Publications by authors named "Austin Dosch"

The development of hepatic metastases is the leading cause of mortality in gastrointestinal (GI) cancers and substantial research efforts have been focused on elucidating the intricate mechanisms by which tumor cells successfully migrate to, invade, and ultimately colonize the liver parenchyma. Recent evidence has shown that perturbations in myeloid biology occur early in cancer development, characterized by the initial expansion of specific innate immune populations that promote tumor growth and facilitate metastases. This review summarizes the pathophysiology underlying the proliferation of myeloid cells that occurs with incipient neoplasia and explores the role of innate immune-host interactions, specifically granulocytes and neutrophil extracellular traps, in promoting hepatic colonization by tumor cells through the formation of the "premetastatic niche".

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Background And Aims: induction of alcoholic chronic pancreatitis (ACP) causes significant acinar damage, increased fibroinflammatory response, and heightened activation of cyclic response element binding protein 1 (CREB) when compared with alcohol (A) or chronic pancreatitis (CP) mediated pancreatic damage. However, the study elucidating the cooperative interaction between CREB and the oncogenic (*) in promoting pancreatic cancer progression with ACP remains unexplored.

Methods: Experimental ACP induction was established in multiple mouse models, followed by euthanization of the animals at various time intervals during the recovery periods.

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Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a KRAS-driven inflammatory program and a desmoplastic stroma, which contribute to the profoundly chemoresistant phenotype. The tumor stroma contains an abundance of cancer-associated fibroblasts (CAF), which engage in extensive paracrine cross-talk with tumor cells to perpetuate protumorigenic inflammation. IL1α, a pleiotropic, tumor cell-derived cytokine, plays a critical role in shaping the stromal landscape.

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Background: The role of neoadjuvant chemotherapy (NAC) in advanced sigmoid colon carcinoma remains to be further characterized. Rationale for NAC includes downstaging on final pathology and optimization of microscopically negative margins (R0 resection). We investigated rates of neoadjuvant chemotherapy use in advanced sigmoid colon cancer at academic cancer centers and assessed factors associated with likelihood of NAC administration.

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Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) is a significant contributor to cancer-related morbidity and mortality, and it is known for its resistance to conventional treatment regimens, including chemotherapy and immune checkpoint blockade (ICB)-based therapies. We have previously shown that Urolithin A (Uro A), a gut microbial metabolite derived from pomegranates, can target and inhibit -dependent PI3K/AKT/mTOR signaling pathways to overcome therapeutic resistance and improve survival in PDAC. However, the effect of Uro A on the tumor immune microenvironment and its ability to enhance ICB efficacy has not been explored.

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Article Synopsis
  • KRAS-TP53 genomic coalteration in pancreatic ductal adenocarcinoma (PDAC) leads to immune exclusion and poor survival, driven by the key mediator Cxcl1 and its interaction with neutrophils.
  • Silencing Cxcl1 in specific PDAC models reprograms neutrophils, enhancing T-cell activity and controlling tumor growth through T-cell dependence.
  • The study reveals that neutrophil-derived TNF plays a crucial role in maintaining immunosuppression and inflammation in PDAC, suggesting that targeting TNF signaling could improve chemotherapy effectiveness.
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Article Synopsis
  • Heavy drinking is a major cause of a disease called alcoholic chronic pancreatitis (ACP), but there aren't many ways to treat or prevent it.
  • In a study with mice, it was found that continuing to drink alcohol makes pancreatic damage worse, but stopping alcohol can help heal it.
  • A special compound called urolithin A (Uro A) was shown to help reduce damage in the pancreas when drinking continues, suggesting it could be a helpful treatment for people with ACP.
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Background & Aims: We have shown that reciprocally activated rat sarcoma (RAS)/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Janus kinase/signal transducer and activator of transcription 3 (STAT3) pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine whether MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC.

Methods: CAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i (ruxolitinib)-treated vs vehicle-treated Ptf1a;LSL-KrasTgfbr2 (PKT) tumors were examined via single-cell RNA sequencing (scRNAseq).

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Co-occurrent KRAS and TP53 mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS-TP53 co-alteration is associated with worse survival compared with either KRAS-alone or TP53-alone altered PDAC in 245 patients with metastatic disease treated at a tertiary referral cancer center, and validate this observation in two independent molecularly annotated datasets. Compared with non-TP53 mutated KRAS-altered tumors, KRAS-TP53 co-alteration engenders disproportionately innate immune-enriched and CD8 T-cell-excluded immune signatures.

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As inflammation plays a critical role in the development and progression of cancer, therapeutic targeting of cytokine pathways involved in both tumorigenesis and dictating response to clinical treatments are of significant interest. Recent evidence has highlighted the importance of the pro-inflammatory cytokine interleukin-1 (IL-1) as a key mediator of tumor growth, metastatic disease spread, immunosuppression, and drug resistance in cancer. IL-1 promotes tumorigenesis through diverse mechanisms, including the activation of oncogenic signaling pathways directly in tumor cells and via orchestrating crosstalk between the cellular constituents of the tumor microenvironment (TME), thereby driving cancer growth.

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Despite increasingly thorough mechanistic understanding of the dominant genetic drivers of gastrointestinal (GI) tumorigenesis (e.g., Ras/Raf, , etc.

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A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense, desmoplastic stroma and the consequent altered interactions between cancer cells and their surrounding tumor microenvironment (TME) that promote disease progression, metastasis, and chemoresistance. We have previously shown that IL6 secreted from pancreatic stellate cells (PSC) stimulates the activation of STAT3 signaling in tumor cells, an established mechanism of therapeutic resistance in PDAC. We have now identified the tumor cell-derived cytokine IL1α as an upstream mediator of IL6 release from PSCs that is involved in STAT3 activation within the TME.

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Activating mutations, a defining feature of pancreatic ductal adenocarcinoma (PDAC), promote tumor growth in part through the activation of cyclin-dependent kinases (CDK) that induce cell-cycle progression. p16 (p16), encoded by the gene , is a potent inhibitor of CDK4/6 and serves as a critical checkpoint of cell proliferation. Mutations in and subsequent loss of the p16 gene occur in PDAC at a rate higher than that reported in any other tumor type and results in Rb inactivation and unrestricted cellular growth.

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Objectives: Colloid carcinoma (CC) of the pancreas is associated with an improved prognosis compared with pancreatic ductal adenocarcinoma (PDAC), yet studies on the optimal management of these rare lesions are lacking.

Methods: Patients with CC or PDAC treated from 2004 to 2014 were identified in the National Cancer Database. Clinicopathologic characteristics were compared between groups and stratified by disease stage.

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Pancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contribute to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to the aggressive biology of cancer along with its immune-evasive microenvironment.

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In 2006, the Surgical Infection Society (SIS) used a modified Delphi process to enlist SIS member-experts to identify 15 research priorities in the field of surgical infectious diseases; it was intended to serve as a research road map for the next one to two decades. We sought to evaluate the progress made in each of these priority areas. We examined the progress achieved with respect to the 15 research areas identified by the Delphi process at that time, hypothesizing that advances in knowledge would be achieved in most domains, if not all.

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Background: Given the growing number of people worldwide living with human immunodeficiency virus (HIV), a larger subset of these patients are now susceptible to sustaining a traumatic injury. However, the impact of HIV on outcomes in trauma with modern antiretroviral treatment remains unclear. We hypothesized mortality and rates of infectious and inflammatory complications would be higher in HIV positive (HIV+) trauma patients.

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Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways.

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Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality following distal pancreatectomy (DP). However, the influence of operative technique on VTE risk after DP is unknown.

Objective: The purpose of this study was to examine the association between the MIS technique versus the open technique and the development of postoperative VTE after DP.

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Introduction: Guidelines surrounding abdominal seat belt sign (SBS) were made prior to the use of modern computed tomography (CT) imaging. We sought to prospectively determine whether a negative CT scan is associated with the absence of hollow viscus injury (HVI), and we hypothesized that trauma patients with an abdominal SBS without CT imaging findings would not have a hollow viscus injury (HVI).

Methods: A prospective cohort of patients with SBS was compiled over one year.

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Article Synopsis
  • In 2016, over 600,000 cases of child abuse or neglect were reported, with nonaccidental trauma (NAT) particularly affecting infants and associated with higher mortality rates compared to accidental trauma (AT).
  • This study analyzed infant trauma cases from 2014-2016, comparing outcomes between NAT and AT victims using a comprehensive database and statistical methods.
  • Results showed a significantly higher mortality rate in NAT infants (41.6%) versus AT infants (13.9%), and specific factors like injury severity and traumatic brain injury were strongly linked to increased mortality risk.
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Background/purpose: Perioperative blood transfusion is common after pancreaticoduodenectomy (PD) and may predispose patients to infectious complications. The purpose of this study is to examine the association between perioperative blood transfusion and the development of post-surgical infection after PD.

Methods: Patients who underwent PD from 2014 to 2015 were identified in the NSQIP pancreas-specific database.

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Bile is composed of multiple macromolecules, including bile acids, free cholesterol, phospholipids, bilirubin, and inorganic ions that aid in digestion, nutrient absorption, and disposal of the insoluble products of heme catabolism. The synthesis and release of bile acids is tightly controlled and dependent on feedback mechanisms that regulate enterohepatic circulation. Alterations in bile composition, impaired gallbladder relaxation, and accelerated nucleation are the principal mechanisms leading to biliary stone formation.

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