Orrboyer6490

Prior research suggests the afferent feedback from the Ia sensory fibers are likely attenuated during walking, while afferent feedback from the β polysynaptic sensory fibers are not. We suggest that the attenuated gamma oscillations seen during walking reflect the gating of the Ia afferents, while the similarity of theta-alpha oscillations across the experimental conditions is associated with the afferent information from the type II (Aα and β) polysynaptic sensory fibers.Background Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. Patients and methods This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib cohort A was twice-daily and cohort B was once-daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary endpoints included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Results Overall, 41 patients were enrolled (cohort A n=22, cohort B n=19). Patients had a median of 2 prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice-daily and for cohort B was 750 mg once-daily. The most common dose-limiting toxicities included thrombocytopenia and AST/ALT elevation. Grade 3/4 AST/ALT elevation occurred in 9/41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in Cohort A and one of 17 (6%) patient in Cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n=6). In cohort B, CBR at 16 weeks was 53% (n=9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 months and 4.1 months, respectively. Conclusion The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases.Background The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, neither for immune checkpoint blockade (ICB) nor conventional chemotherapy. Patients and methods We obtained both whole exome sequencing and RNA-Seq data from pre-treatment samples of 149 TNBC of the recent neoadjuvant ICB trial GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR). Results Median TMB was 1.52 mut/Mb (range 0.02-7.65) and was significantly higher in patients with pCR (median 1.87 vs. 1.39; P=0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 (95% CI 1.33-3.20, P=0.001) among all patients, 1.77 (95% CI 1.00-3.13, P=0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21-6.54, P=0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. Rabusertib When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60%-95%) in the group with both high TMB and GEP, in contrast to only 28% (95% CI 16%-43%) in the group with both low TMB and GEP. Conclusions TMB and immune gene expression profile add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.Lung cancer is one of the leading causes of cancer-related death worldwide. It has aggressive manifestation, high ability to promote metastasis and late diagnosis. In the present study, we investigated the cytotoxic effect of 3,3',5,5'-tetramethoxybiphenyl-4,4'diol (TMBP), against the A549 human non-small cell lung carcinoma lineage. The A549 cell line was treated for 72h with TMBP (12.5-200 μM) with and subsequently defined the 50% inhibitory concentration (148 μM ± 0.05), from which tests were performed to determine the viability, volume, and regulation of the cell cycle. Finally, we investigated the death mechanisms involved in the action of the treatments by flow cytometry and fluorimetry. The TMBP-treatment of primary cells, peritoneal macrophages, and sheep erythrocytes did not reduce the viability of these cells. On the other hand, TMBP was able to reduce the viability of the investigated cell line, by cytotoxic action and to promote the reduction of cell size. Subsequently, we found that TMBP treatment was able to increase the production of reactive oxygen species, cause mitochondrial depolarization, induce cell cycle arrest in G2/M phase and lead to death by direct apoptosis. Thus, this study revealed that TMBP could be a promising candidate for the development of antitumor drugs targeting lung cancer.Phenylketonuria (PKU) is the most prevalent inborn error of amino acid metabolism. The disease is due to the deficiency of phenylalanine (Phe) hydroxylase activity, which causes the accumulation of Phe. Early diagnosis through neonatal screening is essential for early treatment implementation, avoiding cognitive impairment and other irreversible sequelae. Treatment is based on Phe restriction in the diet that should be maintained throughout life. High dietary restrictions can lead to imbalances in specific nutrients, notably lipids. Previous studies in PKU patients revealed changes in levels of plasma/serum lipoprotein lipids, as well as in fatty acid profile of plasma and red blood cells. Most studies showed a decrease in important polyunsaturated fatty acids, namely DHA (226n-3), AA (204n-6) and EPA (205n-6). Increased oxidative stress and subsequent lipid peroxidation have also been observed in PKU. Despite the evidences that the lipid profile is changed in PKU patients, more studies are needed to understand in detail how lipidome is affected.