Von G. Samedi

Blockade of MK2 is protective in inflammation-associated colorectal cancer development.

Chronic inflammation is a risk factor for colorectal cancer. The MAPK‐activated protein kinase 2 (MK2) pathway controls multiple cellular processes including p38‐dependent inflammation. This is the first study to investigate the role of MK2 in development of colitis‐associated colon cancer (CAC). Herein, we demonstrate that MK2−/− mice are highly resistant to neoplasm development when exposed to AOM/DSS, while wild type (WT) C57BL/6 develop multiple neoplasms with the same treatment. MK2‐specific cytokines IL‐1, IL‐6 and TNF‐α were substantially decreased in AOM/DSS treated MK2−/− mouse colon tissues compared with WT mice, which coincided with a marked decrease in macrophage influx. Restoring MK2‐competent macrophages by injecting WT bone marrow derived macrophages into MK2−/− mice led to partial restoration of inflammatory cytokine production with AOM/DSS treatment; however, macrophages were not sufficient to induce neoplasm development. These results indicate that MK2 functions as an inflammatory regulator to promote colonic neoplasm development and may be a potential target for CAC.

Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts. We then isolated the extracellular matrix from a subset of these hearts and performed a proteomic analysis on the isolated matrices. We found that the levels of 26 structural proteins were altered in the DCM-failing isolated cardiac extracellular matrix compared to nonfailing isolated cardiac extracellular matrix. Overall, most of the extracellular matrix proteins showed reduced levels in the DCM-failing hearts, while all of the contractile proteins showed increased levels. There was a mixture of increased and decreased levels of cytoskeletal and nuclear transport proteins. Using immunoprobing, we verified that collagen IV (α2 and α6 isoforms), zyxin, and myomesin protein levels were reduced in the DCM-failing hearts. We expect that these data will add to the understanding of the pathology associated with heart failure with DCM.

Pancreatic neuroendocrine tumor in a patient with a TSC1 variant: case report and review of the literature

The majority of pancreatic neuroendocrine tumors (PNETs) are sporadic while 10–15% are attributable to one of several familial cancer syndromes. Hereditary forms are more commonly associated with Multiple Endocrine Neoplasia Type I and von Hippel Lindau Syndrome. However, patients with Tuberous sclerosis complex also have an increased incidence of PNETs. More often this has been reported in patients with TSC2 variants. In this case report, we summarize the literature regarding PNETs associated with Tuberous sclerosis complex, as well as present a case of a patient with a TSC1 variant and a PNET. This case highlights the association of TSC1 gene variants with these tumors and emphasizes the importance of considering such diagnoses in this patient population.

Chronic Abdominal Pain, Ascites, and Diarrhea: Seeing Red

A 38-year-old male patient, otherwise healthy except for a five year medical history of diet-controlled diabetes mellitus, was initially evaluated in the emergency department with complaints of abdominal pain and diarrhea of 2 months duration. The pain, described as sharp, moderately severe, and intermittent, was located in the right upper and lower quadrants, did not radiate, and lasted only for a few minutes at a time. Multiple episodes of the pain occurred throughout the day, with no obvious precipitating or relieving factors. He also described having had, over the same period, watery diarrhea, 8 to 10 times a day, with no blood or mucus in the stool. The patient denied having had any nausea, vomiting, fever, chills, night sweats, or weight loss. Helicobacter pylori infection, diagnosed by serum antibodies, was treated with pantoprazole, clarithromycin, and amoxicillin for 2 weeks without changes in the abdominal pain pattern or character. Physical examination revealed an overweight patient with normal vital signs. The abdomen was distended with dullness to percussion noted in the flanks with periumbilical resonance and a positively transmitted fluid wave. Bowel sounds were present; there was no tenderness to palpation or overlying skin changes. Jugular venous pressure was not elevated, and ankle edema was absent. Stigmata of chronic liver disease were not apparent. There was no enlargement of the liver, spleen, or regional lymph glands and no additional palpable masses.

Expression of Programmed Death-Ligand 1 by Human Colonic CD90+ Stromal Cells Differs Between Ulcerative Colitis and Crohn’s Disease and Determines Their Capacity to Suppress Th1 Cells

Background and Aims The role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses. Methods Tissues and cells derived from Crohn’s disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture. Results A significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses. Conclusion We present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.

Body Cavity Fluids

Various diseases, neoplastic and non-neoplastic, tend to cause fluid build-up in the cavities between surfaces of body walls (parietal) and of organs (visceral). These body cavities include the thorax, the pericardium, the abdomen, and the tunica vaginalis testis in men. Regardless of the anatomical cavities, the surfaces are lined by serous membranes that are lined by a single layer of cytologically identical, thin and flat mesothelial cells which, when irritated, become plump, cuboidal and hyperplastic.

Female Reproductive System Cytology

This chapter describes mimics (benign lesions that can be mistaken for dysplasia or carcinoma) and confounders (malignant lesions that can be mistaken for benign entities) occurring in a Pap-stained monolayer preparation of the cervix/vagina.

Urinary Tract Cytology

The urinary tract is commonly subjected to stressors that can result in atypical and suspicious findings in a voided urine specimen (see Table 8.1). The most common stressors include indwelling catheters, various toxins, ischemic changes, calculi, bladder and kidney infections, immune mediated cystitis, and inflammatory reactions to radiation therapy, immunotherapy and chemotherapy.

Respiratory Tract Cytology

The respiratory tract is traditionally divided into upper airway (sinonasal space to larynx) and lower airway (trachea to lungs). In this chapter, the focus will be on the lower airway which accounts for the majority of specimens from the respiratory tract that cytopathologists are expected to review. These specimens have increased in number, partly due to the tremendous advances in thoracic imaging which have allowed radiologists to detect an ever-increasing number of thoracic lesions that need cytological evaluation. Often the differential diagnosis includes non-neoplastic conditions (e.g., infections, iatrogenic) vs truly neoplastic entities. The clinical and radiologic findings are however rarely conclusive for the treating physicians. Thus, histological and/or cytological diagnosis of these lesions are required for selecting the appropriate therapeutic management.

Salivary Gland Cytology

The human body harbors both major and minor salivary glands. The major ones are paired and consist of the parotid, the submandibular and the sublingual glands. The minor salivary glands are numerous and are estimated to be from 500 to 1000. Approximately 40 subtypes of neoplasms (benign and malignant) have been described. Fine needle aspiration is considered to be one of the best modalities for initial evaluation of these neoplasms. However, assessing these specimens can be a challenge for the cytopathologist because of significant cytomorphologic diversity and overlap between benign and malignant salivary gland tumors. Judicious attempt is always made to categorize neoplastic entities to best guide appropriate therapeutic interventions. However, one has to also be mindful of the non-neoplastic conditions that share many cytomorphological features with neoplasms. Ancillary studies are often of limited use, but certain cytomorphological features when evaluated in the context of the clinical and radiographic impression may help prevent erroneous interpretation.