Multi-Institutional Clinical Outcomes of Biopsy Gleason Grade Group 5 Prostate Cancers Treated With Contemporary High-Dose Radiation and Long-Term Androgen Deprivation Therapy.

AIMS: This multicentric retrospective study reports long-term clinical outcomes of non-metastatic grade group 5 prostate cancers treated with external beam radiotherapy (EBRT) alone with long-term androgen deprivation therapy (ADT). MATERIALS AND METHODS: Patients treated across 19 institutions were studied. The key endpoints that were evaluated were 5-year biochemical recurrence-free survival (bRFS), metastases-free survival (MFS), overall survival, together with EBRT-related acute and late toxicities. The impact of various prognostic factors on the studied endpoints was analysed using univariate and multivariate analyses. RESULTS: Among the 462 patients, 88% (405) had Gleason 9 disease and 31% (142) had primary Gleason pattern 5. A prostate-specific membrane antigen positron emission tomography-computed tomography scan was used for staging in 33% (153), 80% (371) were staged as T3/T4 and 30% (142) with pelvic nodal disease. The median ADT duration was 24 months; 66% received hypofractionated EBRT and 71.4% (330) received pelvic nodal irradiation. With a median follow-up of 56 months, the 5-year bRFS, MFS and overall survival were 73.1%, 77.4% and 90.5%, respectively. Primary Gleason pattern 5 was associated with worse bRFS, MFS and overall survival with hazard ratios of 0.51 (95% confidence interval 0.35 to 0.73, P < 0.001), 0.64 (95% confidence interval 0.43 to 0.96, P = 0.031) and 0.52 (95% confidence interval 0.28 to 0.97, P = 0.040), respectively, whereas pelvic nodal disease was associated with worse bRFS (hazard ratio 0.67, 95% confidence interval 0.46 to 0.98, P = 0.039) and MFS (hazard ratio 0.56, 95% confidence interval 0.37 to 0.85, P = 0.006). The acute and late radiation-related toxicities were low overall and pelvic nodal irradiation was associated with higher toxicities. CONCLUSION: Contemporary EBRT and long-term ADT led to excellent 5-year clinical outcomes and low rates of toxicity in this cohort of non-metastatic grade group 5 prostate cancers. Primary Gleason pattern 5 and pelvic node disease portends inferior clinical outcomes.

A natural flavonoid, apigenin isolated from Clerodendrum viscosum leaves, induces G2/M phase cell cycle arrest and apoptosis in MCF-7 cells through the regulation of p53 and caspase-cascade pathway

Background With 9.6 million deaths in 2018, cancer remains the second leading cause of death worldwide. Breast cancer is the most deadly type of cancer among females, with 55.2% of crude incidence rate and 16.6% of crude mortality rate. Purpose The present study was aimed to investigate the anti-breast cancer potential of natural dietary flavonoid, apigenin isolated from Clerodendrum viscosum leaves. Methods Apigenin was evaluated for in-depth anticancer activity in MCF-7 cells using cell viability assay, cell cycle analysis, Annexin-V-FLUOS staining, ROS induction, morphological analysis, and western blot analysis. Results Apigenin showed selective cytotoxicity on MCF-7 cells with an IC50-56.72 ± 2.35 µM, while negligible cytotoxicity was observed on WI-38 cells. Further, the flow cytometer-based analysis showed that apigenin halted MCF-7 cells in the G2/M phase arrest followed by dose-dependent apoptosis. Moreover, the FACS and confocal microscopy results confirmed the elevation of intracellular ROS and nuclear fragmentation in apigenin-treated MCF-7 cells. Western blots showed up-regulation of cell cycle regulatory proteins, increased p53 expression, Bax/Bcl-2 ratio, activation of caspases, and cleavage of PARP. Finally, apigenin treatment in the presence of Pifithrin-µ showed decreased apoptotic population and it was further confirmed through western blotting study. The results revealed the vital role of p53 in apigenin-induced apoptosis in MCF-7 cells. Conclusions In the present findings, treatment of apigenin-induced intracellular ROS in MCF-7 cells followed by induction of G2/M phase cell cycle arrest and further apoptosis through the regulation of p53 and caspase-cascade signaling pathway (AU)

A natural flavonoid, apigenin isolated from Clerodendrum viscosum leaves, induces G2/M phase cell cycle arrest and apoptosis in MCF-7 cells through the regulation of p53 and caspase-cascade pathway.

BACKGROUND: With 9.6 million deaths in 2018, cancer remains the second leading cause of death worldwide. Breast cancer is the most deadly type of cancer among females, with 55.2% of crude incidence rate and 16.6% of crude mortality rate. PURPOSE: The present study was aimed to investigate the anti-breast cancer potential of natural dietary flavonoid, apigenin isolated from Clerodendrum viscosum leaves. METHODS: Apigenin was evaluated for in-depth anticancer activity in MCF-7 cells using cell viability assay, cell cycle analysis, Annexin-V-FLUOS staining, ROS induction, morphological analysis, and western blot analysis. RESULTS: Apigenin showed selective cytotoxicity on MCF-7 cells with an IC50-56.72 ± 2.35 µM, while negligible cytotoxicity was observed on WI-38 cells. Further, the flow cytometer-based analysis showed that apigenin halted MCF-7 cells in the G2/M phase arrest followed by dose-dependent apoptosis. Moreover, the FACS and confocal microscopy results confirmed the elevation of intracellular ROS and nuclear fragmentation in apigenin-treated MCF-7 cells. Western blots showed up-regulation of cell cycle regulatory proteins, increased p53 expression, Bax/Bcl-2 ratio, activation of caspases, and cleavage of PARP. Finally, apigenin treatment in the presence of Pifithrin-µ showed decreased apoptotic population and it was further confirmed through western blotting study. The results revealed the vital role of p53 in apigenin-induced apoptosis in MCF-7 cells. CONCLUSIONS: In the present findings, treatment of apigenin-induced intracellular ROS in MCF-7 cells followed by induction of G2/M phase cell cycle arrest and further apoptosis through the regulation of p53 and caspase-cascade signaling pathway.

Modeling the effect of area deprivation on COVID-19 incidences: a study of Chennai megacity, India.

OBJECTIVES: Socio-economic inequalities may affect coronavirus disease 2019 (COVID-19) incidence. The goal of the research was to explore the association between deprivation of socio-economic status (SES) and spatial patterns of COVID-19 incidence in Chennai megacity for unfolding the disease epidemiology. STUDY DESIGN: This is an ecological (or contextual) study for electoral wards (subcities) of Chennai megacity. METHODS: Using data of confirmed COVID-19 cases from May 15, 2020, to May 21, 2020, for 155 electoral wards obtained from the official website of the Chennai Municipal Corporation, we examined the incidence of COVID-19 using two count regression models, namely, Poisson regression (PR) and negative binomial regression (NBR). As explanatory factors, we considered area deprivation that represented the deprivation of SES. An index of multiple deprivations (IMD) was developed to measure the area deprivation using an advanced local statistic, geographically weighted principal component analysis. Based on the availability of appropriately scaled data, five domains (i.e., poor housing condition, low asset possession, poor availability of WaSH services, lack of household amenities and services, and gender disparity) were selected as components of the IMD in this study. RESULTS: The hot spot analysis revealed that area deprivation was significantly associated with higher incidences of COVID-19 in Chennai megacity. The high variations (adjusted R2: 72.2%) with the lower Bayesian Information Criteria (BIC) (124.34) and Akaike's Information Criteria (AIC) (112.12) for NBR compared with PR suggests that the NBR model better explains the relationship between area deprivation and COVID-19 incidences in Chennai megacity. NBR with two-sided tests and P <0.05 were considered statistically significant. The outcome of the PR and NBR models suggests that when all other variables were constant, according to NBR, the relative risk (RR) of COVID-19 incidences was 2.19 for the wards with high housing deprivation or, in other words, the wards with high housing deprivation having 119% higher probability (RR = e0.786 = 2.19, 95% confidence interval [CI] = 1.98 to 2.40), compared with areas with low deprivation. Similarly, in the wards with poor availability of WaSH services, chances of having COVID-19 incidence was 90% higher than in the wards with good WaSH services (RR = e0.642 = 1.90, 95% CI = 1.79 to 2.00). Spatial risks of COVID-19 were predominantly concentrated in the wards with higher levels of area deprivation, which were mostly located in the northeastern parts of Chennai megacity. CONCLUSIONS: We formulated an area-based IMD, which was substantially related to COVID-19 incidences in Chennai megacity. This study highlights that the risks of COVID-19 tend to be higher in areas with low SES and that the northeastern part of Chennai megacity is predominantly high-risk areas. Our results can guide measures of COVID-19 control and prevention by considering spatial risks and area deprivation.

Recent advances in mycotoxins detection.

Mycotoxins contamination in both food and feed is inevitable. Mycotoxin toxicity in foodstuff can occur at very low concentrations necessitating early availability of sensitive and reliable methods for their detection. The present research thrust is towards the development of a user friendly biosensor for mycotoxin detection at both academic and industrial levels to replace conventional expensive chromatographic and ELISA techniques. This review critically analyzes the recent research trend towards the construction of immunosensor, aptasensor, enzymatic sensors and others for mycotoxin detection with a reference to label and label free methods, synthesis of new materials including nano dimension, and transuding techniques. Technological aspects in the development of biosensors for mycotoxin detection, current challenges and future prospects are also included to provide a overview and suggestions for future research directions.

A mitogen-activated protein kinase kinase inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma.

We report three cases of skin toxicity associated with oral mitogen-activated protein kinase kinase (MEK) inhibitor treatment for metastatic malignant melanoma (MM). All three patients developed oedema, and a single patient experienced eyelash trichomegaly. This is the first known report of eyelash trichomegaly secondary to MEK inhibitor use. We also discuss possible mechanisms for MEK inhibitor-associated oedema development. This series supports the role of the dermatologist in the screening and management of patients in the rapidly developing oncology setting, as new targeted agents can give rise to marked skin toxicity.

Factors predicting mortality in newborn ventilation.

OBJECTIVE: Prediction of mortality among newborns on mechanical ventilation is difficult. Our aim was to develop a scoring system for predicting mortality among such neonates. METHODS: This multi centre prospective study was performed to develop and validate a scoring system among two equal cohorts of ventilated newborns in India. Mechanical ventilator was used in pressure-limited time-cycled mode. Arterial blood gas, initial pulmonary pressures, septicemia screen along with other basic parameters were recorded in a pre-structured proforma. Blood samples were analyzed for malondialdehyde to determine the possible role and predictive validity of free radical injury. Multiple logistic regression analysis was done to find out independent predictors of mortality for the variables those were significantly associated with outcome after univariate analysis. RESULTS: On univariate analysis, birth-weight, oxygenation-index, septicaemia, malondialdehyde level, and inotropic support were significantly associated with mortality. However, after multiple regression analysis gestational-age, pH and FiO2 lost their significance as predictors. According to cut-off values of ROC-curve, a scoring system ranging from 0 to 20 and four mortality risk groups were developed. Area under ROC-curve was 0.94, compared to 0.90 for both APACHE-III and CRIB-scores; and 0.92 for PRISM-score. CONCLUSIONS: Birth-weight, oxygenation-index, malondialdehyde level, inotropic support, and septicemia are independent mortality predictors of neonatal ventilation. Increase in malondialdehyde level is associated with higher mortality rate, indicating possible role of free radical injury. Pediatr Pulmonol. 2015; 50:271-275. © 2014 Wiley Periodicals, Inc.

Adaptive radiotherapy in lung cancer: dosimetric benefits and clinical outcome.

OBJECTIVE: Anatomical changes during radiotherapy (RT) might introduce discrepancies between planned and delivered doses. This study evaluates the need for adaptive treatment in lung cancer RT. METHODS: 15 patients with non-small-cell lung cancer, undergoing radical RT with or without concurrent chemotherapy, consecutively underwent planning CT scans at baseline and after 44-46 Gy. Target volumes were delineated on both scans. Phase I delivered 44-46 Gy to the initial planning target volume (PTV). Two Phase II plans for 16-20 Gy were developed on initial and mid-treatment scans, the treatment being delivered with the mid-treatment plan. The second CT structure set was fused with the initial scan data set using dose wash. Volumetric and dosimetric changes in target volumes and critical structures were assessed. RESULTS: There was significant reduction in primary gross tumour volume (34.00%; p = 0.02) and PTV (34.70%; p < 0.01) in the second scan. In Plan 2, delivering the same dose to the initial PTV would have resulted in a significantly higher dose to the lung PTV (V20, 52.18%; V5, 21.76%; mean, 23.93%), contralateral lung (mean, 29.43%), heart (V10, 81.47%; V5, 56.62%; mean, 35.21%) and spinal cord (maximum dose, 37.53%). CONCLUSION: Treatment replanning can account for anatomical changes during RT and thereby enable better normal tissue sparing, while allowing radical target doses with the possibility of maximizing local control. ADVANCES IN KNOWLEDGE: This study supports the sparse dosimetric data regarding the quantitative tumour volume reduction, re-emphasizing the need for adaptive replanning for minimizing normal tissue toxicity without compromising local control, and adds to the existing body of literature.

Association of polymorphisms in 9p21 region with CAD in North Indian population: replication of SNPs identified through GWAS.

Coronary artery disease (CAD) is one of the leading causes of death worldwide that is influenced by both environmental as well as genetic factors. Several recent genome-wide association studies (GWAS) have reported the association of multiple single nucleotide polymorphisms (SNPs) mainly in the 9p21 region with CAD. However, the association of these SNPs with CAD has not been rigorously tested in Indian population, which accounts for the largest incidences of CAD in the world. Herein, we genotyped six such SNPs (rs10116277, rs10757274, rs1333040, rs2383206, rs2383207 and rs1994016) identified through GWAS, in 754 individuals (311 angiography-confirmed CAD patients and 443 treadmill test controls) recruited mainly from North India to evaluate if these SNPs were associated with CAD. The minor allele frequency of these six SNPs was comparable to that reported in the respective GWAS. We found that three of these SNPs (rs10116277, rs1333040 and rs2383206) present at the locus 9p21 were significantly associated with CAD even after controlling for the confounding factors such as age, sex, body mass index, homocysteine, hypertension, diabetes, smoking, diet, etc. In conclusion, the locus 9p21 found to be significantly associated with cardiovascular diseases in the Caucasian populations seems to be also important in North Indian population.

Malignant eccrine spiradenoma of the vulva: a case report and review of the literature.

Malignant eccrine spiradenoma is a rare skin tumor of sweat gland origin. We present the first reported case of this tumor in the female genitalia. Due to the rarity of this tumor, there has yet to be an established standard of care. The present case is that of a 41-year-old woman with malignant eccrine spiradenoma of the periclitoral region. She had an 18-month history of a recurrent, painful mass adjacent to the clitoris. Her diagnosis was made after excision of the cystic tumor. The patient then underwent a partial radical vulvectomy with bilateral sentinel lymph node sampling. As malignant eccrine spiradenoma is a rare tumor, no standard care exists for treatment and postoperative management. Based on our review of the literature, wide local excision appears to be the preferred initial treatment. Furthermore, adjuvant chemotherapy and/or radiation does not seem to improve survival in patients with advanced or recurrent cancer. Although lymph node sampling and/or lymphadenectomy is frequently reported in the treatment of this tumor, hematogenous metastasis can also occur. Therefore, these patients require close postoperative follow-up for recurrent disease.

Why does ethanol induce cellular heat-shock response?

At the time of induction of the periplasmic protein alkaline phosphatase (AP) in Escherichia coli, the presence of ethanol (10% v/v) in the growth medium did not allow the induced AP to be translocated out to the periplasm. The nontransported AP was stored in the cytoplasm as the unfolded precursor form (AP with its amino-terminal signal sequence), which had no enzymatic activity. The presence of 10% v/v ethanol in the growth medium also induced the heat-shock response in E. coli, which was evident from the enhanced syntheses of several heat-shock proteins (HSPs) over their cellular basal levels. These results, in conjunction with our earlier findings on the occurrence of heat-shock response in an AP-signal sequence mutant of E. coli due to the export deficiency of AP precursor, suggest that the membrane protein precursors, stored in the cytoplasm due to the ethanol-mediated inhibition of translocation, behaved to the cells as abnormal proteins, which ultimately triggered the signal for the induction of heat-shock response in E. coli.

Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Recently, echinacea has regained popularity as one of the treatments chosen most commonly by consumers with the expectation that it will reduce the severity and duration of the common cold. However, the results from a limited number of clinical trials for this application have thus far been inconclusive. This incongruity may be the result of investigators utilizing poorly standardized echinacea products, likely devoid of sufficient quantities of active constituents necessary to exert a definitive clinical effect. Therefore, a formulation containing alkamides, cichoric acid, and polysaccharides at concentrations of 0.25, 2.5, and 25 mg/mL, respectively, was prepared from freshly harvested Echinacea purpurea plants (commercially available as Echinilin, Natural Factors Nutritional Products, Inc., Vancouver, BC, Canada). The objective of this study was to test the efficacy of this highly standardized formulation in reducing the severity and duration of symptoms of a naturally acquired common cold. METHODS: In a randomized, double-blind, placebo-controlled trial, 282 subjects aged 18-65 years with a history of two or more colds in the previous year, but otherwise in good health, were recruited. The subjects were randomized to receive either echinacea or placebo. They were instructed to start the echinacea or placebo at the onset of the first symptom related to a cold, consuming 10 doses the first day and four doses per day on subsequent days for 7 days. Severity of symptoms (10-point scale: 0, minimum; 9, maximum) and dosing were recorded daily. A nurse examined the subjects on the mornings of days 3 and 8 of their cold. RESULTS: A total of 128 subjects contracted a common cold (59 echinacea, 69 placebo). The total daily symptom scores were found to be 23.1% lower in the echinacea group than in placebo in those who followed all elements of the study protocol (P<0.01). Throughout the treatment period, the response rate to treatments was greater in the echinacea group. A few adverse event profiles were observed in both groups. CONCLUSIONS: Early intervention with a standardized formulation of echinacea resulted in reduced symptom severity in subjects with naturally acquired upper respiratory tract infection. Further studies with larger patient populations appear to be warranted.