Computational design of anti-cancer peptides tailored to target specific tumor markers.

Anti-cancer peptides (ACPs) are short peptides known for their ability to inhibit tumor cell proliferation, migration, and the formation of tumor blood vessels. In this study, we designed ACPs to target receptors often overexpressed in cancer using a systematic in silico approach. Three target receptors (CXCR1, DcR3, and OPG) were selected for their significant roles in cancer pathogenesis and tumor cell proliferation. Our peptide design strategy involved identifying interacting residues (IR) of these receptors, with their natural ligands serving as a reference for designing peptides specific to each receptor. The natural ligands of these receptors, including IL8 for CXCR1, TL1A for DcR3, and RANKL for OPG, were identified from the literature. Using the identified interacting residues (IR), we generated a peptide library through simple permutation and predicted the structure of each peptide. All peptides were analyzed using the web-based prediction server for Anticancer peptides, AntiCP. Docking simulations were then conducted to analyze the binding efficiencies of peptides with their respective target receptors, using VEGA ZZ and Chimera for interaction analysis. Our analysis identified HPKFIKELR as the interacting residues (IR) of CXCR-IL8. For DcR3, we utilized three domains from TL1A (TDSYPEP, TKEDKTF, LGLAFTK) as templates, along with two regions (SIKIPSS and PDQDATYP) from RANKL, to generate a library of peptide analogs. Subsequently, peptides for each receptor were shortlisted based on their predicted anticancer properties as determined by AntiCP and were subjected to docking analysis. After docking, peptides that exhibited the least binding energy were further analyzed for their detailed interaction with their respective receptors. Among these, peptides C9 (HPKFELY) and C7 (HPKFEWL) for CXCR1, peptides D6 (ADSYPQP) and D18 (AFSYPFP) for DcR3, and peptides P19 (PDTYPQDP) and p16 (PDQDATYP) for OPG, demonstrated the highest affinity and stronger interactions compared to the other peptides. Although in silico predictions indicated a favorable binding affinity of the designed peptides with target receptors, further experimental validation is essential to confirm their binding affinity, stability and pharmacokinetic characteristics.

Revolutionizing cancer care strategies: immunotherapy, gene therapy, and molecular targeted therapy.

Despite the availability of technological advances in traditional anti-cancer therapies, there is a need for more precise and targeted cancer treatment strategies. The wide-ranging shortfalls of conventional anticancer therapies such as systematic toxicity, compromised life quality, and limited to severe side effects are major areas of concern of conventional cancer treatment approaches. Owing to the expansion of knowledge and technological advancements in the field of cancer biology, more innovative and safe anti-cancerous approaches such as immune therapy, gene therapy and targeted therapy are rapidly evolving with the aim to address the limitations of conventional therapies. The concept of immunotherapy began with the capability of coley toxins to stimulate toll-like receptors of immune cells to provoke an immune response against cancers. With an in-depth understating of the molecular mechanisms of carcinogenesis and their relationship to disease prognosis, molecular targeted therapy approaches, that inhibit or stimulate specific cancer-promoting or cancer-inhibitory molecules respectively, have offered promising outcomes. In this review, we evaluate the achievement and challenges of these technically advanced therapies with the aim of presenting the overall progress and perspective of each approach.

A concise overview of advancements in ultrasensitive biosensor development.

Electrochemical biosensing has evolved as a diverse and potent method for detecting and analyzing biological entities ranging from tiny molecules to large macromolecules. Electrochemical biosensors are a desirable option in a variety of industries, including healthcare, environmental monitoring, and food safety, due to significant advancements in sensitivity, selectivity, and portability brought about by the integration of electrochemical techniques with nanomaterials, bio-recognition components, and microfluidics. In this review, we discussed the realm of electrochemical sensors, investigating and contrasting the diverse strategies that have been harnessed to push the boundaries of the limit of detection and achieve miniaturization. Furthermore, we assessed distinct electrochemical sensing methods employed in detection such as potentiometers, amperometers, conductometers, colorimeters, transistors, and electrical impedance spectroscopy to gauge their performance in various contexts. This article offers a panoramic view of strategies aimed at augmenting the limit of detection (LOD) of electrochemical sensors. The role of nanomaterials in shaping the capabilities of these sensors is examined in detail, accompanied by insights into the chemical modifications that enhance their functionality. Furthermore, our work not only offers a comprehensive strategic framework but also delineates the advanced methodologies employed in the development of electrochemical biosensors. This equips researchers with the knowledge required to develop more accurate and efficient detection technologies.

Clinical relevance of circulating non-coding RNAs in metabolic diseases: Emphasis on obesity, diabetes, cardiovascular diseases and metabolic syndrome.

Non-coding RNAs (ncRNAs) participate in the regulation of several cellular processes including transcription, RNA processing and genome rearrangement. The aberrant expression of ncRNAs is associated with several pathological conditions. In this review, we focused on recent information to elucidate the role of various regulatory ncRNAs i.e., micro RNAs (miRNAs), circular RNAs (circRNAs) and long-chain non-coding RNAs (lncRNAs), in metabolic diseases, e.g., obesity, diabetes mellitus (DM), cardiovascular diseases (CVD) and metabolic syndrome (MetS). The mechanisms by which ncRNAs participated in disease pathophysiology were also highlighted. miRNAs regulate the expression of genes at transcriptional and translational levels. circRNAs modulate the regulation of gene expression via miRNA sponging activity, interacting with RNA binding protein and polymerase II transcription regulation. lncRNAs regulate the expression of genes by acting as a protein decoy, miRNA sponging, miRNA host gene, binding to miRNA response elements (MRE) and the recruitment of transcriptional element or chromatin modifiers. We examined the role of ncRNAs in the disease pathogenesis and their potential role as molecular markers for diagnosis, prognosis and therapeutic targets. We showed the involvement of ncRNAs in the onset of obesity and its progression to MetS and CVD. miRNA-192, miRNA-122, and miRNA-221 were dysregulated in all these metabolic diseases. Other ncRNAs, implicated in at least three diseases include miRNA-15a, miRNA-26, miRNA-27a, miRNA-320, and miRNA-375. Dysregulation of ncRNAs increased the risk of development of DM and MetS and its progression to CVD in obese individuals. Hence, these molecules are potential targets to arrest or delay the progression of metabolic diseases.

MDM2- an indispensable player in tumorigenesis.

Murine double minute 2 (MDM2) is a well-recognized molecule for its oncogenic potential. Since its identification, various cancer-promoting roles of MDM2 such as growth stimulation, sustained angiogenesis, metabolic reprogramming, apoptosis evasion, metastasis, and immunosuppression have been established. Alterations in the expression levels of MDM2 occur in multiple types of cancers resulting in uncontrolled proliferation. The cellular processes are modulated by MDM2 through transcription, post-translational modifications, protein degradation, binding to cofactors, and subcellular localization. In this review, we discuss the precise role of deregulated MDM2 levels in modulating cellular functions to promote cancer growth. Moreover, we also briefly discuss the role of MDM2 in inducing resistance against anti-cancerous therapies thus limiting the benefits of cancerous treatment.

Computational Analysis Reveals Distinctive Interaction of miRNAs with Target Genes in the Pathogenesis of Chronic Kidney Disease.

The regulation of genes is crucial for maintaining a healthy intracellular environment, and any dysregulation of gene expression leads to several pathological complications. It is known that many diseases, including kidney diseases, are regulated by miRNAs. However, the data on the use of miRNAs as biomarkers for the diagnosis and treatment of chronic kidney disease (CKD) are not conclusive. The purpose of this study was to elucidate the potential of miRNAs as an efficient biomarker for the detection and treatment of CKD at its early stages. Gene expression profiling data were acquired from the Gene Expression Omnibus (GEO) and differentially expressed genes (DEGs) were identified. miRNAs directly associated with CKD were obtained from an extensive literature search. Network illustration of miRNAs and their projected target differentially expressed genes (tDEGs) was accomplished, followed by functional enrichment analysis. hsa-miR-1-3p, hsa-miR-206, hsa-miR-494 and hsa-miR-577 exhibited a strong association with CKD through the regulation of genes involved in signal transduction, cell proliferation, the regulation of transcription and apoptotic process. All these miRNAs have shown significant contributions to the inflammatory response and the processes which eventually lead to the pathogenesis of CKD. The in silico approach used in this research represents a comprehensive analysis of identified miRNAs and their target genes for the identification of molecular markers of disease processes. The outcomes of the study recommend further efforts for developing miRNA biomarkers set for the early diagnosis of CKD.

Competing Endogenous RNA Regulatory Networks of hsa_circ_0126672 in Pathophysiology of Coronary Heart Disease.

Coronary heart disease (CHD) is a global health concern, and its molecular origin is not fully elucidated. Dysregulation of ncRNAs has been linked to many metabolic and infectious diseases. This study aimed to explore the role of circRNAs in the pathogenesis of CHD and predicted a candidate circRNA that could be targeted for therapeutic approaches to the disease. circRNAs associated with CHD were identified and CHD gene expression profiles were obtained, and analyzed with GEO2R. In addition, differentially expressed miRNA target genes (miR-DEGs) were identified and subjected to functional enrichment analysis. Networks of circRNA/miRNA/mRNA and the miRNA/affected pathways were constructed. Furthermore, a miRNA/mRNA homology study was performed. We identified that hsa_circ_0126672 was strongly associated with the CHD pathology by competing for endogenous RNA (ceRNA) mechanisms. hsa_circ_0126672 characteristically sponges miR-145-5p, miR-186-5p, miR-548c-3p, miR-7-5p, miR-495-3p, miR-203a-3p, and miR-21. Up-regulation of has_circ_0126672 affected various CHD-related cellular functions, such as atherosclerosis, JAK/STAT, and Apelin signaling pathways. Our results also revealed a perfect and stable interaction for the hybrid of miR-145-5p with NOS1 and RPS6KB1. Finally, miR-145-5p had the highest degree of interaction with the validated small molecules. Henchashsa_circ_0126672 and target miRNAs, notably miR-145-5p, could be good candidates for the diagnosis and therapeutic approaches to CHD.

Provocative non-canonical roles of p53 and AKT signaling: A role for Thymosin ß4 in medulloblastoma.

The PI3K/AKT and p53 pathways are key regulators of cancer cell survival and death, respectively. Contrary to their generally accepted roles, several lines of evidence, including ours in medulloblastoma, the most common childhood brain cancer, highlight non-canonical functions for both proteins and show a complex context-dependent dynamic behavior in determining cell fate. Interestingly, p53-mediated cell survival and AKT-mediated cell death can dominate in certain conditions, and these interchangeable physiological functions may potentially be manipulated for better clinical outcomes. This review article presents studies in which p53 and AKT behave contrary to their well-established functions. We discuss the factors and circumstances that may be involved in mediating these changes and the implications of these unique roles of p53 and AKT in devising therapeutic strategies. Lastly, based on our recent finding of Thymosin beta 4-mediated chemosensitivity via an AKT-p53 interaction in medulloblastoma cells, we also discuss the possible implications of Thymosin beta-4 in enhancing drug sensitivity in this deadly childhood disease.

Amniotic stem cells as a source of regenerative medicine to treat female infertility.

Impaired reproductive health is a worldwide problem that affects the psychological well-being of a society. Despite the technological developments to treat infertility, the global infertility rate is increasing significantly. Many infertility conditions are currently treated using various advanced clinical approaches such as intrauterine semination (IUI), in vitro fertilization (IVF), and intracytoplasmic injection (ICSI). Nonetheless, clinical management of some conditions such as dysfunctional endometrium, premature ovarian failure, and ovarian physiological aging still pose significant challenges. Stem cells based therapeutic strategies have a long-standing history to treat many infertility conditions, but ethical restrictions do not allow the broad-scale utilization of adult mesenchymal stromal/stem cells (MSCs). Easily accessible, placental derived or amniotic stem cells present an invaluable alternative source of non-immunogenic and non-tumorigenic stem cells that possess multilineage potential. Given these characteristics, placental or amniotic stem cells (ASCs) have been investigated for therapeutic purposes to address infertility in the last decade. This study aims to summarize the current standing and progress of human amniotic epithelial stem cells (hAECs), amniotic mesenchymal stem cells (hAMSCs), and amniotic fluid stem cells (hAFSCs) in the field of reproductive medicine. The therapeutic potential of these cells to restore or enhance normal ovarian function and pregnancy outcomes are highlighted in this study.

Expansion of human amniotic epithelial cells using condition cell reprogramming technology.

Human amniotic epithelial cells (hAECs) are non-immunogenic epithelial cells that can develop into cells of all three germline lineages. However, a refined clinically reliable method is required to optimize the preparation and banking procedures of hAECs for their successful translation into clinical studies. With the goal of establishing standardized clinically applicable hAECs cultured cells, we described the use of a powerful epithelial cell culture technique, termed Conditionally Reprogrammed Cells (CRC) for ex vivo expansion of hAECs. The well-established CRC culture method uses a Rho kinase inhibitor (Y-27632) and J2 mouse fibroblast feeder cells to drive the indefinite proliferation of all known epithelial cell types. In this study, we used an optimized CRC protocol to successfully culture hAECs in a CRC medium supplemented with xenogen-free human serum. We established that hAECs thrive under the CRC conditions for over 5 passages while still expressing pluripotent stem markers (OCT-4, SOX-2 and NANOG) and non-immunogenic markers (CD80, CD86 and HLA-G) suggesting that even late-passage hAECs retain their privileged phenotype. The hAECs-CRC cells were infected with a puromycin-selectable lentivirus expressing luciferase and GFP (green fluorescent protein) and stably selected with puromycin. The hAECs expressing GFP were injected subcutaneously into the flanks of Athymic and C57BL6 mice to check the tolerability and stability of cells against the immune system. Chemiluminescence imaging confirmed the presence and viability of cells at days 2, 5, and 42 without acute inflammation or any tumor formation. Collectively, these data indicate that the CRC approach offers a novel solution to expanding hAECs in humanized conditions for future clinical uses, while retaining their primary phenotype.

Comparing the Metabolic Profiles Associated with Fitness Status between Insulin-Sensitive and Insulin-Resistant Non-Obese Individuals.

(1) Background: Young non-obese insulin-resistant (IR) individuals could be at risk of developing metabolic diseases including type 2 diabetes mellitus. The protective effect of physical activity in this apparently healthy group is expected but not well characterized. In this study, clinically relevant metabolic profiles were determined and compared among active and sedentary insulin-sensitive (IS) and IR young non-obese individuals. (2) Methods: Data obtained from Qatar Biobank for 2110 young (20-30 years old) non-obese (BMI ≤ 30) healthy participants were divided into four groups, insulin-sensitive active (ISA, 30.7%), insulin-sensitive sedentary (ISS, 21.4%), insulin-resistant active (IRA, 20%), and insulin-resistant sedentary (IRS, 23.3%), using the homeostatic model assessment of insulin resistance (HOMA-IR) and physical activity questionnaires. The effect of physical activity on 66 clinically relevant biochemical tests was compared among the four groups using linear models. (3) Results: Overall, non-obese IR participants had significantly (p ≤ 0.001) worse vital signs, blood sugar profiles, inflammatory markers, liver function, lipid profiles, and vitamin D levels than their IS counterparts. Physical activity was positively associated with left handgrip (p ≤ 0.01) and levels of creatine kinase (p ≤ 0.001) and creatine kinase-2 (p ≤ 0.001) in both IS and IR subjects. Furthermore, physical activity was positively associated with levels of creatinine (p ≤ 0.01) and total vitamin D (p = 0.006) in the IR group and AST (p = 0.001), folate (p = 0.001), and hematocrit (p = 0.007) in the IS group. Conversely, physical inactivity was negatively associated with the white blood cell count (p = 0.001) and an absolute number of lymphocytes (p = 0.003) in the IR subjects and with triglycerides (p = 0.005) and GGT-2 (p ≤ 0.001) in the IS counterparts. (4) Conclusions: An independent effect of moderate physical activity was observed in non-obese apparently healthy individuals a with different HOMA-IR index. The effect was marked by an improved health profile including higher vitamin D and lower inflammatory markers in IRA compared to IRS, and a higher oxygen carrying capacity and lipid profile in ISA compared to the ISS counterparts.

A comparison of isolation and culture protocols for human amniotic mesenchymal stem cells.

The successful translation of mesenchymal stem cells (MSCs) from bench to bedside is predicated upon their regenerative capabilities and immunomodulatory potential. Many challenges still exist in making MSCs a viable and cost-effective therapeutic option, due in part to the challenges of sourcing MSCs from adult tissues and inconsistencies in the characterization of MSCs. In many cases, adult MSC collection is an invasive procedure, and ethical concerns and age-related heterogeneity further complicate obtaining adult tissue derived MSCs at the scales needed for clinical applications. Alternative adult sources, such as post-partum associated tissues, offer distinct advantages to overcome these challenges. However, successful therapeutic applications rely on the efficient ex-vivo expansion of the stem cells while avoiding any culture-related phenotypic alterations, which requires optimized and standardized isolation, culture, and cell preservation methods. In this review, we have compared the isolation and culture methods for MSCs originating from the human amniotic membrane (hAMSCs) of the placenta to identify the elements that support the extended subculture potential of hAMSCs without compromising their immune-privileged, pluripotent regenerative potential.Abbreviations: AM: Human amniotic membrane; ASCs: Adipose tissue-derived stem cells; BM-MSCs: Bone marrow-mesenchymal stem cells; DMEM: Dulbecco's modified eagle medium; DT: Doubling time; EMEM: Eagle's modified essential medium; ESCM: Embryonic stem cell markers; ESCs: Embryonic stem cells; hAECs: Human amniotic epithelial cells; hAMSCs: Human amniotic mesenchymal stem cells; HLA: Human leukocyte antigen; HM: Hematopoietic markers; IM: Immunogenicity markers; MHC: Major histocompatibility complex; MSCs: Mesenchymal stem cells; MCSM: Mesenchymal cell surface markers; Nanog: NANOG homeobox; Oct: Octamer binding transcription factor 4; P: Passage; PM: Pluripotency markers; STRO-1: Stromal precursor antigen-1; SCP: Subculture potential; Sox-2: Sry-related HMG box gene 2; SSEA-4: Stage-specific embryonic antigen; TRA: Tumor rejection antigen.

A Survey and Critical Evaluation of Isolation, Culture, and Cryopreservation Methods of Human Amniotic Epithelial Cells.

Human amniotic epithelial cells (hAECs), derived from an epithelial cell layer of the human amniotic membrane, possess embryonic stem-like properties and are known to maintain multilineage differentiation potential. Unfortunately, an inability to expand hAECs without significantly compromising their stem cell potency has precluded their widespread use for regenerative therapies. This article critically evaluates the methods used for isolation, expansion, and cryopreservation of hAECs. We assessed the impact of these methods on ex-vivo expansion and stem cell phenotype of hAECs. Moreover, the progress and challenges to optimize clinically suitable culture conditions for an efficient ex-vivo expansion and storage of these cells are highlighted. Additionally, we also reviewed the currently used hAECs isolation and characterization methods employed in clinical trials. Despite the developments made in the last decade, significant challenges still exist to overcome limitations of ex-vivo expansion and retention of stemness of hAECs in both xenogeneic and xenofree culture conditions. Therefore, optimization and standardization of culture conditions for robust ex-vivo maintenance of hAECs without affecting tissue regenerative properties is an absolute requirement for their successful therapeutic manipulation. This review may help the researchers to optimize the methods that support ex-vivo survival, proliferation, and self-renewal properties of the hAECs.Abbreviations: AM: Human amniotic membrane; CM-HBSS: Ca++ and Mg++ free HBSS; DMEM: Dulbecco's Modified Eagle Medium; DMEM-HG: DMEM-high glucose; EMEM: Eagle's Modified Essential Medium; EMT: Epithelial-to-mesenchymal transition; EpM: Epi-life complete media; ESC: Embryonic stem cells; ESCM: Epithelial cell surface markers; hAECs: Human amniotic epithelial cells; HLA: Human leukocyte antigen; IM: Immunogenicity markers; iPSC: Induced pluripotent stem cells; KOSR; KSR: Knockout serum replacement; KSI: Key success indicators; CHM: Cell heterogeneity markers; Nanog: NANOG homeobox; Oct-4: Octamer binding transcription factor 4; OR: Operation room; P: Passage; PM: Pluripotency markers; SCM: Stem cell markers for non-differentiated cells; Sox-2: Sry-related HMG box gene 2; SSEA-4: Stage-specific embryonic antigen; TRA: Tumor rejection antigen; UC: Ultra-culture; XF: Xenogeneic free.

Regulation of Chemosensitivity in Human Medulloblastoma Cells by p53 and the PI3 Kinase Signaling Pathway.

In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resistance and with poor long-term outcomes in the p53-mutated sonic hedgehog, MYC-p53, and p53-positive medulloblastoma subgroups. We previously established a direct role for p53 in supporting drug resistance in medulloblastoma cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in medulloblastoma cells with low basal p53 protein expression levels (D283 and UW228) significantly reduced drug responsiveness, suggesting opposing roles for low p53 protein expression levels. Mechanistically, the enhanced cell death by p53 knockdown in high-p53 cells was associated with an induction of mTOR/PI3K signaling. Both mTOR inhibition and p110α/PIK3CA induction confirmed these findings, which abrogated or accentuated the enhanced chemosensitivity response in D556 cells respectively while converse was seen in D283 cells. Co-treatment with G-actin-sequestering peptide, thymosin ß4 (Tß4), induced p-AKTS473 in both p53-high and p53-low cells, enhancing chemosensitivity in D556 cells while enhancing chemoresistance in D283 and UW228 cells. IMPLICATIONS: Collectively, we identified an unexpected role for the PI3K signaling in enhancing cell death in medulloblastoma cells with high basal p53 expression. These studies indicate that levels of p53 immunopositivity may serve as a diagnostic marker of chemotherapy resistance and for defining therapeutic targeting.

Artificial intelligence in the diagnosis and detection of heart failure: the past, present, and future.

Artificial Intelligence (AI) performs human intelligence-dependant tasks using tools such as Machine Learning, and its subtype Deep Learning. AI has incorporated itself in the field of cardiovascular medicine, and increasingly employed to revolutionize diagnosis, treatment, risk prediction, clinical care, and drug discovery. Heart failure has a high prevalence, and mortality rate following hospitalization being 10.4% at 30-days, 22% at 1-year, and 42.3% at 5-years. Early detection of heart failure is of vital importance in shaping the medical, and surgical interventions specific to HF patients. This has been accomplished with the advent of Neural Network (NN) model, the accuracy of which has proven to be 85%. AI can be of tremendous help in analyzing raw image data from cardiac imaging techniques (such as echocardiography, computed tomography, cardiac MRI amongst others) and electrocardiogram recordings through incorporation of an algorithm. The use of decision trees by Rough Sets (RS), and logistic regression (LR) methods utilized to construct decision-making model to diagnose congestive heart failure, and role of AI in early detection of future mortality and destabilization episodes has played a vital role in optimizing cardiovascular disease outcomes. The review highlights the major achievements of AI in recent years that has radically changed nearly all areas of HF prevention, diagnosis, and management.

COVID-19 Associated Mucormycosis: A Systematic Review from Diagnostic Challenges to Management.

The coronavirus disease 2019 (COVID-19) outbreak has caused significant destruction, claiming over three million lives worldwide. Post SARS-COV-2 invasion, immunosuppression with hyperglycemia and elevated ferritin levels along with steroidal treatment creates a perfect storm for opportunistic infections. There is increasing evidence of mucormycosis co-infection in COVID-19 patients, during or post-treatment. A worse prognosis, a late diagnosis, and limited guidelines of screening and management of COVID-19 associated mucormycosis have made healthcare professionals fear an epidemic alongside a pandemic. This review geographically reports cases of COVID-19 associated mucormycosis (CAM), evaluates characteristics, clinical manifestations, and outcomes of mucormycosis in COVID-19 active or recovered patients. It further describes preventive strategies and recommendations for optimal management therapy that can be adopted worldwide to curtail an impending threat to the healthcare system.

Exploring the impact of the COVID-19 pandemic on provision of cardiology services: a scoping review.

The coronavirus disease-19 (COVID-19) pandemic has forced hospitals to prioritize COVID-19 patients, restrict resources, and cancel all non-urgent elective cardiac procedures. Clinical visits have only been facilitated for emergency purposes. Fewer patients have been admitted to the hospital for both ST-segment elevation myocardial infarctions (STEMI) and non-ST segment elevation myocardial infarctions (NSTEMI) and a profound decrease in heart failure services has been reported. A similar reduction in the patient presentation is seen for ischemic heart disease, decompensated heart failure, and endocarditis. Cardiovascular services, including catheterization, primary percutaneous coronary intervention (PPCI), cardiac investigations such as electrocardiograms (ECGs), exercise tolerance test (ETT), dobutamine stress test, computed tomography (CT) angiography, transesophageal echocardiography (TOE) have been reported to have declined and performed on a priority basis. The long-term implications of this decline have been discussed with major concerns of severe cardiac complications and vulnerabilities in cardiac patients. The pandemic has also had psychological impacts on patients causing them to avoid seeking medical help. This review discusses the effects of the COVID-19 pandemic on the provision of various cardiology services and aims to provide strategies to restore cardiovascular services including structural changes in the hospital to make up for the reduced staff personnel, the use of personal protective equipment in healthcare workers, and provides alternatives for high-risk cardiac imaging, cardiac interventions, and procedures. Implementation of the triage system, risk assessment scores, and telemedicine services in patients and their adaptation to the cardiovascular department have been discussed.

Predicting new drug indications for prostate cancer: The integration of an in silico proteochemometric network pharmacology platform with patient-derived primary prostate cells.

BACKGROUND: Drug repurposing enables the discovery of potential cancer treatments using publically available data from over 4000 published Food and Drug Administration approved and experimental drugs. However, the ability to effectively evaluate the drug's efficacy remains a challenge. Impediments to broad applicability include inaccuracies in many of the computational drug-target algorithms and a lack of clinically relevant biologic modeling systems to validate the computational data for subsequent translation. METHODS: We have integrated our computational proteochemometric systems network pharmacology platform, DrugGenEx-Net, with primary, continuous cultures of conditionally reprogrammed (CR) normal and prostate cancer (PCa) cells derived from treatment-naive patients with primary PCa. RESULTS: Using the transcriptomic data from two matched pairs of benign and tumor-derived CR cells, we constructed drug networks to describe the biological perturbation associated with each prostate cell subtype at multiple levels of biological action. We prioritized the drugs by analyzing these networks for statistical coincidence with the drug action networks originating from known and predicted drug-protein targets. Prioritized drugs shared between the two patients' PCa cells included carfilzomib (CFZ), bortezomib (BTZ), sulforaphane, and phenethyl isothiocyanate. The effects of these compounds were then tested in the CR cells, in vitro. We observed that the IC50 values of the normal PCa CR cells for CFZ and BTZ were higher than their matched tumor CR cells. Transcriptomic analysis of CFZ-treated CR cells revealed that genes involved in cell proliferation, proteases, and downstream targets of serine proteases were inhibited while KLK7 and KLK8 were induced in the tumor-derived CR cells. CONCLUSIONS: Given that the drugs in the database are extremely well-characterized and that the patient-derived cells are easily scalable for high throughput drug screening, this combined in vitro and in silico approach may significantly advance personalized PCa treatment and for other cancer applications.

The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a. IMPLICATIONS: The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.

Clinicopathologic and prognostic significance of LGR5, a cancer stem cell marker in patients with colorectal cancer.

AIM: To analyze the clinicopathologic and prognostic significance of Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a cancer stem cell marker expression in a cohort of colorectal cancer patients (CRC). PATIENTS & METHODS: A total of 76 formalin-fixed paraffin-embedded tissue blocks of primary or metastatic tumors from 49 CRC patients were collected for duration 2009-2015. LGR5 expression was assessed through immunohistochemical staining of a tissue microarray. RESULTS: LGR5 was significantly over expressed in CRC tissue samples and found to be a statistically significant independent prognostic marker for an improved overall survival. CONCLUSION: LGR5 expression was higher in colorectal cancer than in normal tissue. LGR5 was an independent prognostic marker for better clinical outcomes and might be used as a potential therapeutic target in CRCs.