The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Effective targeting of PDGFRA-altered high-grade glioma with avapritinib

\ua9 2025 The Authors. PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG

FERRAMENTAS MATEMÁTICAS, SUSCETIBILIDADE MAGNÉTICA E MODELOS DE PAISAGEM APLICADOS NA DELIMITAÇÃO DE ÁREAS DE MANEJO ESPECÍFICO

A identificação de padrões de variabilidade dos atributos do solo permite o uso e a ocupação do solo de maneira sustentável. O objetivo deste trabalho foi delimitar áreas de manejo específico utilizando ferramentas matemáticas, suscetibilidade magnética e modelos de paisagem. A área de estudo localiza-se no município de Guariba, SP. Escolheu-se uma área de 110 ha, onde foram identificadas e mapeadas três superfícies geomórficas (I, II e III). Na área, foram coletadas 204 amostras de solo em uma transeção, nas profundidades de 0,00-0,20 e 0,60-0,80 m. Foram determinados o pH em CaCl2, os teores de areia, argila, matéria orgânica, P, Ca, Mg, K, H+Al, e calculados SB, CTC e V. A suscetibilidade magnética (SM) foi medida com o auxílio de uma balança analítica. Os limites matemáticos da técnica Split Moving Windows Dissimilarity Analysis (SMWDA) utilizando as informações da suscetibilidade magnética ficaram próximos aos limites de campo identificados com base nos modelos de paisagem. A utilização conjunta da suscetibilidade magnética, dos modelos matemáticos e de paisagem permitiu identificar diferentes áreas de manejo, locais com diferentes teores de argila e níveis de fertilidade do solo. A susceptibilidade magnética pode ser adotada como alternativa para identificar e mapear unidades de manejo

EVALUATION OF ANTIMICROBIAL AND CYTOTOXIC ACTIVITIES OF PLANT EXTRACTS FROM SOUTHERN MINAS GERAIS CERRADO

The antimicrobial activity of plant hidroethanolic extracts on bacteria Gram positive, Gram negative, yeasts, Mycobacterium tuberculosis H37 and Mycobacterium bovis was evaluated by using the technique of Agar diffusion and microdilution in broth. Among the extracts evaluated by Agar diffusion, the extract of Bidens pilosa leaf presented the most expressive average of haloes of growth inhibition to the microorganisms, followed by the extract of B. pilosa flower, of Eugenia pyriformis' leaf and seed, of Plinia cauliflora leaf which statistically presented the same average of haloes inhibitory formation on bacteria Gram positive, Gram negative and yeasts. The extracts of Heliconia rostrata did not present activity. Mycobacterium tuberculosis H37 and Mycobacterium bovis (BCG) appeared resistant to all the extracts. The susceptibility profile of Candida albicans and Saccharomyces cerevisiae fungi were compared to one another and to the Gram positive Bacillus subtilis, Enterococcus faecalis and the Gram negative Salmonella typhimurium bacteria (p > 0.05). The evaluation of cytotoxicity was carried out on C6-36 larvae cells of the Aedes albopictus mosquito. The extracts of stem and flower of Heliconia rostrata, leaf and stem of Plinia cauliflora, seed of Anonna crassiflora and stem, flower and root of B. pilosa did not present toxicity in the analyzed concentrations. The highest rates of selectivity appeared in the extracts of stem of A. crassiflora and flower of B. pilosa to Staphylococcus aureus, presenting potential for future studies about a new drug development

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Consumo de medicamentos por trabalhadores de hospital

Medicamentos são um componente essencial da terapêutica, no entanto, informações sobre seu consumo em população trabalhadora são escassas. Para estimar a prevalência, caracterizar o perfil daqueles consumidos e avaliar os fatores associados ao seu uso em trabalhadores foi realizado estudo seccional de dados da linha de base da Coorte "PROSEC" (n=417). A prevalência de consumo de pelo menos um medicamento foi de 72,4%, destacando-se fármacos com ação no sistema nervoso (25,4%), especialmente analgésicos (17,8%). Fatores associados ao uso de qualquer número de medicamentos (pAlthough medication is acknowledged as a key element in treating health problems, there is little information available on the use of medication by hospital workers. To estimate the prevalence and describe the patterns of medication consumption by hospital workers and to identify the factors associated with such consumption in this population, data from the "PROSEC" baseline cohort were analyzed (n=417). The prevalence of overall medication consumption was 72.4%, most of which was for nervous complaints (25.4%), especially analgesics (17.8%). Use of any amount of medication was independently associated with gender, number of medically diagnosed conditions and health problem in the two weeks prior to the interview. Use of a drug was significantly associated with income whereas self-diagnosed health problems were independently related with the use of two or more pharmaceutical products. The high prevalence of medication usage in this population, with analgesics being the most consumed medication, should be seen as a cause for concern, since many consumers are unaware that these products are not exempt from risk. Women and individuals in poor health are the main candidates for intervention programs in order to promote adequate and proper use of these pharmaceutical products