Novel BH4-BCL-2 Domain Antagonists Induce BCL-2-Mediated Apoptosis in Triple-Negative Breast Cancer.

Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical success. The pro-survival B-cell lymphoma 2 (BCL-2) overexpression reported in TNBC plays a central role in deterring apoptosis and is a promising target. Here, we propose three novel BH4 mimetic small molecules, SM396, a covalent binder, and two non-covalent binders, i.e., SM216 and SM949, which show high binding affinity (nM) and selectivity, designed by remodeling the existing BCL-2 chemical space. Our mechanistic studies validate the selectivity of the compounds towards cancerous cells and not on normal cells. A series of functional assays illustrated BCL-2-mediated apoptosis in the tumor cells as a potent anti-cancerous mechanism. Moreover, the compounds exhibited efficacious in vivo activity as single agents in the MDA-MB-231 xenograft model (at nanomolar dosage). Overall, these findings depict SM216, SM396, and SM949 as promising leads, pointing to the clinical translation of these compounds in targeting triple-negative breast cancer.

Myocardial infarction in a patient with WPW syndrome. Lifting the veil.

Wolf-Parkinson-White syndrome (WPW) syndrome can mimic myocardial infarction (MI) due to the prominent repolarization changes secondary to abnormal myocardial activation by accessory pathway. Rarely these repolarization changes might mask the classical electrocardiographic (ECG) picture of MI and present with atypical ECG features, delaying the diagnosis in the emergency room. We present a case, where the onset of the MI in WPW syndrome was identified based on delta-T wave concordance, and QRS fragmentation.

Short term outcomes with dual chamber versus single chamber pacing for atrioventricular block - A crossover trial.

A total of 42 patients were studied for primary outcomes of quality of life and 6MWD between VVIR and DDD modes. At end of 2 months after device implantation, randomization was done and the device was programmed to VVIR or DDD modes. At the end of 2 months in this mode QOL and functional was assessed and the patient was switched to other mode. The same protocol was followed at the end of 2 months. We found no difference in functional capacity and quality of life between the two pacing modes. None of the patients developed pacemaker syndrome and there was no preference for any of the modes.

Catheter ablation of scar based ventricular tachycardia - Procedural characteristics and outcomes.

BACKGROUND: Ventricular tachycardia (VT) is a major cause of morbidity in patients with cardiomyopathy. Radiofrequency ablation has emerged as the mainstay of the management of recurrent sustained VT in these patients. We describe the clinical characteristics, procedural and medium term outcomes of patients undergoing ablation of scar VT in a tertiary care center in India. METHODS: This was a single-center descriptive cohort study. All patients who underwent ablation for scar related VT were included. Endpoints were immediate procedural success, procedural complications and recurrence during follow up. RESULTS: A total of 72 patients with scar VT underwent ablation with electroanatomic mapping. Previous myocardial infarction (MI) was the commonest etiology (69.4%) with arrhythmogenic right ventricular cardiomyopathy (ARVC) being the next common (19.4%). Acute procedural success was achieved in 69.4% patients, partial success in 9.7% and failure in 1 patient (1.4%). Outcome was labeled indeterminate in 19.4% who did not undergo post ablation VT induction. Procedural complications were seen in 4%. Follow up data was available in 95% of the patients with a mean follow up of 28.9 ± 22.8 months. At one year, freedom from VT was 83.8% and mortality was 13.2%. Overall mortality during follow up was 22.1% while VT recurrence was seen in 35.3%. Recurrence rate was higher in ARVC as compared to previous MI. CONCLUSIONS: Ablation of scar VT has high acute success rates. Ablation is safe with low risk of major complications. Rates of recurrence are higher in patients with ARVC as compared to post MI VT.

Procedural and follow-up clinical outcomes after chronic total occlusion revascularization: Data from an Indian public hospital.

BACKGROUND: Chronic total occlusion (CTO) continues to be challenging lesion subset for percutaneous intervention. Last decade has seen tremendous increase in percutaneous coronary intervention (PCI) in this subset owing to improved understanding of the anatomy and enhanced skillset with availability of dedicated hardware. We sought to study the outcomes of CTO PCI in an Indian public hospital. METHODS: This was a single-center non-randomized descriptive follow-up study on CTO PCI. The end-points were procedural success, immediate, and late adverse cardiovascular events [major adverse cardiac event (MACE)] and change in angina and left ventricular function at follow-up. RESULTS: A total 389 CTO lesions were treated with a success rate of 87% (339/389). The mean Japanese chronic total occlusion (J-CTO) score was 1.78 ± 0.12 (mean ± standard deviation). Multivariate analysis of different angiographic components of J-CTO score identified tortuosity (p = 0.001), calcifications (p ≤ 0.001), and blunt stump (p = 0.007) as independent predictors of procedural failure. The periprocedural mortality was less than 1%, and the non-life threatening complications were about 4%. The MACE rate was significantly higher in the procedural failure group (60%) than in the procedural success group (5.3%, p < 0.001). An increase in left ventricular ejection fraction (LVEF) was noted following successful CTO PCI after complete revascularization. CONCLUSIONS: The success rates for CTO PCI in this registry were about 87%. Immediate and long-term clinical outcomes were better with lower MACE (5%) after a successful procedure. A key outcome variable included an increase in LVEF among patients after a successful CTO PCI. The overall periprocedural complications were about 5.5%, but majority were non-life threatening.

Photocatalytic destruction of Escherichia coli in water by V2O5 /TiO2.

Vanadia modified titania (V2O5/TiO2) photo-catalysts are prepared by incipient wet impregnation method using aqueous ammonium metavanadate and anatase (Aldrich) titania. Titania with various loading concentrations of vanadia from 0 to 10 wt.% have been prepared and characterized by X-ray diffraction (XRD), Thermogravimetry (TGA), Laser Raman Spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), X-ray Photoelectron Spectroscopy (XPS), UV-Visible Spectrophotometry and Transmission Electron Microscopy (TEM). XRD study reveals that vanadia loading on titania does not bring any phase change of titania, however, diffuse (UV-Vis) reflectance spectra show that absorption edge of titania shifted from UV to visible region. TEM confirms that titania and vanadia modified titania have the particle size below 50 nm. XPS shows alteration of 2p3/2 peak of V(V) in the V2O5/TiO2 samples whereas no such change is noticed in pure V2O5 indicating the interaction between vanadia and titania support. Antibacterial activity of each sample has been investigated against Escherichia coli present in the water under both UV-Visible irradiation and UV alone. V2O5/TiO2 catalysts exhibit better photocatalytic effect than the unmodified titania and pure V2O5. It is observed that with increasing loading concentrations of V2O5 from 0 to 10 wt.% on titania support, the photocatalytic annihilation of E.coli is also increased and found to be little higher under UV alone than the UV-Visible irradiation.

Advances in chalcones with anticancer activities.

Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489).

Drug and bioactive molecule screening based on a bioelectrical impedance cell culture platform.

This review will present a brief discussion on the recent advancements of bioelectrical impedance cell-based biosensors, especially the electric cell-substrate impedance sensing (ECIS) system for screening of various bioactive molecules. The different technical integrations of various chip types, working principles, measurement systems, and applications for drug targeting of molecules in cells are highlighted in this paper. Screening of bioactive molecules based on electric cell-substrate impedance sensing is a trial-and-error process toward the development of therapeutically active agents for drug discovery and therapeutics. In general, bioactive molecule screening can be used to identify active molecular targets for various diseases and toxicity at the cellular level with nanoscale resolution. In the innovation and screening of new drugs or bioactive molecules, the activeness, the efficacy of the compound, and safety in biological systems are the main concerns on which determination of drug candidates is based. Further, drug discovery and screening of compounds are often performed in cell-based test systems in order to reduce costs and save time. Moreover, this system can provide more relevant results in in vivo studies, as well as high-throughput drug screening for various diseases during the early stages of drug discovery. Recently, MEMS technologies and integration with image detection techniques have been employed successfully. These new technologies and their possible ongoing transformations are addressed. Select reports are outlined, and not all the work that has been performed in the field of drug screening and development is covered.

Synthesis and characterization of titania nanorods from ilmenite for photocatalytic annihilation of E. coli.

Titania nanorod structures have been obtained by thermal plasma reduction of ilmenite (FeTiO3) followed by chemical treatments. Inherently present iron in the titania nanorods acts as a dopant which results in shifting the absorption edge of titania from ultraviolet to visible region. X-ray diffraction (XRD) study confirms the existence of rutile phase of titania. X-ray Photoelectron Spectroscopy (XPS) reveals the presence of Ti(4+), O(2-), Fe(3+) and surface hydroxyl group. Transmission Electron Microscopy (TEM) confirms the formation of nanorod structure having width of 6 nm and length of 32 nm. Photocatalytic annihilation property of titania nanorods derived from ilmenite (titania-I), rutile titania obtained from titanium(IV) butoxide (titania-A) and Degussa P25 titania was studied under UV and UV-Visible irradiation conditions separately and compared. The time required for complete photocatalytic annihilation of Escherichiacoli cells are 10, 15 and 45 min under UV irradiation whereas it has taken 15, 10-15, 30 min under UV-Visible irradiation for titania-A, Degussa P25 titania and titania-I respectively. It is observed that titania-I shows significantly stronger antibacterial property under UV-Visible irradiation compared to UV alone.