Aortopathy: Effects of Lipid-Lowering Therapy.

Aortopathies can be congenital or acquired. Aortic atherosclerosis, abdominal aortic aneurysm, and degenerative aortic stenosis are some of the major manifestations of acquired aortopathy. Dyslipidemia, an imbalance of plasma lipid levels, is strongly associated with common aortopathies. A relationship between abdominal aortic aneurysm, degenerative aortic stenosis, and dyslipidemia has been identified in the literature but finding effective preventive strategies has been challenging. Nevertheless, lipid-lowering therapy remains a mainstay of both treatment and prevention. In patients with aortic atheroma, statins were found to be protective through the review of this study. There is currently no place for statins in the treatment or prevention of disease progression in patients with calcific aortic stenosis. Their low cost, widespread availability, and strong safety profile tip the risk-to-benefit ratio toward statins for abdominal aortic aneurysms but more research is needed. A review of proprotein convertase subtilisin/kexin type 9 inhibitors may yield similar benefits for all aortopathy patients; however, those results are not yet available.

Variations in Mitral Valve Leaflet and Scallop Anatomy on Three-Dimensional Transesophageal Echocardiography.

BACKGROUND: Textbook depictions of the mitral valve (MV) often illustrate it as composed of a single nonscalloped anterior leaflet, with the posterior leaflet having three symmetric and evenly spaced scallops. However, common variations in this anatomy have been noted in autopsy series for decades. Improved cardiac imaging with three-dimensional transesophageal echocardiography (TEE) now affords the ability to detect variations in scallop anatomy in vivo. The aims of this study were to catalog variations in mitral anatomy and to examine for association with mitral regurgitation in patients referred for clinical three-dimensional TEE. METHODS: Three-dimensional transesophageal echocardiographic images of the MV from 107 subjects were reviewed for MV variations. Three-dimensional analysis software was used to characterize mitral leaflet anatomy and assess the relative sizes of posterior leaflet scallops. RESULTS: Variations from the classic MV configuration were seen in 58.9%. Symmetric variations in the posterior leaflet (dominant P2 scallop, accessory P2 scallop, absent P2 scallop, and dichotomous P2 scallop) were seen in 33.6% of the study group. Asymmetric variants in the posterior leaflet (fused P1 and P2, fused P2 and P3, commissural scallop, accessory scallops, dichotomous P1 or P3, and dominant P2 or P3) were seen in 24.3%. Indentations or folds in the anterior leaflet were noted in 5.6%. Leaflet variations were not associated with patient demographics, indication for TEE, mitral regurgitation, mitral annular dimensions, or Carpentier class. CONCLUSIONS: Mitral leaflet morphologic variants were well characterized using three-dimensional TEE. Variants are common and were present with a frequency consistent with autopsy series. Mitral scallop variations were not associated with mitral regurgitation.

Structure-based pharmacophore modeling, virtual screening and simulation studies for the identification of potent anticancerous phytochemical lead targeting cyclin-dependent kinase 2.

Cyclin-dependent kinases are of critical importance in directing various cell cycle phases making them as potential tumor targets. Cyclin-dependent kinase 2 (CDK2) in particular plays a significant part during cell cycle events and its imbalance roots out tumorogenic environment. Herein, we built a structure-based pharmacophore model complementing the ATP pocket site of CDK2 with four pharmacophoric features, using a series of structures obtained from cluster analysis during MD simulation assessment. This was followed by its validation and further database screening against Taiwan indigenous plants database (5284 compounds). The screened compounds were subjected toward Lipinski's rule (RO5) and ADMET filter followed by docking analysis and simulation study. In filtering hits (10 compounds) via molecular docking against CDK2, Schinilenol with -8.1 kcal/mol fetched out as a best lead phytoinhibitor in the presence of standard drug (Dinaciclib). Additionally, pharmacophore mapping analysis also indicated relative fit values of dinaciclib and schinilenol as 2.37 and 2.31, respectively. Optimization, flexibility prediction and the stability of CDK2 in complex with the ligands were also ascertained by means of molecular dynamics for 50 ns, which further proposed schinilenol having better binding stability than dinaciclib with RMSD values ranging from 0.31 to 0.34 nm. Reactivity site, biological activity detection and cardiotoxicity assessment also proposed schinilenol as a better phytolead inhibitor than the existing dinaciclib. Abbreviations: CDK2: Cyclin dependent kinase2; ATP: Adenosine triphosphate; MD: Molecular dynamics, RO5: Rule of five; ADMET: Absorption, distribution, metabolism, and excretion; RMSD: Root mean square deviation; DS: Discovery Studio; SOM: Site of metabolism; RBPM: receptor based pharmacophore model; TIP: Schinilenol; hERG: human Ether-à-go-go - Related GeneCommunicated by Ramaswamy H. Sarma.

Quantitative structure activity relationship and molecular simulations for the exploration of natural potent VEGFR-2 inhibitors: an in silico anti-angiogenic study.

VEGFR-2 has recently become an eye-catching molecular target for the novel therapeutic designs against cancer for its well known role in persuading angiogenesis in tumor cells. The current study set sights on the exploration of novel potent natural compound targeting VEGFR-2 via computational ligand-based modeling and database screening followed by binding pattern analysis, reactivity site prediction and MD simulation studies. The known 53 VEGFR-2 inhibitors (with IC50 ranging from 0.7 nM to 9700 nM) were headed for development of Ligand based pharmacophore model using 3 D QSAR pharmacophore generation module of DS Client. Training set inhibitors (23 compounds) were exploited to create pharmacophore model based on their chemical features. The model was validated through 30 test set inhibitors and exploited further for screening of 62,082 natural compounds from InterBioscreen natural compound database. Screened compounds further went through Drug-Likeliness study, ADMET prediction, Binding pattern analysis, In silico prediction of reactivity sites, Biological activity spectra prediction, pan assay interference compound identification and MD simulation analysis. Out of 5 screened compounds, Compound A and Compound B exhibited highest binding energy judged against the standard drug "Sorafenib". On further conducting reactivity site prediction, BAS prediction, and pan assay interference compound identification, Compound B exhibited better result which was carried forward for MD simulation study for 50 ns. MD simulation results suggested that Compound B exhibited more stable binding to the active site of VEGFR-2 without causing any conformational changes in protein-ligand complex. Thereby, the investigation proposes Compound B to hold potent antiangiogenic potential targeting VEGFR-2. [Formula: see text] Communicated by Ramaswamy H. Sarma.

Nanoinformatics and biomolecular nanomodeling: a novel move en route for effective cancer treatment.

Empowering role of nanoinformatics in design and elucidation of nanoparticles for effective cancer treatment has made this field a fascinating area for researchers, inspiring them to enhance up the quality and efficacy of existing anticancer medicines. Theoretical and computational modeling is being seen as a forefront solution for problems related to surface chemistry, optimized geometry, or other properties in nanoparticle designing and drug delivery. The current review aims to acquaint with the insight story of the incubation of in silico tools and techniques in nanotechnology to develop better anticancer nanomedicines. The review also recapitulates the assets and liabilities of this field and present an outline of existing inventiveness and endeavors of nanoinformatics. We propose how nanoinformatics could hasten up the advancements in anticancer nanomedicines through use of computational tools, nanoparticles repositories & various modeling and simulation methods.

Left Atrial Appendage Occlusion in the Management of Stroke in Patients With Atrial Fibrillation.

Atrial fibrillation (AF) is associated with a substantially higher risk of thromboembolism, particularly stroke events, resulting in significant morbidity and mortality. Oral anticoagulation (OAC), while effective in reducing embolic events in AF patients, is associated with an increased bleeding risk. Thus, not all patients with AF are candidates for OAC and some are only candidates for OAC in the short term. Of the available nonpharmacologic strategies for the management of AF, left atrial appendage occlusion (LAAO) has emerged as a potential approach for reducing the risk of systemic thromboembolism in AF patients eligible for OAC. LAAO can be achieved either surgically or percutaneously using an epicardial, endocardial, or a combined approach. Although available data are limited, currently available LAAO devices, and those being developed, have shown promise in reducing bleeding risk in AF patients because of the reduced overall need for anticoagulation, while maintaining efficacy in preventing thromboembolism. The optimal device will reduce both embolic and hemorrhagic strokes, and other bleeds, with a high implant success rate and a low complication rate. Until that time, anticoagulation remains the gold standard that these devices strive to surpass, and thus LAAO devices are currently indicated in patients with relative contraindication to OAC therapy.

Digital Breast Tomosynthesis as a Tool in Confirming Negative Surgical Margins in Non-palpable Breast Lesions.

Breast cancer is one of the leading killers among women the world over. Widespread mammographic screening programs have led to almost 20% of breast cancers being detected when they are radiologically visible but clinically impalpable. For the localization of these cancers before surgical excision, the Kopan hook wire is the standard technique, but the extent of margins excised still needs to be determined. In this study, we have evaluated the accuracy of specimen mammogram (SM) with digital breast tomosynthesis (DBT) for margin assessment by comparing it to the excised margins as measured in final histopathology. This is a prospective observational study of patients with radiologically suspicious impalpable breast lesions. The patients underwent ultrasound-guided hook wire placement followed by excision of the lesion, subjected to digital tomosynthesis mammogram, and margins were revised on table when indicated. These findings were correlated with final histopathological margin. Our study included 30 patients and out of the 6 lesions, which showed positive margins on specimen mammography, 4 were histologically confirmed to have tumour at the surgical margin and 2 were confirmed to be tumour free. All DBT-positive margins were re-excised at the time of primary surgery. Individual comparison of the margins revealed a good agreement and high level of correlation between DBT and histopathology margins. None of the cases required a second surgery for margin revision. It can be concluded that specimen mammogram with DBT can be used as a reliable tool for intraoperative surgical margin assessment in non-palpable breast lesions to reduce rate of margin revision as well as reduce the volume of breast excised without compromising the oncological safety of the procedure.

Virtual screening,docking and molecular dynamics simulation of selected phytochemical compounds bound to receptor tyrosine kinases:A correlative anti angiogenic study.

Screening of phytochemicals for their anti angiogenic potential has been a growing area of research in the current decade. The following study proposes virtual screening, drug likeliness and ADME filtering of specific phytochemical based compounds retrieved from "TIP - A Database of Taiwan Indigenous Plants". The study further subjects the filtered phytochemicals for their molecular docking analysis and molecular dynamics simulation studies against the prominent receptor tyrosine kinases EGFR, VEGFR-1 and VEGFR-2 involved in angiogenesis phenomenon. Among the various in silico analysis done and precise interpretations, the current study finally proposes 1- Hydroxycryprochine as one of the most potent lead in combating angiogenic phenomenon and thus cancer. The following study involves all such important use of in silico platforms, tools and analysis protocols which are expected to reproduce commendable results in wet lab studies. The proposed compound 1-hydroxycryprochine tends to justify its anti angogenic potential in all interactional and stability studies.

Cancer Nanotechnology-An Excursion on Drug Delivery Systems.

BACKGROUND: Nanotechnology pictures a breakthrough in the domain of cancer therapy owing to its novel properties and functions. This technology is quite amendable as it allows the scientists to engineer drug nanoparticles of dimensions 10nm - 500nm permitting them to pass via leaky vasculature of tumorigenic microenvironment with higher specificity, reduced cytotoxicity and effective release without any after effects. The central part of the review zooms onto the role of nanoparticles and their targeted delivery for the cure of cancer. METHODS: The novel and various versatile nanoparticle platforms viz. polymeric (drug-conjugates, micelles, dendrimers), Lipid-based (liposomes, solid nanoparticle, nanostructured lipid carrier, lipid-polymer hybrid), and stimuli-sensitive (thermoresponsive, ultrasound, pH-responsive, hydrogel) etc. have been designed for a persistent, précised nanodrug delivery and the co-delivery of collegial drug conjugates leading to the formation of safer release of myriad of drugs for cancer chemoprevention. RESULTS: The review concerns about tracing and detailing the drug delivery systems of cancer nanotechnology. CONCLUSION: Nanotechnology is bestowed with the design, depiction, fabrication, and application of nanostructures, and devices with their controlled delivery together with the imaging of the selected target site and drug release at the specific site of action.

IL-10(-592A/C) gene variant a predictor of postoperative atrial fibrillation in the north Indian population.

BACKGROUND: There is an accumulating body of evidence indicating a strong association between inflammation and the pathogenesis of atrial fibrillation (AF) in different ethnicities across the globe. AF increases the risk of stroke and heart failure. Despite various researches on IL-10 response, there is limited clinical evidence present, which demonstrate a role of these immunity regulators in AF. Therefore, this study was designed to decipher the role of IL-10(-592A/C) polymorphism in the development of postoperative AF (post-OP AF). METHOD: The study was designed for north Indian patients. The study included 90 patients with AF and 126 controls in sinus rhythm undergoing surgery at Department of Cardiovascular and thoracic surgery, SGPGIMS, Lucknow, India. DNA samples were genotyped for common single nucleotide polymorphism (SNP) in gene IL-10(-592A/C). The PCR-based RFLP technique was used to assess the genotype frequencies. The multivariable logistic regression analysis was performed to study the association of other risk factors with AF. RESULTS: The distribution of IL-10(-592A/C) genotypes (CC, AC, and AA) was found to be 48.41%, 47.61%, and 3.98% in controls and 41.11%, 45.55%, and 13.34% in cases, respectively (P = .0385). The frequency of allele A in cases was significantly higher than the control group (36.11% vs 27.77%, P = .0654). Compared with CC, AA genotype had increased risk of AF in both unadjusted and adjusted analyses. CONCLUSIONS: This study suggests that IL-10(-592A/C) polymorphism may have significant association with post-OP AF development in north Indian patients.

Molecular Interaction and Computational Analytical Studies of Pinocembrin for its Antiangiogenic Potential Targeting VEGFR-2: A Persuader of Metastasis.

BACKGROUND: Designing a novel antagonist against VEGFR-2 is being applied currently to inhibit cancer growth and metastasis. Because of the unexpected side effects incurred by the contemporary anticancer medications, the focus has been laid towards identifying natural compounds that might carry the potential to inhibit tumor progression. VEGR-2 remains an important target for anticancer drug development as it is the master regulator of vascular growth. OBJECTIVE: The study focuses on virtual screening of compounds from plants of Asteraceae family that bears antiangiogenic potential and thus, inhibiting VEGFR-2 using a computational approach. MATERIALS AND METHODS: Structures of phytochemicals were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, VEGFR-2 was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling were carried out on the phytochemicals of the Asteraceae family and the filtered compounds were further promoted for molecular docking and MD simulation analysis. The study extends towards the SOM analysis of Pinocembrin to predict the possible toxic and non-toxic in vivo metabolites via in silico tools (Xenosite Web and PASS online server). RESULTS: The docking results revealed promising inhibitory potential of Pinocembrin against VEGFR-2 with binding energy of -8.50 kcal/mole as compared to its known inhibitors Sorafenib and YLT192 having binding energy of -6.49 kcal/mole and -8.02 kcal/mol respectively. Further, molecular dynamics (MD) simulations for 10ns were conducted for optimization, flexibility prediction, and determination of folded VEGFR-2 stability. The Hsp90-Pinocembrin complex was found to be quite stable with RMSD value of 0.2nm. Pinocembrin was found to be metabolically stable undergoing phase I metabolism with non-toxic metabolites compared to the standard drug Sorafenib and YLT192. CONCLUSION: Obtained results propose Pinocembrin as a multi-targeted novel lead compound that bears outstanding antiangiogenic potential against VEGFR-2.

Evaluation of Surgical Outcomes of Oncoplasty Breast Surgery in Locally Advanced Breast Cancer and Comparison with Conventional Breast Conservation Surgery.

The purpose of this study was to compare early oncologic outcomes of oncoplastic breast surgery and conventional breast conservation surgery in patients of locally advanced breast cancer. A single-center, prospective, non-randomized study enrolled select cases of locally advanced breast cancer (TNM T3/T4, N0/1/2) who after neoadjuvant chemotherapy, were considered for breast conservation surgery with oncoplasty techniques. The specimen volume resected, the mean margins and mean closest margin obtained were noted. The re-surgery rates, complication rates, and incidence of locoregional recurrence were also noted. Variables were compared with a retrospective cohort of similar patients who had undergone conventional breast conservation surgery. Fifty-seven patients underwent OBS (group 1) and were compared with 43 cases that had undergone conventional BCS (group 2). Majority of the patients in group 1 (73 %) had cT3 with N0 or N+ and a minority (17 %) were with limited skin involvement (cT4 and N0/N+). Relatively larger sized, post-NACT tumors could undergo OBS(4.4 vs 2.3 cm). Relatively greater proportion of tumors in central and lower quadrants were addressed by oncoplasty than traditional BCS (17/57, 29 % vs 4/43, 9 %, p = 0.04). The mean specimen volume excised in group 1 was more than that in group 2. (187.54 vs 125.19; p = 0.01). The mean of the margins were obtained more in group 1 (1.04 vs 0.69 cm); p < 0.01) as also the mean closest margin (0.86 vs 0.49 cm; p < 0.01). The incidence of close or involved margins was lesser in the OBS group (8 vs 24 %). Overall incidence of complications was similar in both groups (8/57, 14 % vs 4/43, 9 %; p = 0.34 NS). The median follow-up period of group 1 is 18 months (range 06-30 months) while group 2 is 34 months (14-44 months. There was no recurrence in group 1, but there were 5 cases (11 %) in group 2. Oncoplasty breast surgery offers more opportunity for breast conservation and oncologic safety than conventional breast conserving surgery.

Evaluation of surgical outcomes following oncoplastic breast surgery in early breast cancer and comparison with conventional breast conservation surgery.

BACKGROUND: The aim of this study was to determine whether oncoplastic breast surgery (OBS) ensures better tumour resection than conventional breast conservation surgery (BCS). METHODS: A prospective comparative study, conducted over a 3-year period, enrolled patients with early breast cancer who underwent OBS. The total volume of glandular resection, tumour volume resection and width of the margins obtained were noted. The incidence of complications, requirement of revision surgery and locoregional recurrence during follow-up period were also noted. The data were compared with matched controls who had undergone convention BCS in the past. RESULTS: Thirty-three patients underwent oncoplastic surgery and the data was compared with 46 patients of conventional breast conservation. The mean volume of specimen was higher in the oncoplastic group (173.5 cm(3) vs 101.4 cm(3), p = 0.03) though the tumour volume excised was similar (43.2 cm(3) vs 36.4 cm(3), p = 0.14). The mean margin widths were larger in the oncoplastic group (14 mm vs 6 mm, p = 0.01). There were more instances of close and positive margins seen in conventional BCS groups. The incidence of complication rate was similar. Median follow-up 18 months for oncoplasty group showed no cases of locoregional recurrence while in median follow-up of 38 months for conventional BCS group, six cases of locoregional relapse were noted. CONCLUSIONS: Oncoplastic surgery results in excision of larger volume of breast tissue and correspondingly obtain wider surgical margins as compared to conventional BCS. Longer follow-up is required to determine if wider resection translates into better locoregional control.

Multi-platform assessment of transcriptional profiling technologies utilizing a precise probe mapping methodology.

BACKGROUND: The arrival of RNA-seq as a high-throughput method competitive to the established microarray technologies has necessarily driven a need for comparative evaluation. To date, cross-platform comparisons of these technologies have been relatively few in number of platforms analyzed and were typically gene name annotation oriented. Here, we present a more extensive and yet precise assessment to elucidate differences and similarities in performance of numerous aspects including dynamic range, fidelity of raw signal and fold-change with sample titration, and concordance with qRT-PCR (TaqMan). To ensure that these results were not confounded by incompatible comparisons, we introduce the concept of probe mapping directed "transcript pattern". A transcript pattern identifies probe(set)s across platforms that target a common set of transcripts for a specific gene. Thus, three levels of data were examined: entire data sets, data derived from a subset of 15,442 RefSeq genes common across platforms, and data derived from the transcript pattern defined subset of 7,034 RefSeq genes. RESULTS: In general, there were substantial core similarities between all 6 platforms evaluated; but, to varying degrees, the two RNA-seq protocols outperformed three of the four microarray platforms in most categories. Notably, a fourth microarray platform, Agilent with a modified protocol, was comparable, or marginally superior, to the RNA-seq protocols within these same assessments, especially in regards to fold-change evaluation. Furthermore, these 3 platforms (Agilent and two RNA-seq methods) demonstrated over 80% fold-change concordance with the gold standard qRT-PCR (TaqMan). CONCLUSIONS: This study suggests that microarrays can perform on nearly equal footing with RNA-seq, in certain key features, specifically when the dynamic range is comparable. Furthermore, the concept of a transcript pattern has been introduced that may minimize potential confounding factors of multi-platform comparison and may be useful for similar evaluations.

Mobile physician reporting of clinically significant events-a novel way to improve handoff communication and supervision of resident on call activities.

OBJECTIVES: Reporting of clinically significant events represents an important mechanism by which patient safety problems may be identified and corrected. However, time pressure and cumbersome report entry procedures have discouraged the full participation of physicians. To improve the process, our internal medicine training program developed an easy-to-use mobile platform that combines the reporting process with patient sign-out. METHODS: Between August 25, 2011, and January 25, 2012, our trainees entered clinically significant events into i-touch/i-phone/i-pad based devices functioning in wireless-synchrony with our desktop application. Events were collected into daily reports that were sent from the handoff system to program leaders and attending physicians to plan for rounds and to correct safety problems. RESULTS: Using the mobile module, residents entered 31 reportable events per month versus the 12 events per month that were reported via desktop during a previous 6-month study period. CONCLUSIONS: Advances in information technology now permit clinically significant events that take place during "off hours" to be identified and reported (via handoff) to next providers and to supervisors via collated reports. This information permits hospital leaders to correct safety issues quickly and effectively, while attending physicians are able to use information gleaned from the reports to optimize rounding plans and to provide additional oversight of trainee on call patient management decisions.

Existing drugs and agents under investigation for pulmonary arterial hypertension.

Pulmonary arterial hypertension is a progressive and debilitating disorder with an associated high morbidity and mortality rate. Significant advances in our understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary hypertension have occurred over the past several decades. This has allowed the development of new therapeutic options in this disease. Today, our selection of therapeutic modalities is broader, including calcium channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators, but the disease remains fatal. This underscores the need for a continued search for novel therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include rho-kinase inhibitors, long-acting nonprostanoid prostacyclin receptor agonists, tyrosine protein kinase inhibitors, endothelial nitric oxide synthase couplers, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.

Oncoplastic breast surgery: Initial experience in an Oncology Center.

BACKGROUND: Oncoplastic breast surgery (OBS) encompasses surgical procedures designed to achieve successful breast tumour excision with good cosmesis. A relatively well established technique in western world, the same is gaining interest in Indian subcontinent too. We present our initial experience with the said technique. METHODS: A retrospective analysis of a series of cases of carcinoma breast who underwent oncoplastic breast surgery procedure over one year period was carried out in an Oncology center of a Command Hospital. RESULTS: In the study period, a total of 18 eligible cases underwent OBS. All patients were female with mean age 33.4 yrs(±5.7). Total nine cases underwent volume replacement procedure in which six patients underwent modified radical mastectomy(MRM) with TRAM flap. Two patients underwent breast conserving surgery with lattisimus dorsi myocutaneous flap (LDMF) reconstruction and one underwent MRM with LDMF reconstruction. Total nine cases underwent volume displacement technique wherein five, two, one and one patients underwent lateral mammaplasty, medial mammaplasty, wise incision and batwing incision respectively. Median follow up has been 05 months. Three patients developed surgery related complications. Early results show acceptable cosmetic results. CONCLUSION: Oncoplastic breast surgery combines the principles of surgical oncology with those of plastic and reconstructive surgery and our initial experience shows that OBS leads to aesthetically pleasing and oncologically sound results.