFC-23 emissions from facilities manufacturing hydrochlorofluorocarbons and hydrofluorocarbons "to the extent practicable" from 2020 onwards8.

Describing the effect of COVID-19 on sexual and healthcare-seeking behaviours of men who have sex with men in three counties in Kenya: a cross-sectional study.

BACKGROUND: While the COVID-19 pandemic disrupted HIV preventative services in sub-Saharan Africa, little is known about the specific impacts the pandemic has had on men who have sex with men (MSM) in Kenya. METHODS: Data were from an HIV self-testing intervention implemented in Kisumu, Mombasa and Kiambu counties in Kenya. Baseline data collection took place from May to July 2019, and endline in August-October 2020, coinciding with the lifting of some COVID-19 mitigation measures. Using endline data, this study characterised the impact the pandemic had on participants' risk behaviours, experience of violence and behaviours related to HIV. Logistic regression was used to understand factors related to changes in risk behaviours and experiences of violence; adjusted AORs (AORs) and 95% CIs are reported. RESULTS: Median age was 24 years (IQR: 21-27). Most respondents (93.9%) reported no change or a decrease in the number of sexual partners (median number of male sexual partners: 2, IQR: 2-4). Some participants reported an increase in alcohol (10%) and drug (16%) consumption, while 40% and 28% reported decreases in alcohol and drug consumption, respectively. Approximately 3% and 10% reported an increase in violence from intimate partners and police/authorities, respectively. Compared with those with primary education, those with post-secondary education were 60% less likely to report an increase in the number of male sexual partners per week (AOR: 0.4, 95% CI: 0.2 to 0.9), while those who were HIV positive were at twofold the odds of reporting an increase or sustained levels of violence from intimate partners (AOR: 2.0, 95% CI: 1.1 to 4.0). CONCLUSION: The results of this study demonstrate heterogeneity in participants' access to preventative HIV and clinical care services in Kenya after the onset of the COVID-19 epidemic. These results indicate the importance of responding to specific needs of MSM and adapting programmes during times of crisis.

Increases in Global and East Asian Nitrogen Trifluoride (NF3) Emissions Inferred from Atmospheric Observations.

Nitrogen trifluoride (NF3) is a potent and long-lived greenhouse gas that is widely used in the manufacture of semiconductors, photovoltaic cells, and flat panel displays. Using atmospheric observations from eight monitoring stations from the Advanced Global Atmospheric Gases Experiment (AGAGE) and inverse modeling with a global 3-D atmospheric chemical transport model (GEOS-Chem), we quantify global and regional NF3 emission from 2015 to 2021. We find that global emissions have grown from 1.93 ± 0.58 Gg yr-1 (± one standard deviation) in 2015 to 3.38 ± 0.61 Gg yr-1 in 2021, with an average annual increase of 10% yr-1. The available observations allow us to attribute significant emissions to China (0.93 ± 0.15 Gg yr-1 in 2015 and 1.53 ± 0.20 Gg yr-1 in 2021) and South Korea (0.38 ± 0.07 Gg yr-1 to 0.65 ± 0.10 Gg yr-1). East Asia contributes around 73% of the global NF3 emission increase from 2015 to 2021: approximately 41% of the increase is from emissions from China (with Taiwan included), 19% from South Korea, and 13% from Japan. For Japan, which is the only one of these three countries to submit annual NF3 emissions to UNFCCC, our bottom-up and top-down estimates are higher than reported. With increasing demand for electronics, especially flat panel displays, emissions are expected to further increase in the future.

Large-scale analysis to identify risk factors for ovarian cancer.

OBJECTIVE: Ovarian cancer is characterized by late-stage diagnoses and poor prognosis. We aimed to identify factors that can inform prevention and early detection of ovarian cancer. METHODS: We used a data-driven machine learning approach to identify predictors of epithelial ovarian cancer from 2920 input features measured 12.6 years (IQR 11.9 to 13.3 years) before diagnoses. Analyses included 221 732 female participants in the UK Biobank without a history of cancer. During the follow-up 1441 women developed ovarian cancer. For factors that contributed to model prediction, we used multivariate logistic regression to evaluate the association with ovarian cancer, with evidence for causality tested by Mendelian randomization (MR) analyses in the Ovarian Cancer Genetics Consortium (25 509 cases). RESULTS: Greater parity and ever-use of oral contraception were associated with lower ovarian cancer risk (ever vs never OR 0.74, 95% CI 0.66 to 0.84). After adjustment for established risk factors, greater height, weight, and greater red blood cell distribution width were associated with increased ovarian cancer risk, while higher aspartate aminotransferase levels and mean corpuscular volume were associated with lower risk. MR analyses confirmed observational associations with anthropometric/adiposity traits (eg, body fat percentage per standard deviation (SD); OR inverse-variance weighted (ORIVW) 1.28, 95% CI 1.13 to 1.46) and aspartate aminotransferase (ORIVW 0.87, 95% CI 0.78 to 0.98). MR also provided genetic evidence for a protective association of higher total serum protein on ovarian cancer, higher lymphocyte count on serous and endometrioid ovarian cancer, and greater forced expiratory volume in 1 s on serous ovarian cancer among other findings. CONCLUSIONS: This study shows that certain risk factors for ovarian cancer are modifiable, suggesting that weight reduction and interventions to reduce the number of ovulations may provide potential for future prevention. We also identified blood biomarkers associated with ovarian cancer years before diagnoses, warranting further investigation.

Association Between Accelerometer-Measured Irregular Sleep Duration and Type 2 Diabetes Risk: A Prospective Cohort Study in the UK Biobank.

OBJECTIVE: To evaluate the association between irregular sleep duration and incident diabetes in a U.K. population over 7 years of follow-up. RESEARCH DESIGN AND METHODS: Among 84,421 UK Biobank participants (mean age 62 years) who were free of diabetes at the time of providing accelerometer data in 2013-2015 and prospectively followed until May 2022, sleep duration variability was quantified by the within-person SD of 7-night accelerometer-measured sleep duration. We used Cox proportional hazard models to estimate hazard ratios (HRs) for incident diabetes (identified from medical records, death register, and/or self-reported diagnosis) according to categories of sleep duration SD. RESULTS: There were 2,058 incident diabetes cases over 622,080 person-years of follow-up. Compared with sleep duration SD ≤ 30 min, the HR (95% CI) was 1.15 (0.99, 1.33) for 31-45 min, 1.28 (1.10, 1.48) for 46-60 min, 1.54 (1.32, 1.80) for 61-90 min, and 1.59 (1.33, 1.90) for ≥91 min, after adjusting for age, sex, and race. We found a nonlinear relationship (P nonlinearity 0.0002), with individuals with a sleep duration SD of >60 vs. ≤60 min having 34% higher diabetes risk (95% CI 1.22, 1.47). Further adjustment for lifestyle, comorbidities, environmental factors, and adiposity attenuated the association (HR comparing sleep duration SD of >60 vs. ≤60 min: 1.11; 95% CI 1.01, 1.22). The association was stronger among individuals with lower diabetes polygenic risk score (PRS; P interaction ≤ 0.0264) and longer sleep duration (P interaction ≤ 0.0009). CONCLUSIONS: Irregular sleep duration was associated with higher diabetes risk, particularly in individuals with a lower diabetes PRS and longer sleep duration.

Emerging treatment landscape for Guillain-Barré Syndrome (GBS): what's new?

INTRODUCTION: Guillain-Barré syndrome (GBS) is a monophasic immune neuropathic disorder characterized by acute paralysis. A significant portion of patients are left with residual deficits, which presents a considerable global healthcare challenge. The precise mechanisms underlying GBS pathogenesis are not fully elucidated. Recent studies have focused on postinfectious molecular mimicry and identified involvement of IgG autoantibodies and innate immune effectors in GBS. Intravenous immunoglobulins (IVIg) and plasma exchange (PE) are two established evidence-based immunomodulatory treatments for GBS, but a significant proportion of GBS patients fails to respond adequately to either therapy. This emphasizes an urgent need for novel and more potent treatments. AREAS COVERED: We discuss novel immunomodulatory therapies presently at different phases of preclinical and clinical investigation. Some drugs in development target pathophysiologic mechanisms such as IgG autoantibody catabolism and complement activation, which are relevant to GBS. EXPERT OPINION: There is an unmet need for more effective immune therapies for GBS. New immunomodulatory therapies under development may provide more potent options for GBS patients who do not respond to IVIg or PE. Future directions may include incorporating neuroprotective interventions based on evolving understanding of mechanisms underlying nerve injury and axonal degeneration.

Unveiling G-protein coupled receptors as potential targets for ovarian cancer nanomedicines: from RNA sequencing data analysis to in vitro validation.

Genetic heterogeneity in ovarian cancer indicates the need for personalised treatment approaches. Currently, very few G-protein coupled receptors (GPCRs) have been investigated for active targeting with nanomedicines such as antibody-conjugated drugs and drug-loaded nanoparticles, highlighting a neglected potential to develop personalised treatment. To address the genetic heterogeneity of ovarian cancer, a future personalised approach could include the identification of unique GPCRs expressed in cancer biopsies, matched with personalised GPCR-targeted nanomedicines, for the delivery of lethal drugs to tumour tissue before, during and after surgery. Here we report on the systematic analysis of public ribonucleic acid-sequencing (RNA-seq) gene expression data, which led to prioritisation of 13 GPCRs as candidates with frequent overexpression in ovarian cancer tissues. Subsequently, primary ovarian cancer cells derived from ascites and ovarian cancer cell lines were used to confirm frequent gene expression for the selected GPCRs. However, the expression levels showed high variability within our selection of samples, therefore, supporting and emphasising the need for the future development of case-to-case personalised targeting approaches.

The sensory shark: high-quality morphological, genomic and transcriptomic data for the small-spotted catshark Scyliorhinus canicula reveal the molecular bases of sensory organ evolution in jawed vertebrates.

Cartilaginous fishes (chimaeras and elasmobranchs -sharks, skates and rays) hold a key phylogenetic position to explore the origin and diversifications of jawed vertebrates. Here, we report and integrate reference genomic, transcriptomic and morphological data in the small-spotted catshark Scyliorhinus canicula to shed light on the evolution of sensory organs. We first characterise general aspects of the catshark genome, confirming the high conservation of genome organisation across cartilaginous fishes, and investigate population genomic signatures. Taking advantage of a dense sampling of transcriptomic data, we also identify gene signatures for all major organs, including chondrichthyan specializations, and evaluate expression diversifications between paralogs within major gene families involved in sensory functions. Finally, we combine these data with 3D synchrotron imaging and in situ gene expression analyses to explore chondrichthyan-specific traits and more general evolutionary trends of sensory systems. This approach brings to light, among others, novel markers of the ampullae of Lorenzini electro-sensory cells, a duplication hotspot for crystallin genes conserved in jawed vertebrates, and a new metazoan clade of the Transient-receptor potential (TRP) family. These resources and results, obtained in an experimentally tractable chondrichthyan model, open new avenues to integrate multiomics analyses for the study of elasmobranchs and jawed vertebrates.

Master equation modeling of water dissociation in small ionic water clusters: Ag+(H2O) n , n = 4-6.

We model temperature-dependent blackbody infrared radiative dissociation (BIRD) rate coefficients of Ag+(H2O) n , n = 4-6, a system with loosely bound water molecules. We employ a master equation modeling (MEM) approach with consideration of absorption and emission of blackbody radiation, comparing single and multiple-well descriptions. The unimolecular dissociation rate coefficients are obtained using the Rice-Ramsperger-Kassel-Marcus (RRKM) theory, employing two approaches to model the sum of states in the transition state, the rigid activated complex (RAC) and the phase space limit (PSL) approach. A genetic algorithm is used to find structures of low-lying isomers for the kinetic modeling. We show that the multiple-well MEM approach with PSL RRKM in the All Wells and Transition States Are Relevant (AWATAR) variant provides a reliable description of Ag+(H2O) n BIRD, in agreement with previously published experimental data. Higher-lying isomers contribute significantly to the overall dissociation rate coefficient, underlying the importance of the multiple-well ansatz in which all isomers are treated on the same footing.

Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer.

Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic 177Lu-PSMA-617 was approved in 2022 for men with PSMA-PET-positive metastatic castration-resistant prostate cancer. However, not all patients respond to PSMA-radioligand therapy, in part owing to the heterogeneity of PSMA expression in the tumour. The PSMA regulatory network is composed of a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) gene promoter, intergenic enhancers and differentially methylated regions. Our understanding of the PSMA regulatory network and the mechanisms underlying PSMA suppression is evolving. Clinically, molecular imaging provides a unique window into PSMA dynamics that occur on therapy and with disease progression, although challenges arise owing to the limited resolution of PET. PSMA regulation and heterogeneity - including intertumoural and inter-patient heterogeneity, temporal changes, lineage dynamics and the tumour microenvironment - affect PSMA theranostics. PSMA response and resistance to radioligand therapy are mediated by a number of potential mechanisms, and complementary biomarkers beyond PSMA are under development. Understanding the biological determinants of cell surface target regulation and heterogeneity can inform precision medicine approaches to PSMA theranostics as well as other emerging therapies.

Metabolomic profiling of upper GI malignancies in blood and tissue: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of case-control and cohort human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on esophageal cancer (EC), cancer of the gastroesophageal junction (GEJ), and gastric cancer (GC) in blood and tissue. BACKGROUND: Upper gastrointestinal cancers (UGC), predominantly EC, GEJ, and GC, are malignant tumour types with high morbidity and mortality rates. Numerous studies have focused on metabolomic profiling of UGC in recent years. In this systematic review and meta-analysis, we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with EC, GEJ and GC. METHODS: Following the PRISMA procedure, a systematic search of four databases (Embase, PubMed, MEDLINE, and Web of Science) for molecular epidemiologic studies on the metabolomic profiles of EC, GEJ and GC was conducted and registered at PROSPERO (CRD42023486631). The Newcastle-Ottawa Scale (NOS) was used to benchmark the risk of bias for case-controlled and cohort studies. QUADOMICS, an adaptation of the QUADAS-2 (Quality Assessment of Diagnostic Accuracy) tool, was used to rate diagnostic accuracy studies. Original articles comparing metabolite patterns between patients with and without UGC were included. Two investigators independently completed title and abstract screening, data extraction, and quality evaluation. Meta-analysis was conducted whenever possible. We used a random effects model to investigate the association between metabolite levels and UGC. RESULTS: A total of 66 original studies involving 7267 patients that met the required criteria were included for review. 169 metabolites were differentially distributed in patients with UGC compared to healthy patients among 44 GC, 9 GEJ, and 25 EC studies including metabolites involved in glycolysis, anaerobic respiration, tricarboxylic acid cycle, and lipid metabolism. Phosphatidylcholines, eicosanoids, and adenosine triphosphate were among the most frequently reported lipids and metabolites of cellular respiration, while BCAA, lysine, and asparagine were among the most commonly reported amino acids. Previously identified lipid metabolites included saturated and unsaturated free fatty acids and ketones. However, the key findings across studies have been inconsistent, possibly due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group. CONCLUSION: Thus far, metabolomic studies have provided new opportunities for screening, etiological factors, and biomarkers for UGC, supporting the potential of applying metabolomic profiling in early cancer diagnosis. According to the results of our meta-analysis especially BCAA and TMAO as well as certain phosphatidylcholines should be implicated into the diagnostic procedure of patients with UGC. We envision that metabolomics will significantly enhance our understanding of the carcinogenesis and progression process of UGC and may eventually facilitate precise oncological and patient-tailored management of UGC.