The liver's anatomic position and immune specialization make it both a major target and a major filter for systemically delivered therapeutics. Because portal venous inflow exposes the liver early to gut-derived molecules and exogenous compounds, many intravenously administered agents, including gene-based medicines and their viral and non-viral delivery systems, preferentially enter and accumulate in hepatic tissue. This review synthesizes how core liver physiology and immunobiology influence the performance, safety, and clinical translation of genomic medicines in hepatology, and outlines near-term practice and research shifts likely to define a genomics-driven future in liver disease care. We review the hepatic microarchitecture relevant to therapeutic trafficking, including sinusoidal transit, the space of Disse, hepatocyte uptake, and hepatobiliary elimination, and highlight the gatekeeping roles of liver sinusoidal endothelial cells and Kupffer cells in clearing particulate material and shaping inflammatory signaling. We then discuss how these same features create both opportunities, such as efficient hepatic targeting, and constraints, including innate immune activation, vector clearance, and variable intrahepatic distribution, for DNA- and RNA-based platforms. Finally, we propose five actionable developments poised to move genomics from a niche tool to a routine component of hepatology practice: earlier genomic testing in unexplained liver disease, multidisciplinary hepatology genome rounds, a centralized liver-specific gene resource, genetics-aware clinical trial design, and expansion of genetic therapies. Integrating liver biology with genomic medicine is essential to improve diagnostic yield, personalize therapy, and accelerate translation of gene-based treatments while mitigating immunologic and delivery-related barriers.
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Chronic pain causes an imbalance of autonomic function, often indicated by reductions in parasympathetic heart rate variability (HRV) indices. This study aimed to investigate HRV measures among patients with chronic pancreatitis (CP), and healthy controls (HCs), and the influence of diabetes on these parameters. HRV measures, which are time and frequency-derived non-invasive measures of autonomic function, were obtained from the electrocardiography (ECG) recordings. Moreover, deceleration capacity, and periodic repolarization dynamics were assessed as measures of parasympathetic and sympathetic activity. A total of 141 participants (38 pain-free CP, 53 painful CP, and 50 healthy controls) were analysed. Painful CP patients exhibited more pronounced parasympathetic reductions assessed with the root mean square of successive differences between normal beats (14.5 ms IQR 11.5-22 versus 21.8 ms IQR 17.6-32.4; P=0.01) and high frequency content (118.2 ms² versus 273.4 ms²; P=0.007) in comparison to pain-free CP. Moreover, there was a decreased standard deviation of normal-to-normal interbeat intervals (31.6±18.7 ms versus 39.9±18.5 ms; P=0.04), and low frequency content (158.9 ms² versus 480.4 ms²; P=0.003) indicating altered sympathovagal balance. Furthermore, the mean RR interval was greater in non-diabetic CP patients (830.5±144.2 ms) compared to those with diabetes (770.7±139.4 ms; P=0.05). Chronic pancreatitis, particularly when painful, is associated with significant autonomic dysregulation, characterized by a pronounced reduction in parasympathetic activity as measured by HRV compared to pain-free patients.
Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic RAS mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS. In this phase 3, international, open-label, randomized trial, we randomly assigned patients with previously treated mPDAC to receive daraxonrasib or chemotherapy of the investigator's choice. The dual primary end points were overall survival and progression-free survival in the subpopulation of patients with RAS G12 mutations (the RAS G12 population). Key secondary end points included overall survival and progression-free survival in the overall population (which included patients with RAS G12, G13, or Q61 mutations or with no RAS mutation identified) and objective response and patient-reported quality of life in the RAS G12 and overall populations. Safety was also assessed. A total of 500 patients, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients). The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001). The median progression-free survival in the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons). Adverse events that occurred after the start of treatment were reported in all the patients in the daraxonrasib group and in 97.7% of those in the chemotherapy group; the incidence of adverse events of grade 3 or higher was 61.8% and 69.6%, respectively. Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group. Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy. (Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.).
The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Colorectal cancer (CRC) is the third most common cancer, with millions of new cases and deaths annually. There is an increasing incidence of CRC among patients <50 years, leading to recommendations for CRC screening initiation at age 45 by the American Cancer Society (ACS) in May 2018. However, it is unclear if CRC screening at ages 45 to 49 has increased the detection of early-stage CRC (ES-CRC). We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from 2015 to 2022, including individuals aged 45 to 49 diagnosed with CRC. The primary outcome was the diagnosis of ES-CRC (stages 1 and 2). The exposure was the time of diagnosis, categorized as preguideline (2015 to 2018) and postguideline (2019 to 2022). Multivariable logistic regression assessed the association between time period and ES-CRC diagnosis, adjusting for demographic and socioeconomic factors. Among 28,532 individuals, 47.0% were diagnosed preguideline and 53.0% postguideline. The proportion of ES-CRC increased significantly postguideline (31.1%) compared with preguideline update (29.8%, P=0.012). Notably, a decline in ES-CRC diagnoses was observed in 2020, likely due to disruptions in cancer screening during the COVID-19 pandemic. The adjusted odds of ES-CRC diagnosis was higher postguideline compared with preguideline update (AOR: 1.068; 95% CI: 1.004-1.137). Subgroup analyses revealed higher odds of ES-CRC diagnosis among females, Asians and Black individuals postguideline update. Following the 2018 ACS guideline change, ES-CRC diagnoses increased among adults aged 45 to 49. These findings suggest the updated screening recommendations may have facilitated earlier detection in this age group.
Proposed treatment algorithms favor the use of upadacitinib in medically refractory Crohn's disease (CD) and ulcerative colitis (UC). There has not yet been data published regarding efficacy of prolonged induction in CD or the efficacy of re-escalation to induction dosing in patients with either CD or UC. The aim of this study was to evaluate the real-world efficacy and safety of prolonged and/or re-escalation upadacitinib therapy in patients with inflammatory bowel disease (IBD) and prior inadequate response to standard upadacitinib treatment. This was a retrospective, dual-center study of the efficacy of prolonged induction or re-escalation of upadacitinib in patients with IBD with prior inadequate response to standard upadacitinib treatment. Fifty-five patients met eligibility criteria. Thirty-nine (70.9%) persisted on upadacitinib therapy while 16 (29.1%) met the primary endpoint for upadacitinib failure. Of those that had comparative objective data, 62.5% had improvement in endoscopic activity, 100% had normalization of an elevated CRP, and 83.3% experienced a decrease in FCP by >50%. There were no new safety signals. Over two-thirds of patients met the primary endpoint of persistence on therapy without requiring surgery, steroids, or additional biologic/small molecule inhibitor during follow-up. In a subset of patients who had adequate baseline and follow up objective data, the majority of patients had improvement in mucosal healing, decrease by 50% in FCP, and normalization of CRP. This study shows promising results that prolonged upadacitinib induction or dose re-escalation may improve clinical outcomes in a medically refractory patient population.
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Retrospective evaluations of multidisciplinary team (MDT) review of pancreatic cystic lesions (PCL) demonstrate improved PCL management. Endoscopic ultrasound (EUS) evaluates PCL for worrisome features; however, its influence on MDT is unclear and may be attenuated by anchoring/confirmation bias. We aimed to evaluate the impact of EUS and the overall performance of MDT evaluation of PCL. Four mock MDT sessions at two institutions were presented imaging from 40 consecutive PCL cases (20 "high-risk" with advanced neoplasia, 20 "low-risk" with pathologic low-grade dysplasia or ≥ 3 years of non-progression on surveillance), with and without upfront EUS/FNA (cytology, CEA, Amylase), in a randomized, crossover design. Group 1 adjudicated without EUS, Group 2 adjudicated with EUS, and Group 3 adjudicated with EUS after initially adjudicating without it. The cohort included branch-duct (n = 20), mixed type (n = 6), and main duct (n = 4) IPMN, MCN (n = 5), and non-mucinous PCL (n = 5). Group 2 (EUS) correctly identified mucinous PCL with 97% sensitivity and 70% specificity, significantly higher than Group 1 (No EUS) (Sensitivity 91%, Specificity 20%; p = 0.04). Group 3 (Unblinded to EUS) performed significantly worse in mucinous PCL identification compared with Group 2, indicating cognitive bias (Sensitivity 97%, Specificity 10% (p = 0.0003)). Group 2 correctly identified high-risk PCL that required surgical intervention with 85% sensitivity and 85% specificity, significantly higher than Group 1 (Sensitivity 60%, Specificity 75%; p = 0.0016) and Group 3 (Sensitivity 73%, Specificity 80%, p = 0.0485). While susceptible to cognitive bias, EUS significantly improves MDT assessment of PCL. MDT establishes a high bar for iterative additions of biomarkers to PCL analysis.
The tumor microenvironment in colorectal cancer (CRC) is richly innervated, yet the contribution of the enteric nervous system (ENS) to CRC biology remains poorly defined. ENS neurons express proenkephalin (PENK), which can be processed by proprotein convertase 1/3 (PCSK1) to generate Methionine-enkephalin (M-ENK), a bioactive peptide with growth-regulatory potential. We hypothesized that an ENS-derived PCSK1-MENK axis restrains CRC proliferation through opioid growth factor receptor (OGFr) signaling and is modulated by stress-associated glucocorticoid receptor (GR) signaling and GLP1 receptor (GLP1R) activity. Publicly available human CRC single-cell RNA-sequencing datasets were analyzed for OGFr expression. PCSK1 and M-ENK expression in murine ENS and tumor-associated tissue was assessed by immunofluorescence. Functional studies were performed using murine CRC organoids, and primary murine ENS neurons in mono- and co-culture. CRC proliferation was quantified by EdU incorporation following treatment with recombinant M-ENK, recombinant PCSK1, OGFr synthetic ligand naloxone, or PCSK1 inhibitors. Effects of dexamethasone and liraglutide on PCSK1 expression in ENS-containing murine tissue were evaluated. OGFr was enriched in CRC cells and positively associated with KRAS gene expression. A subset of adult murine colonic myenteric neurons expressed PCSK1 and M-ENK. M-ENK dose-dependently suppressed proliferation of CRC organoid cells. ENS neurons also suppressed CRC proliferation in a PCSK1-dependent manner. Dexamethasone reduced, whereas liraglutide increased, PCSK1 expression. These findings define a previously unrecognized ENS-derived neuro-oncologic pathway that is associated with reduced CRC cell proliferation and identify the GR/GLP1R-PCSK1-M-ENK axis as a potentially actionable therapeutic node.
Enteric infectious diseases claim more than 1 million lives annually and are among the top ten causes of death in children younger than 5 years. Remarkable global investment has been dedicated to enteric infectious disease prevention and control; however, the shifting global health landscape is testing the continuance of progress. To evaluate the current status and guide future interventions, we present the latest epidemiological estimates of enteric infectious diseases from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 and assess progress towards the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) mortality target of fewer than 20 deaths per 100 000 children younger than 5 years by 2025. We quantified the incidence, mortality, and disability-adjusted life-years (DALYs) of enteric infectious diseases by age, sex, and year across 204 countries and territories from 1990 to 2023. In GBD 2023, the following were considered under the category of enteric infectious diseases: diarrhoeal diseases, enteric fever (typhoid and paratyphoid), invasive non-typhoidal Salmonella spp (iNTS) infections, and other intestinal infectious diseases. We also examined 15 aetiologies contributing to diarrhoeal diseases. Incidence and prevalence were estimated with DisMod-MR (version 2.1), a Bayesian meta-regression tool, drawing on data from systematic reviews, population-based surveys, claims data, and hospital sources. Cause-specific mortality was modelled with Cause of Death Ensemble Modelling based on data from sources including vital registration, mortality surveillance, verbal autopsy, and minimally invasive tissue sampling. Years of life lost and years lived with disability were computed and combined to derive DALYs. For aetiology-specific estimation, population-attributable fractions (PAFs) for 15 pathogens were derived with a counterfactual framework. Point estimates and 95% uncertainty intervals (UIs) were generated from 250 draws from the posterior distribution. In 2023, enteric infectious diseases resulted in an estimated 1·27 million (95% UI 0·963-1·68) deaths globally, declining from 3·69 million (3·04-4·56) in 1990. The global age-standardised mortality rate (ASMR) decreased from 74·1 (62·0-92·9) per 100 000 population to 16·4 (12·6-21·3) per 100 000 population during the same period. Diarrhoeal diseases accounted for most deaths in 2023 (1·11 million [0·811-1·54]), followed by enteric fever and iNTS. South Asia and sub-Saharan Africa remained the most affected regions in 2023, with 599 000 (441 000-882 000) and 501 000 (373 000-648 000) deaths due to enteric infectious diseases, respectively, predominantly from diarrhoeal disease. Rotavirus was the leading cause of all-age diarrhoeal disease deaths (PAF 16·3% [12·0-21·5]), followed by norovirus (10·2% [2·4-17·0]) and Shigella spp (9·3% [5·4-15·2]). Among children younger than 5 years, PAFs of deaths due to diarrhoeal diseases were 40·2% (32·5-48·5) for rotavirus, 24·0% (15·1-36·7) for Shigella spp, and 23·4% (13·7-34·3) for adenovirus. Across 204 countries and territories, 141 met the GAPPD mortality target in 2023. The driving aetiologies among countries that did not meet the target in 2023 varied slightly by GBD super-region, but the highest or second-highest number of deaths in children younger than 5 years were consistently attributed to rotavirus. Astrovirus and sapovirus, newly included in GBD 2023, were responsible for 24 600 (6290-49 000) and 18 800 (4650-44 400) deaths, respectively, in 2023, mainly in children younger than 5 years. Our findings show that mortality and ASMRs of enteric infectious diseases declined substantially between 1990 and 2023. This decline is consistent with the expansion of public health measures and broader socioeconomic development. However, the burden in 2023 remains considerably high, with the highest mortality concentrated in sub-Saharan Africa and south Asia. Considering that more than a quarter of all countries had yet to meet the GAPPD mortality target in 2023, sustained efforts are needed to address the persistent burden in affected countries and to adapt to the changing global health landscape. Gates Foundation.
Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 (CLPTM1L, rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10-8), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.
Chikungunya virus (CHIKV), an emerging arbovirus, is transmitted by Aedes mosquitoes. Climate change and increasing population mobility have driven recent outbreaks beyond traditional endemic regions. Since early July 2025, Guangdong province in southern China has faced an unprecedented outbreak of chikungunya fever. We aim to in-depth describe the epidemic features and theoretically assess the potential impact of vaccination campaigns. In total, the outbreak reported more than 25,000 cases. Foshan and Jiangmen successively emerged as epicenters of the outbreak. Through stringent public health interventions, the outbreak was controlled within two months in these two epicenters, respectively. Phylogenetic analysis revealed close genetic relation of the CHIKV isolates from this outbreak to the recent isolates in Réunion and Mayotte, but distant from the ones previously identified in China. Pre-emptive vaccination, achieving 20, 40%, 60%, and 80% coverage pre-outbreak, would avert up to 57%, 81%, 92%, and 97% infections shown by mathematical modelling, respectively. Achieving a daily vaccination rate comparable to the COVID-19 rollout, covering approximately 4% of the population in Foshan and 2% of the population in Jiangmen per day, could lower cumulative CHIKV infections by 68.7% in Foshan within two months and by 98.4% in Jiangmen within four months, respectively. In summary, the 2025 chikungunya outbreak in Guangdong was likely sparked by case importation. Implementation of stringent public health interventions is possible to control the outbreak, but can provoke significant public concerns. Vaccine campaigns are expected to be effective in both preparedness and response to future chikungunya outbreaks.
Genotype-based drug development has yielded highly effective therapies, notably the triple combinations elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/tezacaftor/deutivacaftor (VTD), now approved in Europe for people with CF having at least one non-class I variant. However not all these people with CF will respond to ETI or VTD, and a few not under the label may respond. Facilitating opportunities to access for patients with rare variants has required a shift in paradigm toward functional testing-based access. This approach assesses the potential benefit of modulator therapy using in vitro functional assays, either in engineered systems expressing defined CFTR variants (theratyping) or in patient-derived tissues (theranostics). We review theranostics as a critical tool for personalized medicine in CF, highlighting its validation in in vitro models derived from patients' own cells such as human intestinal organoids and human nasal epithelial cells. We discuss the current regulatory landscape regarding modulator approval and propose strategies for improving equitable access to effective treatments for all people with CF. Importantly, we advocate for functional assays to be accepted as standalone evidence of drug efficacy for patients with rare variants. Theranostic approaches remain critical when theratyping has not been achieved, and genetic data is not available or clearly interpretable. Indeed, theranostics has emerged as an essential pillar of CF drug access, complementing genotype-driven strategies. As the field advances, continued validation, standardization, and regulatory integration of in vitro functional assays will be key to ensuring that every person with CF-regardless of their genotype-has the opportunity to benefit from precision therapies.
Despite its clinical significance, pharmacological treatment options for alcohol use disorder (AUD) remained limited, which highlights the need for novel therapeutic targets. The ghrelin system has emerged as an important regulator of alcohol craving and intake. Liver-expressed antimicrobial peptide 2 (LEAP2) has recently been identified as an endogenous ghrelin receptor (GHSR) antagonist that influences metabolic and reward-related pathways. As a secondary analysis of five different clinical trials, we measured LEAP2 concentrations in the collected blood samples and examined their association with alcohol craving and the effects of both acute and chronic alcohol use on LEAP2. In addition, we complemented these clinical trial analyses by conducting preclinical experiments in wild-type and GHSR-KO Wistar rats to investigate the effects of alcohol and ghrelin on LEAP2 concentrations. In humans, LEAP2 concentrations negatively correlated with both priming- and cue-induced alcohol craving. Acute alcohol administration reduced LEAP2 concentrations 90min after oral alcohol intake, a response that was attenuated by co-administration of the GHSR inverse agonist PF-5190457. An intraperitoneal alcohol administration after a pre-treatment with ghrelin reduced LEAP2 concentrations in wild-type but not GHSR-KO Wistar rats. In contrast to acute alcohol administration, LEAP2 concentrations did not differ between people with alcohol use disorder and healthy controls and were unaffected by evidence of hepatocyte injury and alcohol abstinence. These results enhance our understanding of the ghrelin system, particularly LEAP2, with regard to alcohol craving and consumption. This work may inform the development of novel interventions for alcohol use disorder.
Pain is one of the most frequent and debilitating symptoms associated with pancreatic ductal adenocarcinoma (PDAC). More than 60% of patients suffer from significant pain at diagnosis. The prevalence increases during the progression of the disease and is associated with anorexia, weight loss, and impaired social interactions. The pathophysiology of pain includes the combined effects of tumor growth and spread, perineural invasion, neuroimmune interactions, peripheral nerve remodeling, and central nervous system sensitization. Pain is additionally modulated by comorbid conditions, such as anxiety or depression, as well as treatment-related toxicity. Previous reports have used simple unidimensional scales to assess pain intensity, but as pain in PDAC is multidimensional, there is a need to develop new and robust instruments to assess pain. The treatment follows the World Health Organization three-step analgesic ladder. Non-opioid analgesics can be used to improve pain, but strong opioids are often used to relieve pain and suffering. When opioids are used, there should be a focus on the management of the side effects. Patients with anxiety and depression may benefit from treatment with selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, and tricyclic antidepressants that also have effects on pain. In some cases, more experimental drugs such as ketamine may be used. Celiac plexus neurolysis and local irradiation therapies are supplementary methods used to treat PDAC pain, but the response is unpredictable, and the durability is relatively short. The reduced survival associated with celiac ganglia injection, especially in patients with advanced disease, has also tempered enthusiasm.
Zinc (Zn) is an essential micronutrient whose concentration and location are tightly regulated by Zn transporters. Mycobacterium tuberculosis (M.tb) resides in macrophage phagosomes, where it requires access to micronutrients, including Zn. Our data show that ZIP8 is the only Zn transporter in human macrophages highly induced by M.tb and is enriched at the M.tb phagosome. Using human and murine macrophages and mice deficient in ZIP8, we found that M.tb exploits ZIP8 to enhance its growth. ZIP8 imports Zn into the cytosol and out of the phagosome to subvert Zn poisoning. Cytosolic Zn dampens NF-κB activation and pro-inflammatory cytokine production while enhancing matrix metalloproteinase (MMP) production. Understanding the Zn- and ZIP8-dependent host response to M.tb infection is critical since dietary Zn deficiency and polymorphic ZIP8 variants are associated with increased susceptibility to tuberculosis and other infectious diseases.
Due to underlying chronic inflammation, inflammatory bowel disease (IBD) is associated with an increased risk of major adverse cardiovascular events (MACE). There is limited data on the role of cardiovascular (CV) risk factors and IBD medications on MACE. We aim to determine the association between MACE and IBD medications in a large national cohort of IBD patients with low baseline CV risk. We conducted a retrospective cohort study between January 1, 2015 and November 15, 2023 using the TriNetX database. Using logistic regression analysis, IBD patients exposed to biologics and small molecules were assessed for outcomes of individual and composite MACE (myocardial infarction [MI], ischemic stroke, percutaneous coronary intervention [PCI]/coronary artery bypass graft [CABG]). Outcomes were adjusted for demographics, non-advanced IBD therapies, statin use, CV risk factors, and prior history of coronary artery disease (CAD). We identified 113 729 IBD patients with an average age of 42 years and low prevalence of CV risk factors (5%-6%). Anti-TNF therapy was associated with a statistically significant decreased risk of composite MACE (adjusted OR [aOR] 0.795, 95% CI, 0.670-0.930, P = .005) and PCI/CABG (aOR 0.56, 95% CI, 0.274-0.562, P = .002), and anti-integrin therapy was associated with a decreased risk of composite MACE (aOR 0.76, 95% CI, 0.580-0.980, P = .035). Anti-IL12/23 and JAK inhibitors showed no increased risk of MACE. In a cohort of young IBD patients with low CV risk, use of anti-TNF and anti-integrins is associated with a decreased risk of MACE, and there was no increased risk of MACE with JAK inhibitors.
Colorectal carcinoma (CRC) remains a leading cause of cancer mortality, largely due to metastasis. Solid tumors, including CRC, must adapt to intratumoral hypoxia and oxidative stress, but the tumor-cell programs that couple these pressures to metastatic competence remain unclear. Across human CRC cohorts and cell lines, HIF-1α was coordinately upregulated and co-expressed with the metabolic effectors GLUT3 and fatty-acid synthase (FASN), most prominently in metastatic lesions. Using HIF-1α (HRE), SREBP1 (SRE), and NRF2 (ARE) transcriptional reporters, we identified HRE-high and SRE-high CRC subpopulations with enhanced clonogenicity and invasion that drove accelerated tumor growth and increased lung metastatic burden across multiple CRC models. Mechanistically, IGF1 and insulin signaling through IGF1R and AKT-mTOR increased HIF-1α and induced FASN and GLUT3, enabling lipogenic, glycolytic, and antioxidant programs to withstand hypoxic and oxidative stress. HIF-1α engaged an HRE-containing proximal region of the human FASN promoter independently of SREBP1. Stress assays revealed functional specialization: FASN promoted NRF2-associated antioxidant capacity and resistance to oxidative injury, whereas GLUT3 preferentially supported hypoxia tolerance. In vivo, lipid nanoparticle-encapsulated echinomycin rapidly suppressed HRE, SRE, and ARE activity, reduced peri-hypoxic induction of FASN and GLUT3, inhibited tumor growth, and eliminated lung metastasis. These findings define a growth factor-responsive, HIF-1α-centered stress-adaptive state and highlight HIF-1α transcriptional activity as a therapeutic target in metastatic CRC.
Osteoporosis is a complication of inflammatory bowel disease (IBD) with an estimated prevalence of 18%-42%. Given the paucity of data, this exploratory study aims to identify racial differences in prevalence, screening, and complications of osteoporosis in patients with IBD. A retrospective cohort study was conducted for patients with IBD and treated at Tufts Medical Center from January 1, 2010 to December 31, 2023. The rates of osteoporosis, osteopenia, and osteoporotic fractures were calculated and compared between White, Black, and Asian patients. Dual energy X-ray absorptiometry (DXA) screening rates were compared between the three races. Fisher's exact test was used to compare categorical variables, and Welch's t-test was used to compare quantitative data. Multivariable regression analysis was performed to assess the relationship between risk factors and the presence of osteoporosis, osteoporotic fractures, and cumulative events. Glucocorticoid exposure was defined as having had one or more glucocorticoid prescriptions during the study period. A total of 2517 patients with IBD were identified. There were 175 (7.0%) Asian, 156 (6.2%) Black, and 2186 (86.8%) White patients. There were statistically higher rates of osteoporosis and osteoporotic fractures in Asian patients compared to Black and White patients, respectively; (17.1% vs. 10.9% vs. 9.8%, P = .013) and (10.9% vs. 5.1% vs. 6.0%, P = 0.049). Black patients had higher rates of glucocorticoid exposure compared to Asians and Whites (39.1% vs. 28.6% vs. 27.2%, P = 0.007). There were no statistically significant differences in DXA screening rates between races. Asian populations with IBD were found to have higher prevalence of osteoporosis and osteoporotic fractures; these differences may reflect unmeasured genetic, environmental, or socioeconomic factors.