The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the ...temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.
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•Longitudinal glioma evolution follows an IDH mutation-dependent trajectory•Hypermutation and CDKN2A deletions underlie increased proliferation at recurrence•Recurrent IDH-wild-type neoplastic cells up-regulate neuronal signaling programs•Mesenchymal transitions associate with distinct myeloid cell interactions
Integrating longitudinal transcriptomic and genomic data from paired diffuse glioma samples with complementary single-cell RNA-seq and multiplex immunofluorescence datasets reveals recurrence-associated genetic and microenvironmental changes that are dependent on IDH mutation status.
Nano-sized silver has drawn a great deal of attention in the field of health sciences owing to its remarkable therapeutic applications. Interestingly, the method applied to synthesize nanoparticles ...and the choice of reagents considerably influence their therapeutic potential and toxicities. Current research has explored the toxicity, anti-inflammatory, antinociceptive, and antioxidant responses of the malonic acid-capped silver nanoparticles (MA-AgNPs (C) by using sodium borohydride as a reducing agent at low temperatures by employing both
and
approaches. Furthermore, it has highlighted the synergistic effect of these novel compounds with conventional anti-inflammatory therapeutic agents. Acute and sub-acute toxicity analysis performed following OECD guidelines showed that the studied MA-AgNPs (C) are safer, and prominent toxic signs have not been detected at the highest studied dose of 2,000 mg/kg. Cytotoxicity evaluation through brine shrimp lethality revealed 20% lethality at the highest concentration of 169.8 μg/mL. Significantly, positive anti-inflammatory and analgesic responses alone as well as synergism with the standard were identified through
as well as
methods which were more potent at a lower dose (200 mg/kg). Notably synergistic outcomes were more pronounced than individual ones, indicating their prominent effect as a feasible drug delivery system. IL-6 and TNF-α assessment in excised paw tissue through RTPCR technique further supported their anti-inflammatory potential. DPPH assay revealed eminent
antioxidant activity which was further corroborated by
antioxidant assessment through evaluation of SOD in excised paw tissue.
Lung cancer is the world's leading cause of cancer death. Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the US National Lung Screening Trial. Here, we present ...the Yorkshire Lung Screening Trial (YLST), which will address key questions of relevance for screening implementation.
Using a single-consent Zelen's design, ever-smokers aged 55-80 years registered with a general practice in Leeds will be randomised (1:1) to invitation to a telephone-based risk-assessment for a Lung Health Check or to usual care. The anticipated number randomised by household is 62 980 individuals. Responders at high risk will be invited for LDCT scanning for lung cancer on a mobile van in the community. There will be two rounds of screening at an interval of 2 years. Primary objectives are (1) measure participation rates, (2) compare the performance of PLCO
(threshold ≥1.51%), Liverpool Lung Project (V.2) (threshold ≥5%) and US Preventive Services Task Force eligibility criteria for screening population selection and (3) assess lung cancer outcomes in the intervention and usual care arms. Secondary evaluations include health economics, quality of life, smoking rates according to intervention arm, screening programme performance with ancillary biomarker and smoking cessation studies.
The study has been approved by the Greater Manchester West research ethics committee (18-NW-0012) and the Health Research Authority following review by the Confidentiality Advisory Group. The results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and on the YLST website.
ISRCTN42704678 and NCT03750110.
Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur.
...Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation.
We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.
Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. ...GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.
Metabolic syndrome (MS) is a collection of pathological metabolic conditions that includes insulin resistance, central or abdominal obesity, dyslipidemia, and hypertension. It affects large ...populations worldwide, and its prevalence is rising exponentially. There is no specific mechanism that leads to the development of MS. Proposed hypotheses range from visceral adiposity being a key factor to an increase in very-low-density lipoprotein and fatty acid synthesis as the primary cause of MS. Numerous pharmaceutical therapies are widely available in the market for the treatment of the individual components of MS. The relationship between MS and vitamin B complex supplementation, specifically folic acid and vitamin B12, has been a subject of investigation worldwide, with several trials reporting a positive impact with vitamin supplementation on MS.In this study, an all-language literature search was conducted on Medline, Cochrane, Embase, and Google Scholar till September 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: “Vitamin B12,” “Folate,” “Metabolic Syndrome,” and “Insulin Resistance.” We explored the literature on MS for its epidemiology, pathophysiology, newer treatment options, with a special focus on the effectiveness of supplementation with vitamins B9 and B12.According to the literature, vitamin B12 and folate supplementation, along with a host of novel therapies, has a considerable positive impact on MS. These findings must be kept in mind while designing newer treatment protocols in the future.
Although there is a growing literature on the use of telepresence robots in institutional dementia care settings, limited research focused on the perspectives of frontline staff members who deliver ...dementia care. Our objective was to understand staff perspectives on using telepresence robots to support residents with dementia and their families. Guided by the Consolidated Framework for Implementation Research, we conducted four focus groups and 11 semi-structured interviews across four long-term care (LTC) homes and one hospital in Canada. We included 22 interdisciplinary staff members (e.g., registered nurses, social workers, occupational therapists, recreational therapists) to understand their experiences with telepresence robots. Thematic analysis identified three key themes: 1) Staff Training and Support; 2) Robot Features; 3) Environmental dynamics for Implementation. Our results underscore the imperative of structural support at micro-, meso- and macro-levels for staff in dementia care settings to effectively implement technology. This study contributes to future research and practice by elucidating factors facilitating staff involvement in technology research, integrating staff voices into technology implementation planning, and devising strategies to provide structural support to staff, care teams, and care homes.
Telepresence robots are being increasingly used in long-term care (LTC) homes for virtual visits between families and residents. This study investigated the impacts and experiences of residents and ...their families using a telepresence robot (Double 3) for 4 to 12 months during the COVID-19 pandemic. A total of 51 participants were recruited through purposive sampling, including 9 residents, 15 family members, and 27 staff from 4 LTC homes in British Columbia, Canada. Conversational interviews were conducted with residents and family members. Focus groups and one-to-one interviews were held with frontline staff. Thematic analysis was performed, with five themes identified: (1) Stay connected, (2) Regain autonomy, (3) Relieve caregiver burden, (4) Environmental and technical issues, and (5) Scheduling concerns. In conclusion, telepresence robots helped maintain social connections between residents and families, despite the COVID-19 restrictions.
Background: Diabetes mellitus (DM) is a highly prevalent non-communicable disease in the world. Current investigations evolved that oxidative stress is also a major risk factor to cause type 2 ...diabetes mellitus due to impairment of antioxidant defense system in various biological fluids.
Methodology: In this cross-sectional study, 70 type 2 diabetes mellitus subjects and 30 normal healthy subjects of both genders were selected from various health care centers of Karachi, Pakistan for a study period of six months June 2017 – December 2017. The total antioxidant capacity (TAC) concentration was measured in serum by enzyme-linked immunosorbent assay (ELISA) technique using Caymans Antioxidant Assay. The biochemical parameters and anthropometric measurements were estimated by standardized methods. Data was analyzed using the statistical program Statistical Package for the Social Sciences (SPSS) version 10.0.
Results: According to the study results TAC was significantly reduced (**0.05 ± 0.00 mmol /L) in type 2 diabetes mellitus subjects compared to normal healthy subjects (0.13 ± 0.02 mmol /L). It was noted that diastolic blood pressure (DBP), body mass index (BMI), and triglycerides (TG’s) were significantly increased while high density lipoprotein-cholesterol (HDL-C) was significantly reduced in diabetic subjects than the comparative healthy individuals.
Conclusion: This study showed that decreased levels of TAC and HDL-C in type 2 DM patients with increased levels of BMI, systolic blood pressure (SBP), fasting blood sugar (FBS), DBP, and total cholesterol (TC) which may cause oxidative stress and increase the progression of cardiovascular disease (CVD) and other metabolic diseases. Modifications in dietary habits and intake of antioxidant foods or supplements may diminish the process of oxidative stress which may consequently decrease CVD and other severe clinical outcomes.
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