Cardiovascular Toxicity in Cancer Therapy: Protecting the Heart while Combating Cancer.

PURPOSE OF REVIEW: This review explores the cardiovascular toxicity associated with cancer therapies, emphasizing the significance of the growing field of cardio-oncology. It aims to elucidate the mechanisms of cardiotoxicity due to radiotherapy, chemotherapy, and targeted therapies, and to discuss the advancements in human induced pluripotent stem cell technology (hiPSC) for predictive disease modeling. RECENT FINDINGS: Recent studies have identified several chemotherapeutic agents, including anthracyclines and kinase inhibitors, that significantly increase cardiovascular risks. Advances in hiPSC technology have enabled the differentiation of these cells into cardiovascular lineages, facilitating more accurate modeling of drug-induced cardiotoxicity. Moreover, integrating hiPSCs into clinical trials holds promise for personalized cardiotoxicity assessments, potentially enhancing patient-specific therapeutic strategies. Cardio-oncology bridges oncology and cardiology to mitigate the cardiovascular side-effects of cancer treatments. Despite advancements in predictive models using hiPSCs, challenges persist in accurately replicating adult heart tissue and ensuring reproducibility. Ongoing research is essential for developing personalized therapies that balance effective cancer treatment with minimal cardiovascular harm.

Generation of induced pluripotent stem cell line from a patient suffering from arterial calcification due to deficiency of CD73 (ACDC).

Arterial calcification due to deficiency of CD73 (ACDC) is an adult onset, rare genetic vascular disorder signified by calcium deposition in lower extremity arteries and joints of hands and feet. Mutations in NT5E gene has been shown to be responsible for the inactivation of enzyme CD73 causing calcium buildup. Here, we report a iPSC line generated from a patient showing signs of ACDC and carrying a missense mutation in NT5E (c.1126A→G,p.T376A) gene. This iPSC line shows normal morphology, pluripotency, karyotype, and capability to differentiate into three germ layers, making it useful for disease modeling and investigating pathological mechanisms of ACDC.

Elective Tracheostomy During Covid-19 Pandemic- A Tertiary Care Centre Experience.

Aims and Objectives: : The aim of our study was to present an experience of elective tracheostomy in COVID-19 patients at our institute. Materials and methods: The present prospective study was conducted, after approval by Institutional Ethics Committee, in the Department of ENT, SMGS Hospital, GMC Jammu from May 2020 to March 2021 over 60 patients having need for prolonged mechanical ventilation and having tested positive for COVID-19 with nasopharyngeal swab on rtPCR assay testing. Detailed information regarding following aspects was gathered :Age, Gender, Comorbidities (Diabetes, Cardiovascular disease, Pulmonary disease, Malignancy), time of endotracheal intubation to tracheostomy, time to wean sedation after tracheostomy, time to wean mechanical ventilation after tracheostomy, surgical complications, mortality, any health care worker in operating team getting infected by SARS-CoV-2. All 60 patients underwent Elective Open Tracheostomy Bed-side in the ICU section of our institute. Results: The mean age of presentation was 55.9 ± 2.34 years, with male preponderance. The most common indication for tracheostomy was ARDS (Acute Respiratory Distress Syndrome) (56.6%). Out of 60 patients, co-morbidities were present in 44 patients (73.3%). The mean time between endotracheal intubation and tracheostomy was 12.2 ± 4.9 days. The mean time to wean mechanical ventilation after tracheostomy was 10.4 ± 2.31 days. The mean time to wean sedation was 2.2 ± 0.83 days. There were no deaths during the procedure. Out of 60 patients, 5 patients (8.3%) died due to complications of COVID-19. Conclusion: Our study provides important clinical data (such as timing of tracheostomy, pre-operative evaluation of patients, recommendations during procedure, outcomes of tracheostomy and postoperative care) on this threatening issue of tracheostomy in COVID-19 patients and might be of immense help to various Otorhinolaryngologists who are dealing with the same situation.

Fabrication, characterization and in vivo assessment of cardiogel loaded chitosan patch for myocardial regeneration.

Cell therapy is one of the promising approaches for cardiac repair, subsequently after infarction or injury. However, contemporary mesenchymal stromal/stem cell (MSCs) delivery strategies result in low retention and poor engraftment of donor cells, thus limiting the therapeutic efficacy. Here, we developed an engineered biomimetic cardiogel patch (EBCP) comprising of the native decellularized cardiac extracellular matrix (ECM) "cardiogel" and chitosan, leading to the efficient regeneration of injured myocardium. We also developed novel bio-adhesive that is capable of suture-free epicardial placement of EBCP to injured myocardium. We have illustrated the potential of the mussels-inspired bioadhesive system, which comprises gelatin catechol and partially oxidized chitosan, which relies on self-crosslinking capability, to promote wet adhesion. In vitro studies with isolated cardiogel promoted cell proliferation, adhesion, and migration while aiding cardiomyogenic differentiation. The EBCP's ability to protect cells from abrasion due to surrounding tissues in the myocardial infarction (MI) rat model makes it more desirable. Furthermore, the epicardial implantation of the EBCP loaded with MSCs improves the initial retention of cells and subsequent functional cardiac recovery with enhanced myocardial tissue restoration. Histological examination showed the presence of EBCP and infiltration of cells to the infarcted heart tissue. The fast and facile synthesis of bioadhesive and major therapeutic benefits of EBCP make it a potential candidate for recuperating the ailing heart.

Otological Assessment in Head Injury Patients: A Prospective Study and Review of Literature.

Head injuries constitute a tragic problem invariably in under-developed, developed and developing countries. The concomitant otological injuries often go unnoticed. The purpose of this study was to assess the various otological manifestations following head injuries. Prospective study with review of literature using PubMed database was done. All the patients were evaluated for their presenting symptoms and signs. Audiological investigations including PTA (Pure tone audiometry), OAE (Otoacoustic emission), Impedance-Audiometry and BERA were done. HRCT temporal bone was advised in cases of suspicion. Relevant literature was reviewed to calculate the pooled prevalence rates. Random-effects model to synthesize overall effects was used. Heterogeneity was evaluated with the I2 statistic. Of 53 patients enrolled in the study, RTA was the most common mode of injury. The audiometric findings showed SNHL, CHL and mixed HL in 34, 20 and 18% of patients respectively. HRCT showed Longitudinal fracture (n = 17; 53.12%); isolated mastoid bone fracture (n = 9; 28.12%), transverse (n = 3; 9.37%) and isolated EAC fracture in (n = 3; 9.37%) patients. The pooled prevalence (n = 1106 patients) of SNHL, CHL, Mixed HL and Normal hearing were-35% (95%CI, 18-55%; I2 = 95.20%; P < 0.00), 24% (95%CI, 16-33%; I2 = 80.01%; P < 0.00), 15%(95%CI, 9-23%; I2 = 79.64%; P < 0.00) and 30% (95%CI, 3-66%; I2 = 98.71%; P < 0.00) respectively. The pooled prevalence (n = 4191 patients) of longitudinal, Transverse, mixed and other fractures were-44% (95%CI, 3-66%;I2 = 99.48%; P < 0.00), 9% (95% CI, 4-16%; I2 = 95.95%; P < 0.00), 4% (95%CI, 1-8%; I2 = 94.13%; P < 0.00) and 1% (95%CI, 0-4%; I2 = 90.37%; P < 0.00) respectively. In patients with head injury coordination between the trauma-surgeon, neurosurgeon and otologist is must to improve the long-term outcomes.

Generation of two induced pluripotent stem cell lines carrying the phospholamban R14del mutation for modeling ARVD/C.

The phospholamban (PLN) R14del mutation is associated with arrhythmogenic right ventricular dysplasia (ARVD/C). ARVD/C is a cardiac disease characterized by arrhythmias and structural abnormalities in the right ventricle. Because PLN is a regulator of calcium release, this mutation can have deleterious effects on tissue integrity and contraction. This mutation is a trinucleotide (AGA) deletion that leads to an arginine deletion at position 14 of the PLN structure. Here we show two lines carrying this mutation with typical iPSC morphology, pluripotency, karyotype, ability to differentiate into the three germ layers in vitro, and readily availability for studying pathological mechanisms or ARVD/C.

Incidence of Olfactory and Gustatory Dysfunctions in the Early Stages of COVID-19: An Objective Evaluation

Abstract Introduction Coronavirus disease 2019 (COVID-19) is a dangerous infectious disease caused by a newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has various clinical presentations. Numerable cases with non-specific olfactory and gustatory dysfunctions in COVID-19 have been reported from all over the globe. This is important as awareness will let people to self-isolate and help in limiting disease spread. Objective To objectively evaluate the frequency of olfactory and gustatory dysfunction, which may occur independently or with other symptoms, in laboratory confirmed COVID-19 patients at an early stage of the disease. Methods Objective evaluation of olfactory and gustatory function of 322 COVID-19 patients treated at our hospital, (SMGS, Government Medical College, Jammu), from August 2020 until November 2020. Results Our study population included 127 (39.4%) males and 195 (60.6%) females. Two hundred and twenty-six (70.2%) COVID-19 patients experienced olfactory and gustatory disorders. One hundred and sixty-five (51.2%) cases experienced both olfactory and gustatory disorders. Isolated olfactory dysfunction was reported in 34 (10.6%) patients, while 27 (8.4%) patients experienced only gustatory dysfunction. Conclusion The olfactory and gustatory dysfunctions, without any nasal obstruction or rhinorrhea, are significant symptoms in the clinical presentation of early COVID-19 patients. This presentation can be recognized at the earliest one, and it can reduce the high communicability of the COVID-19 disease.

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

Injectable hydrogel for co-delivery of 5-azacytidine in zein protein nanoparticles with stem cells for cardiac function restoration.

Heart failure is major cause of mortality associated with mostly Myocardial infarction (MI). Transplanting mesenchymal stem cells (MSC) have exhibited potential role in myocardial regeneration. Secretion of immune-modulatory cytokines and various growth factors after transplantation plays significant role in remodelling process of MI region. However, low retention, higher shear stress during administration and rejection at host infarct environment hinders therapeutic efficacy. Myocardial regeneration demands for accurate spatio-temporal delivery of MSCs with supportive vascular network that leads to improvement of cardiac function. In this study, injectable alginate based microporous hydrogel has been used to deliver 5-Azacytidine (5-Aza) in zein protein nanoparticle with MSCs for attenuating adverse cardiac remodelling after MI. Zein nanoparticles loaded with 5-Aza were prepared by liquid-liquid dispersion, and it was found that 35% of drug was released in 7 days supported with mathematical modelling. The presence of 5-Aza and zein in developed hydrogel supported in vitro MSC proliferation, migration and angiogenesis. Significant increased expression of cardiac specific markers, GATA4, MEF2C, MLC, SERCA and NKX2.5 was observed in vitro. 5-Aza loaded protein nanoparticle with MSCs encapsulated hydrogels in rat MI model also exhibited substantial improvement of functional cardiac parameters such as cardiac output and ejection fraction. Histopathological analysis showed reduced fibrosis, attenuated infarct expansion and cardiac tissue restoration and angiogenesis. In brief, we developed nanocarrier-hydrogel system a promising strategy for co-delivering 5-Aza as cardiac differentiation cue with MSCs to achieve higher cell retention and enhanced improvement in myocardial regeneration after MI.

Multidisciplinary collaborative approach for management of adrenal tumors: Outcomes of minimally invasive adrenalectomy at a single center.

INTRODUCTION: Laparoscopy is currently the gold standard for the management of adrenal tumors as it is associated with less morbidity. Owing to technological advances, even large adrenal tumors are currently amenable to laparoscopic removal. In this work, we describe our multidisciplinary collaborative approach for management of adrenal tumors at a single center. MATERIAL AND METHODS: Between January 2017 and January 2020, 18 patients with adrenal lesions were operated at our center. Five of these patients had incidentalomas. All patients were evaluated in coordination with endocrinologists and anesthetists. All patients underwent transperitoneal laparoscopic adrenalectomy. The surgical complications were classified as per Clavein-Dindo system. All patients with pheochromocytoma and Cushing syndrome were followed up by the endocrinologist for further evaluation and titration of glucocorticoids and antihypertensive medication. RESULTS: Two out of the 18 patients had American Society of Anesthesiologists (ASA) physical status III. Out of the 18 patients, only one required conversion to open surgery. Five patients developed intraoperative hypertensive crisis while three patients developed hypotensive crisis. All patients were ambulated on the first postoperative day and were discharged on the third post operative day. None of the patients developed any major (Clavein-Dindo III-V) intra operative or post operative complications. CONCLUSION: Laparoscopic adrenalectomy is the procedure of choice for adrenal tumors. A multi-disciplinary approach involving the endocrinologist, anesthesiologist, and laparoscopic surgeon can help achieve favorable outcomes.

Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy.

Objective- This study investigates the functional significance of mitochondria present in endothelial microparticles (EMP) and how MK2 (MAPKAPK2 [MAPK-activated protein kinase 2]) governs EMP production and its physiological effect on cardiac hypertrophy. Approach and Results- Flow cytometric analysis, confocal imaging, oxygen consumption rate measurement through Seahorse were used to confirm the presence of functionally active mitochondria in nontreated EMP (EMP derived from untreated control cells), lipopolysaccharide, and oligomycin treatment increased mitochondrial reactive oxygen species activity in EMP (EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin, respectively). The dysfunctional mitochondria contained in EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin induced the expression of proinflammatory mediators in the target endothelial cells leading to the augmented adhesion of human monocytic cell line on EA.hy926 cells. Multiphoton real-time imaging detected the increased adherence of EMP derived from cells treated with oligomycin at the site of carotid artery injury as compared to EMP derived from untreated control cells. MK2 regulates EMP generation during inflammation by reducing E-selectin expression and regulating the cytoskeleton rearrangement through ROCK-2 (Rho-associated coiled-coil containing protein kinase 2) pathway. MK2-deficient EMP reduced the E-selectin and ICAM-1 (intracellular adhesion molecule-1) expression on target endothelial cells leading to reduced monocyte attachment and reduced cardiac hypertrophy in mice. Conclusions- MK2 promotes the proinflammatory effect of EMP mediated through dysfunctional mitochondria. MK2 modulates the inflammatory effect induced during cardiac hypertrophy through EMP.

Inhibition of fatty acid synthase is protective in pulmonary hypertension.

BACKGROUND AND PURPOSE: In pulmonary hypertension (PH), similar to cancer, there is altered energy metabolism, apoptosis resistance and cellular proliferation leading to pulmonary vascular remodelling. Proliferating cells exhibit higher rate of de novo fatty acid synthesis to provide lipids for membrane formation and energy production. As inhibition of de novo fatty acid synthesis proved protective in cancer experimentally, therefore, it was hypothesized that modulation of de novo fatty acid synthesis by inhibition of fatty acid synthase (FAS) may prove beneficial for PH. EXPERIMENTAL APPROACH: For in vitro studies, human pulmonary artery smooth muscle cells (HPASMCs) were exposed to hypoxia and to induce PH in vivo, rats were treated with monocrotaline (MCT). FAS was inhibited by siRNA (60 nM) and C75 (2 mg·kg(-1) , i.p. once a week for 5 weeks) in in vitro and in vivo studies respectively. RESULTS: Increased expression and activity of FAS were observed in hypoxic HPASMCs and lungs of MCT-treated rats. Inhibition of FAS increased apoptosis and glucose oxidation, but decreased proliferation and markers of autophagy, glycolysis and insulin resistance in hypoxic HPASMCs. It also improved the mitochondrial functions as evident by increased level of ATP and restoration of normal level of ROS and membrane potential of mitochondria. In MCT-treated rats, FAS inhibition decreased right ventricular pressure, hypertrophy, pulmonary vascular remodelling (increased apoptosis and decreased proliferation of cells) and endothelial dysfunction in lungs. CONCLUSIONS: Our results demonstrate that FAS activity is modulated in PH, and its inhibition may provide a new therapeutic approach to treat PH.

Curcuma oil reduces endothelial cell-mediated inflammation in postmyocardial ischemia/reperfusion in rats.

Endothelial cells initiated inflammation persisting in postmyocardial infarction needs to be controlled and moderated for avoiding fatal complications. Curcuma oil (C.oil, Herbal Medicament), a standardized hexane soluble fraction of Curcuma longa has possessed neuroprotective effect. However, its effect on myocardial ischemia/reperfusion (MI/RP) and endothelial cells remains incompletely defined. Here, using in vivo rat MI/RP injury model and in vitro cellular approaches using EA.hy926 endothelial cells, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and myograph, we provide evidence that with effective regimen and preconditioning of rats with C.oil (250 mg/kg, PO), before and after MI/RP surgery protects rats from MI/RP-induced injury. C.oil treatment reduces left ventricular ischemic area and endothelial cell-induced inflammation, specifically in the ischemic region (*P < 0.0001) and improved endothelial function by reducing the expression of proinflammatory genes and adhesion factors on endothelial cells both in vitro and in vivo. Furthermore, mechanistic studies have revealed that C.oil reduced the expression of adhesion factors like E-selectin (#P = 0.0016) and ICAM-1 ($P = 0.0069) in initiating endothelial cells-induced inflammation. In line to the real-time polymerase chain reaction expression data, C.oil reduced the adhesion of inflammatory cells to endothelial cells as assessed by the interaction of THP-1 monocytes with the endothelial cells using flow-based adhesion and under inflammatory conditions. These studies provide evidence that salutary effect of C.oil on MI/RP could be achieved with pretreatment and posttreatment of rats, C.oil reduced MI/RP-induced injury by reducing the endothelial cell-mediated inflammation, specifically in the ischemic zone of MI/RP rat heart.

Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors.

The synthetic nuclear bile acid receptor (farnesoid X receptor [FXR]) agonist GW4064 is extensively used as a specific pharmacological tool to illustrate FXR functions. We noticed that GW4064 activated empty luciferase reporters in FXR-deficient HEK-293T cells. We postulated that this activity of GW4064 might be routed through as yet unknown cellular targets and undertook an unbiased exploratory approach to identify these targets. Investigations revealed that GW4064 activated cAMP and nuclear factor for activated T-cell response elements (CRE and NFAT-RE, respectively) present on these empty reporters. Whereas GW4064-induced NFAT-RE activation involved rapid intracellular Ca(2+) accumulation and NFAT nuclear translocation, CRE activation involved soluble adenylyl cyclase-dependent cAMP accumulation and Ca(2+)-calcineurin-dependent nuclear translocation of transducers of regulated CRE-binding protein 2. Use of dominant negative heterotrimeric G-protein minigenes revealed that GW4064 caused activation of Gαi/o and Gq/11 G proteins. Sequential pharmacological inhibitor-based screening and radioligand-binding studies revealed that GW4064 interacted with multiple G protein-coupled receptors. Functional studies demonstrated that GW4064 robustly activated H1 and H4 and inhibited H2 histamine receptor signaling events. We also found that MCF-7 breast cancer cells, reported to undergo GW4064-induced apoptosis in an FXR-dependent manner, did not express FXR, and the GW4064-mediated apoptosis, also apparent in HEK-293T cells, could be blocked by selective histamine receptor regulators. Taken together, our results demonstrate identification of histamine receptors as alternate targets for GW4064, which not only necessitates cautious interpretation of the biological functions attributed to FXR using GW4064 as a pharmacological tool but also provides a basis for the rational designing of new pharmacophores for histamine receptor modulation.

Heart failure due to a post-traumatic calcified pericardial hematoma.

Chest-wall trauma can produce bleeding into the pericardium and initiate a process of inflammation, calcification, and scarring that may eventually produce pericardial constriction. Herein, we present an unusual case of a man who experienced chest trauma at age 16 years, and developed heart failure 40 years later secondary to a large, calcified pericardial hematoma. During its prolonged genesis, the pericardial mass became deeply embedded in the myocardium and produced evidence of both constrictive and restrictive cardiomyopathy. Despite attempted surgical resection, the lesion could not be completely removed, nor could its hemodynamic impact be completely resolved.

Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures.

BACKGROUND: Patients with heparin-induced thrombocytopenia (HIT) (with or without thrombosis) require alternative anticoagulation because of their extreme risk of new thromboembolic complications. The first effective agent for this purpose may be danaparoid, a less-sulfated low molecular weight heparinoid. Recently, direct thrombin inhibitors have been used. OBJECTIVE: Five HIT patients, who developed new thromboembolic complications while receiving danaparoid, were analyzed to consider possible reasons for treatment failure and to promulgate strategies that improve efficacy. RESULTS: Three patients had acute HIT, one had recent HIT, and one with remote HIT was re-exposed to heparin during heart surgery. Danaparoid was started as intravenous bolus and infusion in one patient, and as 1250 units subcutaneously twice daily in four patients. The new complications that emerged on danaparoid were new venous thrombi in three patients (one with pulmonary emboli), lower extremity arterial thrombosis in one, myocardial ischemia in one, thromboembolic cardiovascular accidents in one, and fatal bowel necrosis in one (two patients suffered more than one complication). Platelet counts did not improve or worsened in four, improved partially in the other, and parameters of disseminated intravascular coagulation failed to improve in one patient. Four patients responded relatively dramatically when direct thrombin inhibitors were substituted. Possible reasons for danaparoid failure include that: 1) no treatment is expected to completely prevent complications, 2) antithrombin III consumption can blunt efficacy in some patients, 3) low or intermediate doses may be insufficient, and 4) there was clinically significant cross-reactivity of the pathogenic HIT antibodies. CONCLUSIONS: It is emphasized that the possibility of clinically significant antibody cross-reactivity and that low or intermediate dosage may be inadequate when using danaparoid in therapy of HIT. The latter problem probably extrapolates to other anticoagulants used for HIT.