Toll-like receptor 4 in pancreatic damage and immune infiltration in acute pancreatitis.

Acute pancreatitis is a complex inflammatory disease resulting in extreme pain and can result in significant morbidity and mortality. It can be caused by several factors ranging from genetics, alcohol use, gall stones, and ductal obstruction caused by calcification or neutrophil extracellular traps. Acute pancreatitis is also characterized by immune cell infiltration of neutrophils and M1 macrophages. Toll-like receptor 4 (TLR4) is a pattern recognition receptor that has been noted to respond to endogenous ligands such as high mobility group box 1 (HMGB1) protein and or exogenous ligands such as lipopolysaccharide both of which can be present during the progression of acute pancreatitis. This receptor can be found on a variety of cell types from endothelial cells to resident and infiltrating immune cells leading to production of pro-inflammatory cytokines as well as immune cell activation and maturation resulting in the furthering of pancreatic damage during acute pancreatitis. In this review we will address the various mechanisms mediated by TLR4 in the advancement of acute pancreatitis and how targeting this receptor could lead to improved outcomes for patients suffering from this condition.

The preliminary analysis of lymphatic flow around the connective tissues surrounding SMA and SpA elucidates patients' oncological condition in borderline-resectable pancreatic cancer.

BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), invasion of connective tissues surrounding major arteries is a crucial prognostic factor after radical resection. However, why the connective tissues invasion is associated with poor prognosis is not well understood. MATERIALS AND METHODS: From 2018 to 2020, 25 patients receiving radical surgery for PDAC in our institute were enrolled. HyperEye Medical System (HEMS) was used to examine lymphatic flow from the connective tissues surrounding SMA and SpA and which lymph nodes ICG accumulated in was examined. RESULTS: HEMS imaging revealed ICG was transported down to the paraaortic area of the abdominal aorta along SMA. In pancreatic head cancer, 9 paraaortic lymph nodes among 14 (64.3%) were ICG positive, higher positivity than LN#15 (25.0%) or LN#18 (50.0%), indicating lymphatic flow around the SMA was leading directly to the paraaortic lymph nodes. Similarly, in pancreatic body and tail cancer, the percentage of ICG-positive LN #16a2 was very high, as was that of #8a, although that of #7 was only 42.9%. CONCLUSIONS: Our preliminary result indicated that the lymphatic flow along the connective tissues surrounding major arteries could be helpful in understanding metastasis and improving prognosis in BR-A pancreatic cancer.

Unlocking the Role of Age-Related Changes to Fibroblasts in Pancreatic Cancer.

Pancreatic cancer prevalence increases with age, and disease prognosis is poorer in older individuals. The increased prevalence is driven, undoubtedly, by the multistep accumulation of oncogenic mutations in cancer cells with age. However, fibroblasts are major constituents and key players in pancreatic cancer, and they too undergo age-related changes that may contribute to disease severity. In this issue of Cancer Research, Zabransky and colleagues set out to dissect the effect of age-related changes in pancreatic fibroblasts on pancreatic ductal adenocarcinoma growth and metastasis. They discovered that aged fibroblasts secrete GDF-15, which in turn activates AKT signaling and accelerates tumor progression. These findings provide a mechanistic role for aged fibroblasts in pancreatic cancer, underpinning the importance of normal physiologic processes in tumor progression. See related article by Zabransky et al., p. 1221.

Collagen Lattice Model, Populated with Heterogeneous Cancer-Associated Fibroblasts, Facilitates Advanced Reconstruction of Pancreatic Cancer Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a solid-tumor malignancy. To enhance the treatment landscape of PDAC, a 3D model optimized for rigorous drug screening is essential. Within the PDAC tumor microenvironment, a dense stroma comprising a large extracellular matrix and cancer-associated fibroblasts (CAFs) is well-known for its vital role in modulating tumor growth, cellular heterogeneity, bidirectional paracrine signaling, and chemoresistance. In this study, we employed a fibroblast-populated collagen lattice (FPCL) modeling approach that has the ability to replicate fibroblast contractility in the collagenous matrix to build dense stroma. This FPCL model allows CAF differentiation by facilitating multifaceted cell-cell interactions between cancer cells and CAFs, with the differentiation further influenced by mechanical forces and hypoxia carried within the 3D structure. Our FPCL models displayed hallmark features, including ductal gland structures and differentiated CAFs with spindle shapes. Through morphological explorations alongside in-depth transcriptomic and metabolomic profiling, we identified substantial molecular shifts from the nascent to mature model stages and potential metabolic biomarkers, such as proline. The initial pharmacological assays highlighted the effectiveness of our FPCL model in screening for improved therapeutic strategies. In conclusion, our PDAC modeling platform mirrors complex tumor microenvironmental dynamics and offers an unparalleled perspective for therapeutic exploration.

MicroRNAs in Pancreatic Cancer: Advances in Biomarker Discovery and Therapeutic Implications.

Pancreatic cancer remains a formidable malignancy characterized by high mortality rates, primarily attributable to late-stage diagnosis and a dearth of effective therapeutic interventions. The identification of reliable biomarkers holds paramount importance in enhancing early detection, prognostic evaluation, and targeted treatment modalities. Small non-coding RNAs, particularly microRNAs, have emerged as promising candidates for pancreatic cancer biomarkers in recent years. In this review, we delve into the evolving role of cellular and circulating miRNAs, including exosomal miRNAs, in the diagnosis, prognosis, and therapeutic targeting of pancreatic cancer. Drawing upon the latest research advancements in omics data-driven biomarker discovery, we also perform a case study using public datasets and address commonly identified research discrepancies, challenges, and limitations. Lastly, we discuss analytical approaches that integrate multimodal analyses incorporating clinical and molecular features, presenting new insights into identifying robust miRNA-centric biomarkers.

The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes.

Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.

Molecular pathway of pancreatic cancer-associated neuropathic pain.

The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1ß into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.

ABCD1 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm of the Pancreas.

The diagnosis of solid pseudopapillary neoplasm of the pancreas (SPN) can be challenging due to potential confusion with other pancreatic neoplasms, particularly pancreatic neuroendocrine tumors (NETs), using current pathological diagnostic markers. We conducted a comprehensive analysis of bulk RNA sequencing data from SPNs, NETs, and normal pancreas, followed by experimental validation. This analysis revealed an increased accumulation of peroxisomes in SPNs. Moreover, we observed significant upregulation of the peroxisome marker ABCD1 in both primary and metastatic SPN samples compared with normal pancreas and NETs. To further investigate the potential utility of ABCD1 as a diagnostic marker for SPN via immunohistochemistry staining, we conducted verification in a large-scale patient cohort with pancreatic tumors, including 127 SPN (111 primary, 16 metastatic samples), 108 NET (98 nonfunctional pancreatic neuroendocrine tumor, NF-NET, and 10 functional pancreatic neuroendocrine tumor, F-NET), 9 acinar cell carcinoma (ACC), 3 pancreatoblastoma (PB), 54 pancreatic ductal adenocarcinoma (PDAC), 20 pancreatic serous cystadenoma (SCA), 19 pancreatic mucinous cystadenoma (MCA), 12 pancreatic ductal intraepithelial neoplasia (PanIN) and 5 intraductal papillary mucinous neoplasm (IPMN) samples. Our results indicate that ABCD1 holds promise as an easily applicable diagnostic marker with exceptional efficacy (AUC=0.999, sensitivity=99.10%, specificity=100%) for differentiating SPN from NET and other pancreatic neoplasms through immunohistochemical staining.

Back to the fundamentals: a reply to Basener and Sanford 2018.

Fisher's fundamental theorem of natural selection has haunted theoretical population genetic literature since it was proposed in 1930, leading to numerous interpretations. Most of the confusion stemmed from Fisher's own obscure presentation. By the 1970s, a clearer view of Fisher's theorem had been achieved and it was found that, regardless of its utility or significance, it represents a general theorem of evolutionary biology. Basener and Sanford (J Math Biol 76:1589-1622, 2018) writing in JOMB, however, paint a different picture of the fundamental theorem as one hindered by its assumptions and incomplete due to its failure to explicitly incorporate mutational effects. They argue that Fisher saw his theorem as a "mathematical proof of Darwinian evolution". In this reply, we show that, contrary to Basener and Sanford, Fisher's theorem is a general theorem that applies to any evolving population, and that, far from their assertion that it needed to be expanded, the theorem already implicitly incorporates ancestor-descendant variation. We also show that their numerical simulations produce unrealistic results. Lastly, we argue that Basener and Sanford's motivations were in undermining not merely Fisher's theorem, but the concept of universal common descent itself.

Generating Human Pancreatic Tissue Slices to Study Endocrine and Exocrine Pancreas Physiology.

It is crucial to study the human pancreas to understand the pathophysiological mechanisms associated with type 1 (T1D) and 2 diabetes (T2D) as well as the pancreas endocrine and exocrine physiology and interplay. Much has been learned from the study of isolated pancreatic islets, but this prevents examining their function and interactions in the context of the whole tissue. Pancreas slices provide a unique opportunity to explore the physiology of normal, inflamed, and structurally damaged islets within their native environment, in turn allowing the study of interactions between endocrine and exocrine compartments to better investigate the complex dynamics of pancreatic tissue. Thus, the adoption of the living pancreas slice platform represents a significant advancement in the field. This protocol describes how to generate living tissue slices from deceased organ donors by tissue embedding in agarose and vibratome slicing as well as their utilization to assess functional readouts such as dynamic secretion and live cell imaging.

[Treatment of recurrent incarcerated Bochdalek hernia in an adult]. / Recidív, kizáródott, felnottkori Bochdalek-sérv mutéti megoldása.

Az igen ritka felnottkori nem hiatális, azaz nem paraoesophagealis típusú transdiaphragmaticus sérveket - a veleszületett rekeszizom defektusok mintájára - általánosan Bochdalek, ill. Larey-Morgagni-sérveknek nevezik. Etiológia tekintetében a nem diagnosztizált és kezelt veleszületett eredet, a traumás kontúziós-szakadásos, az iatrogen, ill. a recidív típus említendo meg.Esetismertetésünkben egy felnottkori recidív, kizáródott Bochdalek-sérv sikeres mutéti ellátását ismertetjük. A 23 éves férfi beteg kórelozményében 11 éves korában bal oldali Bochdalek-sérv miatt végzett thoracoscopos rekeszizom sutura szerepel. Epigastrialis fájdalmak, hányinger, hányás, akut hasi megbetegedés klinikai tünetei miatt jelentkezett Intézetünkben. Az elvégzett sürgos mellkasi és hasi CT-vizsgálat a bal mellüregben elhelyezkedo, kizáródott, vékonybélkacsokat tartalmazó Bochdalek-sérvet igazolt. Sürgos laparotomia során az életképesnek bizonyult sérvtartalmat (a vékonybéltraktus 2/3 része, a colon flexura lienalisa és a pancreas farok) a hasüregbe reponáltuk, a sérvkaput direkt suturával zártuk, és szövetszeparáló sebészi hálóval fedtük, valamint a mellüreget draináltuk. A postoperatív szak eseménytelenül zajlott. Kontroll-CT-vizsgálat a reconstruált rekeszizom és pleuro-peritonealis rétegek folytonosságát mutatta. A 10. posztoperatív napon panaszmentesen bocsátottuk otthonába.Megbeszélés: Mint minden kizáródott sérv esetében, a diagnózis mihamarabbi felállítása és az idoben elvégzett mutét kulcsfontosságú. A mellkasi drenázs szükségességét minden esetnél körültekintoen mérlegelni kell. A mutét után a mell- és hasüregben kialakult új anatómiai viszonyok miatt cardialis és respiratoricus szövodmények alakulhatnak ki. Álláspontunk szerint a betegség ritkasága miatt centrumban kezelendo. Ezen ritka állapot sikeres gyógyítása többszakmás együttmuködésen alapul, melynek meghatározó eleme a helyesen megválasztott rekeszi felszínt helyreállító mutéti technika alkalmazása.

OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage.

Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca2+ directly released from acidic Ca2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a) as an organellar Ca2+ regulator protein integral to the membrane of secretory granules that controlled Ca2+ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca2+ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca2+ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.

Traditional and emerging strategies using hepatocytes for pancreatic regenerative medicine.

Although pancreas and islet cell transplantation are the only ways to prevent the late complications of insulin-dependent diabetes, a shortage of donors is a major obstacle to tissue and organ transplantation. Stem cell therapy is an effective treatment for diabetes and other pancreatic-related diseases, which can be achieved by inducing their differentiation into insulin-secreting cells. The liver is considered an ideal source of pancreatic cells due to its similar developmental origin and strong regenerative ability as the pancreas. This article reviews the traditional and emerging strategies using hepatocytes for pancreatic regenerative medicine and evaluates their advantages and challenges. Gene reprogramming and chemical reprogramming technologies are traditional strategies with potential to improve the efficiency and specificity of cell reprogramming and promote the transformation of hepatocytes into islet cells. At the same time, organoid technology, as an emerging strategy, has received extensive attention. Biomaterials provide a three-dimensional culture microenvironment for cells, which helps improve cell survival and differentiation efficiency. In addition, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology has brought new opportunities and challenges to the development of organoid technology.

Pancreaticoureteric fistula following penetrating abdominal trauma: A Case Report.

Pancreaticoureteric Fistula (PUF) is a very rare complication secondary to penetrating abdominal trauma involving the ureter and pancreatic parenchyma. Pancreatic injuries carry h igh morbidity due to the involvem ent of surrounding structures and are d ifficult to diagnose due to thei r retroperitoneal location. A case of a patient is reported at Civil Hospital, Hyderabad who presented with a history of firearm injury and missed pancreatic duct involvement on initial exploration that eventually led to the development of Pan creaticoureteric Fistula. He was managed v ia p erc ut aneous nep hrostomy ( PCN ) for the right ureteric injury and pancreatic duct (PD) stenting was done for distal main pancreatic duct injury (MPD).

Influence of aberrant right hepatic artery on survival after pancreatic resection for ductal adenocarcinoma of the pancreatic head.

PURPOSE: The presence of an aberrant right hepatic artery (aRHA), arising from the superior mesenteric artery, is a common variant of the liver vascular anatomy. Considering that tumor spread occurs along vessels, the question arises, whether the presence of an aRHA influences the oncologic outcome after resection for cancer of the pancreatic head. METHODS: Patients with ductal adenocarcinoma of the pancreatic head, who underwent resection from 2011 to 2020 at the Frankfurt University Hospital, Germany, were analyzed retrospectively. Surgical records and computed tomography imaging were reviewed for the presence of aRHA. Overall and disease-free survival as well as hepatic recurrence were analyzed according to the presence of aRHA. RESULTS: aRHA was detected in 21 out of 145 patients (14.5%). The median overall survival was 26 months (95%CI 20.8-34.4), median disease-free survival was 12.1 months (95%CI 8.1-17.3). There was no significant difference in overall survival (26.1 versus 21.4 months, adjusted hazard ratio 1.31, 95%CI 0.7-2.46, p = 0.401) or disease-free survival (14.5 months versus 12 months, adjusted hazard ratio 0.98, 95%CI 0.57-1.71, p = 0.957) without and with aRHA. The hepatic recurrence rate was 24.4.% with conventional anatomy versus 30.8% with aRHA (adjusted odds ratio 1.36, 95%CI 0.3-5.38, p = 0.669). In the multivariable analysis, only lymphatic vessel invasion was an independent prognostic factor for hepatic recurrence. CONCLUSIONS: The presence of an aRHA does not seem to influence the long-term survival and hepatic recurrence after resection for ductal adenocarcinoma of the pancreatic head.

Optimizing prediction models for pancreatic fistula after pancreatectomy: Current status and future perspectives.

Postoperative pancreatic fistula (POPF) is a frequent complication after pancreatectomy, leading to increased morbidity and mortality. Optimizing prediction models for POPF has emerged as a critical focus in surgical research. Although over sixty models following pancreaticoduodenectomy, predominantly reliant on a variety of clinical, surgical, and radiological parameters, have been documented, their predictive accuracy remains suboptimal in external validation and across diverse populations. As models after distal pancreatectomy continue to be progressively reported, their external validation is eagerly anticipated. Conversely, POPF prediction after central pancreatectomy is in its nascent stage, warranting urgent need for further development and validation. The potential of machine learning and big data analytics offers promising prospects for enhancing the accuracy of prediction models by incorporating an extensive array of variables and optimizing algorithm performance. Moreover, there is potential for the development of personalized prediction models based on patient- or pancreas-specific factors and postoperative serum or drain fluid biomarkers to improve accuracy in identifying individuals at risk of POPF. In the future, prospective multicenter studies and the integration of novel imaging technologies, such as artificial intelligence-based radiomics, may further refine predictive models. Addressing these issues is anticipated to revolutionize risk stratification, clinical decision-making, and postoperative management in patients undergoing pancreatectomy.

Preoperative pancreatic stent placement before the enucleation of insulinoma located in the head and neck of the pancreas in proximity to the main pancreatic duct: study protocol for a multicentre randomised clinical trial in Chinese tertiary medical centres.

INTRODUCTION: The surgical intervention approach to insulinomas in proximity to the main pancreatic duct remains controversial. Standard pancreatic resection is recommended by several guidelines; however, enucleation (EN) still attracts surgeons with less risk of late exocrine/endocrine insufficiency, despite a higher postoperative pancreatic fistula (POPF) rate. Recently, the efficacy and safety of preoperative pancreatic stent placement before the EN have been demonstrated. Thus, a multicentre open-label study is being conducted to evaluate the efficacy and safety of stent placement in improving the outcome of EN of insulinomas in proximity to the main pancreatic duct. METHODS AND ANALYSIS: This is a prospective, randomised, open-label, superiority clinical trial conducted at multiple tertiary centres in China. The major eligibility criterion is the presence of insulinoma located in the head and neck of the pancreas in proximity (≤2 mm) to the main pancreatic duct. Blocked randomisation will be performed to allocate patients into the stent EN group and the direct EN group. Patients in the stent EN group will go through stent placement by the endoscopist within 24 hours before the EN surgery, whereas other patients will receive EN surgery directly. The primary outcome is the assessment of the superiority of stent placement in reducing POPF rate measured by the International Study Group of Pancreatic Surgery standard. Both interventions will be performed in an inpatient setting and regular follow-up will be performed. The primary outcome (POPF rate) will be tested for superiority with the Χ2 test. The difference in secondary outcomes between the two groups will be analysed using appropriate tests. ETHICS AND DISSEMINATION: The study has been approved by the Peking Union Medical College Hospital Institutional Review Board (K23C0195), Ruijin Hospital Ethics Committee (2023-314), Peking University First Hospital Ethics Committee (2024033-001), Institutional Review Board of Xuanwu Hospital of Capital Medical University (2023223-002), Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (XJTU1AF2023LSK-473), Institutional Review Board of Tongji Medical College Tongji Hospital (TJ-IRB202402059), Ethics Committee of Tongji Medical College Union Hospital (2023-0929) and Shanghai Cancer Center Institutional Review Board (2309282-16). The results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05523778.

Metastatic mediastinal hepatoid adenocarcinoma.

Hepatoid adenocarcinoma (HAC) of the mediastinum is a rare extrahepatic tumour that pathologically and morphologically resembles hepatocellular carcinoma. Extrahepatic HACs primarily occur in the stomach, ovaries, lung, gallbladder, pancreas and uterus. Patients with mediastinal HAC tend to be male smokers over forty years of age. Clinical symptoms of HAC are non-specific and varied in nature; therefore, diagnosis can be challenging and often delayed. Diagnostic investigations encompass haematological, radiological and histological assessment. Surgical resection is reserved for early-stage patients; however, since diagnosis may be delayed, most patients present with metastatic disease, for which the treatment of choice is platinum-based chemotherapy.

Pancreatolithiasis: Does Management Depend on Clinical Manifestations?

BACKGROUND Pancreatic calculi (PC) or pancreatolithiasis refers to the presence of stones in the main pancreatic duct (MPD), side branches, or parenchyma of the pancreas. It is highly associated with chronic pancreatitis (CP), and is present in 50-90% of those patients. The stone formation can be attributed to a diversity of factors, all of them leading to obstruction in the duct, hypertension of its distal part, increased intraductal and parenchymal pressure, and inflammation, causing the standard symptom, epigastric pain. Immediate restoration of pancreatic secretion flow is of utmost importance and can be achieved with both endoscopic and surgical techniques. Endoscopic techniques include endoscopic retrograde cholangiopancreatography (ERCP) combined, if possible, with extracorporeal shock wave lithotripsy (ESWL), while surgical techniques consist of drainage and resection procedures. The choice of treatment for PC depends on the location, size, and number of stones, and the existence of other complications. CASE REPORT We present 2 cases that were diagnosed with PC, in which clinical symptoms, laboratory results, and imaging examinations were different, suggesting the variety of manifestations pancreatolithiasis can cause. Each patient was treated differently, according to their clinical situation and the presence or absence of complications. Both patients were discharged and fully recovered. CONCLUSIONS The management of pancreatolithiasis can be demanding in some cases, mostly when there are complications. The purpose of this case report is to indicate the importance of personalized treatment for each patient, as different approaches to the same medical condition should be easily identified and successfully treated.