Cutaneous Crohn disease presenting as "knife-edged" ulcers: a case report.

BACKGROUND: CCD presents as non-caseating granulomas within the skin at a site distant from the GI tract. CCD is a debilitating extraintestinal sequela of CD that can sometimes precede its GI manifestations. In the absence of GI symptoms, the histopathologic and clinical features of CCD can present as a variety of inflammatory skin conditions that can range from ruptured follicle-associated granulomas to cutaneous ulcerations. While a variety of therapeutic options for patients with CCD and concurrent luminal CD have been described in the literature, there is no standard treatment algorithm for the management of refractory CCD with limited or covert GI involvement. CASE REPORT: The authors discuss the case of a 33-year-old female who presented to the wound care clinic with multiple "knife-edged" cutaneous ulcerations involving the intertriginous spaces, found to be consistent with CCD. Her original cutaneous symptoms and diagnosis manifested with minimal GI involvement and responded to IVIG treatment. CONCLUSIONS: This case supports the inclusion of CCD in the differential diagnosis in patients with knife-edged granulomatous skin lesions in intertriginous locations. This clinical condition may present in the setting of no or limited GI symptoms. The management of CCD and a proposed treatment algorithm are also presented.

Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death.

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis, illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how the accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver damage.

Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice.

Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.

Dynamin-2 deficiency causes age- and sex-dependent neutropenia and myelodysplasia in mice.

The dynamins are a family of ubiquitously expressed GTPase proteins, best known for their role in membrane remodeling. Their contribution to hematopoiesis is incompletely recognized. Individuals with Charcot-Marie-Tooth disease with dynamin-2 (DNM2) mutations often develop neutropenia. We previously reported that dynamin (DNM) inhibition impairs SDF1a-mediated migration in megakaryocytes. Here, we report on conditionally Dnm2 deleted mice in hematopoietic tissues using the Vav-Cre murine strain. Homozygous Dnm2 deletion in blood tissues is embryonic lethal. Dnm2het male mice only developed a slightly decreased hemoglobin level. Dnm2het female mice developed leukopenia by 40 weeks of age and neutropenia by 65 weeks of age. Flow cytometry revealed decreased lineage-negative cells and granulocyte-monocyte progenitors in Dnm2het female mice. Immunohistochemical staining of bone marrow (BM) for mature neutrophils with Ly6G was decreased and myelodysplastic features were present in the BM of Dnm2het female mice. A linear distribution of Ly6G+ BM cells along blood vessels was observed in fewer Dnm2het mice than in controls, suggesting that the migration pattern in the marrow is altered. Marrow neutrophils treated with dynamin inhibitor, dynasore, showed increased cell surface CXCR4, suggesting that abnormal migration results in marrow neutrophil retention. Dnm2het female mice also developed splenomegaly secondary to germinal center hyperplasia at younger ages, suggesting perturbed immunity. In summary, female mice with BM Dnm2 haploinsufficiency developed neutropenia as they aged with decreased granulocyte progenitor production and migration defects. Our studies indicate a potential mechanism for the development of chronic idiopathic neutropenia, a disease that predominantly presents in middle-aged women.

Anal Adenocarcinoma Arising From a Fistula-in-Ano: A Case Report.

Crohn's disease (CD) is an inflammatory disease that can affect any portion of the gastrointestinal tract (GIT). Although it can present with a number of complications, perianal fistulae are among the most common consequences in patients with CD. In very rare cases, these patients can develop fistula-associated anal adenocarcinoma (FAAA). In this case report, we discuss a 72-year-old man with a long-term history of CD complicated by perianal fistulae, which failed medical and surgical management, ultimately presenting with acute anal pain in the outpatient setting. The physical examination revealed a seton traversing through a fistula surrounded by circumferential granulation tissue suspicious for malignancy. A biopsy of the tissue confirmed grade 3 mucinous-type infiltrating adenocarcinoma of the perianal skin. The patient was diagnosed with an anal verge malignancy associated with a fistula in the context of long-standing CD, and MRI staging demonstrated a T3N1 lesion with potential left inguinal node involvement. He completed neoadjuvant chemo-radiotherapy using capecitabine for five weeks with minimal tumor response, and subsequently, an abdominoperineal resection (APR) was performed with patient discharge on the fifth post-procedure day. Post-operative chemotherapy with oxaliplatin/leucovorin/fluorouracil was administered with minimal complications. Although rare, this report demonstrates the importance of consistent follow-up and mitigation of risk factors in patients with CD, along with the significance of prompt multimodal treatment in the event of developing FAAA.

Immunoglobulin G4 associated autoimmune cholangitis and pancreatitis following the administration of nivolumab: A case report.

BACKGROUND: Immune checkpoint inhibitors have significantly improved survivals for an increasing range of malignancies but at the cost of several immune-related adverse events, the management of which can be challenging due to its mimicry of other autoimmune related disorders such as immunoglobulin G4 (IgG4) related disease when the pancreaticobiliary system is affected. Nivolumab, an IgG4 monoclonal antibody, has been associated with cholangitis and pancreatitis, however its association with IgG4 related disease has not been reported to date. CASE SUMMARY: We present a case of immune-related pancreatitis and cholangiopathy in a patient who completed treatment with nivolumab for anal squamous cell carcinoma. Patients IgG4 levels was normal on presentation. She responded to steroids but due to concerns for malignant biliary stricture, she opted for surgery, the pathology of which suggested IgG4 related disease. CONCLUSION: We hypothesize this case of IgG4 related cholangitis and pancreatitis was likely triggered by nivolumab.

Plasmablastic Lymphoma Presenting With Rectosigmoid Perforation in a Human Immunodeficiency Virus-Positive Patient.

Plasmablastic lymphoma (PBL) is a rare variant of diffuse large B-cell lymphoma (DLBCL) associated with human immunodeficiency virus (HIV)-positive patients. It accounts for only 2% of all acquired immune deficiency syndrome (AIDS)-related lymphomas (ARLs). We present the case of a 45-year-old male who presented to the emergency department (ED) with a three-month history of abdominal pain, diarrhea, and unintentional 50-lb weight loss. On an earlier presentation to the ED three months prior, the patient was diagnosed with norovirus and Helicobacter pylori infection and received outpatient treatment without resolution of his symptoms. This prompted further investigation with a CT of the abdomen and pelvis with IV contrast that revealed severe sigmoid colitis with pneumoperitoneum and a pericolonic air-containing fluid collection, consistent with a contained perforation with abscess formation. He was admitted, resuscitated, and initially treated with antibiotics and parenteral nutrition. The patient underwent a laparoscopic converted to open anterior resection with end colostomy. Pathology revealed HIV-related PBL. He was subsequently treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy regimen and an autologous stem cell transplant. Despite its rare association with HIV, PBL should be considered a differential diagnosis for HIV-positive patients who present with gastrointestinal (GI) pathology, and additional investigations should be conducted if symptoms do not resolve despite appropriate medical management at the time.

Intraplacental Hepatic Heterotopia.

Background: Placental hepatic heterotopia is a benign lesion with unclear histogenesis hypothesized to be of hepatocytic differentiation of yolk sac elements. Of the 14 hepatic heterotopia cases previously reported, 12 cases occurred in preterm labor.Case report: A case of intraplacental hepatic heterotopia in a 27-year-old female with pre-term delivery at 31 + 5 weeks gestational age is described. Histopathological examination revealed a well-demarcated lesion with cohesive, monotonous cells and pale to clear cytoplasm. The differential diagnoses of this lesion included benign, primary and metastatic malignant entities. The lesional cells expressed HepPar-1, CAM 5.2, Glypican-3, and AFP, consistent with cells of hepatic origin.Conclusion: Intraplacental hepatic heterotopia is associated with premature labor. Distinguishing this lesion from maternal and fetal malignancies with similar histopathological presentation has important clinical implications in patient care.

Amagmatic hydrothermal systems on Mars from radiogenic heat.

Long-lived hydrothermal systems are prime targets for astrobiological exploration on Mars. Unlike magmatic or impact settings, radiogenic hydrothermal systems can survive for >100 million years because of the Ga half-lives of key radioactive elements (e.g., U, Th, and K), but remain unknown on Mars. Here, we use geochemistry, gravity, topography data, and numerical models to find potential radiogenic hydrothermal systems on Mars. We show that the Eridania region, which once contained a vast inland sea, possibly exceeding the combined volume of all other Martian surface water, could have readily hosted a radiogenic hydrothermal system. Thus, radiogenic hydrothermalism in Eridania could have sustained clement conditions for life far longer than most other habitable sites on Mars. Water radiolysis by radiogenic heat could have produced H2, a key electron donor for microbial life. Furthermore, hydrothermal circulation may help explain the region's high crustal magnetic field and gravity anomaly.

Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.

Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (regulatory T cells and myeloid-derived suppressor cells), to analyze intratumoral and draining lymphoid tissues. Tumors were stratified as highly or poorly immunogenic, with highly immunogenic tumors showing a significantly greater presence of T-cell costimulatory molecules and immune suppression in the tumor microenvironment. An absence of tumor-infiltrating cytotoxic T lymphocytes and mature dendritic cells was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine+/-dendritic cells vaccine immunotherapy were associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with the overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens.