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Abstract Background The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient‐derived tumours, and had promising activity in a phase I study. Methods Here, we investigated the impact of selinexor–gemcitabine–nab‐paclitaxel (Sel‐GemPac) combination on LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). Results Sel‐GemPac synergistically inhibited the growth of the KPC tumour‐derived cell line. The Sel‐GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub‐maximum tolerated dose (sub‐MTD) , Sel‐GemPac enhanced the survival of treated mice compared to controls (p

As a chronic inflammatory condition characterized by widespread granulomatous disease (Mahmood et al., 2021), sarcoidosis can precede, present concurrently or follow malignancy (Kim et al., 2014; Murthi et al., 2020). Sarcoidosis has also been shown to be related to oxaliplatin-based chemotherapy, which can be used in the treatment of colorectal carcinomas (Mahmood et al., 2021; Karaosmanoglu et al., 2020; Gallagher et al., 2009; Aedma et al., 2020; Cassidy and Misset, 2002; Choi et al., 2014). The exact mechanism by which sarcoidosis can present in individuals with malignancy is unknown but may be related to both a cellular immune response to tumor-associated antigens and lack of resistance to carcinogenic stimuli (Gallagher et al., 2009). Liver lesions secondary to benign processes such as sarcoidosis can obscure the diagnosis of metastatic disease (Choi et al., 2014; Hammen et al., 2015; del Arco and Aceñero, 2016). Diagnostic differentiation of sarcoid liver nodules from neoplasia is critical in the workup of colorectal cancer as it can significantly alter the primary treatment of the disease. Here, we present a case of rectal adenocarcinoma with pre-operative biopsies of liver lesions showing granulomatous disease and subsequent intraoperative liver biopsies revealing metastatic adenocarcinoma. This case highlights the importance of obtaining an accurate preoperative diagnosis in order to avoid unnecessary or incorrect treatment.

Abstract Treponema pallidum subsp. pallidum, the causative agent of syphilis, is a highly invasive spirochete pathogen that uses the vasculature to disseminate throughout the body. Identification of bacterial factors promoting dissemination is crucial for syphilis vaccine development. An important step in dissemination is bacterial adhesion to blood vessel surfaces, a process mediated by bacterial proteins that can withstand forces imposed on adhesive bonds by blood flow (vascular adhesins). The study of T. pallidum vascular adhesins is hindered by the uncultivable nature of this pathogen. We overcame these limitations by expressing T. pallidum adhesin Tp0751 (pallilysin) in an adhesion-attenuated strain of the cultivable spirochete Borrelia burgdorferi. Under fluid shear stress representative of conditions in postcapillary venules, Tp0751 restored bacterial-vascular interactions to levels similar to those observed for infectious B. burgdorferi and a gain-of-function strain expressing B. burgdorferi vascular adhesin BBK32. The strength and stability of Tp0751- and BBK32-dependent endothelial interactions under physiological shear stress were similar, although the mechanisms stabilizing these interactions were distinct. Tp0751 expression also permitted bacteria to interact with postcapillary venules in live mice as effectively as BBK32-expressing strains. These results demonstrate that Tp0751 can function as a vascular adhesin.

Systemic dissemination of microbes is critical for progression of many infectious diseases and is associated with most mortality due to bacterial infection. The physical mechanisms mediating a key dissemination step, bacterial association with vascular endothelia in blood vessels, remain unknown. Here, we show that endothelial interactions of the Lyme disease spirochete Borrelia burgdorferi under physiological shear stress mechanistically resemble selectin-dependent leukocyte rolling. Specifically, these interactions are mediated by transfer of mechanical load along a series of adhesion complexes and are stabilized by tethers and catch bond properties of the bacterial adhesin BBK32. Furthermore, we found that the forces imposed on adhesive bonds under flow may be small enough to permit active migration driven by bacterial flagellar motors. These findings provide insight into the biomechanics of bacterial-vascular interactions and demonstrate that disseminating bacteria and circulating host immune cells share widely conserved mechanisms for interacting with endothelia under physiological shear stress.

The Jagn1 protein was indentified in a SILAC proteomic screen of proteins that are increased in insulinoma cells expressing a folding-deficient proinsulin. Jagn1 mRNA was detected in primary rodent islets and in insulinoma cell lines and the levels were increased in response to ER stress. The function of Jagn1 was assessed in insulinoma cells by both knock-down and overexpression approaches. Knock-down of Jagn1 caused an increase in glucose-stimulated insulin secretion resulting from an increase in proinsulin biosynthesis. In contrast, overexpression of Jagn1 in insulinoma cells resulted in reduced cellular proinsulin and insulin levels. Our results identify a novel role for Jagn1 in regulating proinsulin biosynthesis in pancreatic β-cells. Under ER stress conditions Jagn1 is induced which might contribute to reducing proinsulin biosynthesis, in part by helping to relieve the protein folding load in the ER in an effort to restore ER homeostasis.

Three distinct gastric carcinoid (GC) tumour types have been described based on differing biological behaviour and prognoses. Type I GC tumours account for the vast majority (70%–80%), are associated with chronic atrophic gastritis and have a low metastatic potential. Type II carcinoid tumours are the least common (5%–10%), are related to Zollinger-Ellison syndrome and occur in relation to multiple neoplasia type I. Sporadic type III tumours (15%–25%) are the most aggressive type, are unrelated to gastrin over secretion and carry the worst prognosis. In this case report, we present a patient with longstanding gastroesophageal reflux disease (GERD) who presented with epigastric abdominal pain and tarry stools and was found to have a large gastric polyp on endoscopy. Despite current literature recommending surgical resection for larger GC tumours, endoscopic resection was successfully used to excise the tumour with pathology demonstrating complete resection with negative margins. [ABSTRACT FROM AUTHOR]