Prognostic and therapeutic potential of STAT3: Opportunities and challenges in targeting HPV-mediated cervical carcinogenesis.

Cervical cancer (CaCx) ranks as the fourth most prevalent cancer among women globally. Persistent infection of high-risk human papillomaviruses (HR-HPVs) is major etiological factor associated with CaCx. Signal Transducer and Activator of Transcription 3 (STAT3), a prominent member of the STAT family, has emerged as independent oncogenic driver. It is a target of many oncogenic viruses including HPV. How STAT3 influences HPV viral gene expression or gets affected by HPV is an area of active investigation. A better understanding of host-virus interaction will provide a prognostic and therapeutic window for CaCx control and management. In this comprehensive review, we delve into carcinogenic role of STAT3 in development of HPV-induced CaCx. With an emphasis on fascinating interplay between STAT3 and HPV genome, the review explores the diverse array of opportunities and challenges associated with this field to harness the prognostic and therapeutic potential of STAT3 in CaCx.

Targeting Cervical Cancer Stem Cells by Phytochemicals.

Cervical cancer (CaCx) poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide. Despite the emergence of advanced treatment strategies, recurrence remains a bottleneck in favorable treatment outcomes and contributes to poor prognosis. The chemo- or radio-therapy resistance coupled with frequent relapse of more aggressive tumors are some key components that contribute to CaCx-related mortality. The onset of therapy resistance and relapse are attributed to a small subset of, slow-proliferating Cancer Stem Cells (CSC). These CSCs possess the properties of tumorigenesis, self-renewal, and multi-lineage differentiation potential. Because of slow cycling, these cells maintain themselves in a semi-quiescent stage and protect themselves from different anti-proliferative anti-cancer drugs. Keeping in view recent advances in their phenotypic and functional characterization, the feasibility of targeting CSC and associated stem cell signaling bears a strong translational value. The presence of CSC has been reported in CaCx (CCSC) which remains a forefront area of research. However, we have yet to identify clinically useful leads that can target CCSC. There is compelling evidence that phytochemicals, because of their advantages over synthetic anticancer drugs, could emerge as potential therapeutic leads to target these CCSCs. The present article examined the potential of phytochemicals with reported anti-CSC properties and evaluated their future in preclinical and clinical applications against CaCx.

In vivo antiangiogenic effect of nimbolide, trans-chalcone and piperine for use against glioblastoma.

BACKGROUND: Angiogenesis is an important hallmark of Glioblastoma (GBM) marked by elevated vascular endothelial growth factor-A (VEGF-A) and its receptor 2 (VEGFR-2). As previously reported nimbolide (NBL), trans-chalcone (TC) and piperine (PPR) possess promising antiangiogenic activity in several cancers however, their comparative efficacy and mechanism of antiangiogenic activity in GBM against VEGFR-2 has not been elucidated. METHODS: 2D and 3D spheroids cultures of U87 (Uppsala 87 Malignant Glioma) were used for evaluation of non-cytotxoic dose for anti-angiogenic activity. The antiangiogenic effect was investigated by the GBM U87 cell line bearing chick CAM model. Excised U87 xenografts were histologically examined for blood vascular density by histochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the presence of avian and human VEGF-A and VEGFR-2 mRNA transcripts. RESULTS: Using 2D and 3D spheroid models, the non-cytotoxic dose of NBL, TC and PPR was ≤ 11 µM. We found NBL, TC and PPR inhibit U87-induced neoangiogenesis in a dose-dependent manner in the CAM stand-alone model as well as in CAM U87 xenograft model. The results also indicate that these natural compounds inhibit the expression of notable angiogenic factors, VEGF-A and VEGFR-2. A positive correlation was found between blood vascular density and VEGF-A as well as VEGFR-2 transcripts. CONCLUSION: Taken together, NBL, TC and PPR can suppress U87-induced neoangiogenesis via a reduction in VEGF-A and its receptor VEGFR-2 transcript expression at noncytotoxic concentrations. These phytochemicals showed their utility as adjuvants to GBM therapy, with Piperine demonstrating superior effectiveness among them all.

Phytochemicals Showing Antiangiogenic Effect in Pre-clinical Models and their Potential as an Alternative to Existing Therapeutics.

Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is an important hallmark of several pathological conditions, such as tumor growth and metastasis, proliferative retinopathies, including proliferative diabetic retinopathy and retinopathy of prematurity, age-related macular degeneration, rheumatoid arthritis, psoriasis, and endometriosis. Putting a halt to pathology-driven angiogenesis is considered an important therapeutic strategy to slow down or reduce the severity of pathological disorders. Considering the attrition rate of synthetic antiangiogenic compounds from the lab to reaching the market due to severe side effects, several compounds of natural origin are being explored for their antiangiogenic properties. Employing pre-clinical models for the evaluation of novel antiangiogenic compounds is a promising strategy for rapid screening of antiangiogenic compounds. These studies use a spectrum of angiogenic model systems that include HUVEC two-dimensional culture, nude mice, chick chorioallantoic membrane, transgenic zebrafish, and dorsal aorta from rats and chicks, depending upon available resources. The present article emphasizes the antiangiogenic activity of the phytochemicals shown to exhibit antiangiogenic behavior in these well-defined existing angiogenic models and highlights key molecular targets. Different models help to get a quick understanding of the efficacy and therapeutics mechanism of emerging lead molecules. The inherent variability in assays and corresponding different phytochemicals tested in each study prevent their immediate utilization in clinical studies. This review will discuss phytochemicals discovered using suitable preclinical antiangiogenic models, along with a special mention of leads that have entered clinical evaluation.

Chick chorioallantoic membrane: a valuable 3D in vivo model for screening nanoformulations for tumor antiangiogenic therapeutics.

Drug discovery is an extensive process. From identifying lead compounds to approval for clinical application, it goes through a sequence of labor-intensive in vitro, in vivo preclinical screening and clinical trials. Among thousands of drugs screened only a few get approval for clinical trials. Furthermore, these approved drugs are often discontinued due to systemic toxicity and comorbidity at clinically administered dosages. To overcome these limitations, nanoformulations have emerged as the most sought-after strategy to safely and effectively deliver drugs within tumors at therapeutic concentrations. Most importantly, the employment of suitably variable preclinical models is considered highly critical for the therapeutic evaluation of candidate drugs or their formulations. A review of literature from the past 10 years on antiangiogenic nanoformulations shows the employment of limited types of preclinical models mainly the 2-dimensional (2D) monolayer cell culture and murine models as the mainstay for drug uptake, toxicity and efficiency studies. To top it all, murine models are highly expensive, time-consuming and require expertise in handling them. The current review highlights the utilization of the age-old chicken chorioallantoic membrane (CAM), a well-defined angiogenic model in the investigation of antiangiogenic compounds and nanoformulations in an economic framework. For practical applicability, we have evaluated the CAM model to demonstrate the screening of antiangiogenic compounds and that tumor cells can be implanted onto developing CAM for growing xenografts by recruiting host endothelial and other cellular components. In addition, the exploitation of CAM tumor xenograft models for the evaluation of nanoparticle distribution has also been reinforced by demonstrating that intravenously administered iron oxide nanoparticles (IONPs) passively accumulate and exhibit intracellular as well as extracellular compartment accumulation in highly vascular xenografts. Finally, the ethical considerations, benefits, and drawbacks, of using CAM as an experimental model for testing potential therapeutics are also highlighted.

Study of Association Between Different Coronary Artery Disease Presentations and Its Effect on Short-Term Mortality, Readmission, and Cost in Patients Undergoing Percutaneous Coronary Interventions.

Introduction Atherosclerotic coronary artery disease (CAD) is the major cause of mortality in the USA. CAD requiring percutaneous coronary intervention (PCI) can have a wide spectrum of presentations. We reviewed the cost of admission and PCI at the tertiary care center stratified for different CAD presentation types. Methods We performed a retrospective study of 7,389 patients undergoing coronary angiogram at our facility from 2015 to 2017. Patients were selected from CathPCI registry. Chart review was done for readmission and death data. Cost data were provided by the finance department. Patients going for coronary artery bypass surgery (CABG) were excluded. We split the patients based on their need for PCI. Cost analysis was based on CAD presentation types (No symptoms, atypical symptoms, stable angina, unstable angina, NSTEMI [non-ST segment elevation myocardial infarction], STEMI [ST-segment elevation myocardial infarction]). Adjusted linear regression was run for the outcomes. Primary outcomes were 30-day readmission and death. The secondary outcome was cost of admission. Results The final sample size was 6,403. The mean age was 65.6 years (SD: 12.5; male: 63.8%). 2444 required PCI (38%; p < 0.001). PCI group had lower mean age (62.5 years; SD: 12.3, p<0.001) with lower BMI (30.6 vs 31.1, p=0.015). PCI group had significantly lower odds for 30-day readmission (OR: 0.63; CI: 0.45-0.89; p=0.009) and 30-day mortality (OR:0.60; CI: 0.41-0.89; p = 0.011). A severe presentation increased the odds of getting PCI. Cost of admission was higher in all groups receiving PCI. Conclusions PCI group had better 30-day readmission and mortality rates. PCI increases the cost of admission in all CAD types.

Probiotic and Antifungal Attributes of Levilactobacillus brevis MYSN105, Isolated From an Indian Traditional Fermented Food Pozha.

The use of probiotics and antifungal capabilities of the lactic acid bacteria (LAB) isolated from different niches is a strategy to prepare functional cultures and biopreservatives for food/feed industries. In the present study, LAB strains isolated from an Indian traditional fermented food, Pozha, were evaluated for their probiotic properties and biocontrol potential. A total of 20 LAB isolates were selected from Pozha samples collected aseptically and screened for their antagonistic activity against Fusarium verticillioides. Among the bioactive isolates, Lacticaseibacillus brevis MYSN105 showed the highest antifungal activity in vitro, causing some morphological alterations such as damaged mycelia and deformed conidia. Cell-free supernatant (CFS) from L. brevis MYSN105 at 16% concentration effectively reduced the mycelial biomass to 0.369 g compared to 1.938 g in control. Likewise, the conidial germination was inhibited to 20.12%, and the seed treatment using CFS induced a reduction of spore count to 4.1 × 106 spores/ml compared to 1.1 × 109 spores/ml for untreated seeds. The internal transcribed spacer (ITS) copy number of F. verticillioides decreased to 5.73 × 107 and 9.026 × 107 by L. brevis MYSN105 and CFS treatment, respectively, compared to 8.94 × 1010 in control. The L. brevis MYSN105 showed high tolerance to in vitro gastrointestinal conditions and exhibited high adhesive abilities to intestinal epithelial cell lines. The comparative genome analysis demonstrated specific secondary metabolite region coding for bacteriocin and T3PKS (type III polyketide synthase) possibly related to survival and antimicrobial activity in the gut environment. Our results suggest that L. brevis MYSN105 has promising probiotic features and could be potentially used for developing biological control formulations to minimize F. verticillioides contamination and improve food safety measures.

Anomalous Coronary Origin and Malignant Course in a Young Patient With Palpitation and Demand Ischemia: A Serendipity or a Syndrome Without a Name?

Anomalous coronary artery remains the second most common cause for sudden cardiac death (SCD) in young athletes. The anomaly most commonly associated with SCD is the one that courses between the aorta and pulmonary artery, the malignant course. We present a case of a young gentleman who presented with symptomatic palpitations and was found to have anomalous right coronary artery from ostial left main coronary artery coursing between the aorta and pulmonary artery.

Eustachian and Tricuspid Valve Endocarditis: A Rare Consequence of the Automatic Implantable Cardioverter-Defibrillator Placement.

Eustachian valve (EV) is usually a rudimentary structure in adults. It is an embryological remnant of sinus venosus that directs oxygenated blood from the inferior vena cava across the foramen ovale and into the left atrium. Intravenous drug use is most commonly associated with infective endocarditis of the right-sided heart structures. Other documented causes of such an occurrence are intracardiac devices like pacemakers and central venous catheters. Patients presenting with concerns of infection and embolic phenomenon should promptly undergo evaluation for infective endocarditis. Although an embryological remnant, the eustachian valve normally regresses after birth, except in a minority of the patients, it persists as a vestigial structure. Here we present an unusual case involving infective endocarditis of the eustachian valve and tricuspid valve both in a patient with recent automatic implantable cardioverter-defibrillator (AICD) placement and history of IV drug abuse and its systemic consequences in a patient with patent foramen ovale.

A Tale of Three Rarities: Secondary Amyloid A (AA) Amyloidosis Caused by Recurrent Sialadenitis and Complicated by Pulmonary Hypertension and Adrenal Insufficiency.

A 48-year-old lady presented with a parotid mass found to be secondary to recurrent sialadenitis. She was also found to have microcytic anemia, renal dysfunction, an elevated gamma gap, and an isolated alkaline phosphatase elevation. Later, she developed altered mental status and shock, and was found to have adrenal insufficiency, pulmonary hypertension, and pulmonary nodules. A liver biopsy was consistent with amyloid deposition. The constellation of findings was consistent with systemic amyloid A (AA) amyloidosis secondary to recurrent sialadenitis with hepatic, renal, pulmonary, and adrenal involvement. The patient later passed away due to acute hypoxic respiratory failure. This case demonstrates rare sequelae of systemic AA amyloidosis of pulmonary hypertension and adrenal insufficiency.

Acute Ostial Right Coronary Artery Occlusion During Valve Deployment of Transcatheter Aortic Valve Replacement Leading to Acute Right Ventricular Failure: A Perfect Storm and Successful Navigation.

Acute coronary obstruction is a relatively rare complication of transcatheter aortic valve replacement (TAVR). Left coronary ostial obstruction is much more common compared to right coronary occlusion due to its relatively lower ostial height from the aortic annulus. We present a case of acute ostial right coronary occlusion immediately upon deployment of a 29-mm Sapien 3 transcatheter aortic valve. The acute right coronary ostial occlusion manifested with ventricular fibrillation, acute right ventricular failure, and right-sided cardiogenic shock. The patient, after undergoing an initial unsuccessful attempt at percutaneous revascularization, was placed on veno-arterial extracorporeal membrane oxygenation (VA-ECMO). This was later transitioned to percutaneous right atrial to pulmonary artery right ventricular support, which led to subsequent recovery.

Bilateral central retinal artery occlusion from catastrophic antiphospholipid syndrome.

A 23-year-old woman with history of systemic lupus erythematous presented with dizziness and headache and was admitted for the stroke workup. During her stay, she had sudden painless loss of vision in her right eye consistent with central retinal artery occlusion (CRAO). Ocular massage and paracentesis were attempted without success to resume the flow. She was started on oral high-dose steroids (1 mg/kg) for lupus flare and therapeutic anticoagulation for antiphospholipid syndrome (positive for anticardiolipin and beta-2 microglobulin antibodies). On day 4, she started having painful bluish discoloration of her left index finger and right fifth toe, and on day 5 she had acute onset of left blurry vision with findings consistent with CRAO. She fulfilled the criteria of catastrophic antiphospholipid syndrome and was started on intravenous pulse steroids, plasmapheresis and higher international normalised ratio goal of 3-3.5 with improvement in her left eye vision from 20/200 to 20/20 on near card test by the end of treatment.

Meta-Analysis Comparing Dual Antiplatelet Therapy Versus Single Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation.

The present American College of Cardiology/American Heart Association guidelines (Grade IIb, level of evidence C) recommend dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 6 months followed by lifelong aspirin after transcathter aortic valve implantation (TAVI). However, studies that have compared DAPT to single antiplatelet therapy (SAPT) after TAVI have questioned this recommendation as DAPT has been associated with more bleeding events compared with SAPT. We performed a meta-analysis of all the trials that compared DAPT to SAPT in patients who underwent TAVI. Three randomized trials and 4 nonrandomized studies were included. The primary endpoint was the rate of ischemic stroke. Secondary end points were the rates of myocardial infarction, life threatening bleeding (LTB), significant bleeding (LTB and major bleeding), and death. The Mantel-Haenszel random effects model was used to calculate the combined odds ratios (OR) and 95% confidence intervals (CI) for outcomes at 30days and up to 6 to 12months follow-up. The LTB (OR 2.73, 95% CI 1.31 to 5.69, p = 0.007) and significant bleeding rates (OR 2.76, 95% CI 1.57 to 4.85, p = 0.0004) were significantly higher in DAPT arm at 30days. Significant bleeding (OR 2.24, 95% CI 1.33 to 3.79, p = 0.002) was still significantly higher in the DAPT arm but there was only a nonsignificant trend toward higher LTB (OR 1.93 95% CI 0.61 to 6.03, p = 0.26) at 6 to 12 month follow up. There was no difference in mortality, ischemic stroke and myocardial infarction at 30days or 6 to 12month follow up. In conclusion, our meta-analysis shows that DAPT after TAVI does not confer any additional benefit over SAPT in TAVI.

Performance of J-CTO and PROGRESS CTO Scores in Predicting Angiographic Success and Long-term Outcomes of Percutaneous Coronary Interventions for Chronic Total Occlusions.

Patient selection for and predicting clinical outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) remain challenging. We hypothesized that both J-CTO (Multicenter Chronic Total Occlusion Registry of Japan) and PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) scores will predict not only angiographic success but also long-term clinical outcomes of the patients who underwent PCI of CTO. Of 325 CTO PCIs performed at 2 Emory University hospitals from January 2012 to August 2015, 249 patients with complete baseline clinical, angiographic and follow-up data, were included in this analysis. Major adverse cardiovascular events (MACEs) consisted of a composite of death, myocardial infarction, and target vessel revascularization. Mean age was 63 ± 11 years old and mean follow-up was 19.8 ± 13.1 months. Angiographic success rates increased from 74.5% in 2012 to 85.7% in 2015. Greater J-CTO and PROGRESS CTO scores were not only associated with lower likelihood of angiographic success but also higher rates of long-term MACE. Compared with the scores of 0 to 2, J-CTO and PROGRESS CTO scores of ≥3 were associated with higher MACE. Multivariable analysis demonstrated that PROGRESS CTO scores of ≥3, male sex, and peripheral vascular disease were independent predictors of MACE. In conclusion, J-CTO and PROGRESS CTO scores are useful in predicting procedural success. In addition, the PROGRESS CTO score, and to a lesser degree J-CTO score, have predictive value for long-term outcomes in patients who underwent CTO PCI.

Vasomotor Function Comparative Assessment at 1 and 2 Years Following Implantation of the Absorb Everolimus-Eluting Bioresorbable Vascular Scaffold and the Xience V Everolimus-Eluting Metallic Stent in Porcine Coronary Arteries: Insights From In Vivo Angiography, Ex Vivo Assessment, and Gene Analysis at the Stented/Scaffolded Segments and the Proximal and Distal Edges.

OBJECTIVES: The purpose of this study was to assess and compare in vivo the restoration of vasomotor function following Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) and metallic Xience V (XV) (Abbott Vascular, Santa Clara, California) stent implantations in porcine coronary arteries at 1 and 2 years. BACKGROUND: Drug-eluting metallic coronary stents induce sustained vasomotor dysfunction, and preliminary observations from arteries with bioresorbable scaffolds have indicated partially restored vasoreactivity. METHODS: A total of 15 Absorb BVS (3.0 × 18.0 mm) and 14 XV (3.0 × 18.0 mm or 3.0 × 12.0 mm) stents were randomly implanted in the main coronaries of 12 nonatherosclerotic swine. The effect of implant on vasomotor performance (constrictive and expansive) was measured in the stented/scaffolded segments and the 5-mm proximal and distal adjacent segments in vivo by angiography assessing mean luminal diameter changes following infusion of vasoactive agents at 1 year (n = 6) and 2 years (n = 6) as well as ex vivo at 2 years using a tissue chamber apparatus. Endothelial cell function and smooth muscle cell phenotype gene marker levels were evaluated with quantitative real-time polymerase chain reaction. RESULTS: The scaffolded Absorb BVS segments showed fully restored constrictive response compared with XV implanted vessels at 1 year: -24.30 ± 14.31% versus -1.79 ± 6.57% (p < 0.004) and at 2 years: -28.13 ± 14.60% versus -3.90 ± 6.44% (p < 0.004). The early restoration of vasomotor function within the scaffolded segments reached a peak at 1 year and did not significantly change up to 2 years. The vasoactive responses of Absorb BVS-implanted vessels within the scaffolded segments were similar to those observed within the proximal and distal edge segments at both time points. Conversely, the stented XV segments demonstrated significantly impaired constrictive response compared with the distal XV edges at 1 year: -1.79 ± 6.57% versus -21.89 ± 7.17% (p < 0.0002) and at 2 years: -3.90 ± 6.44% versus -21.93 ± 15.60% (p < 0.03). Ex vivo assessment of contraction induced by PGF2α and relaxation induced by substance P of isolated BVS segments compared with XV-treated segments generated greater contraction force of 3.94 ± 0.97 g versus 1.83 ± 1.03 g (p < 0.05), and endothelial-dependent relaxation reached 35.91 ± 24.74% versus 1.20 ± 3.79% (p < 0.01). Quantitative real-time polymerase chain reaction gene analysis at 2 years demonstrated increased Connexin 43 messenger ribonucleic acid levels of Absorb BVS-treated vessels compared with XV-treated vessels: 1.92 ± 0.23 versus 0.77 ± 12 (p < 0.05). CONCLUSIONS: Absorb BVS-implanted coronary arteries demonstrate early functional restoration of the scaffolded and adjacent segments at 1 year, which is preserved up to 2 years.