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.
A malignant peripheral nerve sheath tumor (MPNST) is an aggressive tumor that can arise from the malignant transformation of benign neurofibromas in patients with neurofibromatosis type 1 (NF1). ...MPNST occurs in 2% of patients with NF1, contributing to significant mortality in these patients. Here, we report the case of a 67-year-old female with a known history of neurofibromatosis type 1 who was referred to general surgery after the discovery of a large left-sided adrenal mass on CT imaging five months earlier. Lab workup revealed elevated urine catecholamines, concerning pheochromocytoma. As pheochromocytoma is also common in those with NF-1, appropriate medical management followed by surgical resection was performed. The final pathology report revealed an MPNST.
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.
Display omitted
•Biomechanical characterization of bacterial-vascular interactions•Identified catch bond-mediated bacterial vascular adhesion mechanism•Conserved vascular interaction strategies in bacteria and host cells
Bacteria overcome forces generated by blood flow in order to adhere to vascular surfaces during spread of blood-borne infections. The biomechanics of this process are not understood. Ebady et al. show that bacteria exploit force generated by blood flow to strengthen their interactions with endothelia using mechanisms that are remarkably similar to the mechanisms supporting leukocyte rolling on vascular surfaces.
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.
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.
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 < .05). Immunohistochemical analysis of residual KPC tumours showed re‐organisation of tumour stromal architecture, suppression of proliferation and nuclear retention of tumour suppressors, such as Forkhead Box O3a (FOXO3a). DSP revealed the downregulation of tumour promoting genes such as chitinase‐like protein 3 (CHIL3/CHI3L3/YM1) and multiple pathways including phosphatidylinositol 3'‐kinase‐Akt (PI3K‐AKT) signalling. The snRNAseq demonstrated a significant loss of cellular clusters in the Sel‐GemPac‐treated mice tumours including the CD44+ stem cell population.
Conclusion
Taken together, these results demonstrate that the Sel‐GemPac treatment caused broad perturbation of PDAC‐supporting signalling networks in the KPC mouse model.
Highlights
The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac).
Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse derived cell line and enhanced the survival of mice.
Digital spatial profiling shows that Sel‐GemPac causes broad perturbation of PDAC‐supporting signalling in the KPC model.
The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nab‐paclitaxel (GemPac). Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse derived cell lines and enhanced the survival of mice. Digital spatial profiling shows that Sel‐GemPac causes broad perturbation of PDAC‐supporting signalling in the KPC model.
Endoplasmic reticulum (ER) stress is implicated in pancreatic β-cell dysfunction and death resulting in type 2 diabetes. Activating transcription factor 6 (ATF6) is an essential component of the ...Unfolded Protein Response (UPR) and consists of two isoforms, ATF6α and ATF6β. Here we investigated the role of ATF6β. ATF6β mRNA was detected in pancreatic β-cell lines and rodent and human islets. We also detected ATF6β protein and production of the active form (ATF6βp60) in response to ER stress. Knock-down of ATF6β in INS-1 832/13 insulinoma cells did not affect mRNA induction of several major UPR genes in response to ER stress, suggesting ATF6β is not essential for the basic UPR. Expressing active ATF6βp60 or ATF6αp50 followed by microarray analysis showed that they regulate similar UPR genes, although some genes such as Wfs1 are ATF6β-specific. ATF6β, but not ATF6α, is able to bind the Wfs1 promoter and induce Wfs1 gene and protein expression. Knock-down of ATF6β increased the susceptibility of β-cells to ER stress-induced apoptosis, while overexpression of active ATF6βp60 reduced apoptosis. Thus, ATF6β is not essential for induction of most UPR genes, but is required to maintain cell survival in β-cells undergoing chronic ER stress, which in part relates to its ability to induce Wfs1, a pro-survival gene.
ATF6β is an ER stress response protein expressed in pancreatic β-cells and islets.ATF6β is not required for induction of major Unfolded Protein Response genes.ATF6β regulates the Wfs1 gene and ATF6β depletion sensitizes cells to apoptosis.ATF6β has a prosurvival role in pancreatic β-cells.
Introduction
Minimally invasive or open Graham Patch repair remains the gold standard approach for management of perforated peptic ulcers (PPU). Herein, we report outcomes of laparoscopic technique ...and compare it with open approach at a community hospital.
Methods
Retrospective observational study conducted comparing laparoscopic modified Cellan-Jones repair (mCJR) versus the standard open repair of PPU. Patients aged 18–90 years during 2016–2021 were offered either a minimally invasive or open approach depending on surgeon laparoscopic capability, and were compared in terms of demographics, co-morbidities, intra-operative details, and short-term outcomes.
Results
A total of 49 patients were included (46.9% males, mean age 52.9 years, mean BMI 25.0, ASA ≥ III 75.5%, 75.5% smokers, 26.5% current NSAIDs use, and 71.4% alcohol drinkers). Duodenum was the most common perforation site (57.1%), and majority of ulcers were 1–2 cm (72.9%). Laparoscopic approach was performed in 16 consecutive patients (32.7%) by a single surgeon, with no conversions. Preoperative characteristics were similar for both groups. Compared to open approach, laparoscopic group were taken to operation immediately (< 4 h) (87.5% vs. 15.2%,
p
< 0.001), had lower estimated blood loss (11.8 ml vs. 73.8 ml,
p
= 0.063), and longer operative time (117.1 min vs. 85.6 min,
p
= 0.010). Postoperatively, nasogastric tube was removed earlier in laparoscopic group (POD1-2, 87.5% vs. 24.2%,
p
= 0.001), with earlier resumption of diet (POD1-2, 62.6% vs. 9.1%,
p
= 0.002), less narcotic usage (< 3 days, 58.3% vs. 6.1%,
p
< 0.001), earlier return of bowel function (POD1-2, 43.8% vs. 9.1%,
p
= 0.003) and shorter length of stay (LOS) (3.7 days vs. 16.1 days,
p
< 0.001). Both in-house mortality and morbidity rates were lower in the laparoscopic group, but not statistically significant (0% vs. 6.1%,
p
= 0.347) and (12.5% vs. 39.4%,
p
= 0.500), respectively.
Conclusion
Laparoscopic mCJR is a feasible method for repair of PPU, and it is associated with shorter LOS, and less narcotics usage in comparison to the open repair approach.
Graphical abstract
Activating transcription factor 6 (ATF6) is one of three principle endoplasmic reticulum (ER) stress response proteins and becomes activated when ER homeostasis is perturbed. ATF6 functions to ...increase ER capacity by stimulating transcription of ER-resident chaperone genes such as GRP78. Using an antibody that recognizes active ATF6α-p50, we found that active ATF6α was detected in insulinoma cells and rodent islets even under basal conditions and the levels were further increased by ER stress. To examine the function of ATF6α-p50, we depleted endogenous ATF6α-p50 levels using small interfering RNA in insulinoma cells. Knockdown of endogenous ATF6α-p50 levels by ∼60% resulted in a reduction in the steady-state levels of GRP78 mRNA and protein levels in nonstressed cells. Furthermore, ATF6α knockdown resulted in an apoptotic phenotype. We hypothesized that removal of the ATF6α branch of the unfolded protein response (UPR) would result in ER stress. However, neither the PKR-like endoplasmic reticulum kinase (PERK), nor the inositol requiring enzyme 1 (IRE1) pathways of the UPR were significantly activated in ATF6α knockdown cells, although these cells were more sensitive to ER stress-inducing compounds. Interestingly, phosphorylation of JNK, p38, and c-Jun were elevated in ATF6α knockdown cells and inhibition of JNK or p38 kinases prevented apoptosis. These results suggest that ATF6α may have a role in maintaining β-cell survival even in the absence of ER stress.
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.
PDF
