Comparative analysis of Doxycycline and Ayurvedic herbs to target metastatic breast cancer: An in-silico approach.

Background: Metastasis of breast cancer cells to distant sites including lungs, liver, lymph node, brain and many more have substantially affected the overall survival outcome and distant metastasis free survival rate amongst the diseased individuals. Several pre-clinical and clinical studies were carried out to determine the potency of vigorous inhibitors but they extensively deteriorated the patient's quality of life. Hence, there exists an urgent need to explore potent natural remedy to fight against metastatic breast cancer. Methods: Ayurvedic medicinal plants documented in literature for their ability to fight against breast cancer was screened and their respective active moieties were evaluated to exert inhibitory effect against MMP9. Drug like efficacy of phytochemicals were determined using Molecular docking, MD Simulation, ADMET and MM-PBSA and were further compared with synthetic analogs i.e. Doxycycline. Results: Out of 1000 phytochemicals, 12 exerted highest binding affinity (BA) even more than -9.0 kcal/mol that was significantly higher in comparison to Doxycycline which exhibited BA of -7.3 kcal/mol. In comparison to 37 × 30 × 37 Å, 53 × 45 × 66 Å offered best binding site and the highest BA was exhibited by Viscosalactone at LYS104, ASP185, MET338, LEU39, ASN38. During MD Simulation, Viscosalactone-MMP9 complex remained stable for 20 ns and the kinetic, electrostatic and potential energies were observed to be better than Doxycycline. Furthermore, Viscosalactone obtained from Withania somnifera justified the Lipinski's Rule of 5. Conclusion: Viscosalactone obtained from W. somnifera may act as promising drug candidate to fight against metastatic breast cancer.

Tumor Suppressive Role of MicroRNAs in Triple Negative Breast Cancer.

Triple-negative breast cancers are highly aggressive, a heterogeneous form of breast cancer with a high re-occurrence rate that further lacks an efficient treatment strategy and prognostic marker. The tumor microenvironment of the disease comprises cancer-associated fibroblasts, cancer stem cells, immunological molecules, epithelial-mesenchymal transition, and a metastatic microenvironment that contributes to disease progression and metastasis to distant sites. Emerging evidence indicated that miRNA clusters would be of clinical utility as they exert an oncogenic or tumor suppressor role in TNBC. The present review article aims to highlight the therapeutic significance of miRNA in targeting the above-mentioned signaling cascades and modulating the intracellular crosstalk in the tumor microenvironment of TNBC. Prognostic implications of miRNAs to depict disease-free survival, distant metastasis-free survival, relapse-free survival, and overall survival outcome were also unveiled.

Unveiling Role of MicroRNAs in Metastasizing Triple Negative Breast Cancer: From Therapeutics to Delivery.

Triple negative breast cancers are malignant, heterogeneous tumors with high histological grades, increased reoccurrence, and cancer-related death rates. TNBC metastasis to the brain, lungs, liver, and lymph nodes is a complex process regulated by epithelial to mesenchymal transition, intravasation, extravasation, stem cell niche, and migration. Aberrant expression of miRNAs, also known as a transcriptional regulators of genes, may function as oncogenes or tumor suppressors. In this review, we systematically elucidated the biogenesis and tumor suppressor role of miRNA in targeting distant metastasis of TNBC cells and the above-mentioned underlying mechanisms involved in complicating the disease. Apart from their therapeutic implications, the emerging roles of miRNAs as prognostic markers have also been discussed. To overcome delivery bottlenecks, RNA nanoparticles, nano-diamonds, exosomes, and mesoporous silica nanoparticle-mediated delivery of miRNAs have been contemplated. Altogether, the present review article uncovers the potential role of miRNA in antagonizing distant metastasis of TNBC cells, and highlights their clinical significance as prognostic markers and possible drug delivery strategies to enhance the likely outcome of miRNA-based therapy against the disease.

Risk Factors Predicting the Need for Phototherapy in Glucose 6 Phosphate Dehydrogenase-Deficient Infants in a Large Retrospective Cohort Study.

INTRODUCTION: Glucose 6-phosphate dehydrogenase (G6PD) deficiency increases the risk of severe neonatal hyperbilirubinemia. This study evaluates the risk factors predicting the need for phototherapy in G6PD-deficient neonates after 72 h of age and assesses the safety of early discharge. METHODS: A retrospective cohort study of 681 full-term G6PD-deficient infants with a birth weight ≥2,500 g over 4 years was conducted. We compared the baseline characteristics, bilirubin level on day 4 (after 72 h of life), day of peak bilirubin, G6PD levels, and concomitant ABO incompatibility between the group that required phototherapy (Group A) and those who did not (Group B). RESULTS: 396 infants (58%), predominantly males, required phototherapy in the first week of life. The infants who required phototherapy had a lower median gestational age (38.3 vs. 38.7 weeks, p < 0.01) and had lower G6PD levels (2.3 ± 2.5 vs. 3 ± 3.4 IU, p < 0.05) compared to the controls. The mean day-four total serum bilirubin (TSB) levels were higher (213 ± 32 vs. 151 ± 37 µmol/L, p < 0.01), with bilirubin level peaking earlier (3 vs. 4 days of life, p < 0.01) in group A. Regression analysis identified TSB levels on day 4, Chinese race, lower gestation, and concomitant ABO incompatibility as the significant predictors for the need for phototherapy in the study population. In particular, coexisting ABO blood group incompatibility increased the risk of jaundice requiring phototherapy (OR 4.27, 95% CI: 1.98-121, p < 0.01). Day four TSB values above 180 µmol/L predicted the need for phototherapy with 86% sensitivity and 80% specificity. The findings were similar across both male and female infants with G6PD deficiency. CONCLUSION: G6PD-deficient infants with day four TSB levels of >180 µmol/L (10.5 mg/dL) and associated ABO blood group incompatibility have a higher risk of requiring phototherapy in the first week of life and should be closely monitored.

Impact of an Auditory Mediated Patient Health Education (PHE) Program on Treatment Compliance and Satisfaction Among Patients Seeking Prosthodontic Care During COVID Pandemic - A Prospective Interventional Study.

Background: Patients health education by healthcare workers has been affected by pandemic guidelines. This study aimed to evaluate the influence of an audio-mediated intervention for patient health education (PHE) on treatment compliance and treatment satisfaction among patients seeking prosthodontic treatment during the Covid pandemic. Methods: A total of 666 patients (aged 40-70 years) who fulfilled the study criteria were treated for denture-associated disease. PHE for 5 different categories was performed using an educational audio (MP3) in the experimental group (Group E), and traditional methods (oral/verbal) in the control group (Group C). Patient/clinician satisfaction with the PHE program was evaluated with a pre-validated questionnaire, whereas treatment compliance and satisfaction were evaluated using a denture hygiene index (DHI) and a visual analog scale (VAS). Differences between qualitative variables were determined using the chi-square test, whereas continuous variables were assessed using an unpaired t-test. Differences were considered to be statistically significant at p ≤ 0.05. Results: Patient satisfaction with PHE was significantly higher and differed in the Group E for two parameters: education method (80%), educational material (94%). For all parameters of procedural education, patient/clinician satisfaction was significantly higher for Group E [method (93%), material (85%), patient preparation (89%), personalized education (84%), program (93%)]. From three different ratings of disease education, 70% in Group E rated education as "effective" as compared to 41% in the Group C. Effectiveness of post treatment, education measured through DHI, revealed a lower hygiene score in Group E (m = 1.18) as compared to Group C (m = 2.92), with differences being significant. For treatment satisfaction, patients in Group E rated higher for speech (m = 8.21), ease of chewing (m = 7.36), and general satisfaction (m = 7.9). Conclusion: This study concluded that using audio as a means of imparting PHE positively influences the treatment compliance and satisfaction among outpatients and overcomes the drawback of wearing mask during the pandemic.

Standardized Outcome Measures for Preterm and Hospitalized Neonates: An ICHOM Standard Set.

INTRODUCTION: Approximately, one in ten infants is born preterm or requires hospitalization at birth. These complications at birth have long-term consequences that can extend into childhood and adulthood. Timely detection of developmental delay through surveillance could enable tailored support for these babies and their families. However, the possibilities for follow-up are limited, especially in middle- and low-income countries, and the tools to do so are either not available or too expensive. A standardized and core set of outcomes for neonates, with feasible tools for evaluation and follow-up, could result in improving quality, enhance shared decision-making, and enable global benchmarking. METHODS: The International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group, which was comprised of 14 health-care professionals (HCP) and 6 patient representatives in the field of neonatal care. An outcome set was developed using a three-round modified Delphi process, and it was endorsed through a patient representative-validation survey and an HCP survey. RESULTS: A literature review revealed 1,076 articles and 26 registries which were screened for meaningful outcomes, patient-reported outcome measures, clinical measures, and case mix variables. This resulted in a neonatal set with 21 core outcomes covering three domains (physical, social, and mental functioning) and 14 tools to assess these outcomes at three timepoints. DISCUSSION: This set can be implemented globally and it will allow comparison of outcomes across different settings and countries. The transparent consensus-driven development process which involved stakeholders and professionals from all over the world ensures global relevance.

Unveiling Novel Therapeutic Drug Targets and Prognostic Markers of Triple Negative Breast Cancer.

Triple negative breast cancer represents multiple genomic and transcriptomic heterogeneities. Genetic and epigenetic changes emerging in TNBC help it in acquiring resistance against immunological response. Distant metastasis, lack of clinically targeted therapies and prognostic markers make it the most aggressive form of breast cancer. In this review, we showed that driver alterations in targeted genes AR, ERR, TIL, TAM, miRNA, mTOR and immunosuppressive cytokines are predominantly involved in complicating TNBC by inducing cell proliferation, invasion and metastasis, and by inhibiting apoptosis. The role of node status, cathepsin-D, Ki-67 index, CD3+TIL, BRCA1 promoter methylation value and p53 as an efficient prognostic factor have also been studied to predict the disease free and overall survival rate in TNBC patients. The present review article is an attempt to gain an insight with a new vision on the etiology of TNBC, its treatment strategies and prognostic marker to identify the outcome of standard therapies and to re-design future treatment strategies to provide maximum benefit to patients.

Computational Evidences of Phytochemical Mediated Disruption of PLpro Driven Replication of SARS-CoV-2: A Therapeutic Approach against COVID-19.

BACKGROUND: COVID-19 caused by SARS-CoV-2 has been declared as a global pandemic by WHO. Comprehensive analysis of this unprecedented outbreak may help to fight against the disease and may play a pivotal role in decreasing the mortality rate linked with it. Papain-like protease (PLpro), a multifunctional polyprotein, facilitates the replication of SARS-CoV-2 and evades it from the host immunological response by antagonizing cytokines, interferons and may be considered as a potential drug target to combat the current pandemic. METHODS: Natural moieties obtained from medicinal plants were analysed for their potency to target PLpro of SARS-CoV-2 by molecular docking study and were compared with synthetic analogs named as remdesivir, chloroquine and favipiravir. The stability of complexes of top hits was analysed by MD Simulation, and interaction energy was calculated. Furthermore, average RMSD values were computed and deepsite ligand-binding pockets were predicted using Play Molecule. Drug-like-abilities of these moieties were determined using ADMET and bond distance between the ligand and active site was assessed to predict the strength of the interaction. RESULTS: Nimbocinol (-7.6 Kcal/mol) and sage (-7.3 Kcal/mol) exhibited maximum BA against PLpro SARS-CoV-2 as evident from molecular docking study, which was found to be even better than remdesivir (-6.1 Kcal/mol), chloroquine (-5.3 Kcal/mol) and favipiravir (-5.7 Kcal/mol). Both nimbocinol- PLpro and sage-PLpro SARS-CoV-2 complex exhibited stable conformation during MD Simulation of 101ns at 310 K, and potential, kinetic and electrostatic interaction energies were computed, which was observed to be concordant with results of molecular docking study. RMSD average values were found to be 0.496 ± 0.015 Å and 0.598 ± 0.023 Å for nimbocinol and sage, respectively, thus revealing that both the deviation and fluctuations during MD Simulation were observed to be least. Deepsite prediction disclosed that both compounds occupied cryptic pockets in receptor and non-bond distance analysis revealed the formation of hydrogen bonds during ligand-receptor interaction. ADMET exploration further validated the drug-like properties of these compounds. CONCLUSION: Present study revealed that active constituents of Azadirachta indica and Salvia officinalis can be potentially used to target SARS-CoV-2 by hindering its replication process.

Potential Role of miRNA in Metastatic Cascade of Triple-Negative Breast Cancer.

Triple-negative breast cancer presents an aggressive form of breast cancer subtype, which further lacks efficient treatment strategies and prognostic markers. Genomic heterogeneity in TNBC has led to the relapse of tumor and cancer stem cells with a higher likelihood of distal metastasis. Several studies supported the notion that miRNAs may act as oncogene or tumor suppressors in TNBC. miRNAs may function as a global regulator of TNBC by targeting post-transcriptional regulation of several genes involved in influencing metastatic events, but the exact mechanism involved in inducing the effect is yet to be elucidated. In this review, we summarized miRNA expression, which can functionally suppress metastatic cascade in TNBC by targeting epithelial to mesenchymal transition, metastatic colonization, cancer stem cells, invasion, migration and metastasis. miRNAs may appear as a metastatic biomarker to predict distal reoccurrence of TNBC in lungs, brain and lymph nodes. miRNA can act as a prognostic marker in metastatic TNBC, thereby predicting overall survival, disease-free survival and distant metastasis-free survival in affected patients. The present review article is an attempt to gain an insight into the repertoire of miRNA that may emerge out as an effective treatment strategy, novel biomarker of distal reoccurrence and prognostic marker in metastatic TNBC.

Comparison of orthodontic space closure using micro-osteoperforation and passive self-ligating appliances or conventional fixed appliances.

OBJECTIVES: To examine the effect of micro-osteoperforation (MOP) on the space closure rate using passive self-ligating or conventional brackets. MATERIALS AND METHODS: This was a two-arm parallel randomized controlled trial undertaken at the outpatient department of a dental college. There were 60 participants (30 women and 30 men) who fulfilled the inclusion criteria. Both the study and control groups were subjected to MOPs throughout the period of space closure. MOPs were repeated every 28 days. The experimental group (mean age 19.5 ± 1.66 years) was bonded with passive self-ligating brackets while the control group (mean age 19.9 ± 1.13 years) was bonded with conventional brackets. Both groups were examined and compared for rate of space closure. An evaluation was conducted for both groups until the entire extraction space was closed and confirmed by evaluation of a tight contact between the canine and the second premolar using a piece of dental floss. RESULTS: Before the initiation of retraction, all initial criteria were similar between the two groups (P > .05). No difference was observed between the two groups in the rate of space closure (P > .05). CONCLUSIONS: MOP in conjunction with passive self-ligation does not increase the rate of orthodontic space closure when compared with MOP used with conventional brackets.

Emotional and Behavioural disorders in a cohort with Down syndrome using the Strengths and Difficulties Questionnaire: A pilot study.

BACKGROUND: Globally, mental health disorders and behavioural problems afflict persons with Down syndrome (DS) with a high prevalence reported in some studies. However, data on behavioural and emotional disorders in DS cohort in Asian countries are lacking. AIMS: To assess the mental health status of children and adults with DS, using the Strength and Difficulties Questionnaire (SDQ) and its impact on caregivers using the impact supplement. METHODS: The questionnaires were administered to caregivers of eligible participants aged ≥4 years. In addition, Down syndrome participant's ≥ 11 years old attempted the self-report. Scoring was done as per standard SDQ guidelines. RESULTS: The total difficulties score was observed to be at least borderline high in 30.6% (19/62) of the participants. Peer relationships and conduct subscale issues were rated high, with abnormal internalizing scores predominating over externalizing scores. From parents' perspective, behavioural issues impacted 41.9% (26/62) of participants' in areas of education, peer relationship and leisure. However, only 3.8% (1/26) of the caregivers whose children had behavioural issues perceived them as a burden. CONCLUSIONS: Mental health difficulties are a significant morbidity in our DS cohort. SDQ is a useful user-friendly tool for identification of behavioural problems enabling timely referral for intervention and therapy.

Unveiling Role of MicroRNAs as Treatment Strategy and Prognostic Markers in Triple Negative Breast Cancer.

Triple negative breast cancer is the highly aggressive form of breast cancer with high reoccurrence rate and is short of effective treatment strategy. The prognostic markers of it are also not well understood. miRNAs are the global regulators of various cancers on the virtue of its ability to post transcriptional regulation of genes involved in various pathways involved in complicating TNBC. In this review we studied the expression of miRNAs at different stages of TNBC and the role of miRNAs as a tumor suppressor to inhibit cell proliferation, angiogenesis, invasion and metastasis and to induce apoptosis and thereby proposing these miRNAs as an effective treatment strategy against TNBC. miRNA also acts as chemosenstizer in enhancing chemosensitivity of conventional drugs against resistant TNBC cells. The present review emphasizes the importance of miRNAs as prognostic markers to determine the overall survival, disease free survival and distant metastasis free survival rate in TNBC patients. We speculate that miRNA can present themselves as an effective treatment strategy and prognostic marker against TNBC.

Comparison of rate of tooth movement and pain perception during accelerated tooth movement associated with conventional fixed appliances with micro-osteoperforations - a randomised controlled trial.

OBJECTIVES: To investigate the influence of micro-osteoperforation (MOP) on rate of orthodontic tooth movement and pain perception with fixed appliances. DESIGN: 2 arm parallel randomized controlled trial with an allocation ratio of 1:1. SETTING: The outpatient department of a dental college. PARTICIPANTS: 105 patients were screened, out of which 60 met the inclusion criteria and consented to participate; consisting of 33 females and 27 males requiring en-masse retraction following first premolar extractions. METHODS: The experimental group consisted of patients bonded with a fixed appliance (Gemini 3M) who received MOP distal to canines throughout the period of retraction every 28 days. These were compared with a control group treated with identical brackets without MOP and were assessed for rate of tooth movement (canine retraction) and pain perception using a Visual Analogue Scale (VAS) of 10 mm. RESULTS: Prior to commencement, all baseline parameters were matched between the two groups (p>0.05). A statistically significant increase in rate of tooth movement in the MOP group (p<0.05). CONCLUSION: MOP appears to enhance the rate of tooth movement with no differences in pain perception.

Heteronemin, a marine natural product, sensitizes acute myeloid leukemia cells towards cytarabine chemotherapy by regulating farnesylation of Ras.

Cytarabine is a conventionally used chemotherapeutic agent for treating acute myeloid leukemia (AML). However, chemoresistance, toxic side-effects and poor patient survival rates retard the efficacy of its performance. The current study deals with the chemosensitization of AML cells using heteronemin, a marine natural product towards cytarabine chemotherapy. Heteronemin could effectively sensitize HL-60 cells towards sub-toxic concentration of cytarabine resulting in synergistic toxicity as demonstrated by MTT assay and [3H] thymidine incorporation studies, while being safe towards healthy blood cells. Flow cytometry for Annexin-V/PI and immunoblotting for caspase cleavage proved that the combination induces enhancement in apoptosis. Heteronemin being a farnesyl transferase inhibitor (FTI) suppressed cytarabine-induced, farnesyl transferase-mediated activation of Ras, as assessed by Ras pull-down assay. Upon pre-treating cells with a commercial FTI, L-744,832, the synergism was completely lost in the combination, confirming the farnesyl transferase inhibitory activity of heteronemin as assessed by thymidine incorporation assay. Heteronemin effectively down-regulated cytarabine-induced activation of MAPK, AP-1, NF-κB and c-myc, the down-stream targets of Ras signaling, which again validated the role of Ras in regulating the synergism. Hence we believe that the efficacy of cytarabine chemotherapy can be improved to a significant extent by combining sub-toxic concentrations of cytarabine and heteronemin.

Clinical characterization of posterior polymorphous corneal dystrophy in patients of Indian ethnicity.

PURPOSE: To characterize the clinical presentation of posterior polymorphous corneal dystrophy (PPCD) in eyes of Indian ethnicity. DESIGN: Retrospective cohort study from January 1995 to December 2015. PARTICIPANTS: Patients with the diagnosis of posterior polymorphous corneal dystrophy. METHODS: Medical records of the patients were reviewed for clinical presentation. Histology of corneal specimens of those that underwent keratoplasty was assessed. MAIN OUTCOME MEASURES: Descriptive analysis of clinical condition. RESULTS: Mean age at first evaluation was 32.5 years (range 1-73 years), male:female = 35:18. Majority (44/53; 83 %) of the patients had bilateral involvement. 5/9 (44 %) patients with unilateral presentation were amblyopic in the affected eye. The clinical features documented were vesicles in 94 eyes, band-like pattern in 32 eyes, edema of varying degree in 23 eyes (12 patients, 1 patient was one eyed), and anterior segment changes in 1 eye. 8/45 (17 %) eyes had a regular astigmatism with steep axis >47 D (range 47.2-56.2 D). 16 eyes of 12 patients who had clinically evident corneal edema underwent keratoplasty. Mean age at keratoplasty was 58 years (range 1-73 years). 8 patients had penetrating keratoplasty (PK) and 8 had Descemet stripping endothelial keratoplasty (DSEK). Mean follow-up after keratoplasty was 4.2 years (1 month to 13 years). Except one, all grafts remained clear till the last follow-up. In all specimens, the Descemet membrane was grossly thickened. CONCLUSIONS: In our study, 12/53 (22.6 %) patients required keratoplasty for visually significant corneal edema. Except one, all were older adults. The patients who needed keratoplasty were bilaterally afflicted and had visually significant cornea edema in both eyes. With a mean follow-up duration of 4.2 years after keratoplasty, no recurrences were noted.