The diagnosis of invasive adenocarcinoma of the gallbladder can sometimes be challenging. The presence of true desmoplastic reaction facilitates the diagnosis of invasion. However, desmoplasia-like ...changes can be observed in benign gallbladder conditions, and recognition of desmoplasia may be challenging based on morphology. In this study, we tested the expression pattern of microfibril-associated protein 5 (MFAP5), a promising immunohistochemical marker for desmoplasia, in benign gallbladders with desmoplasia-like reaction and gallbladders with invasive adenocarcinoma. We also evaluated the diagnostic utility of MFAP5 in challenging cases with an interobserver agreement study. The results showed that all benign cases retained intact/positive MFAP5 staining pattern in periglandular connective tissue, whereas 79.3% (23 out of 29) of cases of adenocarcinomas demonstrated diffuse and complete loss of MFAP5 staining in the tumor stroma. Interobserver agreement was improved by 2.66 times when images of MFAP5 immunohistochemistry were provided. In conclusion, MFAP5 expression is downregulated in the desmoplastic stroma of gallbladder adenocarcinoma and may provide a useful diagnostic marker in difficult cases.
Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement ...in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.
Both myofibroblastic hepatic stellate cells (HSC) and hepatic epithelial progenitors accumulate in damaged livers. In some injured organs, the ability to distinguish between fibroblastic and ...epithelial cells is sometimes difficult because cells undergo epithelial-mesenchymal transitions (EMT). During EMT, cells coexpress epithelial and mesenchymal cell markers. To determine whether EMT occurs in adult liver cells, we analyzed the expression profile of primary HSC, two HSC lines, and hepatic epithelial progenitors. As expected, all HSC expressed HSC markers. Surprisingly, these markers were also expressed by epithelial progenitors. In addition, one HSC line expressed typical epithelial progenitor mRNAs, and these epithelial markers were inducible in the second HSC line. In normal and damaged livers, small ductular-type cells stained positive for an HSC marker. In conclusion, HSC and hepatic epithelial progenitors both coexpress epithelial and mesenchymal markers, providing evidence that EMT occurs in adult liver cells.
INTRODUCTION: We designed a race-conscious study to assess the presence of Helicobacter pylori v irulence factor cagA in a retrospective cohort of patients with active H. pylori infection. METHODS: ...We compared cagA status by race in gastric tissue samples from 473 patients diagnosed with active H. pylori infection from 2015 to 2019. RESULTS: H. pylori + Black patients were 2 times more likely to be cagA + than H. pylori + White patients (82% vs 36%, P < .0001). DISCUSSION: Presence of cagA is common among endoscopy patients with active H. pylori infection; appropriate testing and treatment of H. pylori can both reduce gastric cancer risk and address health disparities.
We designed a race-conscious study to assess the presence of Helicobacter pylori (Hp) virulence factor cagA in a retrospective cohort of patients with active Hp infection.
We compared cagA status by ...race in gastric tissue samples from 473 patients diagnosed with active Hp infection from 2015-2019.
Hp+ Black patients were two times more likely to be cagA+ than Hp+ White patients (82% vs. 36%, P < .0001).
Presence of cagA is common among endoscopy patients with active Hp infection; appropriate testing and treatment of Hp can both reduce gastric cancer risk and address health disparities.
In bile duct-ligated (BDL) rodents, as in humans with chronic cholangiopathies, biliary obstruction triggers proliferation of bile ductular cells that are surrounded by fibrosis produced by adjacent ...myofibroblastic cells in the hepatic mesenchyme. The proximity of the myofibroblasts and cholangiocytes suggests that mesenchymal–epithelial crosstalk promotes the fibroproliferative response to cholestatic liver injury. Studying BDL mice, we found that bile duct obstruction induces activity of the Hedgehog (Hh) pathway, a system that regulates the viability and differentiation of various progenitors during embryogenesis. After BDL, many bile ductular cells and fibroblastic-appearing cells in the portal stroma express Hh ligands, receptor and/or target genes. Transwell cocultures of an immature cholangiocyte line that expresses the Hh receptor, Patched (Ptc), with liver myofibroblastic cells demonstrated that both cell types produced Hh ligands that enhanced each other's viability and proliferation. Further support for the concept that Hh signaling modulates the response to BDL was generated by studying PtcLacZ mice, which have an impaired ability to constrain Hh signaling due to a heterozygous deficiency of Ptc. After BDL, PtcLacZ mice upregulated fibrosis gene expression earlier than wild-type controls and manifested an unusually intense ductular reaction, more expanded fibrotic portal areas, and a greater number of lobular necrotic foci. Our findings reveal that adult livers resurrect developmental signaling systems, such as the Hh pathway, to guide remodeling of the biliary epithelia and stroma after cholestatic injury.
Defects in renal proximal tubule transport manifest in a number of human diseases. Although variable in clinical presentation, disorders such as Hartnup disease, Dent's disease, and Fanconi syndrome ...are characterized by wasting of solutes commonly recovered by the proximal tubule. One common feature of these disorders is aminoaciduria. There are distinct classes of amino acid transporters located in the apical and basal membranes of the proximal tubules that reabsorb >95% of filtered amino acids, yet few details are known about their regulation. We present our physiological characterization of a mouse line with targeted deletion of the gene collectrin that is highly expressed in the kidney. Collectrin-deficient mice display a reduced urinary concentrating capacity due to enhanced solute clearance resulting from profound aminoaciduria. The aminoaciduria is generalized, characterized by loss of nearly every amino acid, and results in marked crystalluria. Furthermore, in the kidney, collectrin-deficient mice have decreased plasma membrane populations of amino acid transporter subtypes B(0)AT1, rBAT, and b(0,+)AT, as well as altered cellular distribution of EAAC1. Our data suggest that collectrin is a novel mediator of renal amino acid transport and may provide further insight into the pathogenesis of a number of human disease correlates.
Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its ...downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.
Aims
Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether ...histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC).
Methods and results
We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment‐naïve high‐grade columnar dysplasia (HGD) or EAC, and 23 non‐EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin‐stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non‐EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour.
Conclusions
We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non‐EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC.
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