The inhibitor of MyoD Family A (I-MFA) regulates megakaryocyte lineage commitment and terminal differentiation.

Hematopoiesis and lineage commitment are regulated by several conserved cell-intrinsic signaling pathways, including MAPKs and ß-catenin/TCF/LEF. The Inhibitor of MyoD Family A (I-MFA), a transcriptional repressor and tumor suppressor gene, interacts with these pathways and is dysregulated in chronic and acute myeloid leukemias, suggesting it may play a role in development and differentiation during hematopoiesis. To study this, immune cell populations in the bone marrow (BM) and periphery were analyzed in mice lacking Mdfi, encoding I-MFA (I-MFA-/-), and wild type (WT) controls. I-MFA-/- mice had reduced spleen and BM cellularity, with significant hyposplenism, compared to WT mice. In blood, total red blood cells and platelet counts were significantly reduced in I-MFA-/- mice, accompanied by a reduction in megakaryocyte (MK)/erythrocyte progenitor cells and an increase in myeloid progenitors in BM compared to WT mice. The K562 cell line exhibits PMA-induced MK differentiation, and shRNA knockdown of I-MFA resulted in reduced differentiation compared to control, with an increase and prolongation in phospho-JNK and phospho-ERK signaling. Overexpression of I-MFA promoted MK differentiation. These results suggest I-MFA plays a cell-intrinsic role in the response to differentiation signals, an effect that can be explored in the context of hematological cancers or other blood proliferative disorders.

Insights into the Functional Role of ADTRP (Androgen-Dependent TFPI-Regulating Protein) in Health and Disease.

The novel protein ADTRP, identified and described by us in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the major inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. Single-nucleotide polymorphisms in ADTRP associate with coronary artery disease and myocardial infarction, and deep vein thrombosis/venous thromboembolism. Some athero-protective effects of androgen could exert through up-regulation of ADTRP expression. We discovered a critical role of ADTRP in vascular development and vessel integrity and function, manifested through Wnt signaling-dependent regulation of matrix metalloproteinase-9. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory effects and can control metabolic disorders. Here we summarize and analyze the knowledge on ADTRP and try to decipher its functions in health and disease.

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis.

Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9. RA101295 reduced the E. coli-induced "oxidative burst," as well as leukocyte activation, without affecting host phagocytosis of E. coli RA101295 treatment reduced plasma LPS content in E. coli-challenged baboons, implying reduced complement-mediated bacteriolysis, whereas treated animals showed slightly improved bacterial clearance during the bacteremic stage compared with controls. Treatment with RA101295 also improved consumptive coagulopathy and preserved endothelial anticoagulant and vascular barrier functions. RA101295 abolished sepsis-induced surges in proinflammatory cytokines and attenuated systemic circulatory and febrile responses, likely reflecting decreased systemic levels of LPS and C5a. Overall, RA101295 treatment was associated with significant organ protection and markedly reduced mortality compared with nontreated controls (four of five animals survived in a 100% lethal model). We therefore conclude that inhibition of C5 cleavage during the bacteremic stage of sepsis could be an important therapeutic approach to prevent sepsis-induced inflammation, consumptive coagulopathy, and subsequent organ failure and death.

ENPP1 121Q functional variant enhances susceptibility to coronary artery disease in South Indian patients with type 2 diabetes mellitus.

Insulin resistance is associated with endothelial dysfunction and ensuing cardiovascular diseases in type 2 diabetes mellitus (T2DM) patients. ENPP1 is a key modulator of insulin signaling and its polymorphism, K121Q, increases the potency to competitively inhibit insulin receptor binding. We investigated the association of ENPP1 121Q variant with coronary artery disease (CAD) in patients with and without T2DM in South Indian population. Our study was conducted in 913 subjects: 198 patients with CAD, 284 patients in whom T2DM and CAD co-exists, 160 patients with T2DM and no CAD history, and 271 healthy volunteers. Genotyping was performed using PCR-RFLP and PCR-DNA sequencing. Genotype frequency of ENPP1 121Q was higher in disease groups compared to healthy subjects (p < 0.05). T2DM patients who carried polymorphic AC/CC genotypes were at 12.8-fold enhanced risk to CAD (95% CI 4.97-37.18, p < 0.01). Moreover we observed that 121Q, both in heterozygous and homozygous polymorphic states, was a risk factor for CAD without diabetes (OR 4.15, p < 0.01). 121Q variant was associated with T2DM patients with no CAD history too, but the risk was statistically insignificant after multivariate logistic regression analysis (OR 2.32, p > 0.05). We conclude that ENPP1 121Q variant is associated with increased risk for CAD in patients with T2DM in South Indian population. We also report that 121Q variant of ENPP1 was an independent risk factor for CAD irrespective of diabetic milieu. Factors which enhance insulin resistance increase the risk for onset and progression of coronary atherosclerosis irrespective of a diabetic background.

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD.

Nephronophthisis (NPHP) and autosomal dominant Polycystic Kidney Disease (ADPKD) are two genetically distinct forms of Polycystic Kidney Disease (PKD), yet both diseases present with kidney cysts and a gradual decline in renal function. Prevailing dogma in PKD is that changes in kidney architecture account for the decline in kidney function, but the molecular/cellular basis of such coupling is unknown. To address this question, we induced a form of proteome reprogramming by deleting Fbxw7 encoding FBW7, the recognition receptor of the SCF FBW7 E3 ubiquitin ligase in different segments of the kidney tubular system. Deletion of Fbxw7 in the medulla led to a juvenile-adult NPHP-like phenotype, where the decline in renal function was due to SOX9-mediated interstitial fibrosis rather than cystogenesis. In contrast, the decline of renal function in ADPKD is coupled to cystic expansion via the abnormal accumulation of FBW7 in the proximal tubules and other cell types in the renal cortex. We propose that FBW7 functions at the apex of a protein network that determines renal function in ADPKD by sensing architectural changes induced by cystic expansion.

Hiccups: Nerve Irritation or Masquerading as Acute Coronary Syndrome.

The typical clinical presentation of acute coronary syndrome (ACS) includes chest pain that may radiate to the left arm, shoulder, jaw, and neck, accompanied by diaphoresis, dyspnea, nausea, vomiting, and hiccups, which have been observed as the sole symptom of presentation. The mechanism of hiccups involves the activation of the vagus and phrenic nerves, leading to the activation of the diaphragm and intercostal muscles. Several hypotheses link hiccups to ACS, associating irritation of the left anterior descending artery with activation of sympathetic phrenic and vagal nerves. This case report highlights the occurrence of hiccups in patients with inferior and right ventricular myocardial infarction (MI), indicating possible nerve synapse involvement. Timely recognition of hiccups as a possible atypical symptom of ACS can facilitate early evaluation and management, preventing delays in patient care and ensuring better outcomes.

Tissue-specific sex difference in the metabolism of fatty acid esters of hydroxy fatty acids.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to Adtrp mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. Adtrp deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex effects on FAHFA metabolism in humans.

Gold Nanoparticles Inhibit Macropinocytosis by Decreasing KRAS Activation.

The RAS-transformed cells utilize macropinocytosis to acquire amino acids to support their uncontrolled growth. However, targeting RAS to inhibit macropinocytosis remains a challenge. Here, we report that gold nanoparticles (GNP) inhibit macropinocytosis by decreasing KRAS activation. Using surface-modified and unmodified GNP, we showed that unmodified GNP specifically sequestered both wild-type and mutant KRAS and inhibited its activation, irrespective of growth factor stimulation, while surface-passivated GNP had no effect. Alteration of KRAS activation is reflected on downstream signaling cascades, macropinocytosis and tumor cell growth in vitro, and two independent preclinical human xenograft models of pancreatic cancer in vivo. The current study demonstrates NP-mediated inhibition of macropinocytosis and KRAS activation and provides translational opportunities to inhibit tumor growth in a number of cancers where activation of KRAS plays a major role.

Meta-analysis and Systematic Review of Bronchoscopic Lung Volume Reduction Through Endobronchial Valves in Severe Emphysema.

BACKGROUND: Pharmacologic therapeutics for advanced emphysema have limited benefit. Bronchoscopic lung volume reduction with endobronchial valves (EBVs) have reported improvements in lung function, breathlessness, and quality of life through randomized clinical trials, with less morbidity as comparted to Surgical Lung volume Reduction. We here present a Meta-analysis and systematic review of bronchoscopic lung volume reduction in advanced chronic obstructive lung disease patients. METHODS: PubMed (NLM), Embase (Elsevier), and Web of Science (Clarivate Analytics) search was conducted using a combination of keywords and subject headings. The search was confined to the last 15 years and was completed on October 23, 2020. Only placebo-controlled randomized control trials of emphysema patients with EBV were included. Quality assessment was done by 2 independent reviewers. RESULTS: Nine studies were included for the meta-analysis with a total number of 1383 patients of whom 888 received EBV and 495 standard of care (SOC) medications. Our Metanalysis show statistically significant improvement in forced expiratory volume in first second, percentage forced expiratory volume in first second, St. George's respiratory questionnaire, and 6-minute walk distance in EBV group compared with SOC. Residual volume had statistically significant reduction after EBV placement compared with SOC. These differences continued to be present during short-term (<=6 mo) and long-term follow-up (>=6 mo). These improvements were even higher when the EBV patients'. Collateral ventilation was negative/fissure was intact (CV-/FI >90%). The rate of hemoptysis and pneumothorax was higher in the EBV group compared with SOC, however, did not lead to increased fatal outcomes. CONCLUSION: In conclusion, EBV has favorable effects on patients' outcomes in patients who have heterogeneous emphysema particularly with no collateral ventilation.

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study.

Increasing evidence suggests that prolonged antibiotic therapy in preterm infants is associated with increased mortality and morbidities, such as necrotizing enterocolitis (NEC), a devastating gastrointestinal pathology characterized by intestinal inflammation and necrosis. While a clinical correlation exists between antibiotic use and the development of NEC, the potential causality of antibiotics in NEC development has not yet been demonstrated. Here, we tested the effects of systemic standard-of-care antibiotic therapy for ten days on intestinal development in neonatal mice. Systemic antibiotic treatment impaired the intestinal development by reducing intestinal cell proliferation, villi height, crypt depth, and goblet and Paneth cell numbers. Oral bacterial challenge in pups who received antibiotics resulted in NEC-like intestinal injury in more than half the pups, likely due to a reduction in mucous-producing cells affecting microbial-epithelial interactions. These data support a novel mechanism that could explain why preterm infants exposed to prolonged antibiotics after birth have a higher incidence of NEC and other gastrointestinal disorders.

Insights into the Regulation of Ciliary Disassembly.

The primary cilium, an antenna-like structure that protrudes out from the cell surface, is present in most cell types. It is a microtubule-based organelle that serves as a mega-signaling center and is important for sensing biochemical and mechanical signals to carry out various cellular processes such as proliferation, migration, differentiation, and many others. At any given time, cilia length is determined by a dynamic balance of cilia assembly and disassembly processes. Abnormally short or long cilia can cause a plethora of human diseases commonly referred to as ciliopathies, including, but not limited to, skeletal malformations, obesity, autosomal dominant polycystic kidney disease, retinal degeneration, and bardet-biedl syndrome. While the process of cilia assembly is studied extensively, the process of cilia disassembly and its biological role(s) are less well understood. This review discusses current knowledge on ciliary disassembly and how different cellular processes and molecular signals converge to carry out this process. This information will help us understand how the process of ciliary disassembly is regulated, identify the key steps that need further investigation, and possibly design therapeutic targets for a subset of ciliopathies that are causally linked to defective ciliary disassembly.

Sarcoidosis: An FP's primer on an enigmatic disease.

Management includes ruling out alternate diagnoses, identifying occult/overt organ involvement, determining treatment, and recognizing worrisome features.

Adipokine Apelin/APJ Pathway Promotes Peritoneal Dissemination of Ovarian Cancer Cells by Regulating Lipid Metabolism.

Adipose tissue, which can provide adipokines and nutrients to tumors, plays a key role in promoting ovarian cancer metastatic lesions in peritoneal cavity. The adipokine apelin promotes ovarian cancer metastasis and progression through its receptor APJ, which regulates cell proliferation, energy metabolism, and angiogenesis. The objective of this study was to investigate the functional role and mechanisms of the apelin-APJ pathway in ovarian cancer metastasis, especially in context of tumor cell-adipocyte interactions. When co-cultured in the conditioned media (AdipoCM) derived from 3T3-L1 adipocytes, which express and secrete high apelin, human ovarian cancer cells with high APJ expression showed significant increases in migration and invasion in vitro. We also found that cells expressing high levels of APJ had increased cell adhesion to omentum ex vivo, and preferentially "home-in" on the omentum in vivo. These apelin-induced pro-metastatic effects were reversed by APJ antagonist F13A in a dose-dependent manner. Apelin-APJ activation increased lipid droplet accumulation in ovarian cancer cells, which was further intensified in the presence of AdipoCM and reversed by F13A or APJ knockdown. Mechanistically, this increased lipid uptake was mediated by CD36 upregulation via APJ-STAT3 activation, and the lipids were utilized in promoting fatty acid oxidation via activation of AMPK-CPT1a axis. Together, our studies demonstrate that adipocyte-derived apelin activates APJ-expressing tumor cells in a paracrine manner, promoting lipid uptake and utilization and providing energy for ovarian cancer cell survival at the metastatic sites. Hence, the apelin-APJ pathway presents a novel therapeutic target to curb ovarian cancer metastasis. IMPLICATIONS: Targeting the APJ pathway in high-grade serous ovarian carcinoma is a novel strategy to inhibit peritoneal metastasis.

Outcomes of Patients Undergoing Cardiac Catheterization After a Three-Day Holiday Weekend Versus a Two-Day Weekend.

OBJECTIVES: The study aim is to determine whether invasive cardiac procedures following a 3-day (holiday) weekend have worse outcomes compared with procedures following a 2-day (normal) weekend. BACKGROUND: Catheterization laboratory schedules after 3-day holiday weekends tend to be overloaded with urgent procedures for patients who have waited up to 3 days. We hypothesized that this would be reflected by more procedural complications in patients undergoing procedures after a 3-day weekend. METHODS: Invasive cardiac procedures that occurred after a weekend at Geisinger Medical Center from July 2012 to December 2019 were included. Baseline characteristics, presentation, periprocedural variables, adverse events, and clinical outcomes were compared between catheterizations on the day following a 2-day weekend and catheterizations following a 3-day weekend. Independent correlates of adverse events were identified by logistic regression analysis. RESULTS: We identified 13,704 invasive cardiac procedures performed after a weekend, of which 722 occurred after a 3-day (holiday) weekend. Baseline demographics, presentation, and case volumes were similar between the 2 groups. Procedures after a 3-day weekend were not associated with any differences in in-hospital mortality, myocardial infarction, or stroke compared with those after a standard 2-day weekend. By univariate analysis, procedural complications were more frequent after a 3-day weekend (15.1% vs 12.3%; P=.03), but this difference was not significant on multivariate analysis (odds ratio, 1.22; P=.30). CONCLUSIONS: Cardiac catheterization procedures performed after a 3-day weekend were not associated with differences in in-patient mortality, myocardial infarction, stroke, or procedural complications.

Etoposide as Salvage Therapy for Cytokine Storm Due to Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality because of a lack of effective therapies. Therapeutic strategies under investigation target the overactive cytokine response with anti-cytokine or immunomodulators therapies. We present a unique case of severe cytokine storm resistant to multiple anti-cytokine therapies, but eventually responsive to etoposide. Thus, etoposide may have a role as salvage therapy in treatment of cytokine storm in COVID-19. To our knowledge, this is the first reported case of use of etoposide in COVID-19.

Prevalence and Predictors of Obstructive Coronary Artery Disease in Nonlow-risk Acute Chest Pain Patients Who Rule Out for Myocardial Infarction in the High-sensitivity Troponin Era.

OBJECTIVES: The best management approach for chest pain patients who rule out for myocardial infarction (MI) in the high-sensitivity troponin (hsTn) era remains elusive. Patients, especially those with nonlow clinical risk scores, are often referred for inpatient ischemic testing to uncover obstructive coronary artery disease (CAD). Whether the prevalence of obstructive CAD in this cohort is high enough to justify routine testing is not known. METHODS: We conducted a retrospective cohort analysis of 1517 emergency department chest pain patients who ruled out for MI by virtue of a stable high-sensitivity troponin T (hsTnT) levels (defined as <5 ng/L intermeasurements increase) and were admitted for inpatient testing. RESULTS: Abnormal ischemia evaluation (including 5.9% with evidence of fixed wall motion or perfusion defects) was 11.9%. Of those undergoing invasive angiography (n = 292), significant coronary stenoses (≥70% or unstable lesions) and multivessel CAD occurred in 16.8% and 5.5%, respectively. In a multivariate logistic regression model, known CAD, prior MI, chest pain character, mildly elevated hsTnT, and left ventricular ejection fraction <40% were predictive of an abnormal ischemia evaluation result, whereas electrocardiography findings and the modified History, EKG, Age, Risk factors, and troponin (HEART) score were not. Of note, 30-day adverse cardiac events were strikingly low at 0.4% with no deaths despite an overwhelming majority (>90%) of patients scoring intermediate or high on the modified HEART score. CONCLUSIONS: A considerable percentage of acute chest pain patients who rule out for MI by hsTn had evidence of obstructive CAD, and the modified HEART score was not predictive of an abnormal ischemia evaluation.

Safety and efficacy of catheter directed thrombolysis (CDT) in elderly with pulmonary embolism (PE).

INTRODUCTION: Acute pulmonary embolism (PE) remains a common cause for morbidity and mortality in patients over 65 years. Given the increased risk of bleeding in the elderly population with the use of systemic thrombolysis, catheter-directed therapy (CDT) is being increasingly used for the treatment of submassive PE. Nevertheless, the safety of CDT in the elderly population is not well studied. We, therefore, aimed to evaluate the safety of CDT in our elderly patients. METHODS: We conducted a retrospective observational study of consecutive patients aged >65 years with a diagnosis of PE from our Pulmonary Embolism Response Team database. We compared the treatment outcomes of CDT versus anticoagulation (AC) in elderly. Propensity score matching was used to construct two matched cohorts for final outcomes analysis. RESULTS: Of 346 patients with acute PE, 138 were >65 years, and of these, 18 were treated with CDT. Unmatched comparison between CDT and AC cohorts demonstrated similar in-hospital mortality (11.1% vs 5.6%, p=0.37) and length of stay (LOS) (3.81 vs 5.02 days, p=0.5395), respectively. The results from the propensity-matched cohort mirrored results of the unmatched cohort with no significant difference between CDT and AC in-hospital mortality (11.8% vs 5.9%, p=0.545) or median LOS (3.76 vs 4.21 days, p=0.77), respectively. CONCLUSION: In this observational study using propensity score-matched analysis, we found that patients >65 years who were treated with CDT for management of acute PE had similar mortality and LOS compared with those treated with AC. Further studies are required to confirm these findings.

Utility of the ROX Index in Predicting Intubation for Patients With COVID-19-Related Hypoxemic Respiratory Failure Receiving High-Flow Nasal Therapy: Retrospective Cohort Study.

BACKGROUND: The use of high-flow nasal therapy (HFNT) to treat COVID-19 pneumonia has been greatly debated around the world due to concerns about increased health care worker transmission and delays in invasive mechanical ventilation (IMV). Herein, we analyzed the utility of the noninvasive ROX (ratio of oxygen saturation) index to predict the need for and timing of IMV. OBJECTIVE: This study aimed to assess whether the ROX index can be a useful score to predict intubation and IMV in patients receiving HFNT as treatment for COVID-19-related hypoxemic respiratory failure. METHODS: This is a retrospective cohort analysis of 129 consecutive patients with COVID-19 admitted to Temple University Hospital in Philadelphia, PA, from March 10, 2020, to May 17, 2020. This is a single-center study conducted in designated COVID-19 units (intensive care unit and other wards) at Temple University Hospital. Patients with moderate and severe hypoxemic respiratory failure treated with HFNT were included in the study. HFNT patients were divided into two groups: HFNT only and intubation (ie, patients who progressed from HFNT to IMV). The primary outcome was the value of the ROX index in predicting the need for IMV. Secondary outcomes were mortality, rate of intubation, length of stay, and rate of nosocomial infections in a cohort treated initially with HFNT. RESULTS: Of the 837 patients with COVID-19, 129 met the inclusion criteria. The mean age was 60.8 (SD 13.6) years, mean BMI was 32.6 (SD 8) kg/m², 58 (45%) were female, 72 (55.8%) were African American, 40 (31%) were Hispanic, and 48 (37.2%) were nonsmokers. The mean time to intubation was 2.5 (SD 3.3) days. An ROX index value of less than 5 at HFNT initiation was suggestive of progression to IMV (odds ratio [OR] 2.137, P=.052). Any further decrease in ROX index value after HFNT initiation was predictive of intubation (OR 14.67, P<.001). Mortality was 11.2% (n=10) in the HFNT-only group versus 47.5% (n=19) in the intubation group (P<.001). Mortality and need for pulmonary vasodilators were higher in the intubation group. CONCLUSIONS: The ROX index helps decide which patients need IMV and may limit eventual morbidity and mortality associated with the progression to IMV.

Non-bacterial thrombotic endocarditis: a rare presentation and literature review.

A 66-year-old woman with a remote history of breast cancer and prior tobacco use presented to the hospital with chest pain. She was found to have an elevated troponin consistent with a diagnosis of a non-ST segment elevation myocardial infarction (NSTEMI). A left heart catheterisation revealed non-obstructive coronary disease, and subsequent transthoracic and transoesophageal echocardiograms demonstrated vegetations on both the mitral and aortic valves. Multiple blood cultures showed no growth raising suspicion for non-bacterial thrombotic endocarditis (NBTE). A CT of the chest, abdomen and pelvis was obtained that was consistent with metastatic pancreatic cancer. Her hospital course was complicated by recurrent embolic strokes leading to a rapid clinical deterioration. As a result, she was transitioned to comfort measures and passed away shortly thereafter. To our knowledge, this is the first reported case of an NSTEMI as the initial presentation of NBTE due to underlying malignancy.