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Objective Chronic pancreatitis (CP) is a fibro-inflammatory syndrome characterized by irreversible tissue damage leading to exocrine and endocrine insufficiency, persistent pain, and an increased risk of pancreatic cancer. This study investigates the role of IL-18 in the activation process of pancreatic stellate cells (PSCs) and the progression of pancreatic fibrosis in CP. Materials and Methods A total of 69 CP and 32 normal pancreatic tissue samples were analyzed using qRT-PCR and IH) to assess IL-18R1 expression. Primary PSCs were isolated from murine pancreata and cultured. Effects of recombinant IL-18 on PSC activation were evaluated using qRT-PCR and flow cytometry. Additionally, the impact of IL-18 binding protein (IL-18BP) and IL-18R1 antibody on PSC activation was examined. Results IL-18R1 expression was significantly upregulated in CP tissues compared to normal pancreatic tissues, correlating with fibrosis severity. Cultured PSCs showed increased α-SMA and IL-18R1 expression over time, indicating activation. Treatment with recombinant IL-18 induced a dose-dependent increase in α-SMA expression, confirming PSC activation. Furthermore, cultured PSCs secreted IL-18, suggesting an autocrine activation mechanism. IL-18BP and IL-18R1 antibody treatments reduced PSC activation, underscoring IL-18's regulatory role. Conclusion Upregulation of IL-18R1 and its correlation with fibrosis severity in CP highlights IL-18's significant role in PSC activation and pancreatic fibrosis. These findings suggest that targeting the IL-18/IL-18R1 axis could be a promising therapeutic strategy to mitigate pancreatic fibrosis in CP, offering potential new avenues for treatment.

BACKGROUND: Some patients with chronic myeloid leukemia (CML) are eligible for tyrosine kinase inhibitor (TKI) discontinuation, which can reduce health system costs and may result in fewer adverse effects (AEs). This project sought to evaluate the potential cost avoidance and health outcomes associated with TKI discontinuation, including CML relapse, changes in reported AEs, long-term remission, and TKI withdrawal syndrome. OBSERVATIONS: Patients with chronic phase CML who had an active order for a TKI were eligible for discontinuation. Patients needed to be on TKI therapy for ≥ 3 years and have a stable molecular response. Patients were excluded if they had a history of advanced accelerated phase CML, a previous TKI discontinuation trial, nonadherence, or if they did not want to discontinue TKI. Oncology clinical pharmacy practitioners at each Veterans Integrated Services Network (VISN) 21 facility were notified of eligible patients. Fifteen VISN 21 patients were eligible for discontinuation as of October 2024, with a potential annual cost avoidance of $1.2 million if discontinued. A dashboard was developed to allow for ongoing TKI discontinuation in eligible patients. CONCLUSIONS: Discussions of TKI discontinuation with patients with CML led to collaboration with the patient care team and potential for significant cost avoidance without negatively impacting patient outcomes. Barriers to therapy discontinuation included patient concern for relapse, risk of discontinuation syndrome, the need for close monitoring, and required clinician buy-in.

Herlyn-Werner-Wunderlich syndrome, also known as obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome, is a rare congenital Müllerian duct anomaly, occurring in approximately 1 in 1,000,000 females. It is characterised by a triad of uterine didelphys, obstructed hemivagina and ipsilateral renal agenesis. Patients typically present with chronic pelvic pain, dysmenorrhea and endometriosis, which can lead to diagnostic bias and the misattribution of all pelvic pain to their underlying gynaecological condition. We present the case of a 19-year-old female with a known diagnosis of OHVIRA syndrome who presented with acute right iliac fossa (RIF) pain and raised inflammatory markers. Despite her complex gynaecological background, imaging confirmed a diagnosis of acute appendicitis with impending perforation. She underwent a successful laparoscopic appendicectomy. The patient had experienced multiple prior episodes of RIF pain, previously attributed to her gynaecological condition, without further surgical evaluation. This case underscores the importance of maintaining a broad differential diagnosis in patients with complex gynaecological anomalies and highlights the risk of diagnostic overshadowing. A comprehensive assessment for acute surgical pathology should always be considered in this cohort to avoid delays in diagnosis and treatment.

Familial Parkinson's disease (PD) and vascular parkinsonism (VP) present overlapping features and may co-exist. To investigate whether PD and VP may share a potential pathogenic link and to what extent white matter hyperintensities may influence PD phenotype, we used the modified Scheltens scale and presented a descriptive and exploratory analysis of the classic neuroradiological features of cerebral small vessel disease (cSVD) in the axial T2-FLAIR MRI sequences in a cohort of 104 familial PD and PD prodromal patients and 48 age-matched controls from the PPMI publicly available database. We next performed whole exome sequencing to examine the protein coding variability in the main PD-causing and risk genes (VPS35, DJ1, PINK1, ATP13A2, PRKN, SNCA, LRRK2, GBA, MAPT, LAMP3, STK39) in a cohort of 96 patients with familial cSVD and 243 elderly healthy individuals (HEX database). In this cohort, patients with familial and prodromal PD present a moderate burden of superficial frontal white matter hyperintensities (p-value = 3.46e-06, Bonferroni-corrected), linked to a mild reduction of motor and cognitive function and an increased LRRK2 p.G2019S and p.R1441C variant penetrance, and bilateral basal ganglia periventricular enlarged spaces (p-value = 2.64e-03, Bonferroni-corrected). Moreover, one-third of familial PD patients displayed a burden of lacunar thalamic strokes (p-value = 0.058), associated with a moderate hypokinetic-rigid syndrome. Finally, we report no known pathogenic coding variant in the main PD causative genes and risk factors in a cohort of 96 early-onset cSVD Caucasian patients. Our study adds to the understanding of potential cSVD hallmarks within this familial LRRK2, GBA and SNCA PD-PD prodromal cohort.

Understanding the molecular mechanisms of aging guides the development of prevention, intervention, and treatment strategies to reduce the incidence of common age-associated diseases. Over the past decades, the proposed key features (hallmarks) of aging cells have directly or indirectly provided us clues, furthering our understanding of the causes of disease and assisting with the development of therapeutic strategies for diseases such as rare premature aging diseases like Werner syndrome and ataxia telangiectasia (A-T), as well as the common age-related diseases like dementia and sarcopenia. In this editorial, we take a closer look at three of these hallmarks including genomic instability, defective macroautophagy, and mitochondrial dysfunction, and the applications of these concepts in understanding the progress of complex diseases. Mounting studies from the laboratory, supported by emerging clinical evidence, point to the reduction of the oxidized form of nicotinamide adenine dinucleotide (NAD+) as a commonality between many of these hallmarks of aging. Intriguingly, stimulating mitochondrial autophagy (mitophagy) via improvement of NAD+ availability appears to be a promising and effective therapeutic strategy for many diseases relating to aging. Future studies on the hallmarks of aging should address their internal linkages and clinical interventions.