Computational analysis followed by in vitro studies to explore cytokines (TNF-α, IL-6 and IL-1ß) inhibition potential of the new natural molecule polonilignan.

Targeting pro-inflammatory cytokines and their production is found to be of therapeutic benefit for the regulation of inflammation in various chronic autoimmune diseases. Our continued efforts to discover small molecular-weight pro-inflammatory cytokine inhibitors resulted in identifying a novel natural lignan molecule named polonilignan, isolated from the culture broth extract of an endophytic fungus Penicillium polonicum. An in silico study (molecular docking, ADME predictions, binding free energy calculation and molecular dynamics simulation) of the polonilignan over the pro-inflammatory cytokines proteins TNF-α, IL-6 and IL-1ß was performed using Schrodinger LLC software to understand the binding interactions, drug-like properties, and stability of the ligand-protein complex. Further, in-vitro testing of inhibition of TNF-α, IL-6 and IL-1ß by polonilignan was carried out using ELISA and RT-PCR on LPS-induced RAW 264.7 cell lines along with the testing of nitrite production effect (Griess assay) and cytotoxicity (MTT) analysis. Under the computational study, polonilignan revealed good docking scores, binding interactions, and stability under MDS and desirable in silico ADME results over the proteins TNF-α, IL-1ß and IL-6. Poloniligan showed significant inhibition of IL-1ß, IL-6 and TNF-α with IC50 values of 2.01 µM, 6.59 µM and 42.10 µM, respectively. Also, it reduced the translocation of the NF-κB subunit p65 to the nucleus (confocal microscopy). The mRNA expression levels of pro-inflammatory markers IL-1ß, TNF-α and IL-6 levels were lowered significantly (p < .001) by the compound, and the diminution was higher with IL-1ß. Further, the lignan was non-cytotoxic and effective in attenuating nitrite release (IC50 48.56 µM). Thus, polonilignan has been identified as a new pan-cytokine and NO inhibitor, it is recommended to optimise a method for the synthesis of this small molecular weight lignan and explore its pharmacokinetic characteristics, toxicity and therapeutic effect under various chronic inflammatory disease models.

EUS-Guided Cholecystoduodenostomy for a Poor Surgical Candidate With Chronic Octreotide-Associated Gallstones From Metastatic Neuroendocrine Tumor.

Chronic octreotide use has been associated with gallstone formation. Historically, cholecystectomy has been the defining treatment for those who have gallstone-related disease. For those who are poor surgical candidates, percutaneous and endoscopic approaches have been used. We describe the endoscopic management of a 74-year-old man with significant gallstone burden and associated sequelae because of chronic octreotide for metastatic neuroendocrine tumor through endoscopic ultrasound-guided cholecystoduodenostomy with gallstone extraction using lumen-apposing metal stents.

Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

BACKGROUND: Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab. METHODS: Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing. RESULTS: Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here. CONCLUSIONS: This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.

Declining Colectomy Rates for Nonmalignant Colorectal Polyps in a Large, Ethnically Diverse, Community-Based Population.

INTRODUCTION: Despite studies showing improved safety, efficacy, and cost-effectiveness of endoscopic resection for nonmalignant colorectal polyps, colectomy rates for nonmalignant colorectal polyps have been increasing in the United States and Europe. Given this alarming trend, we aimed to investigate whether colectomy rates for nonmalignant colorectal polyps are increasing or declining in a large, integrated, community-based healthcare system with access to advanced endoscopic resection procedures. METHODS: We identified all individuals aged 50-85 years who underwent a colonoscopy between 2008 and 2018 and were diagnosed with a nonmalignant colorectal polyp(s) at the Kaiser Permanente Northern California integrated healthcare system. Among these individuals, we identified those who underwent a colectomy for nonmalignant colorectal polyps within 12 months after the colonoscopy. We calculated annual colectomy rates for nonmalignant colorectal polyps and stratified rates by age, sex, and race and ethnicity. Changes in rates over time were tested by the Cochran-Armitage test for a linear trend. RESULTS: Among 229,730 patients who were diagnosed with nonmalignant colorectal polyps between 2008 and 2018, 1,611 patients underwent a colectomy. Colectomy rates for nonmalignant colorectal polyps decreased significantly from 125 per 10,000 patients with nonmalignant polyps in 2008 to 12 per 10,000 patients with nonmalignant polyps in 2018 (P < 0.001 for trend). When stratified by age, sex, and race and ethnicity, colectomy rates for nonmalignant colorectal polyps also significantly declined from 2008 to 2018. DISCUSSION: In a large, ethnically diverse, community-based population in the United States, we found that colectomy rates for nonmalignant colorectal polyps declined significantly over the past decade likely because of the establishment of advanced endoscopy centers, improved care coordination, and an organized colorectal cancer screening program.

Asymmetric spermatic cord vessel enhancement on CT: a sign of epididymitis or testicular neoplasm.

PURPOSE: To determine whether asymmetric spermatic cord vessel enhancement (ASE) on contrast-enhanced computed tomography (CECT) indicates scrotal pathology. METHODS: Sixty-one male patients with scrotal symptoms who underwent both scrotal ultrasound (US) and CECT within 24 h were identified through a radiology information system. Twenty-eight emergency department patients who underwent CECT only for unrelated symptoms were included for comparison. Two blinded radiologists independently reviewed each CECT scan for qualitative ASE. These data were compared with US diagnoses, when present. A third blinded radiologist reviewed each CECT scan for quantitative ASE by measuring Hounsfield unit (HU) density ratios. McNemar, Kappa, Student's t test, and ANOVA were used for analysis. RESULTS: Eighty-nine total patients included 28 with CECT only and 61 with CECT and US, of which 41 had abnormal US: 15 acute epididymitis and/or orchitis, 7 testicular neoplasms, 11 varicoceles, and 8 with other pathologies. Twenty patients with normal US and 28 patients with CECT only served as control groups. Identification of ASE agreed with US diagnosis of epididymitis (and/or orchitis) or testicular neoplasm (reader 1: κ = 0.79, reader 2: κ = 0.75) with average 95.5% sensitivity and 88.8% specificity, and no significant difference between readers (p = 0.58). For epididymitis (and/or orchitis) or testicular neoplasm patients, the average ratio of spermatic cord HU density (ipsilateral:contralateral) was significantly different from other patients (4.01 vs. 1.26, p = 0.0025). CONCLUSION: ASE on CECT shows stronger correlation with epididymitis (and/or orchitis) and testicular neoplasm compared with other scrotal pathologies. If discovered on CECT, this should prompt further clinical and/or imaging workup.

Primary cardiac angiosarcoma: A diagnostic challenge in a young man with recurrent pericardial effusions.

Cardiac angiosarcomas are rare, rapidly progressive tumours that often present as diagnostic dilemmas resulting in delayed diagnosis. They should be considered in patients with recurrent pericardial effusions.A 33-year-old man presented for evaluation of a recurrent pericardial effusion. Infectious and rheumatological workups were negative. Pericardial fluid cytology and pericardial biopsy were unremarkable. Imaging, including echocardiogram and magnetic resonance imaging, were nondiagnostic.While awaiting surgical intervention, the patient developed respiratory failure requiring urgent intubation. Intraoperatively, he experienced significant hemorrhage from the myocardium. Hemostasis could not be achieved and the patient expired. Pathology reports revealed metastatic angiosarcoma.The present case illustrates a rare case of primary cardiac angiosarcoma posing a diagnostic dilemma in a young man. The authors present the challenges in diagnosis, and review the most current diagnostic and therapeutic strategies in the care of patients with this condition.

Dynamic Cellular Adhesion Mediated by Copolymeric Nanofilm Substrates.

Amphiphilic block copolymers are finding increased potential in biological and medical research due to their innate alternating hydrophilic and hydrophilic blocks/segments which can be used to package therapeutics, or coat a broad array of biological interfaces. Some studies are already directed towards utilizing these copolymers' ability to form micelles or vesicles to develop novel methods of drug delivery to prevent inflammation or pro-cancer activity. Our study, however, aims to investigate the more fundamental cell-block copolymer interaction for use in protective nanofilms to prevent bio-fouling of non-tissue based implantable devices. Block copolymers could potentially fill the demand for biologically inert, highly functionalizable biomaterials desirable for this type of application. Two such polymers used in our study include PMOXA-PDMS-PMOXA triblock copolymer and PEO/PMMA diblock copolymer. Each block copolymer possesses hydrophilic and hydrophobic blocks that enable it to mimic the cell lipid membrane. So far we have shown that triblock copolymer is capable of inhibiting the accumulation of murine macrophages onto glass substrates. Preliminary evidence has suggested that the triblock copolymer has anti-adsorptive as well as non-inflammatory capabilities during short incubation periods (7 days) in vitro. While the diblock copolymer displays minimal anti-adsorptive activities, nanofilms comprised of a mixture of the two copolymers were able to significantly reduce macrophage accumulation onto glass substrates. The disparate behavior seen by macrophages on the different materials may be due to specific inherent properties such as preference for hydrophobic vs. hydrophilic surfaces and/or rough vs. smooth nano-textures. Furthermore, the specific end groups of the two polymers may exhibit varying capacities to resisting non-specific protein adsorption. Continued investigation outlining the physical and chemical properties desirable for an anti-adsorptive nano-film coating will serve as a basis upon which to design durable implant-tissue interfaces that can react to various external stimuli.