Geranylgeranyl diphosphate synthase inhibition impairs osteoclast differentiation, morphology, and resorptive activity.

Nitrogen bisphosphonates, such as zoledronic acid, target the enzyme farnesyl diphosphate synthase (FDPS) in the isoprenoid biosynthetic pathway (IBP), and are the frontline treatment for osteolytic bone diseases. A strong affinity of these agents for bone limits their distribution out of the skeleton. Geranylgeranyl diphosphate synthase (GGDPS) is directly downstream to FDPS in the IBP and novel GGDPS inhibitors such as RAM2061 have been shown to have key drug-like features including prolonged half-life, metabolic stability, and systemic distribution.

MUC16 Retention after Neoadjuvant Chemotherapy in Pancreatic Ductal Adenocarcinoma.

: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Currently, surgical resection is the only potentially curative treatment. Unfortunately, less than 20% of PDAC patients are eligible for surgical resection at diagnosis.

Nasopharyngeal Carcinoma: Connecting Antemortem and Postmortem Findings to Highlight a Rare Case of EBV and HPV Negativity.

Nasopharyngeal carcinoma is an endemic entity with a strong association with Epstein-Barr virus and a new recognition of human papilloma virus-mediated effects in nonendemic areas. Here, we discuss a nasopharyngeal carcinoma suspected as based on imaging results with metastasis to the lymph nodes, lung, spleen, bone, and liver. Gross and microscopic findings from the autopsy were clinicopathologically correlated with antemortem clinical studies and investigations.

Pathology teaching in different undergraduate medical curricula within and outside the United States: a pilot study.

Pathology education is taught using different curricula in the United States (USA) and abroad. We evaluate and compare the hours spent in different forms of pathology teaching such as lectures, team-based learning (TBL), problem-based learning (PBL), and other methods taught in general and systemic pathology amongst different medical schools within the USA and outside the USA. The total number of lecture hours taught in general and systemic pathology combined was greater in outside schools than within the USA (141 h vs 97.

Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis.

Dysregulation of both the gut barrier and microbiota (dysbiosis) promotes susceptibility to and severity of Inflammatory Bowel Diseases (IBD). Leaky gut and dysbiosis often coexist; however, potential interdependence and molecular regulation are not well understood. Robust expression of claudin-3 (CLDN3) characterizes the gut epithelium, and studies have demonstrated a positive association between CLDN3 expression and gut barrier maturity and integrity, including in response to probiotics.

Repeated Social Defeat Stress Induces an Inflammatory Gut Milieu by Altering the Mucosal Barrier Integrity and Gut Microbiota Homeostasis.

Background: Posttraumatic stress disorder (PTSD) is a mental health condition triggered by exposure to traumatic events in an individual's life. Patients with PTSD are also at a higher risk for comorbidities. However, it is not well understood how PTSD affects human health and/or promotes the risk for comorbidities.

Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing.

Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC.

Combination Therapy with Gallium Protoporphyrin and Gallium Nitrate Exhibits Enhanced Antimicrobial Activity and against Methicillin-Resistant .

There is a major need for the development of new therapeutics to combat antibiotic-resistant . Recently, gallium (Ga)-based complexes have shown promising antimicrobial effects against various bacteria, including multidrug-resistant organisms, by targeting multiple heme/iron-dependent metabolic pathways. Among these, Ga protoporphyrin (GaPP) inhibits bacterial growth by targeting heme pathways, including aerobic respiration.

P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium.

Impaired autophagy promotes Inflammatory Bowel Disease (IBD). Claudin-2 is upregulated in IBD however its role in the pathobiology remains uncertain due to its complex regulation, including by autophagy. Irrespective, claudin-2 expression protects mice from DSS colitis.

Anti-miR-96 and Hh pathway inhibitor MDB5 synergistically ameliorate alcohol-associated liver injury in mice.

Alcohol-associated liver disease (ALD) and its complications are significant health problems worldwide. Several pathways in ALD are influenced by alcohol that drives inflammation, fatty acid metabolism, and fibrosis. Although miR-96 has become a key regulator in several liver diseases, its function in ALD remains unclear.

Elevated PAF1-RAD52 axis confers chemoresistance to human cancers.

Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing.

MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis.

Background: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood.

Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.

MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with Kras and Trp53 mutations remains unknown. Deletion of Muc16 with activating mutations Kras and Trp53 in mice significantly decreased progression and prolonged overall survival in Kras; Trp53; Pdx-1-Cre; Muc16 (KPCM) and Kras; Pdx-1-Cre; Muc16 (KCM), as compared to Kras; Trp53; Pdx-1-Cre (KPC) and Kras; Pdx-1-Cre (KC) mice, respectively.

Combining Gallium Protoporphyrin and Gallium Nitrate Enhances and Efficacy against : Role of Inhibition of Bacterial Antioxidant Enzymes and Resultant Increase in Cytotoxic Reactive Oxygen Species.

is a highly antibiotic-resistant opportunistic pathogenic bacteria that is responsible for thousands of deaths each year. Infections with disproportionately impact individuals with compromised immune systems as well as cystic fibrosis patients, where lung infection is a leading cause of morbidity and mortality. In previous work, we showed that a combination of gallium (Ga) nitrate and Ga protoporphyrin worked well in several bacterial infection models but its mechanism of action (MOA) is unknown.

Upregulation of Nox4 induces a pro-survival Nrf2 response in cancer-associated fibroblasts that promotes tumorigenesis and metastasis, in part via Birc5 induction.

Background: A pro-oxidant enzyme, NADPH oxidase 4 (Nox4) has been reported to be a critical downstream effector of TGFβ-induced myofibroblast transformation during fibrosis. While there are a small number of studies suggesting an oncogenic role of Nox4 derived from activated fibroblasts, direct evidence linking this pro-oxidant to the tumor-supporting CAF phenotype and the mechanisms involved are lacking, particularly in breast cancer.

Methods: We targeted Nox4 in breast patient-derived CAFs via siRNA-mediated knockdown or administration of a pharmaceutical inhibitor (GKT137831).

Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice.

Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear.

Design and Evaluation of a Novel Health Security, Infectious Diseases, Health Systems Science, and Service Learning Course During the COVID-19 Pandemic.

During the COVID-19 pandemic, academic health centers suspended clinical clerkships for students. A need emerged for innovative virtual curricula to continue fostering professional competencies. In March 2020, a multidisciplinary team from the University of Nebraska Medical Center had 2 weeks to create a course on the impact of infectious diseases that addressed the COVID-19 pandemic in real time for upper-level medical and physician assistant students.

Preclinical Evaluation of a Humanized, Near-Infrared Fluorescent Antibody for Fluorescence-Guided Surgery of MUC16-Expressing Pancreatic Cancer.

Surgery remains the only potentially curative treatment option for pancreatic cancer, but resections are made more difficult by infiltrative disease, proximity of critical vasculature, peritumoral inflammation, and dense stroma. Surgeons are limited to tactile and visual cues to differentiate cancerous tissue from normal tissue. Furthermore, translating preoperative images to the intraoperative setting poses additional challenges for tumor detection, and can result in undetected and unresected lesions.

Identification of Immunoglobulin G Autoantibody Against Malondialdehyde-Acetaldehyde Adducts as a Novel Serological Biomarker for Ulcerative Colitis.

Introduction: Inflammatory bowel disease (IBD) is associated with immune responses with oxidative stress wherein high levels of malondialdehyde result in the formation of a highly stable and immunogenic malondialdehyde-acetaldehyde adduct (MAA). Thus, this study evaluated the status of MAA and anti-MAA antibody isotypes in IBD and their potential as novel serological biomarkers for differentiating ulcerative colitis (UC) from Crohn's disease (CD).

Methods: Levels of MAA and anti-MAA antibodies were examined in patients with IBD (171), non-IBD gastrointestinal diseases (77), and controls (83) from 2 independent cohorts using immunohistochemistry and enzyme-linked immunosorbent assay.

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma.

Background: Multiple myeloma (MM) remains an incurable malignancy, despite the advent of therapies such as proteosome inhibitors (PIs) that disrupt protein homeostasis and induce ER stress. We have pursued inhibition of geranylgeranyl diphosphate synthase (GGDPS) as a novel mechanism by which to target protein homeostasis in MM cells. GGDPS inhibitors (GGSI) disrupt Rab geranylgeranylation, which in turn results in perturbation of Rab-mediated protein trafficking, leading to accumulation of intracellular monoclonal protein, induction of ER stress and apoptosis.

Teaching About Intergenerational Dynamics: An Exploratory Study of Perceptions and Prevalence in US Medical Schools.

Purpose: Prior studies suggest a role for promoting recognition of generational differences as a part of workplace ethics. To our knowledge, there is no published comprehensive analysis demonstrating how commonly or by what methods intergenerational dynamics are taught as structured coursework in medical school curricula. To address this gap, we carried out a survey of curriculum leaders of US medical schools to assess the current practices and attitudes toward content related to generational differences in medical school coursework.

Faculty Versus Resident Self-Assessment Using Pathology Milestones: How Aligned Are We?

Competent physicians must be able to self-assess skill level; however, previous studies suggest that medical trainees may not accurately self-assess. We utilized Pathology Milestones (PM) data to determine whether there were discrepancies in self- versus Clinical Competency Committee (CCC) ratings by sex, program year (PGY), time of evaluation, and question category (Patient Care, Medical Knowledge, Systems-Based Practice [SBP], Practice-Based Learning and Improvement [PBL], Professionalism [PRO], and Interpersonal and Communication Skills) and Residency In-Service Examination (RISE) score. We completed retrospective analyses of PM evaluation scores from 2016 to 2019 (n = 23 residents) 2 times per year.

MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB).

Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors.

QuPath Digital Immunohistochemical Analysis of Placental Tissue.

Background: QuPath is an open-source digital image analyzer notable for its user-friendly design, cross-platform compatibility, and customizable functionality. Since it was first released in 2016, at least 624 publications have reported its use, and it has been applied in a wide spectrum of settings. However, there are currently limited reports of its use in placental tissue.