A Landscape of Pharmacogenomic Interactions in Cancer.

Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.

Belzutifan: a novel therapeutic for the management of von Hippel-Lindau disease and beyond.

The identification of the VHL gene and its role in regulating the hypoxia-inducible factor signaling pathway has helped to revolutionize the treatment of renal cell carcinoma (RCC). Belzutifan is a novel small-molecule inhibitor of hypoxia-inducible factor 2α which has demonstrated efficacy in treating von Hippel-Lindau (VHL) disease, earning regulatory approvals for this indication. There is also early evidence for efficacy in sporadic RCC. Belzutifan has a favorable safety profile. Several clinical trials are currently ongoing, which should help in identifying this promising drug's role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.

The novel drug belzutifan was developed after years of research in identifying the VHL gene and how genetic abnormalities in VHL may result in tumor growth. Belzutifan has been approved for use in patients with VHL disease ­ a rare familial disorder first described in the 19th century that presents with a variety of cancerous and noncancerous tumors, including kidney cancer. Growing evidence supports belzutifan's use in non-familial kidney cancer as well. This is important because most patients eventually develop resistance to the currently available cancer treatments, highlighting the need for drugs with a different mechanism of action. Belzutifan works by blocking a protein called HIF-2a, which causes tumor growth in patients with VHL disease. Belzutifan is well tolerated, with the most common side effects being low energy, hemoglobin and blood oxygen. This review summarizes the history, mechanism of action and research evidence to date supporting the use of belzutifan in VHL disease and cancer treatment. We also discuss future directions, including remaining clinical questions and areas of ongoing research.

Cell death classification: A new insight based on molecular mechanisms.

Cells tend to disintegrate themselves or are forced to undergo such destructive processes in critical circumstances. This complex cellular function necessitates various mechanisms and molecular pathways in order to be executed. The very nature of cell death is essentially important and vital for maintaining homeostasis, thus any type of disturbing occurrence might lead to different sorts of diseases and dysfunctions. Cell death has various modalities and yet, every now and then, a new type of this elegant procedure gets to be discovered. The diversity of cell death compels the need for a universal organizing system in order to facilitate further studies, therapeutic strategies and the invention of new methods of research. Considering all that, we attempted to review most of the known cell death mechanisms and sort them all into one arranging system that operates under a simple but subtle decision-making (If \ Else) order as a sorting algorithm, in which it decides to place and sort an input data (a type of cell death) into its proper set, then a subset and finally a group of cell death. By proposing this algorithm, the authors hope it may solve the problems regarding newer and/or undiscovered types of cell death and facilitate research and therapeutic applications of cell death.

Evaluation of the c-Fos expression in the hippocampus after fatigue caused by one session of endurance exercise in pre-pubertal and adult rats.

PURPOSE: Central fatigue plays an important role in reducing endurance exercise activity during brain development. c-Fos gene expression in the hippocampus was examined as an indicator of neuronal activation after exhaustion. METHODS: Eighteen pre-pubertal male rats at four weeks old and 18 adult rats at eight weeks were randomly divided into three groups: Control (C), Constant time exercise (CTEx), Endurance Exercise until Exhaustion (ExhEx), which started at two minutes and ended in 20 min, the main swimming test was performed with a weight equal to 5% of the bodyweight attached to the rats' tail as a single session in experimental groups and was recorded at the end of their time, while to evaluate the force loss, the Grip strength was measured before and after the activity. The brain activation rate was examined by c-Fos gene expression and Nissl staining in CA3 and dentate gyrus (DG) in the hippocampus of all groups. RESULTS: Power grip and Nissl positive neurons in CA3 and DG have been significantly higher in pre-pubertal rats than in adults, both in the CTEx group (p = 0.04) and in the ExhEx group (p < 0.001). Also, real-time exhaustion in the pre-pubertal group was significantly longer than in adults. c-Fos gene expression was significantly reduced in adults' hippocampus in comparison to preadolescence (p < 0.01) and control (p < 0.001). CONCLUSION: These findings clarified that increased strength and longer fatigue in pre-puberal rats may lead to c-Fos gene expression and decreased neurons in the hippocampus. Perhaps this is a protective effect to suppress stress hormones.

Less force loss and longer real-time exhaustion in pre-pubertal subjects.There was no significant reduction in c-Fos gene expression in the hippocampus of pre-pubertal rats after exhaustion.The Nissl positive neurons in CA3 and DG of the Hippocampus are significantly lower in the exhausted adult rat in comparison with the pre-pubertal group.

TP53 Alterations Are Associated With Poor Survival in Patients With Primary Mediastinal Nonseminoma Germ Cell Tumors.

BACKGROUND: Primary mediastinal nonseminoma germ cell tumors (PMNSGCT) are a subgroup of nonseminoma germ cell tumors (GCT) with poor prognosis. In this study, PMNSGCT-specific genomic landscape was analyzed and correlated with clinical outcomes. METHODS: DNA was extracted and sequenced from 28 archival tumor tissue of patients with mediastinal GCT (3 seminoma and 25 nonseminoma). Overall survival (OS) and association with gene alterations were estimated using the Kaplan-Meier and univariate Cox regression methods. RESULTS: Three patients (11%) had a karyotype XXY, 17/28 (61%) tumor samples presented chromosome 12p amplification. Somatic mutations were detected in 19/28 (68%) samples. The most frequently mutated genes were: TP53 (13/28; 46%), KIT (5/28; 18%), and KRAS (5/28; 18%). Deleterious TP53 alterations were associated with significantly reduced overall survival (HR: 7.16; P = .012). CONCLUSIONS: TP53 alterations are common in PMNSGCT and are associated with reduced overall survival, potentially underlying the poor sensitivity to chemotherapy observed in these patients.

Emerging Role of Biomarkers in Testicular Germ Cell Tumors.

PURPOSE OF REVIEW: This review will focus on biomarkers in testicular germ cell tumors (TGCT), focusing on microRNAs with high potential clinical application to drive management of TGCT. We explore the mechanism of action of microRNAs, literature to date, and how microRNAs may be incorporated into clinical practice in the near future. RECENT FINDINGS: MicroRNAs are small non-coding RNAs found in blood which play an important role in post-transcriptional gene regulation and have been explored in TGCT for the past 15 years. More recently, results show they are promising biomarkers for diagnosis with impressive sensitivity and specificity, while also being cost-effective. MicroRNAs will likely play a critical role in areas of unmet need in GCT in the next decade, as they have many of the characteristics of an ideal biomarker. Ongoing prospective clinical trials evaluating microRNA-371 will be eagerly awaited and will help inform decision-making in real-world application.

Avelumab and axitinib combination therapy for the treatment of advanced renal cell carcinoma.

Owing to an improved understanding of the immunobiological profile of renal cell carcinoma (RCC), the past few years have ushered in significant changes in systemic therapies for advanced stage RCC. First-line treatment with single-agent tyrosine kinase inhibitors (TKI) has been virtually replaced for most patients by immunotherapy combinations. The first of such treatments was the dual immune checkpoint inhibitor combination of ipilimumab and nivolumab. More recently, the combination of an immune checkpoint inhibitor and a TKI has also moved into the first-line setting. This review summarizes the pharmacologic properties, evidence for use and safety of avelumab, a PD-L1 inhibitor and axitinib a small-molecule TKI, each as monotherapy, and in combination for the management of metastatic RCC.

The Effects of Melatonin Supplementation on Parameters of Mental Health, Glycemic Control, Markers of Cardiometabolic Risk, and Oxidative Stress in Diabetic Hemodialysis Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: This study evaluated the effects of melatonin supplementation on parameters of mental health, glycemic control, markers of cardiometabolic risk, and oxidative stress in diabetic hemodialysis (HD) patients. DESIGN: A randomized, double-blind, placebo-controlled clinical trial was conducted in 60 diabetic HD patients, 18-80 years of age. Participants were randomly divided into 2 groups to take either melatonin (2 x 5mg/day) (n = 30) or placebo (n = 30) 1 hour before bedtime for 12 weeks. The effects of melatonin on mental health, metabolic status, and gene expression related to metabolic status were assessed using multiple linear regression adjusting for age and BMI. RESULTS: Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (P = .007), Beck Depression Inventory index (P = .001), and Beck Anxiety Inventory index (P = .01) compared with the placebo. Additionally, melatonin administration significantly reduced fasting plasma glucose (ß = -21.77 mg/dL, 95% CI -33.22 to -10.33, P < .001), serum insulin levels (ß = -1.89 µIU/mL, 95% CI -3.34 to -0.45, P = .01), and homeostasis model of assessment-insulin resistance (ß = -1.45, 95% CI -2.10 to -0.80, P < .001), and significantly increased the quantitative insulin sensitivity check index (ß = 0.01, 95% CI 0.007-0.02, P < .001) compared with placebo treated subjects. In addition, melatonin administration resulted in a significant reduction in serum high sensitivity C-reactive protein (ß = -1.92 mg/L, 95% CI -3.02 to -0.83, P = .001) and plasma malondialdehyde (ß = -0.21 µmol/L, 95% CI -0.36 to -0.06, P = .005); also, significant rises in plasma total antioxidant capacity (ß = 253.87 mmol/L, 95% CI 189.18-318.56, P < .001) and nitric oxide levels (ß = 2.99 µmol/L, 95% CI 0.71-5.28, P = .01) were observed compared with the placebo. CONCLUSION: Overall, melatonin supplementation for 12 weeks to diabetic HD patients had beneficial effects on mental health, glycemic control, inflammatory markers, and oxidative stress.

Curcumin ameliorates experimental autoimmune encephalomyelitis in a C57BL/6 mouse model.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Although the exact etiology of the disease is largely unknown, it is identified that cytokines may play an important role in the pathogenesis of MS. In this study, the effects of curcumin has been investigated on the expression levels of selected cytokine coding genes as well as the extent of demyelination in the corpus callosum of C57BL/6 experimental autoimmune encephalomyelitis (EAE) model of MS. Gene expression analyses revealed that treatment with curcumin could lead to a significant reduction in the expression levels of pro-inflammatory cytokine coding genes including IL-6 (p = 0.001), IL-17 (p = 0.001), tumor necrosis factor (TNF)-α (p = 0.008), and interferon (IFN)-γ (p = 0.033) as well as a significant increase in the expression level of transforming growth factor (TGF)-ß (p = 0.006) as an anti-inflammatory cytokine. Moreover, the expression of glutathione peroxidase (GPX)-1 gene and the activity of anti-oxidant enzymes were significantly higher (p < 0.001) in curcumin-treated mice. Luxol fast blue staining also confirmed a significant reduction in the extent of demyelination in the curcumin-treated group (p < 0.001). Our results have confirmed that curcumin is an effective therapeutic agent that could ameliorate the severity of EAE.

Electron transport in polycyclic aromatic hydrocarbons/boron nitride hybrid structures: density functional theory combined with the nonequilibrium Green's function.

We investigate the electronic transport properties of two types of junction based on single polyaromatic hydrocarbons (PAHs) and PAHs embedded in boron nitride (h-BN) nanoribbons, using nonequilibrium Green's functions (NEGF) and density functional theory (DFT). In the PAH junctions, a Fano resonance line shape at the Fermi energy in the transport feature can be clearly seen. In hybrid junctions, structural asymmetries enable interactions between the electronic states, leading to observation of interface-based transport. Our findings reveal that the interface of PAH/h-BN strongly affects the transport properties of the structures.

The dynamics of electric powered wheelchair sideways tips and falls: experimental and computational analysis of impact forces and injury.

BACKGROUND: To reduce the occurrence of wheelchair falls and to develop effective protection systems, we aimed to quantify sideways tip and fall dynamics of electric power wheelchairs (EPWs). We hypothesized that driving speed, curb height and angle of approach would affect impact forces and head injury risk for wheelchair riders. We further expected that fall dynamics and head injury risk would be greater for unrestrained riders compared to restrained riders. METHODS: Sideways wheelchair tip and fall dynamics were reconstructed using a remotely operated rear wheel drive EPW and a Hybrid III test dummy driving at different approach angles (5 to 63°) over an adjustable height curb (0.30 to 0.41 m) at speeds of 0.6-1.5 m/s. Rigid body dynamics models (Madymo, TASS International, Livonia, MI) were developed in parallel with the experiments to systematically study and quantify the impact forces and the sideways tip or fall of an EPW user in different driving conditions. RESULTS: Shallower approach angles (25°) (p < 0.05) and higher curbs (0.4 m) (p < 0.05) were the most significant predictors of tipping for restrained passengers. Unrestrained passengers were most affected by higher curbs (0.4 m) (p < 0.005) and fell forward from the upright wheelchair when the approach angle was 60°. Head impact forces were greater in unrestrained users (6181 ± 2372 N) than restrained users (1336 ± 827 N) (p = 0.00053). Unrestrained users had significantly greater head impact severities than restrained users (HIC = 610 ± 634 vs HIC = 29 ± 38, p = 0.00013) and several tip events resulted in HICs > 1000 (severe head injury) in unrestrained users. CONCLUSIONS: Sideways tips and forward falls from wheelchairs were most sensitive to curb height and approach angle but were not affected by driving speed. Sideways tips and falls resulted in impact forces that could result in concussions or traumatic brain injury and require injury prevention strategies. Seat belts eliminated the risk of falling from an upright chair and reduced head impact forces in sideways wheelchair tips in this study; however, their use must be considered within the ethical and legal definitions of restraints.

Combined therapeutic effects of low power laser (980nm) and CoQ10 on Neuropathic Pain in adult male rat.

BACKGROUND: Neuropathic pain (NP) is one of the most suffering medical conditions that often fail to respond to certain pain therapy. Although its exact etiology is still unknown the role of reactive oxygen species (ROS) and oxidative stress were explored by many researchers. Neuropathies either central or peripheral lead to painful condition as well as social and economic isolation, thus various therapies were used to treat or reduce the pain. Laser therapy and antioxidant drugs have separately considered as treatment for NP, but the combination of them have not been used yet. In order to study the combination effects of Low Level Laser Therapy (LLLT) and Coenzyme Q10 (CoQ10) the present study was designed. METHODS: Sixty adult male rats (230-320g) were used in this experimental study that divided into six groups (n=10). Chronic constriction injury (CCI) was used to induce neuropathic pain. The CoQ10 or vehicle, a low level laser of 980nm was used for two consecutive weeks. Thermal and mechanical paw withdrawal thresholds were assessed before and after surgery on 7(th) and 14(th) days. RESULTS: As we expected CCI decreased the pain threshold, whereas CoQ10 administration for two weeks increased mechanical and thermal threshold. The same results obtained for laser therapy using the CCI animals. Combination of laser 980nm with CoQ10 also showed significant differences in CCI animals. CONCLUSION: Based on our findings the combination of CoQ10 with LLLT showed better effects than each one alone. In this regard we believe that there might be cellular and molecular synergism in simultaneous use of CoQ10 and LLLT on pain relief.

Graphsene as a novel porous two-dimensional carbon material for enhanced oxygen reduction electrocatalysis.

Graphene allotropes with varied carbon configurations have attracted significant attention for their unique properties and chemical activities. This study introduces a novel two-dimensional carbon-based material, termed Graphsene (GrS), through theoretical study. Comprising tetra-, penta-, and dodeca-carbon rings, GrS's cohesive energy calculations demonstrate its superior structural stability over existing graphene allotropes, including graphyne and graphdiyne families. Phonon dispersion analysis confirms GrS's dynamic stability and its relatively low thermal conductivity. All calculated GrS elastic constants meet the Born criteria, ensuring mechanical stability. Ab-initio molecular dynamic simulations show GrS maintains its structure at 300 K. HSE06 calculations reveal a narrow electronic bandgap of 20 meV, with the electronic band structure featuring a highly anisotropic Dirac-like cone due to its intrinsic structural anisotropy along armchair and zigzag directions. Notably, GrS is predicted to offer exceptional catalytic performance for the oxygen reduction reaction, favoring the four-electron reduction pathway with high selectivity under both acidic and alkaline conditions. This discovery opens promising avenues for developing metal-free catalyst materials in clean energy production.

Dental Implant Abutment Screw Loss: Presentation of 10 Cases.

Re-tightening the loosened dental implant abutment screw is an accepted procedure, however the evidence that such screw will hold sufficiently is weak. The purpose of this study was material analysis of lost dental implant abutment screws made of the TiAlV alloy from various manufacturers, which became lost due to unscrewing or damaged when checking if unscrewed; undamaged screws could be safely re-tightened. Among 13 failed screws retrieved from 10 cases, 10 screws were removed due to untightening and 3 were broken but without mechanical damage at the threads. Advanced corrosion was found on nine screws after 2 years of working time on all surfaces, also not mechanically loaded. Sediments observed especially in the thread area did not affect the corrosion process because of no pit densification around sediments. Pitting corrosion visible in all long-used screws raises the question of whether the screws should be replaced after a certain period during service, even if they are well-tightened. This requires further research on the influence of the degree of corrosion on the loss of the load-bearing ability of the screw.

Circulating microRNA-155-3p levels predicts response to first line immunotherapy in patients with metastatic renal cell carcinoma.

Predictive biomarkers of response to immune checkpoint-based therapies (ICI) remain a critically unmet need in the management of advanced renal cell carcinoma (RCC). The complex interplay of the tumour microenvironment (TME) and the circulating immune response has proven to be challenging to decipher. MicroRNAs have gained increasing attention for their role in post-transcriptional gene expression regulation, particularly because they can have immunomodulatory properties. We evaluated the presence of immune-specific extracellular vesicle (EV) microRNAs in the plasma of patients with metastatic RCC (mRCC) prior to initiation of ICI. We found significantly lower levels of microRNA155-3p (miR155) in responders to ICI, when compared to non-responders. This microRNA has unique immunomodulatory properties, thus providing potential biological rationale for our findings. Our results support further work in exploring microRNAs as potential biomarkers of response to immunotherapy.

Corpus Callosum Functional Activities in Children with Cerebral Palsy.

Background: Since cerebral palsy (CP) is a corollary to brain damage, persistent treatment should accompany an alteration in brain functional activity in line with clinical improvements. In this regard, the corpus callosum (CC), as a connecting bridge between the two hemispheres, plays an essential role. Objective: This study aimed to investigate the therapeutic effects of occupational therapy (OT) on CC functional activity and walking capacity in children with cerebral palsy. Material and Methods: In this clinical trial study, 4 children with CP (8.25±1.71 years) received 45 min OT sessions 3 times weekly for 8 weeks. Functional magnetic resonance imaging (fMRI) was acquired while conducting passive motor tasks to quantify CC activation. The pre-post activation changes in CC following therapy were quantified in terms of activated voxels. Walking capacity was evaluated using the timed-up-and-go (TUG), 6-minute walk test (6 MWT), and 10-meter walk test (10 MWT) in pre-and post-treatment. Results: The number of activated voxels in CC indicated significant improvement in participants. Post-treatment activated voxels substantially exceeded pre-treatment active voxels. Clinical measures, including TUG, 6 MWT, and 10 MWT are improved by 11.9%, 12.6%, and 25.4%, respectively. Conclusion: Passive task-based fMRI can detect the effects of OT on CC functional activity in children with CP. According to the results, OT improves CC functional activity in addition to gait and balance performance.

Confirmatory factor analysis and gender invariance of Persian version of the modified Yale food addiction scale (mPYFAS) 2.0: insight from a large scale Iranian sample.

BACKGROUND: The Modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) was developed with the primary objective of evaluating food addiction (FA). The present study aimed to undertake the translation, pilot testing, and evaluation of the psychometric properties of the mYFAS 2.0 within the Persian-speaking population. METHODS: The transcultural adaptation of the mYFAS 2.0 to the Persian language was conducted. Data collection was carried out through an anonymous online questionnaire. Participants completed the Persian versions of the mYFAS 2.0, Binge Eating Scale (BES), Barratt Impulsivity Scale (BIS-11), and Connor-Davidson Resilience Scale (CD-RISC). The assessment encompassed the evaluation of internal consistency reliability, factor structure, as well as convergent and discriminant validity of the aforementioned questionnaires. RESULTS: Confirmatory factor analysis revealed that the single-factor model of the Persian translation of mYFAS 2.0 performed satisfactorily, with comparative fit index (CFI) and Tucker-Lewis index (TLI) values exceeding 0.95, standardized root mean square residual (SRMR) less than or equal to 0.09, and root mean square error of approximation (RMSEA) below 0.03. The internal consistency and composite reliability of the mYFAS 2.0 were favorable in the entire sample, as well as in both male and female groups, with alpha (α) values of 0.83, ordinal alpha (αord) of 0.93, and composite reliability (CR) of 0.86. Additionally, significant relationships were observed between the total score of BES (r = 0.59, p < 0.001), BIS-11 (r = - 0.16, p < 0.001), and CD-RISC (r = 0.22, p < 0.001) with mYFAS 2.0-diagnosed FA presence, severity, and symptom count. CONCLUSIONS: The Persian version of the mYFAS 2.0 exhibited satisfactory psychometric properties.

In this study, researchers developed a Persian version of the Modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) to assess food addiction in Persian-speaking individuals. They translated and tested the scale's reliability and validity through an online survey with 9606 Persian speaking participants. The results showed that the Persian mYFAS 2.0 performed well, with a reliable single-factor model. The internal consistency and reliability were good across the entire sample and in both male and female groups. The relationships between mYFAS 2.0 and other scales measuring binge eating, impulsivity, and resilience were significant. The findings suggest that the Persian version of mYFAS 2.0 is a reliable tool for assessing food addiction in the Persian-speaking population. The study used statistical analyses like confirmatory factor analysis, indicating the scale's robustness. Overall, the psychometric properties of the Persian mYFAS 2.0 were satisfactory, providing a valuable instrument for researchers and healthcare professionals studying and addressing food addiction in this population. The study contributes to cross-cultural research and enhances our understanding of food addiction in diverse linguistic communities.

Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer.

No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org ). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.