Pilot Evaluation of Perioperative High Dose Rate Brachytherapy in Head Neck Cancers.

Perioperative high dose rate brachytherapy involves insertion of brachytherapy catheter over the tumor bed during surgical removal of disease followed by radiation in the postoperative period. It has applications in radiotherapy dose escalation or reirradiation and for extending the surgical margins. We report here initial results of treatment in five cases of locally advanced head and neck cancers.

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers.

BACKGROUND AND OBJECTIVES: BI 1358894, a novel small-molecule inhibitor of transient receptor potential canonical ion channels, is under development for treatment of major depressive disorder. Phase I trials assessing the safety and pharmacokinetics of BI 1358894 in Caucasian male healthy volunteers (HVs) have been performed. This Phase I, double-blind, placebo-controlled, parallel-group trial assessed the safety, tolerability and pharmacokinetics of BI 1358894 in Japanese male HVs. METHODS: Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50 mg, 100 mg, 200 mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894. RESULTS: Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4-6 h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70 h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. CONCLUSION: BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

Efficacy and Safety of Cryoablation Compared with Cooled Radiofrequency Ablation of Genicular Nerves in Advanced Osteoarthritis of the Knee: A Study Protocol of Single-Centric, Assessor-Blinded, Randomized, Parallel-Group, Non-inferiority Study.

PURPOSE: In patients with symptomatic osteoarthritis knee (OAK), cryoneurolysis (CRYO) and cooled radiofrequency ablation (C-RFA) are reported to be effective and safe; however, they have not been compared directly. The objective of this study is to compare CRYO and C-RFA of the genicular nerve (GN) in terms of efficacy and safety profile in patients with Kellgren and Lawrence (KL) grade ≥ 3 OAK. METHODS: This single-centric, assessor-blinded, randomized, parallel-group, non-inferiority study will include 80 patients with KL grade ≥ 3 OAK. The patients with ≥ 50% pain relief on diagnostic block of three GNs will be randomized to one of the two groups, i.e., CRYO (n = 40) or C-RFA (n = 40). The three target GNs for the interventions will include: superior medial, superior lateral, and inferior medial. The primary outcome will be efficacy of CRYO or C-RFA at 2, 12, and 24 weeks post-procedure based on the 11-point Numerical Pain Rating Scale. The secondary outcomes will be functional improvement based on 12-item Oxford Knee Score and safety of both the procedures. The study is registered in the Clinical Trials Registry-India. CONCLUSION: CRYO and C-RFA provide pain relief and improve functional outcome by preventing transmission of pain signals, though by distinct mechanisms. While C-RFA is an established treatment modality, recent evidence supports CRYO in patients with OAK. This study intends to demonstrate non-inferiority of CRYO against C-RFA, thereby supporting the use of CRYO as an additional treatment modality in patients with KL grade ≥ 3 OAK.

Modulation of gut-microbiota through probiotics and dietary interventions to improve host health.

Dietary patterns play an important role in regards to the modulation and control of the gut microbiome composition and function. The interaction between diet and microbiota plays an important role in order to maintain intestinal homeostasis, which ultimately affect the host's health. Diet directly impacts the microbes that inhabit the gastrointestinal tract (GIT), which then contributes to the production of secondary metabolites, such as short-chain fatty acids, neurotransmitters, and antimicrobial peptides. Dietary consumption with genetically modified probiotics can be the best vaccine delivery vector and protect cells from various illnesses. A holistic approach to disease prevention, treatment, and management takes these intrinsically linked diet-microbes, microbe-microbe interactions, and microbe-host interactions into account. Dietary components, such as fiber can modulate beneficial gut microbiota, and they have resulting ameliorative effects against metabolic disorders. Medical interventions, such as antibiotic drugs can conversely have detrimental effects on gut microbiota by disputing the balance between Bacteroides and firmicute, which contribute to continuing disease states. We summarize the known effects of various dietary components, such as fibers, carbohydrates, fatty acids, vitamins, minerals, proteins, phenolic acids, and antibiotics on the composition of the gut microbiota in this article in addition to the beneficial effect of genetically modified probiotics and consequentially their role in regards to shaping human health. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Comparison of diagnostic capability of macular ganglion cell complex vs retinal fiber layer thickness in primary open angle glaucoma patients of Indian origin.

PURPOSE: Comparison of diagnostic capability of macular ganglion cell complex thickness vs. retinal nerve fiber layer (RNFL) thickness in patients of primary open-angle glaucoma (POAG). SETTINGS AND DESIGN: This cross-sectional observational study was carried out between June 2021 and October 2022 at a tertiary care hospital in North India. METHODS: A total of 118 eyes were included in the study with 30 control and the rest 88 eyes with POAG were divided into three groups based on visual field loss Group 1 (30 eyes): early field loss with mean deviation (MD) < -6 dB; Group 2 (30 eyes): moderate field loss with MD -6 to -12 dB; and Group 3 (28 eyes): severe field loss with MD > -12 dB. Optical coherence tomography (OCT) scans to measure RNFL loss and ganglion cell inferior plexiform layer (GCIPL) loss were taken for each patient. STATISTICAL ANALYSIS USED: Categorical variables were analyzed using either the Chi-square test or Fisher's exact test. A receiver operating characteristics analysis was calculated to determine optimal cut-off values of superior, inferior, and average GCIPL and RNFL for determining the severity of field loss as compared to controls (30 normal eyes). RESULTS: In the mild field loss group the sensitivity of superior, inferior, and average GCIPL was 86.7, 96.7, and 96.7%, respectively. Similarly, the specificity was 96.7, 93.3, and 100%, respectively. In the same group, the sensitivity of superior, inferior, and average RNFL was 70, 93, and 66%, respectively. Similarly, the specificity was 46.7, 83.3, and 70%, respectively. In the moderate and severe groups, the results were comparable. CONCLUSION: The sensitivity and specificity of GCIPL loss are significantly better than that of RNFL parameters in the mild field loss group.

Eco-friendly approaches to phytochemical production: elicitation and beyond.

Highly ameliorated phytochemicals from plants are recognized to have numerous beneficial effects on human health. However, obtaining secondary metabolites directly from wild plants is posing a great threat to endangered plant species due to their over exploitation. Moreover, due to complicated structure and stereospecificity chemical synthesis of these compounds is a troublesome procedure. As a result, sustainable and ecofriendly in vitro strategy has been adopted for phytochemicals production. But, lack of fully differentiated cells lowers down cultured cells productivity. Consequently, for enhancing yield of metabolites produced by cultured plant cells a variety of methodologies has been followed one such approach includes elicitation of culture medium that provoke stress responses in plants enhancing synthesis and storage of bioactive compounds. Nevertheless, for conclusive breakthrough in synthesizing bioactive compounds at commercial level in-depth knowledge regarding metabolic responses to elicitation in plant cell cultures is needed. However, technological advancement has led to development of molecular based approaches like metabolic engineering and synthetic biology which can serve as promising path for phytochemicals synthesis. This review article deals with classification, stimulating effect of elicitors on cultured cells, parameters of elicitors and action mechanism in plants, modern approaches like metabolic engineering for future advances.

Microbial cell-free DNA detection: Minimally invasive diagnosis of infectious diseases.

BACKGROUND: Detection of infectious diseases, especially among immunocompromised and patients on prolonged anti-microbial treatment, remains challenging, limited by conventional techniques with low sensitivity and long-turnaround time. Molecular detection by polymerase chain reaction (PCR) also has limited utility as it requires a targeted approach with prior suspicion of the infecting organism. Advancements in sequencing methodologies, specifically next-generation sequencing (NGS), have presented a promising opportunity to identify pathogens in cases where conventional techniques may be inadequate. However, the direct application of these techniques for diagnosing invasive infections is still limited by the need for invasive sampling, highlighting the pressing need to develop and implement non-invasive or minimally invasive approaches to improve the diagnosis of invasive infections. OBJECTIVES: The objectives of this article are to explore the notable features, clinical utility, and constraints associated with the detection of microbial circulating cell-free DNA (mcfDNA) as a minimally invasive diagnostic tool for infectious diseases. CONTENT: The mcfDNA detection provides an opportunity to identify micro-organisms in the blood of a patient. It is especially beneficial in immunocompromised patients where invasive sampling is not possible or where repeated cultures are negative. This review will discuss the applications and constraints of detecting mcfDNA for diagnosing infections and the various platforms available for its detection.

Effects of Single and Multiple Ascending Doses of BI 1358894 in Healthy Male Volunteers on Safety, Tolerability and Pharmacokinetics: Two Phase I Partially Randomised Studies.

INTRODUCTION: The transient receptor potential canonical (TRPC) ion channels have been implicated in the pathophysiology of major depressive disorder (MDD), and TRPC inhibition has been shown to reduce depressive-like behaviour in rodent models of depression. BI 1358894, a small-molecule inhibitor of TRPC ion channels, is currently being developed for the treatment of MDD. OBJECTIVE: Two phase I studies assessed the safety, tolerability, and pharmacokinetics (PK) of oral BI 1358894 in fed and fasted states following a single ascending dose (SAD) [NCT03210272/1402-0001] and multiple ascending doses (MAD) [NCT03754959/1402-0002] in healthy male volunteers. In addition, any potential food effect was evaluated after a single dose. METHODS: In both studies, eligible healthy male volunteers (aged 18-45 years; body mass index of 18.5-29.9 kg/m2) were allocated to receive BI 1358894 or placebo. In the SAD study (1402-0001), volunteers were randomised 3:1 to receive BI 1358894 or placebo in fasted (3, 6, 10, 25, 50, 100, or 200 mg) and fed states (200 mg). The food effect part was conducted as an open-label, randomised, two-way crossover study at doses of 50 and 100 mg in fasted and fed states (high-calorie, high-fat breakfast). For the MAD study (1402-0002), volunteers were randomised 4:1 to receive BI 1358894 (10, 25, 50, 100, or 200 mg) or placebo once daily for 14 days under fed conditions. Primary endpoint (both studies): number of volunteers with drug-related adverse events (DRAEs). Secondary PK endpoints for study 1402-0001: area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), and AUC from time zero to the last quantifiable data time point (AUC0-tz). Secondary PK endpoints for study 1402-0002: AUC over 0-24 h (AUC0-24), Cmax after the first dose, and steady-state AUC and Cmax over a uniform dosing interval (AUCτ,ss and Cmax,ss, respectively) after the last dose. RESULTS: BI 1358894 was well tolerated at doses ≤ 200 mg under all tested conditions and no dose dependency was observed in DRAE frequency for either study. In the SAD study, BI 1358894 exposure increased dose proportionally across 3-50 mg in the fasted state and across 50-200 mg in the fed state. A positive food effect was observed at the tested doses. In the MAD study, BI 1358894 exposure increased less than dose proportionally across 10-200 mg. CONCLUSIONS: These studies demonstrate that BI 1358894 is well tolerated in healthy male volunteers following single and multiple doses, with no dose dependency observed in DRAE frequency. BI 1358894 exposure increased dose dependently in both the SAD and MAD studies, with higher exposure of BI 1358894 observed in the fed state. CLINICALTRIALS REGISTRATION: These trials have been registered on ClinicalTrials.gov: NCT03210272/1402-0001 (registered on 6 July 2017) and NCT03754959/1402-0002 (registered on 27 November 2018).

Effect of BI 1358894 on Cholecystokinin-Tetrapeptide (CCK-4)-Induced Anxiety, Panic Symptoms, and Stress Biomarkers: A Phase I Randomized Trial in Healthy Males.

INTRODUCTION: Depression, anxiety, and/or panic disorder are often comorbid and have a complex etiology mediated through the same neuronal network. Cholecystokinin-tetrapeptide (CCK-4), a synthetic analog of the endogenous neuropeptide cholecystokinin (CCK), is thought to be implicated in this network. The CCK-4 challenge model is an accepted method of investigating the pathophysiology of panic and has been shown to mediate neuronal activation via the transient receptor potential canonical (TRPC) ion channels. OBJECTIVES: This study aimed to assess the pharmacodynamic effects of BI 1358894, a small-molecule inhibitor of TRPC ion channel members 4 and 5 (TRPC4/5), on CCK-4-induced anxiety/panic-like symptoms and evaluate circuit engagement. METHODS: Twenty healthy male CCK-4-sensitive volunteers entered a Phase I, double blind, randomized, two-way cross-over, single dose, placebo-controlled trial. Randomization was to oral BI 1358894 100 mg in the fed state followed by oral placebo in the fed state, or vice versa. Treatments were administered 5 h prior to intravenous CCK-4 50 µg. The primary endpoint was maximum change from baseline of the Panic Symptom Scale (PSS) sum intensity score after CCK-4 injection. Further endpoints included the emotional faces visual analog score (EVAS), the Spielberger State-Trait Anxiety Inventory (STAI), plasma adrenocorticotropic hormone (ACTH), and serum cortisol values. The safety and tolerability of BI 1358894 was assessed based on a number of parameters including occurrence of adverse events (AEs). All pharmacodynamic, pharmacokinetic, and safety endpoints were analyzed using descriptive statistics. RESULTS: Single oral doses of BI 1358894 were generally well tolerated by the healthy male volunteers included in this study. Adjusted mean maximum change from baseline in PSS sum intensity score was 24.4 % lower in volunteers treated with BI 1358894 versus placebo, while adjusted mean maximum change from baseline of EVAS was reduced by 19.2 % (BI 1358894 vs placebo). The STAI total score before CCK-4 injection was similar in both groups (placebo: 25.1; BI 1358894: 24.3). Relative to placebo, BI 1358894 reduced CCK-4-induced mean maximum plasma ACTH and serum cortisol values by 58.6 % and 27.3 %, respectively. Investigator-assessed drug-related AEs were reported for 13/20 participants (65.0 %). There were no serious or severe AEs, AEs of special interest, AEs leading to discontinuation of trial medication, or deaths. CONCLUSIONS: Overall, BI 1358894 reduced psychological and physiological responses to CCK-4 compared with placebo, as measured by PSS, subjective EVAS and objectively measured stress biomarkers. BI 1358894 had a positive safety profile, and single oral doses were well tolerated by the healthy volunteers. This trial (NCT03904576/1402-0005) was registered on Clinicaltrials.gov on 05.04.19.

Clinical Profile and Renal Survival of Anti-Glomerular Basement Membrane Disease Patients: A Retrospective Case Series from Northern India.

Introduction: Anti-glomerular basement membrane (anti-GBM) disease is a rare organ-specific autoimmune disease. The overall and renal outcomes of patients have mostly been reported in small-sized cohorts. We aimed to study the clinical profile, overall survival, and renal survival of anti-glomerular basement membrane disease patients at our center. Methods: We conducted a retrospective analysis of the data regarding the clinical profile and renal survival of patients diagnosed with anti-GBM disease from October 2019 to March 2022, having a minimum follow-up of 12 months. Results: There were 15 patients in the study, with the mean age of presentation being 51.6 ± 13.7 years. The median duration of symptoms onset to the nephrologist opinion was 15 (10-23) days. The extrarenal manifestations were seen in the respiratory, otorhinolaryngological, and neurological systems. The mean serum anti-GBM titers were 154.5 (14.9-263.5) U/mL. Serum anti-GBM titers were present in 13/15 (86.6%) patients, and 12/13 (92.3%) patients had above the reference range. Anti-neutrophil cytoplasm antibody (ANCA) levels were assessed in 12/15 (80%) patients, and 9/12 (75%) had higher levels. Renal biopsy was available in 14 patients with more than 50% crescents. Along with crescents, necrotizing lesions, rupture of the Bowman's capsule, and granulomatous lesions were also seen. Among the initial therapies, the steroid pulse was given to 13 (86.6%) patients, whereas membrane plasmapheresis was given to 8 (53.3%) patients. Inj. cyclophosphamide and inj. rituximab were given to 8 (53.3%) and 4 (26.6%) patients, respectively. No difference was seen in clinical characteristics, renal biopsy features, treatment received, and outcomes with ANCA positivity except for age, where patients who were ANCA positive were older compared to patients who were ANCA negative. One-year renal and patient survival was seen in 4 (26.6%) and 6 (40%) patients, respectively. Conclusion: Most patients of anti-GBM disease have active sediments, raised creatinine, and non-specific symptomatology. There is poor renal and patient outcome as most patients present with advanced renal failure.

Brassinosteroids as promoters of seedling growth and antioxidant activity under heavy metal zinc stress in mung bean (Vigna radiata L.).

The escalation of harmful pollutants, including heavy metals, due to industrialization and urbanization has become a global concern. To mitigate the negative impacts of heavy metal stress on germination and early plant development, growth regulators have been employed. This study aimed to evaluate the response of mung bean (Vigna radiata L.) to zinc stress in the presence of brassinosteroids, focusing on seedling growth and antioxidant potential. Mung bean seedlings were treated with three concentrations of 24-epibrassinolide (EBL) (0.1, 0.2, and 0.4 PPM) with or without zinc. Results demonstrated that the application of brassinosteroids, combined with zinc stress, significantly enhanced germination percentage (about 47.06, 63.64, and 120%), speed of germination (about 39.13, 50, and 100%), seedling growth (about 38% in case of treatment combined 0.4 PPM 24-EBL and 1.5 mM ZnSO4) and seedling vigor index (204% in case of treatment combined 0.4 PPM 24-EBL and 1.5 mM ZnSO4) compared to zinc-treated seedlings alone after 24 h. The activities of antioxidative enzymes (catalase, ascorbate peroxidase, polyphenol oxidase, and peroxidase) and total soluble protein content decreased, while lipid peroxidation and proline content exhibited a significant increase (p ≤ 0.05) when compared to the control. However, the negative effects induced by heavy metal stress on these parameters were significantly mitigated by EBL application. Notably, the most effective concentration of EBL in overcoming zinc stress was found to be 0.4 PPM. These findings underscore the potential of exogenously applied brassinosteroids as a valuable tool in phytoremediation projects by ameliorating heavy metal stress.

Toxicities and clinical outcome of adjuvant dysphagia optimized versus standard intensity-modulated radiotherapy for post-operative oral cavity cancers: A prospective comparative study.

BACKGROUND: We prospectively assessed acute and late toxicity in post-operative oral cavity squamous cell carcinoma (PO-OCSCC) treated with adjuvant dysphagia optimized intensity-modulated radiotherapy (Do-IMRT) versus standard IMRT (S-IMRT). MATERIAL AND METHODS: Fifty-six patients of PO-SCC without indications of concurrent chemotherapy were alternatively allocated to adjuvant Do-IMRT (n = 28) versus S-IMRT (n = 28) arms. High- and low-risk planning target volume received 60 and 54 Gy, respectively, in 30 fractions over 6 weeks. Dysphagia aspiration-related structures (DARS) were contoured in both arms. While dosimetric constraints were given in Do-IMRT arm, doses to DARS were only observed without dose constraints in S-IMRT arm. Acute and late toxicity were assessed by common terminology criteria for adverse events (CTCAE) v5.0 and RTOG criteria, respectively. RESULTS: The primary site of disease was buccal mucosa (64% vs. 53%) and oral tongue (21% vs. 32%), in Do-IMRT and S-IMRT, respectively. The mean doses to DARS was significantly less with Do-IMRT (all p < 0.001) as compared to S-IMRT. Median follow-up was 24.2 months. Grade ≥2 oral pain was less in the Do-IMRT arm (50% vs. 78.6%, p = 0.05). Grade ≥2 late dysphagia at 2 years were significantly less in Do-IMRT arm (0% vs. 17.9%, p = 0.016). Two-year locoregional control was 89.2% in Do-IMRT and 78.5% in S-IMRT (p = 0.261). CONCLUSION: DARS can be spared in PO-OCSCC patients treated with Do-IMRT without compromising coverage of the target volumes. Limiting doses to DARS leads to lesser acute and late toxicity without compromising locoregional control.

A Comprehensive Review Uncovering the Challenges and Advancements in the In Vitro Propagation of Eucalyptus Plantations.

The genus Eucalyptus is a globally captivated source of hardwood and is well known for its medicinal uses. The hybrid and wild species of Eucalyptus are widely used as exotic plantations due to their renowned potential of adapting to various systems and sites, and rapid large-scale propagation of genetically similar plantlets, which further leads to the extensive propagation of this species. Tissue culture plays a crucial role in the preservation, propagation, and genetic improvement of Eucalyptus species. Despite unquestionable progression in biotechnological and tissue culture approaches, the productivity of plantations is still limited, often due to the low efficiency of clonal propagation from cuttings. The obtained F1 hybrids yield high biomass and high-quality low-cost raw material for large-scale production; however, the development of hybrid, clonal multiplication, proliferation, and post-developmental studies are still major concerns. This riveting review describes the problems concerning the in vitro and clonal propagation of Eucalyptus plantation and recent advances in biotechnological and tissue culture practices for massive and rapid micropropagation of Eucalyptus, and it highlights the Eucalyptus germplasm preservation techniques.

Potent inhibitors of tumor associated carbonic anhydrases endowed with cathepsin B inhibition.

Twenty-one novel extended analogs of acetazolamide were synthesized and screened in vitro for their inhibition efficacy against human carbonic anhydrase (hCA) isoforms I, II, IX, XII, and cathepsin B. The majority of the compounds were found to be effective inhibitors of tumor-associated hCA IX and XII, and poor inhibitors of cytosolic hCA I. Despite the strong to moderate inhibition potential possessed by these compounds toward another cytosolic isoform hCA II, some of them demonstrated better potency against hCA IX and/or XII isoforms as compared to hCA II. Four compounds (11f, 11g, 12c, and 12g) effectively inhibited hCA IX and/or XII isoforms with considerable selectivity over the off-targets hCA I and II. Interestingly, five compounds, including 11f, 11g, 12c, 12d, and 12g, inhibited hCA IX even better than the clinically used acetazolamide. Some of the novel synthesized compounds exhibited higher anti-cathepsin B potential than acetazolamide, with % inhibition of around 50%, at a concentration of 10-7 M. Further, two compounds (12g and 12c) that showed effective and selective inhibition activity profiles against hCA IX and XII were additionally found to be effective inhibitors of cathepsin B.

Advancement in Epilepsy Pharmacotherapy: An Insight into the Pharmacophoric Approaches of Recent Drugs.

Epilepsy is the most general, extensive, and severe neurological disorder, affecting more than 50 million individuals globally. Initially, conventional medicines and simple salts like potassium bromide were employed as antiepileptic medication candidates. Nowadays, many anticonvulsant drugs have been discovered as first-generation and second-generation and newer drugs and are still in development phases. The pharmacophore-based drug design process includes pharmacophore modeling and validation, pharmacophore-based virtual screening, virtual hits profiling, and lead identification with special reference. This comprehensive article reviews recently developed anticonvulsant derivatives on the basis of pharmacophoric approaches. A literature survey was performed using various search engines like Google Scholar, Scopus, Sci Finder, ScienceDirect, Science gate, Scilit, PubMed, NINDS database of NIH, Bentham Sciences, and other online and print journals and scientific databases. The presented review discusses such kinds of newer drugs that are in the market as well as in clinical trial phases. Detailed outcomes of pharmacophoric modeling have been discussed for newly derived derivatives like targets involved in Epilepsy, lead molecules etc., for the treatment of epilepsy. This exhaustive review will assist the researchers in the further development of potential antiepileptic agents.

Functional implications and therapeutic targeting of androgen response elements in prostate cancer.

The androgen receptor (AR) plays an essential role in the growth and progression of prostate cancer (CaP). Ligand-activated AR inside the nucleus binds to the androgen response element (ARE) of the target genes in dimeric form and recruits transcriptional machinery to facilitate gene transcription. Pharmacological compounds that inhibit the AR action either bind to the ligand binding domain (LBD) or interfere with the interactions of AR with other co-regulatory proteins, slowing the progression of the disease. However, the emergence of resistance to conventional treatment makes clinical management of CaP difficult. Resistance has been associated with activation of androgen/AR axis that restores AR transcriptional activity. Activated AR signaling in resistance cases can be mediated by several mechanisms including AR amplification, gain-of-function AR mutations, androgen receptor variant (ARVs), intracrine androgen production, and overexpression of AR coactivators. Importantly, in castration resistant prostate cancer, ARVs lacking the LBD become constitutively active and promote hormone-independent development, underlining the need to concentrate on the other domain or the AR-DNA interface for the identification of novel actionable targets. In this review, we highlight the plasticity of AR-DNA binding and explain how fine-tuning AR's cooperative interactions with DNA translate into developing an alternative strategy to antagonize AR activity.

A novel carissic acid from fruits of Carissa carandas induced apoptotic cell death in A-549 cells following the activation of caspases.

This study was designed to identify cytotoxic compounds from Carissa carandas extract. The cytotoxic activity of extract and fractions were assessed against eight cancer cell lines. The chloroform fraction obtained from methanolic extract exhibited significant activity against MCF-7, HT-29, A-549 with IC50 values of 3.98 µg/mL (MCF-7), 1.28µg/mL (HT-29) and 1.48 µg/mL (A-549) respectively. Further investigation led to the isolation of novel compound carissic acid (CA), which was confirmed by detailed spectroscopy studies. CA exhibited notable activity with IC50 values of 3.47 µM for A-549, 2.65 µM for HT-29 and 13.58 ± 0.59 µM for MCF-7 cells. CAcaused chromatin condensation with decrease of mitochondrial membrane potential and also confirmed cell death via Reactive Oxygen Species (ROS) generation and significantly decreased the colony formation in dose-dependent manner. The overall findings suggested that CA demonstrates cytotoxic effect by inhibiting cell proliferation and promoting apoptosis in lung (A-549) carcinoma cell line.

Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database.

BACKGROUND: Thoracic aortic disease and bicuspid aortic valve (BAV) likely have a heritable component, but large population-based studies are lacking. This study characterizes familial associations of thoracic aortic disease and BAV, as well as cardiovascular and aortic-specific mortality, among relatives of these individuals in a large-population database. METHODS: In this observational case-control study of the Utah Population Database, we identified probands with a diagnosis of BAV, thoracic aortic aneurysm, or thoracic aortic dissection. Age- and sex-matched controls (10:1 ratio) were identified for each proband. First-degree relatives, second-degree relatives, and first cousins of probands and controls were identified through linked genealogical information. Cox proportional hazard models were used to quantify the familial associations for each diagnosis. We used a competing-risk model to determine the risk of cardiovascular-specific and aortic-specific mortality for relatives of probands. RESULTS: The study population included 3 812 588 unique individuals. Familial hazard risk of a concordant diagnosis was elevated in the following populations compared with controls: first-degree relatives of patients with BAV (hazard ratio [HR], 6.88 [95% CI, 5.62-8.43]); first-degree relatives of patients with thoracic aortic aneurysm (HR, 5.09 [95% CI, 3.80-6.82]); and first-degree relatives of patients with thoracic aortic dissection (HR, 4.15 [95% CI, 3.25-5.31]). In addition, the risk of aortic dissection was higher in first-degree relatives of patients with BAV (HR, 3.63 [95% CI, 2.68-4.91]) and in first-degree relatives of patients with thoracic aneurysm (HR, 3.89 [95% CI, 2.93-5.18]) compared with controls. Dissection risk was highest in first-degree relatives of patients who carried a diagnosis of both BAV and aneurysm (HR, 6.13 [95% CI, 2.82-13.33]). First-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality (HR, 2.83 [95% CI, 2.44-3.29]) compared with controls. CONCLUSIONS: Our results indicate that BAV and thoracic aortic disease carry a significant familial association for concordant disease and aortic dissection. The pattern of familiality is consistent with a genetic cause of disease. Furthermore, we observed higher risk of aortic-specific mortality in relatives of individuals with these diagnoses. This study provides supportive evidence for screening in relatives of patients with BAV, thoracic aneurysm, or dissection.

Microalgae in Bioplastic Production: A Comprehensive Review.

The current era of industrialization includes a constantly increasing demand for plastic products, but because plastics are rarely recycled and are not biodegradable plastic pollution or "white pollution" has been the result. The consumption of petroleum-based plastics will be 20% of global annual oil by 2050, and thus there is an inevitable need to find an innovative solution to reduce plastic pollution. The biodegradable and environmentally benign bioplastics are suitable alternative to fossil-based plastics in the market due to sustainability, less carbon footprint, lower toxicity and high degradability rate. Microalgal species is an innovative approach to be explored and improved for bioplastic production. Microalgae are generally present in abundant quantity in our ecosystem, and polysaccharide in the algae can be processed and utilized to make biopolymers. Also, these species have a high growth rate and can be easily cultivated in wastewater streams. The review aims to determine the recent status of bioplastic production techniques from microalgal species and also reveal optimization opportunities involved in the process. Several strategies for bioplastic production from algal biomass are being discussed nowadays, and the most prominent are "with blending" (blending of algal biomass with bioplastics and starch) and "without blending" (microalgae as a feedstock for polyhydroxyalkanoates production). The advanced research on modern bioengineering techniques and well-established genetic tools like CRISPR-Cas9 should be encouraged to develop recombinant microalgae strains with elevated levels of PHA/PHB inside the cell.