Acyl-CoA-binding protein (ACBP, encoded by diazepam binding inhibitor, DBI) is an abundant intracellular regulator of lipid metabolism that also circulates systemically, yet the mechanisms governing its release and its relationship to organ injury remain unresolved. Herein, we combine human multi-omics, mechanistic mouse models and controlled cell death assays to identify cell death-driven liberation of intracellular ACBP/DBI as a unifying mechanism underlying its elevation in disease. In a cohort of 1198 hospitalized adults, among whom 75% were acutely infected by SARS-CoV-2, plasma ACBP/DBI tightly correlated with inflammatory markers and biochemical signatures of cardiac, hepatic, renal, metabolic and hematologic dysfunction. SomaScan proteomics further revealed that ACBP/DBI co-varies with organ-enriched proteins, particularly those originating from skeletal muscle and pancreas, implicating tissue injury as a major determinant of its circulating abundance. Multiple forms of acute organ damage in mice, including hepatic or renal ischemia-reperfusion, bile duct ligation, pancreatitis and rhabdomyolysis, triggered rapid and robust increases in plasma ACBP/DBI. Using defined in vitro paradigms, we demonstrate that apoptosis, ferroptosis and necroptosis each cause loss of intracellular ACBP/DBI and its release upon plasma membrane permeabilization, independent of the upstream lethal pathway. These mechanistic insights translated in vivo: hepatocyte apoptosis, ferroptosis and necroptosis each elevated circulating ACBP/DBI in a manner attenuated by pathway-specific inhibitors. Finally, meta-analysis of >100,000 individuals across diverse populations revealed that elevated plasma ACBP/DBI consistently associates with systemic and organ-specific disease and predicts future morbidity. Together, our findings identify cell death-driven ACBP/DBI release as a conserved mechanism linking organ injury to increased plasma ACBP/DBI, positioning this molecule as an integrative biomarker of tissue damage across species, organs, and cell death modalities.

Immunoglobulin G4-related disease (IgG4-RD) is a rare chronic immune-mediated multisystem disease with renal manifestations of tubulointerstitial nephritis (IgG4-TIN) and membranous nephropathy (IgG4-MN). IgG4-RD and its sequelae are treated with immunosuppressive therapy, including steroids and rituximab (RTX), which have demonstrated high efficacy in achieving disease remission. We describe a patient who was diagnosed with pancreatitis secondary to IgG4-RD through laboratory and imaging studies. Despite being on RTX, he developed acute kidney injury (AKI) and was diagnosed with IgG4-TIN via kidney biopsy. He was treated with prednisone and RTX, and his symptoms and renal function improved. Despite RTX reaching peak efficacy 6 months after administration, our patient had a breakthrough IgG4-TIN during this period. This case highlights the importance of maintaining a high index of suspicion for renal involvement (IgG4-TIN or IgG4-MN) in patients with AKI superimposed on IgG4-RD, and that maintenance therapy with RTX retreatment was associated with longer relapse-free survival at 12 months of follow-up. Our patient had no severe infections or hypogammaglobulinemia (≤5 g/l) with RTX, confirming RTX's safety and efficacy in maintenance remission therapy for recurrent IgG4-TIN.

Type IV paraesophageal hiatal hernias are rare but carry a significant risk of life-threatening complications, including gastric volvulus, incarceration, and the involvement of other intra-abdominal organs. Pancreatic herniation and associated pancreatitis are exceedingly uncommon. We report the case of a 74-year-old woman with Barrett's esophagus, chronic obstructive pulmonary disease (COPD), and obesity who presented with nausea, vomiting, and abdominal pain after a recent increase in the dose of tirzepatide. Imaging demonstrated a massive type IV paraesophageal hernia with organoaxial gastric volvulus. Initial laparoscopic reduction was aborted due to dense adhesions and a foreshortened esophagus. She subsequently developed progressive herniation involving the stomach, colon, and pancreatic body and tail, and ultimately underwent delayed robotic-assisted repair. The patient's postoperative course was complicated by multiple recurrences, including episodes of volvulus, duodenal obstruction, and mild pancreatitis. She ultimately required open repair with mesh reinforcement and gastropexy after unsuccessful endoscopic detorsion. Despite temporary improvement, she later developed recurrent herniation and severe gastroparesis, likely secondary to injury to the vagal nerve. This report highlights the complexity of managing massive type IV paraesophageal hernias, particularly with multi-organ involvement and recurrence. Even with advanced surgical approaches, recurrence and long-term complications remain significant challenges.

Necrotic death of pancreatic acinar cells leads to premature activation of digestive enzymes and is a central driver of inflammation in acute pancreatitis (AP). In contrast, apoptosis is a non-lytic, regulated form of cell death that prevents the release of intracellular content and is therefore considered less damaging. The induction of the intrinsic apoptotic pathway is tightly regulated by the balance between pro- and anti-apoptotic members of the BCL2 protein family. Pharmacological inhibitors of anti-apoptotic BCL2 proteins - BH3 mimetics - have thus emerged as tools to therapeutically shift cell fate from necrosis to apoptosis. Early-generation BH3 mimetics such as HA14-1 and BH3I-2' used to validate this concept were hindered by limited potency and significant off-target effects, including disruption of calcium homeostasis. More selective and potent second-generation agents - particularly Navitoclax (ABT-263) and Venetoclax (ABT-199) - have overcome these limitations, with Venetoclax now approved for clinical use in haematological malignancies. Here, we explore the therapeutic potential of BCL2 inhibitors in pancreatic diseases, with a focus on AP and a comparison to chronic pancreatitis (CP). In AP models, BCL2 inhibition - especially with Venetoclax - redirects cell death from necrosis to apoptosis, preserving intracellular ATP, attenuating aberrant Ca2+ signalling, and reducing tissue damage and inflammation, without overt toxicity to healthy acinar cells in the absence of injurious stimuli. In contrast, in CP, a disease marked by fibrosis and prevailing apoptotic loss of parenchyma, BCL2 inhibition provides no benefit and may exacerbate acinar atrophy and fibrogenesis. We discuss the mechanistic basis of these divergent effects, including the role of BCL2 proteins in cell death regulation and calcium dynamics. Finally, we highlight future directions, including the rationale for clinical testing of Venetoclax in AP, and discuss cautionary considerations for its use in CP, particularly in patients with coexisting conditions such as leukaemia, who may already be receiving BH3 mimetics.

Single nucleotide variation (SNV), as a key biomarker for disease diagnosis and personalized treatment, faces challenges in rapid and accurate detection. This study developed a single-tube accelerated recognition of SNVs strategy named STAR-CRISPR, which could accomplish SNV detection within only 20 min. This method integrated isothermal amplification and CRISPR/Cas12b cleavage system in one pot, and results could be directly identified by the naked eye. This method could accurately distinguish single-base differences, and could detect as low as 1% mutations against high background interference. We verified the proposed method by testing 70 clinical samples of idiopathic chronic pancreatitis, pancreatic cancer and acute myeloid leukemia. Results showed 100% consistency with next-generation sequencing results, demonstrating good accuracy and reliability of the proposed method. To further facilitate point-of-care diagnosis, we developed integrated miniature microfluidic chips, which greatly simplified sample identification and enabled logical interpretation of results. The combined STAR-CRISPR and microfluidic platform not only identifies SNVs but also supports simultaneous visual genotyping of wild-type, homozygous, and heterozygous mutations. Consequently, the proposed strategy is accurate, rapid, and versatile, holding significant potential for next-generation molecular diagnostics.

Secondary membranous nephropathy (MN) is an increasingly recognized manifestation of immunoglobulin G4 (IgG4)-related disease (IgG4-RD). It is typically seen alongside tubulointerstitial nephritis but may occur independently. In this study, we discuss the case of a 65-year-old man who was initially investigated for steatorrhea and marked weight loss. He was diagnosed with idiopathic chronic pancreatitis, which spontaneously resolved with conservative management. He later represented with profound nephrotic syndrome, lymphadenopathy, and cutaneous lesions. There were no detectable antiphospholipase A2 receptor antibodies in the blood, but he was found to have elevated serum IgG4 levels. A kidney biopsy demonstrated antiphospholipase A2 receptor-negative MN with no evidence of tubulointerstitial inflammation. He was investigated for secondary causes of MN with a positron emission tomography-computed tomography scan, which showed increased uptake in the gastric mucosa and thoracic lymph nodes. An endobronchial lymph node biopsy showed reactive changes only; the diagnosis of multisystem IgG4-RD was made on a gastric biopsy, which detected marked polyclonal infiltration with IgG4+ plasma cells. He showed an excellent clinical and radiological response to induction therapy, with a tapering course of prednisolone followed by rituximab. This case adds to the limited body of evidence reporting MN without tubulointerstitial inflammation in the context of pancreatic IgG4-RD.

The Diabetes-Pancreatic Ductal Adenocarcinoma Working Group (DM-PDAC WG) was formed within the Consortium for Study of Chronic Pancreatitis Diabetes and Pancreatic Cancer (CPDPC) to study the link between new-onset diabetes and pancreatic cancer. Its goals were to i) estimate the risk of PDAC in a prospectively assembled cohort of individuals with NOD identified at its glycemic onset (GNOD), ii) Establish a biobank of clinically annotated bio-specimens from GNOD subjects with pre-symptomatic PDAC and control new-onset type 2 DM, iii) Conduct Phase 3 validation studies of promising biomarkers for identification of occult PDAC in GNOD; iv) Provide a platform for development of a future interventional screening protocol for early detection of PDAC in NOD patients that incorporates imaging studies and clinical algorithms. The study identified >20,000 subjects with GNOD and assembled a biobank of serial blood samples in 2270 GNOD subjects. The risk of PDAC in GNOD and the distribution of lead time from GNOD to PDAC clinical diagnosis have been definitively defined in a cohort of 18,838 GNOD subjects identified during the course of the study. Ongoing biomarker and metabolomics studies will not only provide data on performance of tested biomarkers, but also an unprecedented repository of data on a large number of type 2 DM subjects. There are also ongoing studies on the "science of NOD" to understand its pathogenesis. Overall, the DM-PDAC Working Group has been successful in its mission to further our understanding of the link between diabetes pancreatic cancer.

Recurrence of acute pancreatitis (AP) is common, leading to cumulative pancreatic injury and reduced quality of life. While aetiology-based treatments and lifestyle interventions are effective, long-term adherence is often poor due to insufficient health awareness and a lack of continuous reminders. We designed the PROGRESS (PROactive GRadEd follow-up Strategy for reducing recurrence in acute pancreatitiS) trial to evaluate whether a physician-initiated, proactive and graded follow-up strategy can reduce AP recurrence.

This is the summary of an April 2025 Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) workshop highlighting the accomplishments of INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE)-2. INSPPIRE-2 goals and objectives have been to study the risk factors, natural history and outcomes of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Structured patient and physician questionnaires have been used to collect information on demographics, clinical history, family and social history, and disease outcomes. Biosamples have been collected primarily for DNA isolation and analysis of key genes associated with pancreatitis, alongside ancillary studies aimed at elucidating disease pathophysiology and advancing the development of improved diagnostic and therapeutic strategies. Twenty-six sites have enrolled >1000 subjects into the INSPPIRE-2 database with available prospective data to evaluate disease progression, phenotypes, complications and outcomes. The available resources are outlined along with key discoveries offering readers topic specific information about INSPPIRE's progress.