Thirty-day hospital readmission in females with acute heart failure and breast cancer: A retrospective cohort study from national readmission database.

BACKGROUND: Breast Cancer and cardiovascular diseases are amongst the two leading causes of mortality in the United States, and the two conditions are connected in part because of recognized cardiotoxicity of cancer treatments. The aim of this study is to investigate the predictors risk factors for thirty-day readmission in female breast cancer survivors presenting with acute heart failure. METHODS: This is a retrospective cohort study of acute heart failure (AHF) hospitalization in female patients with breast cancer in 2019 using the National Readmission Database (NRD), which is the largest publicly available all-payer inpatient readmission database in the United States. Our study sample included adult female patients aged 18 years and older. The primary outcome of interest was the rate of 30- day readmission. RESULTS: In 2019, there were 8332 total index admissions for AHF in females with breast cancer and 7776 patients were discharged alive. The mean age was 74.4 years (95% CI: 74, 74.7). The percentage of readmission at 30 days among those discharged alive was 21.8% (n = 1699). Hypertensive heart disease with chronic kidney disease accounted for the majority of readmission in AHF with breast cancer followed by sepsis, acute kidney injury, respiratory failure, pneumonia, and atrial fibrillation. Demographic factors including higher burden of comorbidities predict readmission. The total in-hospital mortality in index admission was 6.67% (n = 556) and for readmitted patients was 8.77% (n = 149). The mean length of stay for index admission was 7.5 days (95% CI: 7.25, 7.75). CONCLUSIONS: Readmission of female breast cancer survivors presenting with AHF is common and largely be attributed to high burden of comorbidities including hypertension, and chronic kidney disease. A focus on close outpatient follow-up will be beneficial in lowering readmissions.

Tumor-derived Hsp70-CD14 interaction enhances the antitumor potential of cytotoxic T cells by activating tumor-associated macrophages to express CC chemokines and CD40 costimulatory molecules.

Heat shock proteins are a widely distributed group of proteins. It is constitutively expressed in almost all organisms and shows little variation throughout evolution. Previously, HSPs, particularly Hsp70, were recognized as molecular chaperones that aid in the proper three-dimensional folding of newly synthesized polypeptides in cells. Recently, researchers have focused on the potential induction of immune cells, including macrophages, antigen-specific CD8+ cytotoxic T cells, and PBMCs. It induces the expression of CC chemokines such as MIP-1α and RANTES, which are responsible for the chemotactic movement and migration of immune cells at the site of infection to neutralize foreign particles in vivo and in vitro in several cell lines but their effect on tumor-associated macrophages is still not known. These cytokines are also known to influence the movement of several immune cells, including CD8+ cytotoxic T cells, toward inflammatory sites. Therefore, the effect of tumor-derived autologous Hsp70 on the expression of MIP-lα and RANTES in tumor-associated macrophages (TAMs) was investigated. Our results indicated that Hsp70 treatment-induced MIP-lα and RANTES expression was significantly greater in TAMs than in NMOs. According to the literature, the CC chemokine shares the same receptor, CCR5, as HIV does for their action, and therefore could provide better completion to the virus for ligand binding. Furthermore, Hsp70-preactivated TAMs induced increased IL-2 and IFN-γ expression in T cells during coculture for 48 h and upregulated the antitumor immune response of the host. Therefore, the outcome of our study could be useful for developing a better approach to restricting the growth and progression of tumors.

Enhancing cancer immunotherapy: Exploring strategies to target the PD-1/PD-L1 axis and analyzing the associated patent, regulatory, and clinical trial landscape.

Cancer treatment modalities and their progression is guided by the specifics of cancer, including its type and site of localization. Surgery, radiation, and chemotherapy are the most often used conventional treatments. Conversely, emerging treatment techniques include immunotherapy, hormone therapy, anti-angiogenic therapy, dendritic cell-based immunotherapy, and stem cell therapy. Immune checkpoint inhibitors' anticancer properties have drawn considerable attention in recent studies in the cancer research domain. Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) checkpoint pathway are key regulators of the interactions between activated T-cells and cancer cells, protecting the latter from immune destruction. When the ligand PD-L1 attaches to the receptor PD-1, T-cells are prevented from destroying cells that contain PD-L1, including cancer cells. The PD-1/PD-L1 checkpoint inhibitors block them, boosting the immune response and strengthening the body's defenses against tumors. Recent years have seen incredible progress and tremendous advancement in developing anticancer therapies using PD-1/PD-L1 targeting antibodies. While immune-related adverse effects and low response rates significantly limit these therapies, there is a need for research on methods that raise their efficacy and lower their toxicity. This review discusses various recent innovative nanomedicine strategies such as PLGA nanoparticles, carbon nanotubes and drug loaded liposomes to treat cancer targeting PD-1/PD-L1 axis. The biological implications of PD-1/PD-L1 in cancer treatment and the fundamentals of nanotechnology, focusing on the novel strategies used in nanomedicine, are widely discussed along with the corresponding guidelines, clinical trial status, and the patent landscape of such formulations.

Nose-to-brain Drug Delivery System: An Emerging Approach to Chemotherapy-induced Cognitive Impairment.

The rise in global cancer burden, notably breast cancer, emphasizes the need to address chemotherapy-induced cognitive impairment, also known as chemobrain. Although chemotherapy drugs are effective against cancer, they can trigger cognitive deficits. This has triggered the exploration of preventive strategies and novel therapeutic approaches. Nanomedicine is evolving as a promising tool to be used for the mitigation of chemobrain by overcoming the blood-brain barrier (BBB) with innovative drug delivery systems. Polymer and lipid-based nanoparticles enable targeted drug release, enhancing therapeutic effectiveness. Utilizing the intranasal route of administration may facilitate drug delivery to the central nervous system (CNS) by circumventing first-pass metabolism. Therefore, knowledge of nasal anatomy is critical for optimizing drug delivery via various pathways. Despite challenges, nanoformulations exhibit the potential in enhancing brain drug delivery. Continuous research into formulation techniques and chemobrain mechanisms is vital for developing effective treatments. The intranasal administration of nanoformulations holds promise for improving therapeutic outcomes in chemobrain management. This review offers insights into potential future research directions, such as exploring novel drug combinations, investigating alternative delivery routes, or integrating emerging technologies to enhance the efficacy and safety of nanoformulations for chemobrain management.

Ultrasonication-assisted synthesis of transition metal carbide of MXene: an efficient and promising material for photocatalytic organic dyes degradation of rhodamine B and methylene blue in wastewater.

Water pollutants of non-biodegradable toxic aromatic dye including Methylene blue (MB) and Rhodamine (RhB) are extremely carcinogenic thiazines used in various industries such as leather industry, paper industry, and the dyeing industry. The presence of dyes in wastewater causes severe threats to human health that are responsible for various harmful chronic or acute diseases and also shows an adverse impact on the environment as it reduces transparency and is harmful to water microorganisms. To overcome severe issues, many traditional techniques have been used to remove toxic pollutants, but these methods are insufficient to remove chemically stable dyes that remain in the treated wastewater. However, the photocatalytic degradation process is an efficient approach to degrade the dye up to the maximum extent with improved efficiency. Therefore, in this work, a new class of two-dimensional (2D) transition metal carbide of Titanium Carbide (Ti3C2Tx) MXene material was used for the organic dyes degradation such as MB and RhB using a photocatalytic process. A layered structure of hexagonal lattice symmetry of Ti3C2Tx MXene was successfully synthesized from the Titanium Aluminum Carbide of Ti3AlC2 bulk phase using an exfoliation process. Further, the XRD spectrum confirms the transformation of bulk MAX phase having (002) plane at 9.2° to Ti3C2Tx MXene of (002) plane at 8.88° confirms the successful removal of Al layer from MAX phase. A smooth, transparent, thin sheet-like morphology of Ti3C2Tx nanosheet size were found to be in the range of 70 to 150 nm evaluated from TEM images. Also, no holes or damages in the thin sheets were found after the treatment with strong hydrofluoric acid confirms the formation Ti3C2Tx layered sheets. The synthesized Ti3C2Tx MXene possesses excellent photocatalytic activity for the degradation of dyes MB, RhB, and mixtures of MB and RhB dyes. MB dye degraded with a degradation percentage efficiency of 99.32% in 30 min, while RhB dye was degraded upto 98.9% in 30 min. Also, experiments were conducted for degradation of mixture of MB and RhB dyes by UV light, and the degradation percentage efficiency were found to be 98.9% and 99.75% for mixture of MB and RhB dye in 45 min, respectively. Moreover, reaction rate constant (k) was determined for each dye of MB, RhB, and mixtures of MB and RhB and was found to be 0.0215 min-1 and 0.0058 min-1, and for mixtures, it was 0.0020 min-1 and 0.009 min-1, respectively.

Targeting epidermal growth factor receptor and its downstream signaling pathways by natural products: A mechanistic insight.

The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that maintains normal tissues and cell signaling pathways. EGFR is overactivated and overexpressed in many malignancies, including breast, lung, pancreatic, and kidney. Further, the EGFR gene mutations and protein overexpression activate downstream signaling pathways in cancerous cells, stimulating the growth, survival, resistance to apoptosis, and progression of tumors. Anti-EGFR therapy is the potential approach for treating malignancies and has demonstrated clinical success in treating specific cancers. The recent report suggests most of the clinically used EGFR tyrosine kinase inhibitors developed resistance to the cancer cells. This perspective provides a brief overview of EGFR and its implications in cancer. We have summarized natural products-derived anticancer compounds with the mechanistic basis of tumor inhibition via the EGFR pathway. We propose that developing natural lead molecules into new anticancer agents has a bright future after clinical investigation.

Tackling Nontuberculous Mycobacteria by Repurposable Drugs and Potential Leads from Natural Products.

Nontuberculous Mycobacteria (NTM) refer to bacteria other than all Mycobacterium species that do not cause tuberculosis or leprosy, excluding the species of the Mycobacterium tuberculosis complex, M. leprae and M. lepromatosis. NTM are ubiquitous and present in soils and natural waters. NTM can survive in a wide range of environmental conditions. The direct inoculum of the NTM from water or other materials is most likely a source of infections. NTMs are responsible for several illnesses, including pulmonary alveolar proteinosis, cystic fibrosis, bronchiectasis, chronic obstructive pneumoconiosis, and pulmonary disease. Recent reports suggest that NTM species have become insensitive to sterilizing agents, antiseptics, and disinfectants. The efficacy of existing anti-NTM regimens is diminishing and has been compromised due to drug resistance. New and recurring cases of multidrug-resistant NTM strains are increasing. Thus, there is an urgent need for ant-NTM regimens with novel modes of action. This review sheds light on the mode of antimicrobial resistance in the NTM species. Then, we discussed the repurposable drugs (antibiotics) that have shown new indications (activity against NTM strains) that could be developed for treating NTM infections. Also, we have summarised recently identified natural leads acting against NTM, which have the potential for treating NTM-associated infections.

Targeting Mycobacterium tuberculosis iron-scavenging tools: a recent update on siderophores inhibitors.

Among the various bacterial infections, tuberculosis (TB) remains a life-threatening infectious disease responsible as the most significant cause of mortality and morbidity worldwide. The co-infection of human immunodeficiency virus (HIV) in association with TB burdens the healthcare system substantially. Notably, M.tb possesses defence against most antitubercular antibiotic drugs, and the efficacy of existing frontline anti-TB drugs is waning. Also, new and recurring cases of TB from resistant bacteria such as multidrug-resistant TB (MDR), extensively drug-resistant TB (XDR), and totally drug-resistant TB (TDR) strains are increasing. Hence, TB begs the scientific community to explore the new therapeutic class of compounds with their novel mechanism. M.tb requires iron from host cells to sustain, grow, and carry out several biological processes. M.tb has developed strategic methods of acquiring iron from the surrounding environment. In this communication, we discuss an overview of M.tb iron-scavenging tools. Also, we have summarized recently identified MbtA and MbtI inhibitors, which prevent M.tb from scavenging iron. These iron-scavenging tool inhibitors have the potential to be developed as anti-TB agents/drugs.

Fluorescent Turn-On Anthracene-Based Aluminum(III) Sensor for a Therapeutic Study in Alzheimer's Disease Model of Drosophila.

A new anthracene-based probe (E)-N'-(1-(anthracen-9-yl)ethylidene)-2-hydroxybenzohydrazide (AHB) has been efficiently synthesized and characterized by various spectroscopic methods. It exhibits extremely selective and sensitive fluorometric sensing of Al3+ ions with a large enhancement in the fluorescent intensity due to the restricted photoinduced electron transfer (PET) mechanism with a chelation-enhanced fluorescence (CHEF) effect. The AHB-Al3+ complex shows a remarkably low limit of detection at 0.498 nM. The binding mechanism has been proposed based on Job's plot, 1H NMR titration, Fourier transform infrared (FT-IR), high-resolution mass spectrometry (HRMS), and density functional theory (DFT) studies. The chemosensor is reusable and reversible in the presence of ctDNA. The practical usability of the fluorosensor has been established by a test strip kit. Further, the therapeutic potential of AHB against Al3+ ion-induced tau protein toxicity has been tested in the eye of Alzheimer's disease (AD) model of Drosophila via metal chelation therapy. AHB shows great therapeutic potential with 53.3% rescue in the eye phenotype. The in vivo interaction study of AHB with Al3+ in the gut tissue of Drosophila confirms its sensing efficiency in the biological environment. A detailed comparison table included evaluates the effectiveness of AHB.

Predicting Risk of Cardiac Arrest in Young Asian Americans: Insights from an Artificial Neural Network Analysis of the Nationwide Cohort.

We used the Artificial Neural Network (ANN) model to identify predictors of Sudden Cardiac Arrest (SCA) in a national cohort of young Asian patients in the United States. The National Inpatient Sample (2019) was used to identify young Asians (18-44-year-old) who were hospitalized with SCA. The neural network's predicted criteria for SCA were selected. After eliminating missing data, young Asians (n = 65,413) were randomly divided into training (n = 45,094) and testing (n = 19347) groups. Training data (70%) was used to calibrate ANN while testing data (30%) was utilized to assess the algorithm's accuracy. To determine ANN's performance in predicting SCA, we compared the frequency of incorrect prediction between training and testing data and measured the area under the Receiver Operating Curve (AUC). The 2019 young Asian cohort had 327,065 admissions (median age 32 years; 84.2% female), with SCA accounting for 0.21%. The exact rate of error in predictions vs. tests was shown by training data (0.2% vs 0.2%). In descending order, the normalized importance of predictors to accurately predict SCA in young adults included prior history of cardiac arrest, sex, age, diabetes, anxiety disorders, prior coronary artery bypass grafting, hypertension, congenital heart disease, income, peripheral vascular disease, and cancer. The AUC was 0.821, indicating an excellent ANN model for SCA prediction. Our ANN models performed excellently in revealing the order of important predictors of SCA in young Asian American patients. These findings could have a considerable impact on clinical practice to develop risk prediction models to improve the survival outcome in high-risk patients.

Brain-targeted Nano-architectures for Efficient Drug Delivery and Sensitization in Glioblastoma.

Due to ineffective diagnosis and analysis, glioblastoma multiforme (GBM), is still the most aggressive form of all cancers. Standard therapy for GBM comprises resection surgery following chemo and radiotherapy, which offers less efficacious treatment to the malignant nature of glioma. Several treatment strategies involving gene therapy, immunotherapy, and angiogenesis inhibition have been employed recently as alternative therapeutics. The main drawback of chemotherapy is resistance, which is mainly due to the enzymes involved in the therapeutic pathways. Our objective is to provide a clear insight into various nano-architectures used in the sensitization of GBM and their importance in drug delivery and bioavailability. This review includes the overview and summary of articles from Pubmed and Scopus search engines. The present era's synthetic and natural drugs used in the treatment of GBM are facing poor Blood Brain Barrier (BBB) permeability issues due to greater particle size. This problem can be resolved by using the nanostructures that showcase high specificity to cross the BBB with their nano-scale size and broader surface area. Nano-architectures act as promising tools for effective brain-targeted drug delivery at a concentration well below the final dose of free drug, thus resulting in safe therapeutic effects and reversal of chemoresistance. The present review focuses on the mechanisms involved in the resistance of glioma cells to chemotherapeutic agents, nano-pharmacokinetics, diverse types of nano-architectures used for potent delivery of the medicine and sensitization in GBM, their recent clinical advances, potential challenges, and future perspective.

Concurrent Cardio-Cerebral Infarctions in COVID-19: A Systematic Review of Published Case Reports/Series.

Twelve CCI patients were studied with confirmed or suspected COVID-19 infection. The majority of these patients were males (83.3%) with a median age of 55 years from three geographical locations, constituting the Middle East (7), Spain (3), and the USA (1). In 6 patients, IgG/IgM was positive for COVID-19, 4 with high pretest probability and 2 with positive RT-PCR. Type 2 DM, hyperlipidemia, and smoking were the primary risk factors. Right-sided neurological impairments and verbal impairment were the most common symptoms. Our analysis found 8 (66%) synchronous occurrences. In 58.3% of cases, neuroimaging showed left Middle Cerebral Artery (MCA) infarct and 33.3% right. Carotid artery thrombosis (16.6%), tandem occlusion (8.3%), and carotid stenosis (1%) were also reported in imaging. Dual antiplatelet therapy (DAPT) and anticoagulants were conservative therapies (10). Two AMI patients had aspiration thrombectomy, while three AIS patients had intravenous thrombolysis/tissue plasminogen activator (IVT-tPA), 2 had mechanical thrombectomy (MT), and 1 had decompressive craniotomy. Five had COVID-19-positive chest X-rays, whereas 4 were normal. four of 8 STEMI and 3 NSTEMI/UA patients complained chest pain. LV, ICA, and pulmonary embolism were further complications (2). Upon discharge, 7 patients (70%) had residual deficits while 1 patient unfortunately died.

Vinpocetine mitigates DMH-induce pre-neoplastic colon damage in rats through inhibition of pro-inflammatory cytokines.

Colorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4 mg/kg/day p.o.) for 15 days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1ß, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.

Cardiovascular Disease Risk Factors and Outcomes of Acute Myocardial Infarction in Young Adults: Evidence From 2 Nationwide Cohorts in the United States a Decade Apart.

The purpose of this study was to evaluate 2 national in-patient cohorts of young adults (18-44 years) hospitalized with acute myocardial infarction (AMI) a decade apart to highlight its prevalence, associated comorbidities, and in-hospital outcomes. We identified hospitalizations for AMI in young adults in 2007 and 2017 using the weighted data from the National Inpatient Sample. We compared admission rates, sociodemographic characteristics, in-hospital morbidity, complications, mortality, rate of coronary interventions, and healthcare utilization between the 2 cohorts. We found that the admission rate of AMI increased among young adults in 2017 vs 2007. The overall admission rate was higher in males, although with a decline (77.1% vs 66.1%), whereas it rose from 28.9% to 33.9% in females. Hypertension (47.8% vs 60.7%), smoking (49.7% vs 55.8%), obesity (14.8% vs 26.8%), and diabetes mellitus (22.0% vs 25.6%) increased in the 2017 cohort. Post-AMI complications: cardiogenic shock (aOR = 1.16 [1.06-1.27]) and fatal arrhythmias heightened with comparable all-cause mortality (aOR = 1.01 [0.93-1.10], P = 0.749). Reperfusion interventions, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) decreased in the 2017 cohort (PCI; aOR = 0.95 [0.91-0.98], CABG; aOR = 0.66 [0.61-0.71], P < 0.001). Our study highlights the rise in AMI hospitalizations, plateauing of mortality, sex-based and racial disparities, the surge in post-MI complications, and a reassuring decline in the requirement of reperfusion interventions in young AMI patients over the decade.

Chimeric Antigen Receptor T-cell Therapy in Cancer: A Critical Review.

Targeted cancer therapy acts on targeted molecules, is less toxic to normal cells, and acts more specifically on cancer cells. The two primary strategies for preventing malignancy growth are the blocking of T-cell repression signals or forwarding of T-cell to tumor target with both T and tumor-specific antibodies. The CAR comprises three domains, the extracellular antigen recognition domain and the intracellular T-cell signaling domain, which participate in activating T-cells. The two most common adverse effects of CAR T-cell treatment are cytokine release syndrome (CRS) and cell-associated neurotoxicity syndrome (CANS). The adaptability of intracellular signaling domains inside CARs allows the cell to counterbalance the downregulation of costimulatory molecules produced by tumor cells, either indirectly or directly. The major disadvantage of CAR-T cell therapy is off-target toxicity. Treatment with CARs expressing CD3, CD123, Lewis Y, CLL-1, CD44v6, FLT3, and folate receptors showed promising results in preclinical models of acute myeloid leukemia (AML). A recent study has revealed that B7-H3 CART cells exhibit significant anticancer efficacy in a variety of solid tumor preclinical models, including PDAC, ovarian cancer, neuroblastoma, and various pediatric malignancies. The notion of SUPRA CAR, with its unique capacity to alter targets without the need to re-engineer, is a recent innovation in CAR. Given the importance of NK cells in tumor development and metastatic defence, NK cell-based immunotherapies, including adoptive transfer of NK cells, have garnered a lot of interest. With the advancement of improved cellular manufacturing methods, novel cellular engineering strategies, precision genome editing technologies, and combination therapy approaches, we firmly believe that CAR-T cells will soon become an off-the-shelf, cost-effective, and potentially curative therapy for oncogenesis.

Graphene oxide-supported nickel(II) complex as a reusable nano catalyst for the synthesis of bis(indolyl)methanes.

A novel catalytic system of a nickel(II) complex of (E)-N'-((2-amino-5-chlorophenyl)(phenyl)methylene)-2-hydroxy-benzohydrazide (APH) supported on graphene oxide (GO) has been prepared. Detailed characterization of the synthesized catalyst has been carried out using NMR, FTIR, HRMS, PXRD, Raman, SEM, TEM, EDX and XPS. Its catalytic efficiency has been explored for the synthesis of various bis(indolyl)methane derivatives. The optimized reaction conditions prove that the catalyst is highly efficient, performs under mild conditions and is required in a very small amount (2 wt%). A diversified library of bis(indolyl)methane derivatives containing various electron donating and withdrawing substituents has been developed in high to excellent yields. The catalyst is equally efficient towards heterocyclic aldehydes. Moreover, owing to the strong covalent interaction between the APH-Ni(II) complex and GO, the catalyst shows outstanding recyclability for six subsequent cycles without any significant loss in activity.

Temozolomide Resistance: A Multifarious Review on Mechanisms Beyond O-6-Methylguanine-DNA Methyltransferase.

BACKGROUND: Chemotherapy with the oral alkylating agent temozolomide still prevails as a linchpin in the therapeutic regimen of glioblastoma alongside radiotherapy. Because of the impoverished prognosis and sparse chemotherapeutic medicaments associated with glioblastoma, the burgeoning resistance to temozolomide has made the whole condition almost irremediable. OBJECTIVE: The present review highlights the possible mechanisms of drug resistance following chemotherapy with temozolomide. METHODS: The review summarizes the recent developments, as published in articles from Scopus, PubMed, and Web of Science search engines. DESCRIPTION: One of the prime resistance mediators, O-6-methylguanine-DNA methyltransferase, upon activation, removes temozolomide-induced methyl adducts bound to DNA and reinstates genomic integrity. In the bargain, neoteric advances in the conception of temozolomide resistance have opened the door to explore several potential mediators like indirect DNA repair systems, efflux mechanisms, epigenetic modulation, microenvironmental influences, and autophagy-apoptosis processes that constantly lead to the failure of chemotherapy. CONCLUSION: This review sheds light on recent discoveries, proposed theories, and clinical developments in the field of temozolomide resistance to summarize the complex and intriguing involvement of oncobiological pathways.

Avanafil mediated dual inhibition of IKKß and TNFR1 in an experimental paradigm of Alzheimer's disease: in silico and in vivo approach.

In Alzheimer's disease pathology, inhibitors of nuclear factor kappa-ß kinase subunit ß (IKKB) and Tumor necrosis factor receptor 1 (TNFR1) signaling are linked to neuroinflammation-mediated cognitive decline. We explored the role of a phosphodiesterase 5 inhibitor (PDE5I) with dual antagonistic action on IKKB and TNFR1 to inhibit nuclear factor kappa B (NF-kB) and curb neuroinflammation. In the in silico approach, the FDA-approved Zinc 15 library was docked with IKKB and TNFR1. The top compound with dual antagonistic action on IKKB and TNFR1 was selected based on bonding and non-bonding interactions. Further, induced fit docking (IFD), molecular mechanics-generalized Born and surface area (MMGBSA), and molecular dynamic studies were carried out and evaluated. Lipopolysaccharide (LPS) administration caused a neuroinflammation-mediated cognitive decline in mice. Two doses of avanafil were administered for 28 days while LPS was administered for 10 days. Morris water maze (MWM) along with the passive avoidance test (PAT) were carried out. Concurrently brain levels of inflammatory markers, oxidative parameters, amyloid beta (Aß), IKKB and NF-kB levels were estimated. Avanafil produced good IKKB and TNFR1 binding ability. It interacted with crucial inhibitory amino acids of IKKB and TNFR1. MD analysis predicted good stability of avanafil with TNFR1 and IKKB. Avanafil 6 mg/kg could significantly improve performance in MWM, PAT and oxidative parameters and reduce Aß levels and inflammatory markers. As compared to avanafil 3 mg/kg, 6 mg/kg dose was found to exert better efficacy against elevated Aß , neuroinflammatory cytokines and oxidative markers while improving behavioural parameters.Communicated by Ramaswamy H. Sarma.

Cationic RGD peptidomimetic nanoconjugates as effective tumor targeting gene delivery vectors with antimicrobial potential.

Gene delivery combined with systemic targeting approach has shown promising potential in cancer gene therapy. Peptides are ideal functional motif for constructing biocompatible non-viral gene delivery vehicles. RGD peptides, in particular, are known to recognize the integrin αVß3, which is expressed specifically on angiogenic blood vessels and, therefore, is considered vital for anti-angiogenesis strategies and cancer treatment. In recent times, several RGD peptide-based non-viral gene delivery vectors have been utilized for targeted gene delivery, however, lack in proteolytic stability. In the current study, we have investigated a series of non-naturally modified RGD peptide mimic (MOH) nanoconjugates with low molecular weight branched polyethylenimine (bPEI 1.8 kDa). The projected peptide mimic, Fmoc-FFARKA (MOH), has already been demonstrated to have high binding efficiency for αVß3 integrins and enhanced cell adhesive ability with high stability compared to the natural RGD counterpart. The polymer-peptide, PEI-MOH (PMOH), nanoconjugate vectors have been designed to enhance the tumor targeting ability, therapeutic proficiency, transfection efficiency and proteolytic stability. The synthesized nanoconjugates showed the ability to protect the bound DNA with low cytotoxicity and their pDNA complexes displayed enhanced transfection efficiency. Furthermore, a competitive study confirmed their selective behavior towards liver cancer cells, HepG2. Lastly, PMOH nanoconjugates also exerted significant antimicrobial effects against drug-resistant pathogens. Altogether, the data suggest that nanosized non-naturally modified RGD peptide mimic-based gene vectors hold great potential as efficient biomaterials for targeted gene delivery and antimicrobial applications.

Hypertensive Crisis-Related Hospitalizations and Subsequent Major Adverse Cardiac Events in Young Adults with Cannabis Use Disorder: A Nationwide Analysis.

Background and Objectives: With the growing recreational cannabis use and recent reports linking it to hypertension, we sought to determine the risk of hypertensive crisis (HC) hospitalizations and major adverse cardiac and cerebrovascular events (MACCE) in young adults with cannabis use disorder (CUD+). Material and Methods: Young adult hospitalizations (18−44 years) with HC and CUD+ were identified from National Inpatient Sample (October 2015−December 2017). Primary outcomes included prevalence and odds of HC with CUD. Co-primary (in-hospital MACCE) and secondary outcomes (resource utilization) were compared between propensity-matched CUD+ and CUD- cohorts in HC admissions. Results: Young CUD+ had higher prevalence of HC (0.7%, n = 4675) than CUD- (0.5%, n = 92,755), with higher odds when adjusted for patient/hospital-characteristics, comorbidities, alcohol and tobacco use disorder, cocaine and stimulant use (aOR 1.15, 95%CI:1.06−1.24, p = 0.001). CUD+ had significantly increased adjusted odds of HC (for sociodemographic, hospital-level characteristics, comorbidities, tobacco use disorder, and alcohol abuse) (aOR 1.17, 95%CI:1.01−1.36, p = 0.034) among young with benign hypertension, but failed to reach significance when additionally adjusted for cocaine/stimulant use (aOR 1.12, p = 0.154). Propensity-matched CUD+ cohort (n = 4440, median age 36 years, 64.2% male, 64.4% blacks) showed higher rates of substance abuse, depression, psychosis, previous myocardial infarction, valvular heart disease, chronic pulmonary disease, pulmonary circulation disease, and liver disease. CUD+ had higher odds of all-cause mortality (aOR 5.74, 95%CI:2.55−12.91, p < 0.001), arrhythmia (aOR 1.73, 95%CI:1.38−2.17, p < 0.001) and stroke (aOR 1.46, 95%CI:1.02−2.10, p = 0.040). CUD+ cohort had fewer routine discharges with comparable in-hospital stay and cost. Conclusions: Young CUD+ cohort had higher rate and odds of HC admissions than CUD-, with prevalent disparities and higher subsequent risk of all-cause mortality, arrhythmia and stroke.