Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia–reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (−14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.Faculty of Medicine, and Faculty of Science, Ain Shams UniversityPrincess Nourah bint Abdulrahman Universit

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Infectious Keratitis in Corneal Graft following Astigmatic Keratotomy: A Case Report and Literature Review

Femtosecond laser-assisted astigmatic keratotomy (FSAK) is recognized as a safe and effective therapeutic option for addressing high corneal astigmatism in corneal transplants. Although the incidence of corneal infection after FSAK in corneal transplants is very low, early detection and treatment is necessary to optimize visual outcomes and prevent devastating sequelae. This report describes a rare case of an early-onset infectious keratitis occurring in a corneal transplant after FSAK. A 38-year-old man with previous history of penetrating keratoplasty and FSAK presented to emergency department with deep corneal infiltration at the FASK incision site along with a decline in his baseline best corrected visual acuity 1 month after FSAK. Corneal scraping was performed, and topical fortified antibiotic eyedrops were started. Culture results showed no growth. Three weeks later, the corneal infiltrate resolved with residual scarring at the FSAK incision site, and the patient regained his baseline best corrected visual acuity with no sequelae

Precision Medicine Management of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries, with an incidence of approximately 5.1/100,000 new cases per year. Some patients may never require treatment, whereas others relapse early after front line therapeutic approaches. Recent whole genome and whole exome sequencing studies have allowed a better understanding of CLL pathogenesis and the identification of genetic lesions with potential clinical relevance. Consistently, precision medicine plays a pivotal role in the treatment algorithm of CLL, since the integration of molecular biomarkers with the clinical features of the disease may guide treatment choices. Most CLL patients present at the time of diagnosis with an early stage disease and are managed with a watch and wait strategy. For CLL patients requiring therapy, the CLL treatment armamentarium includes both chemoimmunotherapy strategies and biological drugs. The efficacy of these treatment strategies relies upon specific molecular features of the disease. TP53 disruption (including both TP53 mutation and 17p deletion) is the strongest predictor of chemo-refractoriness, and the assessment of TP53 status is the first and most important decisional node in the first line treatment algorithm. The presence of TP53 disruption mandates treatment with biological drugs that inhibit the B cell receptor or, alternatively, the B-cell lymphoma 2 (BCL2) pathway and can, at least in part, circumvent the chemorefractoriness of TP53-disrupted patients. Beside TP53 disruption, the mutational status of immunoglobulin heavy variable (IGHV) genes also helps clinicians to improve treatment tailoring. In fact, patients carrying mutated IGHV genes in the absence of TP53 disruption experience a long-lasting and durable response to chemoimmunotherapy after fludarabine, cyclophosphamide, and rituximab (FCR) treatment with a survival superimposable to that of a matched general population. In contrast, patients with unmutated IGHV genes respond poorly to chemoimmunotherapy and deserve treatment with B cell receptor inhibitors. Minimal residual disease is also emerging as a relevant biomarker with potential clinical implications. Overall, precision medicine is now a mainstay in the management and treatment stratification of CLL. The identification of novel predictive biomarkers will allow further improvements in the treatment tailoring of this leukemia

New Frontiers in Monoclonal Antibodies for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Simple Summary Forty percent of patients with diffuse large B-cell lymphoma (DLBCL) have a refractory or relapsed (R/R) disease. In this setting, prognosis is poor, particularly for patients not eligible for autologous stem-cell transplantation or CAR-T-cell therapy, thus representing an unmet need in the field of hematological malignancies. Currently, the optimal treatment approach for these patients remains controversial. Over the last few decades, monoclonal antibodies (mAbs) have dramatically changed the therapeutic landscape for cancer patients. The aim of our review is focused on novel and emerging therapeutic strategies based on different types of mAbs, including monospecific and bispecific mAbs as well as antibody-drug conjugates and immune checkpoint inhibitors, in the challenging setting of R/R DLBCL.Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Approximately 60% of patients are cured with R-CHOP as a frontline treatment, while the remaining patients experience primary refractory or relapsed disease (R/R). The prognosis for R/R DLBCL patients who are neither eligible for autologous stem-cell transplantations nor CAR-T-cell treatment is poor, representing an important unmet need. Monoclonal antibodies (mAbs) have dramatically improved therapeutic options in anti-cancer strategies, offering new opportunities to overcome chemo-refractoriness in this challenging disease, even in cases of primary non-responder DLBCL. Several novel mAbs, characterized by different mechanisms of action and targets, are now available for R/R DLBCL. Unbound mAbs induce an immune response against cancer cells, triggering different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), activation of antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). Antibody-drug conjugates (ADCs) and radioimmunotherapy (RIT), respectively, deliver a cytotoxic payload or a beta-emitter radionuclide to the targeted cells and nearby bystanders. Bispecific T-cell engagers (BiTes) and immune checkpoint inhibitors (ICIs) redirect and enhance the immune response against tumor cells. Here, we review therapeutic strategies based on monoclonal antibodies for R/R DLBCL

New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent an unmet clinical need whose prognosis is still dismal. Alterations of immune response play a prominent role in AML/MDS pathogenesis, revealing novel options for immunotherapy. Among immune system regulators, CD47, immune checkpoints, and toll-like receptor 2 (TLR2) are major targets. Magrolimab antagonizes CD47, which is overexpressed by AML and MDS cells, thus inducing macrophage phagocytosis with clinical activity in AML/MDS. Sabatolimab, an inhibitor of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which disrupts its binding to galectin-9, has shown promising results in AML/MDS, enhancing the effector functions of lymphocytes and triggering tumor cell death. Several other surface molecules, namely CD33, CD123, CD45, and CD70, can be targeted with monoclonal antibodies (mAbs) that exert different mechanisms of action and include naked and conjugated antibodies, bispecific T-cell engagers, trispecific killer engagers, and fusion proteins linked to toxins. These novel mAbs are currently under investigation for use as monotherapy or in combination with hypomethylating agents, BCL2 inhibitors, and chemotherapy in various clinical trials at different phases of development. Here, we review the main molecular targets and modes of action of novel mAb-based immunotherapies, which can represent the future of AML and higher risk MDS treatment

Prognostic value of clonal evolution identified by sequential FISH in untreated chronic lymphocytic leukaemia

Aim: The aim of the current study was to evaluate the potential clinical impact of clonal evolution detected by fluorescence in situ hybridization (FISH) in untreated chronic lymphocytic leukaemia (CLL) patients managed with a watch -and -wait strategy. Methods: We performed both overall survival (OS) and time to first treatment (TTFT) analysis. For the first one, we exploited a real -life cohort of 123 consecutive CLL patients followed at our institution, for which at least a second FISH evaluation during watch and wait was available. For TTFT analysis, we considered only patients treated after the second FISH sample (n = 69). Results: Considering the original cohort, patients who acquired a FISH abnormality displayed a worse outcome with a median OS of 91.9 months compared to 147.3 months for patients who did not acquire any FISH abnormalities (P = 0.007). Unmutated immunoglobulin heavy chain gene (IGHV) genes were associated with a higher probability of acquiring a FISH abnormality (P = 0.04). Turning to TTFT analysis, patients who gained at least one FISH abnormality (n = 7, 10%) were characterised by an earlier treatment requirement with a median TTFT of 1.1 months, compared to 2.7 months in patients who did not acquire any FISH abnormalities (n = 62, 90%) (P = 0.025). Conclusions: The dynamic acquisition of karyotypic abnormalities by FISH predicts poor outcomes and early treatment requirement in CLL patients. Our results suggest that FISH analysis could be integrated with other clinical and biological features to obtain dynamic scores that are able to predict outcomes at different phases of disease history

Prevalence of Undiagnosed Diabetes and Quality of Care in Diabetic Patients Followed at Primary and Tertiary Clinics in Abu Dhabi, United Arab Emirates

AIMS: To investigate the prevalence of undiagnosed type 2 diabetes (T2D) at primary health care (PHC) clinics, and to assess the quality of care of diabetic patients followed at a tertiary hospital diabetes center in Abu Dhabi, United Arab Emirates (UAE). METHODS: Between May 2009 and October 2010, adult patients attending two PHC clinics, and adult diabetic patients attending the diabetes center, were invited to participate in the study. After overnight fast, participants returned for interview and laboratory tests. Undiagnosed T2D was defined by FPG ≥ 7.0 mmol/l or HbA1c ≥ 6.5%. Quality of care was assessed by reported care practices and achievement of internationally recognized targets. RESULTS: Out of 239 patients at PHC clinics without history of T2D, 14.6% had undiagnosed T2D, and 31% had increased risk of diabetes (FPG 5.6-7.0 mmol/l or HbA1c 5.7-6.5%). The independent predictors of undiagnosed T2D were age (adjusted OR per year 1.07, 95% CI 1.04-1.11, p < 0.001) and BMI ≥ 25 (adjusted OR 4.2, 95% CI 0.91-19.7, p = 0.033). Amongst all 275 diagnosed T2D patients, including those attending PHC clinics and those followed at the diabetes center, it was found that 40.1% followed dietary recommendations, 12% reported visiting a diabetes educator, 28.2% walked for exercise, and 13.5% attained recognized targets of HbA1c < 7%, blood pressure < 130/80 mmHg, and LDL cholesterol < 2.6 mmol/l. CONCLUSIONS: Almost half of the adult patients attending PHC clinics had undiagnosed T2D, or increased diabetes risk. Care practices, and achievement of treatment targets, were suboptimal