Expedited Proton Relay in Enzyme-Inspired Cobaloximes Facilitates Organic Transformations.

Developing a water-soluble, oxygen-tolerant, and acid-stable synthetic H2 production catalyst is vital for renewable energy infrastructure. To access such an effective catalyst, we strategically incorporated enzyme-inspired, multicomponent outer coordination sphere elements around the cobaloxime (Cl-Co-X) core with suitable axial coordination (X). Our cobaloximes with axial imidazole or L-histidine coordination in photocatalytic HAT including the construction of anilines via a non-canonical cross-coupling approach is found superior compared to commonly used cobaloxime catalysts. The reversible Co(II)/Co(I) process is influenced by the axial N ligand's nature. Imidazole/ L-histidine with a higher pKa promptly produces H2 upon irradiation, leading to the improved reactivity compared to previously employed axial (di)chloride or pyridine analogue.

The Recent Development of Luteolin-loaded Nanocarrier in Targeting Cancer.

INTRODUCTION: Luteolin (LUT), a naturally occurring flavonoid found in vegetables, fruits, and herbal medicines, has been extensively studied for its pharmacological activities, including anti-proliferative and anticancer effects on various cancer lines. It also exhibits potent antioxidant properties and pro-apoptotic activities against human cancers. However, its therapeutic potential is hindered by its poor solubility in water (5 µg/ml at 45°C) and low bioavailability. This research on the development of luteolin-loaded nanocarrier aims to overcome these limitations, thereby opening up new possibilities in cancer treatment. METHODS: This paper covers several nanoformulations studied to increase the solubility and bioavailability of LUT. The physicochemical characteristics of the nanoformulation that influence luteolin's solubility and bioavailability have been the subject of more in-depth investigation. Furthermore, it examines how LUT's anti-inflammatory and antioxidant properties aid in lessening the side effects of chemotherapy. RESULTS: Most nanoformulations, including phytosomes, lipid nanoparticles, liposomes, protein nanoparticles, polymer micelles, nanoemulsions, and metal nanoparticles, have shown promising results in improving the solubility and bioavailability of LUT. This is a significant step forward in enhancing the therapeutic potential of LUT in cancer treatment. Furthermore, the study found that LUT's ability to scavenge free radicals can significantly reduce the side effects of cancer treatment, further highlighting its potential to improve patient outcomes. CONCLUSION: Nanoformulations, because of their unique surface and physiochemical properties, improve the solubility and bioavailability of LUT. However, poor in-vitro and in-vivo correlation and scalability of nanoformulations need to be addressed to achieve good clinical performance of LUT in oncology.

Exploring the Labyrinth: Imaging in Systemic Vasculitis.

Systemic vasculitis is an immune-mediated group of disorders broadly classified based on the involved vessel type. It has myriad clinical presentations, adding to the challenge of timely diagnosis and management. Thus, imaging has taken center stage in the diagnosis of these disorders as there is a lack of definitive clinical diagnostic markers. Various available imaging modalities can be used for diagnosis and follow-up on these patients. The coronavirus disease 2019 (COVID-19) has added a new dimension to the already existing problem of vasculitis. The virus has shown great affinity for the vascular endothelium, leading to multisystem organ vasculitis. There has been a spike in vasculitis cases in the COVID-19 pandemic era, thus necessitating more research and studies in this field for a better understanding of the disease. In this review, we wish to summarize the various imaging spectrums of classical systemic vasculitis along with the new addition of COVID-19-related vasculitis to the already long list.

Neuroendocrine tumor of the liver in pregnancy: A very rare case report.

Neuroendocrine neoplasms (NENs) of the liver represent a rare entity. Amongst this group of uncommon diseases primary hepatic neuroendocrine neoplasm (PH-NEN) represent only 0.3% of all NENs. Moreover, PH-NEN has very rarely been reported in pregnancy. We report a 28-year-old young patient with metastatic small cell neuroendocrine carcinoma of the liver complicated with pregnancy. She was evaluated and managed through a multidisciplinary team approach and received two cycles of chemotherapy with a cisplatin/etoposide regimen during the antenatal period and delivered at 37 weeks period of gestation (POG). This case highlights the importance of major challenges faced during the diagnosis and management of this very rare disease in pregnancy and the successful fetomaternal outcome.

Mitophagy at the crossroads of cancer development: Exploring the role of mitophagy in tumor progression and therapy resistance.

Preserving a functional mitochondrial network is crucial for cellular well-being, considering the pivotal role of mitochondria in ensuring cellular survival, especially under stressful conditions. Mitophagy, the selective removal of damaged mitochondria through autophagy, plays a pivotal role in preserving cellular homeostasis by preventing the production of harmful reactive oxygen species from dysfunctional mitochondria. While the involvement of mitophagy in neurodegenerative diseases has been thoroughly investigated, it is becoming increasingly evident that mitophagy plays a significant role in cancer biology. Perturbations in mitophagy pathways lead to suboptimal mitochondrial quality control, catalyzing various aspects of carcinogenesis, including establishing metabolic plasticity, stemness, metabolic reconfiguration of cancer-associated fibroblasts, and immunomodulation. While mitophagy performs a delicate balancing act at the intersection of cell survival and cell death, mounting evidence indicates that, particularly in the context of stress responses induced by cancer therapy, it predominantly promotes cell survival. Here, we showcase an overview of the current understanding of the role of mitophagy in cancer biology and its potential as a target for cancer therapy. Gaining a more comprehensive insight into the interaction between cancer therapy and mitophagy has the potential to reveal novel targets and pathways, paving the way for enhanced treatment strategies for therapy-resistant tumors in the near future.

Safety and Efficacy of 177 Lu-DOTATATE in Children and Young Adult Population : A Single-Center Experience.

PURPOSE: This single-center retrospective study explores the safety and efficacy of 177 Lu-DOTATATE in children and young adult population with metastatic/inoperable neuroendocrine tumors (NETs). PATIENTS AND METHODS: This study is a retrospective analysis of all children and young adult patients (≤29 years) with advanced inoperable/metastatic epithelial or nonepithelial NETs who were administered a median of 4 cycles of 177 Lu-DOTATATE therapy and low-dose oral capecitabine as a radiosensitizer every 8-12 weeks, except 2 patients who received CAPTEM chemotherapy. The radiological response was assessed using RECIST 1.1 on interim and end-of-treatment 68 Ga-DOTANOC PET/CT. The primary endpoint was objective response rate, whereas disease control rate, toxicity profile, progression-free survival, and overall survival were secondary endpoints. RESULTS: Nineteen biopsy-proven NET patients (median age, 22 ± 10 years) with 8 of them adolescents (10-18 years) and the remaining young adults (19-29 years) were included. Fourteen patients had gastroenteropancreatic neuroendocrine tumor (pancreas being most common primary site), whereas the rest had non-gastroenteropancreatic neuroendocrine tumor. A total of 65 cycles of 177 Lu-DOTATATE (range, 1-6 cycles) were administered with a median cumulative activity of 600 mCi (range, 100-1000 mCi). The objective response rate and disease control rate were 41% and 94%, respectively. Grade 1 and 2 adverse events were observed in 14 (74%) and 5 (26%) of 19 patients, respectively. In a total of 8 events (42%), 4 events each of disease progression and death occurred during a median follow-up of 80.1 months with an estimated 5-year progression-free survival and overall survival of 54% (95% confidence interval, 30-78) and 63% (95% confidence interval, 39-87), respectively. CONCLUSIONS: 177 Lu-DOTATATE appears safe and effective in children and young adults with metastatic/inoperable NETs. Large prospective trials are required to validate these results.

Deep-learning enabled ultrasound based detection of gallbladder cancer in northern India: a prospective diagnostic study.

Background: Gallbladder cancer (GBC) is highly aggressive. Diagnosis of GBC is challenging as benign gallbladder lesions can have similar imaging features. We aim to develop and validate a deep learning (DL) model for the automatic detection of GBC at abdominal ultrasound (US) and compare its diagnostic performance with that of radiologists. Methods: In this prospective study, a multiscale, second-order pooling-based DL classifier model was trained (training and validation cohorts) using the US data of patients with gallbladder lesions acquired between August 2019 and June 2021 at the Postgraduate Institute of Medical Education and research, a tertiary care hospital in North India. The performance of the DL model to detect GBC was evaluated in a temporally independent test cohort (July 2021-September 2022) and was compared with that of two radiologists. Findings: The study included 233 patients in the training set (mean age, 48 ± (2SD) 23 years; 142 women), 59 patients in the validation set (mean age, 51.4 ± 19.2 years; 38 women), and 273 patients in the test set (mean age, 50.4 ± 22.1 years; 177 women). In the test set, the DL model had sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of 92.3% (95% CI, 88.1-95.6), 74.4% (95% CI, 65.3-79.9), and 0.887 (95% CI, 0.844-0.930), respectively for detecting GBC which was comparable to both the radiologists. The DL-based approach showed high sensitivity (89.8-93%) and AUC (0.810-0.890) for detecting GBC in the presence of stones, contracted gallbladders, lesion size <10 mm, and neck lesions, which was comparable to both the radiologists (p = 0.052-0.738 for sensitivity and p = 0.061-0.745 for AUC). The sensitivity for DL-based detection of mural thickening type of GBC was significantly greater than one of the radiologists (87.8% vs. 72.8%, p = 0.012), despite a reduced specificity. Interpretation: The DL-based approach demonstrated diagnostic performance comparable to experienced radiologists in detecting GBC using US. However, multicentre studies are warranted to explore the potential of DL-based diagnosis of GBC fully. Funding: None.

Exploring the Biofilm Inhibition Potential of a Novel Phytic Acid-Crosslinked Chitosan Nanoparticle: In Vitro and In Vivo Investigations.

The primary factor underlying the virulence of Candida albicans is its capacity to form biofilms, which in turn leads to recurrent complications. Over-the-counter antifungal treatments have proven ineffective in eliminating fungal biofilms and the inflammatory cytokines produced during fungal infections. Chitosan nanoparticles offer broad and versatile therapeutic potential as both antifungal agents and carriers for antifungal drugs to combat biofilm-associated Candida infections. In our study, we endeavoured to develop chitosan nanoparticles utilising chitosan and the antifungal crosslinker phytic acid targeting C. albicans. Phytic acid, known for its potent antifungal and anti-inflammatory properties, efficiently crosslinks with chitosan. The nanoparticles were synthesised using the ionic gelation technique and subjected to analyses including Fourier transform infrared spectroscopy, dynamic light scattering, and zeta potential analysis. The synthesised nanoparticles exhibited dimensions with a diameter (Dh) of 103 ± 3.9 nm, polydispersity index (PDI) of 0.33, and zeta potential (ZP) of 37 ± 2.5 mV. These nanoparticles demonstrated an antifungal effect with a minimum inhibitory concentration (MIC) of 140 ± 2.2 µg/mL, maintaining cell viability at approximately 90% of the MIC value and reducing cytokine levels. Additionally, the nanoparticles reduced ergosterol content and exhibited a 62% ± 1.2 reduction in biofilm susceptibility, as supported by colony-forming unit (CFU) and XTT assays-furthermore, treatment with nanoparticles reduced exopolysaccharide production and decreased secretion of aspartyl protease by C. albicans. Our findings suggest that the synthesised nanoparticles effectively combat Candida albicans infections. In vivo studies conducted on a mouse model of vaginal candidiasis confirmed the efficacy of the nanoparticles in combating fungal infections in vivo.

Contrast Enhanced CT Versus MRI for Accurate Diagnosis of Wall-thickening Type Gallbladder Cancer.

Introduction: Diagnosis of wall-thickening type gallbladder cancer (GBC) is challenging. Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly utilized to evaluate gallbladder wall thickening. However, there is a lack of data comparing the performance of CT and MRI for the detection of wall-thickening type GBC. Aim: We aim to compare the diagnostic accuracy of CT and MRI in diagnosis of wall-thickening type GBC. Materials and methods: This prospective study comprised consecutive patients suspected of wall-thickening type GBC who underwent preoperative contrast-enhanced CT and MRI. The final diagnosis was based on the histopathology of the resected gallbladder lesion. Two radiologists independently reviewed the characteristics of gallbladder wall thickening at CT and MRI. The association of CT and MRI findings with histological diagnosis and the interobserver agreement of CT and MRI findings were assessed. Results: Thirty-three patients (malignancy, 13 and benign, 20) were included. None of the CT findings were significantly associated with GBC. However, at MRI, heterogeneous enhancement, indistinct interface with the liver, and diffusion restriction were significantly associated with malignancy (P = 0.006, <0.001, and 0.005, respectively), and intramural cysts were significantly associated with benign lesions (P = 0.012). For all MRI findings, the interobserver agreement was substantial to perfect (kappa = 0.697-1.000). At CT, the interobserver agreement was substantial to perfect (k = 0.631-1.000). Conclusion: These findings suggest that MRI may be preferred over CT in patients with suspected wall thickening type GBC. However, larger multicenter studies must confirm our findings.

Harnessing the cobalt complex for bidirectional O2/H2O transformation in neutral water via electrocatalysis/photocatalysis.

Bidirectional oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalysts are crucial for renewable energy transduction via electrolyzers and fuel cell. Here, we present a protocol for harnessing the cobalt complex for bidirectional O2/H2O transformation in neutral water via electrocatalysis/photocatalysis. We describe steps for monitoring ORR and OER in neutral aqueous solution, measuring O2 concentration, and identifying the probable catalytic mechanism for ORR and OER. We then detail procedures for examining catalyst behavior under photocatalytic conditions in neutral aqueous surroundings. For complete details on the use and execution of this protocol, please refer to Saini et al.1.

Wound Healing Activity of Topical Herbal Gels Containing Barringtonia acutangula Fruit Extract: In silico and In vivo Studies.

The current study describes the efficacy of B. acutangula fruit extract in wound healing via incorporation within topical gels. B. acutangula fruit extract was produced by solvent extraction method. The bioactive extract was incorporated within Carbopol 940-based topical gels, which were applied topically over the excision and incision wounds. The change in healing process was observed till 20 days. The percentages of closure of excision wound area were 92.89 % and 93.43 %, when treated with topical herbal gels containing B. acutangula fruit extract of 5 % and 10 %, respectively. The tensile strengths of incision area in rats treated with topical herbal gels containing 5 % and 10 % methanol extract of B. acutangula fruits were found to be 25±5.12 g and 30±4.10 g, respectively. The wound healing activity of topical herbal gels containing B. acutangula fruit extract in rats was found to be significant when compared with that of the reference standard and untreated groups. In addition, in silico studies suggested about good skin permeability and binding to the proteins responsible for delaying wound healing. It can be concluded that this topical herbal gels containing B. acutangula fruit extract could be used clinically for the treatment of wounds.

Corrosion inhibition of mild steel by Praecitrullus fistulosus (tinda fruit and peel) extracts.

Metal corrosion has recently emerged as a growing concern, impacting both local and industrial operations and disrupting conventional production methods. The utilization of green inhibitors to mitigate the metal degradation has garnered extensive attention from researchers and industrial professionals due to their prominent advantages: high efficiency, cost-effectiveness, and eco-friendliness. A novel ecofriendly inhibitor was prepared from Praecitrullus fistulosus (tinda fruit and peel) for mild steel (MS) corrosion in 1 M HCl. The presence of phenol, 3,5-bis (1,1-dimethyl ethyl)-, 9-octadecenoic acid, methyl ester, hexadecanoic acid 15-methyl-, methyl ester, 9, 12-octadecadienoic acid, methyl ester, 9, 12, 15-octadecatrienoic acid, methyl ester, (Z,Z,Z-), ascorbic acid, and phytol were identified as major constituent through LC/MS analysis of tinda extracts. The existence of these compounds was further confirmed through FTIR analysis, which shows the presence of various functional groups, such as -OH, CO, C-O-C, CC, and aromatic rings in the tinda extracts. Electrochemical and gravimetric analyses were used to investigate the inhibitory effect of tinda extracts. Outcomes of Tafel analysis revealed that both tinda extracts significantly reduced the corrosion current as compared to blank and achieved 83.73 % and 87.59 % inhibition efficiencies at 200 mg L-1 of tinda peel extract (TPE) and tinda fruit extract (TFE), respectively. The change in corrosion potential (Ecorr) was within an ±85 mV range compared to that of the uninhibited system, indicating that both tinda extracts demonstrated a mixed-type inhibition behavior. During adsorption studies, the best fit was obtained for the Langmuir adsorption model. The obtained values of standard Gibbs free energy (ΔG°ads) for TPE and TFE lie between -20 and - 40 kJ mol-1 but close to -20 kJ mol-1, which reveals preferential physical adsorption of the extracts on the metal surface. Thermodynamic parameters, including activation energy, enthalpy, and entropy, were computed across the temperature range of 303 to 323 K, suggesting that corrosion occurs spontaneously by the endothermic process. FESEM analysis depicted that inhibited systems exhibited smooth and crack-free surfaces as compared to blank system. AFM images demonstrated that surface roughness was significantly reduced for the inhibited system. In EDX analysis, the weight percentage of Cl was reduced in the presence of tinda extracts as compared to blank, and in XRD analysis, iron chloride (FeCl2) peak did not appear in the presence of inhibitor but it was in the uninhibited system. All surface-related findings signify that tinda extracts are adsorbed on the MS surface and form a protective layer that separates the metal from the corrosive solution.

Intravoxel incoherent motion and diffusion kurtosis imaging and their machine-learning-based texture analysis for detection and assessment of prostate cancer severity at 3 T.

OBJECTIVES: To evaluate the role of combined intravoxel incoherent motion and diffusion kurtosis imaging (IVIM-DKI) and their machine-learning-based texture analysis for the detection and assessment of severity in prostate cancer (PCa). MATERIALS AND METHODS: Eighty-eight patients underwent MRI on a 3 T scanner after giving informed consent. IVIM-DKI data were acquired using 13 b values (0-2000 s/mm2) and analyzed using the IVIM-DKI model with the total variation (TV) method. PCa patients were categorized into two groups: clinically insignificant prostate cancer (CISPCa) (Gleason grade ≤ 6) and clinically significant prostate cancer (CSPCa) (Gleason grade ≥ 7). One-way analysis-of-variance, t test, and receiver operating characteristic analysis was performed to measure the discriminative ability to detect PCa using IVIM-DKI parameters. A chi-square test was used to select important texture features of apparent diffusion coefficient (ADC) and IVIM-DKI parameters. These selected texture features were used in an artificial neural network for PCa detection. RESULTS: ADC and diffusion coefficient (D) were significantly lower (p < 0.001), and kurtosis (k) was significantly higher (p < 0.001), in PCa as compared with benign prostatic hyperplasia (BPH) and normal peripheral zone (PZ). ADC, D, and k showed high areas under the curves (AUCs) of 0.92, 0.89, and 0.88, respectively, in PCa detection. ADC and D were significantly lower (p < 0.05) as compared with CISPCa versus CSPCa. D for detecting CSPCa was high, with an AUC of 0.63. A negative correlation of ADC and D with GS (ADC, ρ = -0.33; D, ρ = -0.35, p < 0.05) and a positive correlation of k with GS (ρ = 0.22, p < 0.05) were observed. Combined IVIM-DKI texture showed high AUC of 0.83 for classification of PCa, BPH, and normal PZ. CONCLUSION: D, f, and k computed using the IVIM-DKI model with the TV method were able to differentiate PCa from BPH and normal PZ. Texture features of combined IVIM-DKI parameters showed high accuracy and AUC in PCa detection.

Novel Drug Delivery Approaches for the Localized Treatment of Cervical Cancer.

Cervical cancer (CC) is the fourth leading cancer type in females globally. Being an ailment of the birth canal, primitive treatment strategies, including surgery, radiation, or laser therapy, bring along the risk of infertility, neonate mortality, premature parturition, etc. Systemic chemotherapy led to systemic toxicity. Therefore, delivering a smaller cargo of therapeutics to the local site is more beneficial in terms of efficacy as well as safety. Due to the regeneration of cervicovaginal mucus, conventional dosage forms come with the limitations of leaking, the requirement of repeated administration, and compromised vaginal retention. Therefore, these days novel strategies are being investigated with the ability to combat the limitations of conventional formulations. Novel carriers can be engineered to manipulate bioadhesive properties and sustained release patterns can be obtained thus leading to the maintenance of actives at therapeutic level locally for a longer period. Other than the purpose of CC treatment, these delivery systems also have been designed as postoperative care where a certain dose of antitumor agent will be maintained in the cervix postsurgical removal of the tumor. Herein, the most explored localized delivery systems for the treatment of CC, namely, nanofibers, nanoparticles, in situ gel, liposome, and hydrogel, have been discussed in detail. These carriers have exceptional properties that have been further modified with the aid of a wide range of polymers in order to serve the required purpose of therapeutic effect, safety, and stability. Further, the safety of these delivery systems toward vital organs has also been discussed.

Minimally Invasive Mitral Valve Repair Using Transcatheter Chordal Attachments.

The advent of transcatheter mitral chordal replacement techniques has offered an alternative approach that is less invasive and may be more suitable for select patients compared with surgical repair. These systems involve introducing artificial chordae, via catheter, to replace or supplement damaged or elongated natural chordae. These artificial chordae are anchored at one end to the mitral leaflet and the other end to the papillary muscle or directly to the left ventricular apex, restoring the leaflet's coaptation and reducing regurgitation. Early trials and studies suggest promising results in terms of safety and efficacy in reducing MR severity and improving symptoms.

Theoretical investigation on the solid-liquid phase transition of gallium through free energy analysis.

CONTEXT: Gallium, renowned for its notably low melting point and unique property of becoming liquid at room temperature, is a valuable constituent in phase change materials. In this study, we investigate the solid-liquid phase transition of gallium using the modified embedded atom method (MEAM) potential. It addresses the technique to compute the free energy difference between the solid and liquid without using a reference state. We examine various thermodynamic and dynamic properties, including density, specific heat capacity, diffusivity, and radial distribution functions. We compute the coexistence temperature of the solid-liquid phase transitions of gallium from free energy analysis. This information is crucial for understanding the behavior of the material under different pressure conditions and can be valuable for various applications, such as materials processing and high-pressure studies. The analysis, findings, and insights of the present work will be of great significance to the broad scientific and engineering communities in the field of phase transformation of materials. METHODS: A series of molecular dynamics(MD) simulations were conducted using the LAMMPS software packages. The gallium atoms are modeled using the modified embedded atom method (MEAM) potential. To accurately predict the solid-liquid phase transitions of gallium, we calculated free energy by employing the "constrained λ integration" method, coupled with multiple histogram reweighting (MHR). The solid-liquid coexistence line is determined through the Gibbs-Duhem integration technique.

Carboplatin in Patients With Metastatic Castration-Resistant Prostate Cancer Harboring Somatic or Germline Homologous Recombination Repair Gene Mutations: Phase II Single-Arm Trial.

BACKGROUND: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. OBJECTIVE: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. METHODS: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0). RESULTS: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. CONCLUSIONS: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54086.

Chemometric profiling and anti-arthritic activity of aerial parts of Glinus oppositifolius (L.) Aug. DC.

ETHNOPHARMACOLOGICAL RELEVANCE: Glinus oppositifolius (L.) Aug. DC. belongs to the family Molluginaceae, an annual prostrate herb traditionally used to treat inflammations, arthritis, malarial, wounds, fevers, diarrhoea, cancer, stomach discomfort, jaundice, and intestinal parasites. However, the anti-arthritic activity of the aerial part has still not been reported. AIM OF THE STUDY: To investigate the antioxidant and anti-arthritic activity of G. oppositifolius in Complete Freund's Adjuvant (CFA) induced rats. MATERIALS AND METHODS: The dried aerial parts of this plant material were defatted with n-hexane and extracted by methanol using a soxhlet apparatus. The in vitro anti-arthritic activity of methanolic extract of G. oppositifolius (MEGO) was evaluated in protein denaturation, membrane stabilization, and inhibition of proteinase assay at 25, 50, 100, 200, and 400 µg/ml concentrations. Female Wistar rats were immunized sub-dermally into the right hind paw with 0.1 ml of CFA. Rats were administered with MEGO at doses of 200 and 400 mg/kg once daily for fourteen days after arthritis induction. Assessment of arthritis was performed by measuring paw diameter, arthritic index, arthritic score, body weight, organ weight, and hematological and biochemical parameters, followed by the analysis of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin-1-beta (IL-1ß), cyclooxygenase-2 (COX-2), interleukin 13 (IL-13) and interleukin 10 (IL-10) and histopathological study. In vivo antioxidant effect was investigated in enzymatic assays. The presence of phytoconstituents was analyzed by Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS), respectively. In silico molecular docking study of the compounds was carried out against COX-2, IL-1ß, IL-6, and TNF-α using AutoDock 4.2 and BIOVIA-Discovery Studio Visualizer software. RESULTS: MEGO's in vitro anti-arthritic activity showed dose-dependent inhibition of protein denaturation, membrane stabilization, and proteinase inhibition, followed by significant in vivo anti-arthritic activity. The rats treated with MEGO showed tremendous potential in managing arthritis-like symptoms by restoring hematological, biochemical, and histological changes in CFA-induced rats. MEGO (200 and 400 mg/kg) showed a significant alleviation in the levels of hyper expressed inflammatory mediators (TNF-α, IL-1ß, and IL-6) and oxidative stress (SOD, CAT, GSH, and LPO) in CFA-induced rats. Spergulagenin-A as identified by LC-MS analysis, exhibited the highest binding affinity against COX-2 (-8.6), IL-1ß (7.2 kcal/mol), IL-6 (-7.4 kcal/mol), and TNF-α (-6.5 kcal/mol). CONCLUSIONS: Provided with the comprehensive investigation, methanolic extract of G. oppositifolius against arthritic-like condition is a proof of concept that revalidates its ethnic claim. The presence of Spergulagenin-A might be responsible for the anti-arthritic activity.

Agreement of Gallbladder Reporting and Data System for Gallbladder Wall Thickening at Ultrasonography: A Multireader Validation Study.

Objective: This article aims to evaluate the intrareader and interreader agreement of ultrasound (US) gallbladder reporting and data system (GB-RADS) and validate the risk of malignancy in each GB-RADS category. Materials and methods: This retrospective study comprised consecutive patients with nonacute gallbladder wall thickening who underwent US evaluation between January 2019 and December 2022. Three radiologists independently read the static US images and cine-loops for GB-RADS findings and assigned GB-RADS categories. The intraobserver (static images) and interobserver (static images and cine-loops) agreement was calculated using kappa statistics and Krippendorff's alpha. Another radiologist assigned a consensus GB-RADS category. The percentage of malignancy in each GB-RADS category was calculated. Results: Static US images of 414 patients (median age, 56 years; 288 women, benign = 45.6% and malignant = 54.4%) and cine-loops of 50 patients were read. There was weak to moderate intrareader agreement for most GB-RADS findings and moderate intrareader agreement for the GB-RADS category for all readers. On static images, the interreader agreement was acceptable for GB-RADS categories. On cine-loops, the interreader agreement for GB-RADS findings and categories was better than static images. The percentage of malignancy was 1.2%, 37%, 71.1%, and 89.1% in GB-RADS 2, 3, 4, and 5 categories. Conclusion: GB-RADS has moderate intrareader for GB-RADS categories. As originally proposed, the risk of malignancy is negligible in GB-RADS 2 category and highest in GB-RADS 5 category. However, the discriminatory performance of GB-RADS 3 and 4 categories is low. Larger multicenter studies with more readers must assess the reader agreement and validate the GB-RADS systems for wider clinical utilization.

NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.

The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 expression is abnormally gained in prostate cancer cells and its functional inhibition impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites, which is greater than 65% of the AR tumor cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and instead contain the canonical palindromic motifs. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in the physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Concordantly, a dual NSD1/2 PROTAC degrader, called LLC0150, was preferentially cytotoxic in AR-dependent prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo-enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 as viable paralog co-targets in advanced prostate cancer.