A Multistep In Silico Approach Identifies Potential Glioblastoma Drug Candidates via Inclusive Molecular Targeting of Glioblastoma Stem Cells.

Glioblastoma (GBM) is the highest grade of glioma for which no effective therapy is currently available. Despite extensive research in diagnosis and therapy, there has been no significant improvement in GBM outcomes, with a median overall survival continuing at a dismal 15-18 months. In recent times, glioblastoma stem cells (GSCs) have been identified as crucial drivers of treatment resistance and tumor recurrence, and GBM therapies targeting GSCs are expected to improve patient outcomes. We used a multistep in silico screening strategy to identify repurposed candidate drugs against selected therapeutic molecular targets in GBM with potential to concomitantly target GSCs. Common differentially expressed genes (DEGs) were identified through analysis of multiple GBM and GSC datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). For identification of target genes, we selected the genes with most significant effect on overall patient survival. The relative mRNA and protein expression of the selected genes in TCGA control versus GBM samples was also validated and their cancer dependency scores were assessed. Drugs targeting these genes and their corresponding proteins were identified from LINCS database using Connectivity Map (CMap) portal and by in silico molecular docking against each individual target using FDA-approved drug library from the DrugBank database, respectively. The molecules thus obtained were further evaluated for their ability to cross blood brain barrier (BBB) and their likelihood of resulting in drug resistance by acting as p-glycoprotein (p-Gp) substrates. The growth inhibitory effect of these final shortlisted compounds was examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values were obtained from GDSC portal. We identified RPA3, PSMA2, PSMC2, BLVRA, and HUS1 as molecular targets in GBM including GSCs with significant impact on patient survival. Our results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. Through this work, we identified repurposed candidate therapeutics against GBM utilizing a GSC inclusive targeting approach, which demonstrated high in vitro efficacy and can prospectively evade drug resistance. These drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes.

A comprehensive review on ecology, life cycle and use of Tecoma stans (bignoneaceae).

Tecoma stans is a widely distributed tall ornamental shrub in the plains of Indian subcontinent and is considered an invasive species across Argentina, Australia, South Africa, Pacific Islands and tropical regions of Asia. Besides having an ornamental significance, T. stans has been extensively investigated for its pharmaceutical applications as a source of bioactive compounds. In addition, the shrub is cultivated commercially as a potted flowering plant. We believe that T. stans, being a hardy, invasive and aggressively growing species, holds a considerable potential and a promising solution for re-greening waste and degraded lands outside its invasive range, due to its wider adaptability and drought tolerant characteristics. The shrub is an excellent source of pollen and nectar, that attracts diverse insect-pollinators and several species of birds. The prudent plantation of this shrub has the potential to restore the ecology of barren landscapes, that can change its perspective of 'being invasive' to 'being ecologically healthy' across the tropical, semi-arid and subtropical regions worldwide. This paper reviews the current updates on ecology, life cycle including morphology, plant growth characteristics, flowering phenology, reproductive biology, breeding system and fruiting of T. stans. In addition, details on insect-pollinator diversity and natural regeneration potential have also been discussed, besides highlighting its therapeutic and landscape use.

Reducing Cancer Drug Cost: 3-Year Analysis of Automated Dose Rounding in Electronic Health Records.

PURPOSE: Globally, cancer drug expenditure exceeds $185 in US dollars (USD) billion, with the United States contributing $75 (USD) billion. Many cancer drug doses are calculated on the basis of body weight or body surface area, which often results in leftover drug in partially used single-dose vials (SDVs). The cost of wasted drug is a huge financial burden on the US health care system. We evaluated the cost savings resulting from the reduction of SDV wastage, achieved through the implementation of automated dose rounding rules in electronic health records (EHRs). METHODS: Mayo Clinic implemented automated dose rounding rules within the EHR. These rules were designed to round calculated doses to the nearest SDV if the vial size closely matched the original calculated dose, within a 10% threshold. We assessed doses administered between January 2019 and December 2021, and computed cost-savings, waste reduction, and cost of waste for chemotherapy drugs. RESULTS: In 3 years, 36.1% of doses were rounded down, 35.8% were rounded up, and 28.1% were exact doses. By rounding doses down to a vial size, we achieved cost-savings of $39.75 (USD) million and prevented 62,065 SDV of cancer drugs from going to waste. By rounding doses up, we avoided wasting $9.95 (USD) million worth of drugs. However, there were still instances where the rounding fell outside of the 10%, resulting in wasted drugs worth $25 (USD) million. CONCLUSION: The substantial burden imposed on patients and the US health care system because of cancer drug wastage is of significant concern. Although the automated dose rounding system represents a partial solution for this issue, a comprehensive approach involves the imperative development of policy and legislative solutions to effectively mitigate the challenges associated with cancer drug waste.

NiOx/PANI nanocomposite doped carbon paste as electrode for long-term stable and highly efficient perovskite solar cells.

Carbon-based perovskite solar cells (PSCs) have emerged as a hopeful alternative in the realm of photovoltaics. They are considered promising due to their affordability, remarkable durability in humid environments, and impressive electrical conductivity. One approach to address the cost issue is to use affordable counter electrodes in PSCs that do not require organic hole transport materials (HTMs). This study utilized an innovative and economical method to create NiOx/PANI nanocomposites. Later, these nanoparticles were integrated into a carbon paste to act as an HTM. This incorporation is intended to optimize charge extraction, improve interfacial contact, align energy levels, reduce energy loss, minimize charge recombination, and protect the perovskite (FAPbI3) surface from degradation. The optoelectronic properties of these devices were investigated, and all cells showed improved efficiency compared to control cells. The NiOx/PANI doped carbon (NiOx/PANI+CE) exhibited excellent performance due to strong hole conductivity, well-aligned energy levels, and the formation of stepwise band alignment at the perovskite interface.

Durable Objective Response to Lurbinectedin in Small Cell Bladder Cancer with TP53 Mutation: A Molecular-Directed Strategy.

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following the development of lurbinectedin resistance showed a new actionable ERBB2 alteration without significant change in the tumor mutation burden (six mutations/Mb). The present report suggests that lurbinectedin may be active and should be further explored in SCBC harboring TP53 mutations and amplifications in E2F3 and MYC family complexes.

Enhancement of the photocatalytic activity of rGO/NiO/Ag nanocomposite for degradation of methylene blue dye.

The current study focuses on boosting the photocatalytic ability of reduced graphene oxide (rGO) by decorating the rGO nano-sheets with nickel oxide (NiOx) and silver (Ag) nanomaterials. The developed ternary nanomaterials were investigated using FTIR, XRD, FESEM, TEM, Raman, and UV-vis to evaluate the photo-degradation process. The rGO/NiOx/Ag ternary system showed promising photocatalytic dye degradation under simulated sunlight irradiance. The addition of NiOx and Ag nanomaterials widened the catalytic activity spectrum from the visible region to the UV-region. Besides, these materials hindered the electron-hole recombination, boosting the catalytic activity. The reusability results also clearly showed that the synthesized ternary nanomaterials have good reproducibility and stability for photocatalytic degradation of industrial wastewater.

Effect of Bacille Calmette-Guérin for Non-Muscle-Invasive Bladder Cancer After Prostate Radiotherapy.

BACKGROUND: Little is known about the impact of prior prostate radiation therapy (RT) on the Bacille Calmette-Guerin (BCG) immunotherapy response in patients with non-muscle invasive bladder cancer (NMIBC). OBJECTIVE: We hypothesized that the damaging radiation effects on the bladder could negatively influence BCG efficacy. METHODS: Men with a history of high-risk NMIBC were identified within the Surveillance, Epidemiology, and End Results-Medicare database. All patients completed adequate BCG defined as at least 5 plus 2 treatments completed within 12 months. Patients were stratified into 2 groups: with prior RT for prostate cancer and without prior RT before the diagnosis of NMIBC. The primary endpoint was a 5-year composite for progression defined as disease progression requiring systemic chemotherapy, checkpoint inhibitors, radical or partial cystectomy, or cancer-specific death. RESULTS: We identified 3,466 patients with NMIBC, including 145 with prior RT for prostate cancer. Five-year progression occurred in 471 patients (13.6%). Patients with prior RT were older than patients without prior RT (77.0 vs 75.0 years; P < .001). The distribution of T stage was significantly different at diagnosis between the RT and non-RT groups (RT: Ta, 44.8%; Tis, 18.6%; T1, 36.6%; without RT: Ta, 40.9%; Tis, 10.8%; T1, 48.3%; P = .002). No difference in the risk of total progression was observed between patients with and without prior RT (P = .67). Similarly, no difference was observed after multivariable adjustment (hazard ratio, 0.99; 95% CI, 0.61-1.58; P = .95). CONCLUSION: For patients with NMIBC who undergo adequate BCG treatment, prior RT for prostate cancer was not associated with worse 5-year progression-free survival.

Gastrointestinal and Neuropsychological Symptoms Are Associated With Distinct Vomiting Profiles in Patients Receiving Chemotherapy.

OBJECTIVES: To identify subgroups of patients with distinct chemotherapy-induced vomiting (CIV) profiles; determine how these subgroups differ on several demographic, clinical, and symptom characteristics; and evaluate factors associated with chemotherapy-induced nausea and CIV profiles. SAMPLE & SETTING: Adult patients (N = 1,338) receiving cancer chemotherapy. METHODS & VARIABLES: Data were collected on demographic, clinical, and symptom characteristics. Differences among subgroups of patients with distinct CIV profiles were evaluated using parametric and nonparametric tests. RESULTS: Three CIV profiles (None, Decreasing, and Increasing) were identified. Compared with the None class, Decreasing and Increasing classes were more likely to have lower household income and a higher comorbidity burden, as well as to report higher rates of dry mouth, nausea, diarrhea, depression, anxiety, sleep disturbance, morning fatigue, and pain interference. IMPLICATIONS FOR NURSING: Clinicians need to assess common and distinct risk factors for CIV and chemotherapy-induced nausea.

A Comprehensive Analysis of Clinical, Biochemical, and Polysomnographic Characteristics in Patients With Type 2 Diabetes Mellitus With and Without Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) has been a significant contributor to mortality all across the globe. The most attributing factors to pathogenesis are metabolic syndrome, obesity, diabetes, and so on, but the indicators of its early detection are still elusive. OBJECTIVE: The study aimed to compare the clinical, biochemical, and polysomnographic characteristics of type 2 diabetes patients with and without OSA. DESIGN AND METHODS: This cross-sectional study was conducted at the Department of Medicine and Endocrinology Unit of Dayanand Medical College and Hospital, Ludhiana. A total of 584 patients with type 2 diabetes were assessed using the Berlin questionnaire, with 302 fulfilling the criteria for a high risk of OSA. Out of 302 patients who met the criteria for the high-risk category, 110 patients underwent a sleep study. RESULTS:  Three hundred and two patients satisfying the inclusion and exclusion criteria were enrolled in the study. A total of 110 patients underwent a sleep study, of which 68 (61.8%) had evidence of OSA. The waist-to-hip ratio was considerably higher in the OSA patients than in the non-OSA group (1.09 vs 0.930, p = 0.001). HbA1c >7% was found in 58.8% of OSA patients contrary to 38.1% of non-OSA patients. Fasting plasma glucose levels (>126 mg/dl) were identified in a substantially larger proportion of OSA patients than the non-OSA patients (64.7% vs 45.2%, p = 0.04). Similarly, peripheral neuropathy was found more commonly in the OSA patients than in the non-OSA patients (47% vs. 26.1%, p = 0.02). Prevalence of retinopathy, nephropathy, coronary artery disease, stroke, heart failure, and peripheral vascular disease did not differ significantly between the two groups. CONCLUSIONS: OSA frequently occurs among individuals diagnosed with type 2 diabetes mellitus. The prompt identification of OSA within this demographic is imperative to pinpoint those at an elevated risk of succumbing to conditions such as peripheral neuropathy, the exacerbation of glycemic control, and the onset of unmanaged hypertension. Moreover, there exists a positive correlation between the waist-to-hip ratio and the prevalence of OSA in persons with type 2 diabetes mellitus, highlighting the critical role of waist-to-hip ratio assessments in this patient population.

Fully Automated Agatston Score Calculation From Electrocardiography-Gated Cardiac Computed Tomography Using Deep Learning and Multi-Organ Segmentation: A Validation Study.

To evaluate deep learning-based calcium segmentation and quantification on ECG-gated cardiac CT scans compared with manual evaluation. Automated calcium quantification was performed using a neural network based on mask regions with convolutional neural networks (R-CNNs) for multi-organ segmentation. Manual evaluation of calcium was carried out using proprietary software. This is a retrospective study of archived data. This study used 40 patients to train the segmentation model and 110 patients were used for the validation of the algorithm. The Pearson correlation coefficient between the reference actual and the computed predictive scores shows high level of correlation (0.84; P < .001) and high limits of agreement (±1.96 SD; -2000, 2000) in Bland-Altman plot analysis. The proposed method correctly classifies the risk group in 75.2% and classifies the subjects in the same group. In total, 81% of the predictive scores lie in the same categories and only seven patients out of 110 were more than one category off. For the presence/absence of coronary artery calcifications, the deep learning model achieved a sensitivity of 90% and a specificity of 94%. Fully automated model shows good correlation compared with reference standards. Automating process reduces evaluation time and optimizes clinical calcium scoring without additional resources.

Squatting biomechanics following physiotherapist-led care or hip arthroscopy for femoroacetabular impingement syndrome: a secondary analysis from a randomised controlled trial.

Background: Femoroacetabular impingement syndrome (FAIS) can cause hip pain and chondrolabral damage that may be managed non-operatively or surgically. Squatting motions require large degrees of hip flexion and underpin many daily and sporting tasks but may cause hip impingement and provoke pain. Differential effects of physiotherapist-led care and arthroscopy on biomechanics during squatting have not been examined previously. This study explored differences in 12-month changes in kinematics and moments during squatting between patients with FAIS treated with a physiotherapist-led intervention (Personalised Hip Therapy, PHT) and arthroscopy. Methods: A subsample (n = 36) of participants with FAIS enrolled in a multi-centre, pragmatic, two-arm superiority randomised controlled trial underwent three-dimensional motion analysis during squatting at baseline and 12-months following random allocation to PHT (n = 17) or arthroscopy (n = 19). Changes in time-series and peak trunk, pelvis, and hip biomechanics, and squat velocity and maximum depth were explored between treatment groups. Results: No significant differences in 12-month changes were detected between PHT and arthroscopy groups. Compared to baseline, the arthroscopy group squatted slower at follow-up (descent: mean difference -0.04 m∙s-1 (95%CI [-0.09 to 0.01]); ascent: -0.05 m∙s-1 [-0.11 to 0.01]%). No differences in squat depth were detected between or within groups. After adjusting for speed, trunk flexion was greater in both treatment groups at follow-up compared to baseline (descent: PHT 7.50° [-14.02 to -0.98]%; ascent: PHT 7.29° [-14.69 to 0.12]%, arthroscopy 16.32° [-32.95 to 0.30]%). Compared to baseline, both treatment groups exhibited reduced anterior pelvic tilt (descent: PHT 8.30° [0.21-16.39]%, arthroscopy -10.95° [-5.54 to 16.34]%; ascent: PHT -7.98° [-0.38 to 16.35]%, arthroscopy -10.82° [3.82-17.81]%), hip flexion (descent: PHT -11.86° [1.67-22.05]%, arthroscopy -16.78° [8.55-22.01]%; ascent: PHT -12.86° [1.30-24.42]%, arthroscopy -16.53° [6.72-26.35]%), and knee flexion (descent: PHT -6.62° [0.56- 12.67]%; ascent: PHT -8.24° [2.38-14.10]%, arthroscopy -8.00° [-0.02 to 16.03]%). Compared to baseline, the PHT group exhibited more plantarflexion during squat ascent at follow-up (-3.58° [-0.12 to 7.29]%). Compared to baseline, both groups exhibited lower external hip flexion moments at follow-up (descent: PHT -0.55 N∙m/BW∙HT[%] [0.05-1.05]%, arthroscopy -0.84 N∙m/BW∙HT[%] [0.06-1.61]%; ascent: PHT -0.464 N∙m/BW∙HT[%] [-0.002 to 0.93]%, arthroscopy -0.90 N∙m/BW∙HT[%] [0.13-1.67]%). Conclusion: Exploratory data suggest at 12-months follow-up, neither PHT or hip arthroscopy are superior at eliciting changes in trunk, pelvis, or lower-limb biomechanics. Both treatments may induce changes in kinematics and moments, however the implications of these changes are unknown. Trial registration details: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549. Trial registered 2/11/2015.