Highly connected manifolds with positive Ricci curvature

We prove the existence of Sasakian metrics with positive Ricci curvature on certain highly connected odd dimensional manifolds. In particular, we show that manifolds homeomorphic to the 2k-fold connected sum of S^{2n-1} x S^{2n} admit Sasakian metrics with positive Ricci curvature for all k. Furthermore, a formula for computing the diffeomorphism types is given and tables are presented for dimensions 7 and 11.Comment: This is the version published by Geometry & Topology on 29 November 200

Safety and Feasibility of Carboplatin and Paclitaxel followed by Fluoropyrimidine Analogs and Radiation as Adjuvant Therapy for Gastric Cancer

Background: Adjuvant 5-fluorouracil (5FU)-based chemo-radiotherapy is currently considered a standard of care for the treatment of gastric cancer. The impact of 5FU-based adjuvant therapy on the rate of distant recurrence has been modest. In order to improve the systemic effects of adjuvant therapy, we have been treating patients with resected gastric cancer with carboplatin and paclitaxel followed by fluoropyrimidine analogue and radiation. Methods: We report on the outcomes of 21 consecutive gastric cancer patients treated off protocol with adjuvant carboplatin (area under the curve 5 mg/ml × min) and paclitaxel (175–200 mg/m2) every 3 weeks, followed by concurrent pyrimidine analogs (either capecitabine 1,600–2,000 mg/m2/day in 17 patients, or 5FU 200 mg/m2/day in 4 patients) and radiation (45–50.4 Gy). Patients received a total of 4–6 cycles of carboplatin and paclitaxel. Results: The median age at diagnosis was 60 years. Sixteen patients had stage 3 disease and 7 of them had positive surgical margins (6 with R1 and 1 with R2 resection), 3 patients were stage 2, and 2 patients were stage 1 (all had R0 resection). All patients had D1/D2 (4 had D2 and 17 had D1) lymph node dissection. The incidence of grade 3 or higher overall, hematologic, or gastrointestinal toxicity in the patients receiving carboplatin and paclitaxel was 57, 48 and 10%, respectively. No treatment-related deaths were observed. After adjuvant treatment 15 patients developed recurrent disease, 10 of whom had distant metastases. The median recurrence-free survival (RFS) was 12.3 months. The median overall survival (OS) was 16.0 months. Patients with R0 resection had significantly longer OS than did those with positive surgical margins (log-rank p = 0.0060). Median OS for the R0 resection group was 28.8 months. Conclusions: Carboplatin and paclitaxel added to radiation plus fluoropyrimidine analogs is a well-tolerated regimen in the adjuvant setting. The activity of this regimen in this relatively high-risk group of gastric cancer patients is of interest for future development

CA19-9 as a predictor of tumor response and survival in patients with advanced pancreatic cancer treated with gemcitabine based chemotherapy

The aim of this study was to determine the predictive role of pretreatment carbohydrate antigen 19-9 (CA19-9) measurement and its change after one cycle of gemcitabine-based therapy for response, time to progression (TTP) and overall survival (OS).Analyses were derived from three consecutive gemcitabine-containing phase II clinical trials between 1997 and 2004.A total of 111 patients with pancreas cancer was studied. Baseline CA19-9 concentrations were dichotomized near the median. Lower baseline CA19-9 levels were positively associated with OS (median 9.1 vs 6.1 months, P  = 0.0057) and TTP (median 6.4 vs 4.2 months, P  = 0.0044).The covariate adjusted hazard ratio (HR) for progression among patients with baseline CA19-9 ≥ 1000 ng/mL was HR = 1.94 (95% CI 1.24–3.02), with P  = 0.0035. The covariate adjusted risk of death among patients with baseline CA19-9 ≥ 1000 ng/ml was similarly elevated: HR = 1.90 (95% CI 1.23–2.94), with P  = 0.0039. Change in CA19-9 levels from baseline to the end of treatment cycle 1 did not predict objective response ( P  = 0.75). There was somewhat longer OS (median 8.7 vs 7.1 months) and TTP (median 7.1 vs 5.4 months) in patients with ≥50% reduction in serum CA19-9 concentrations, but this was not statistically significant ( P  = 0.74 and 0.81, respectively).Baseline CA19-9 levels may predict survival in patients with advanced pancreas cancer. The change in CA19-9 levels determined within 1 month of the initiation of therapy did not predict treatment outcome.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79310/1/j.1743-7563.2010.01290.x.pd

Heat stress decreases metabolic flexibility in skeletal muscle of growing pigs

Heat-stressed pigs experience metabolic alterations, including altered insulin profiles, reduced lipid mobilization, and compromised intestinal integrity. This is bioenergetically distinct from thermal neutral pigs on a similar nutritional plane. To delineate differences in substrate preferences between direct and indirect (via reduced feed intake) heat stress effects, skeletal muscle fuel metabolism was assessed. Pigs (35.3 ± 0.8 kg) were randomly assigned to three treatments: thermal neutral fed ad libitum (TN, 21°C, n=8), heat stress fed ad libitum (HS, 35°C, n=8), and TN, pair-fed to HS intake (PF, n=8) for 7 days. Body temperature (TB) and feed intake (FI) were recorded daily. Longissimus dorsi muscle was biopsied for metabolic assays on days -2, 3, and 7 relative to initiation of environmental treatments. Heat stress increased TB and decreased FI (P \u3c 0.05). Heat stress inhibited incomplete fatty acid oxidation (P \u3c 0.05) and did not alter glucose oxidation. Metabolic flexibility decreased in HS pigs compared to TN and PF controls (P \u3c 0.05). Both phosphofructokinase and pyruvate dehydrogenase (PDH) activities increased in PF (P \u3c 0.05), however, TN and HS did not differ. Heat stress inhibited citrate synthase and beta hydroxyacyl-CoA dehydrogenase (βHAD) activities (P \u3c 0.05). Heat stress did not alter PDH phosphorylation or carnitine palmitoyltransferase 1 abundance, but reduced acetyl-CoA carboxylase 1(ACC1) protein abundance (P \u3c 0.05). In conclusion, HS decreased skeletal muscle fatty acid oxidation and metabolic flexibility, likely involving βHAD and ACC regulation

Computational design of transmembrane pores.

Transmembrane channels and pores have key roles in fundamental biological processes1 and in biotechnological applications such as DNA nanopore sequencing2-4, resulting in considerable interest in the design of pore-containing proteins. Synthetic amphiphilic peptides have been found to form ion channels5,6, and there have been recent advances in de novo membrane protein design7,8 and in redesigning naturally occurring channel-containing proteins9,10. However, the de novo design of stable, well-defined transmembrane protein pores that are capable of conducting ions selectively or are large enough to enable the passage of small-molecule fluorophores remains an outstanding challenge11,12. Here we report the computational design of protein pores formed by two concentric rings of α-helices that are stable and monodisperse in both their water-soluble and their transmembrane forms. Crystal structures of the water-soluble forms of a 12-helical pore and a 16-helical pore closely match the computational design models. Patch-clamp electrophysiology experiments show that, when expressed in insect cells, the transmembrane form of the 12-helix pore enables the passage of ions across the membrane with high selectivity for potassium over sodium; ion passage is blocked by specific chemical modification at the pore entrance. When incorporated into liposomes using in vitro protein synthesis, the transmembrane form of the 16-helix pore-but not the 12-helix pore-enables the passage of biotinylated Alexa Fluor 488. A cryo-electron microscopy structure of the 16-helix transmembrane pore closely matches the design model. The ability to produce structurally and functionally well-defined transmembrane pores opens the door to the creation of designer channels and pores for a wide variety of applications

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy

Objective: The MAST family of microtubule-associated serine–threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at \u3c2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. Interpretation: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274–284

Translation and validation of the Cardiac Depression Scale to Arabic

Background The Cardiac Depression Scale (CDS) has been designed to measure depressive symptoms in patients with heart disease. There is no Arabic version of the CDS. We translated and validated the CDS in an Arabic sample of patients with heart disease. Methods Forward and back translation of the CDS was followed by assessment of cultural relevance and content validity. The Arabic version of the CDS (A-CDS) and the Arabic version of the Hospital Anxiety and Depression Scale (A-HADS) were then administered to 260 Arab in-patients with heart disease from 18 Arabic countries. Construct validity was assessed using exploratory factor analysis with polychoric correlations. Internal consistency was assessed using ordinal reliability alpha and item-to-factor polychoric correlations. Concurrent validity was assessed using Pearson's correlation coefficient between the A-CDS and the depression subscale of the A-HADS (A-HADS-D). Results Cultural relevance and content validity of the A-CDS were satisfactory. Exploratory factor analysis revealed three robust factors, without cross-loadings, that formed a single dimension. Internal consistency was high (ordinal reliability alpha for the total scale and the three factors were .94, .91, .86, and .87, respectively; item-to-factor correlations ranged from .77 to .91). Concurrent validity was high (r?=?.72). The A-CDS demonstrated a closer to normal distribution of scores than the A-HADS-D. Limitations Sensitivity and specificity of the A-CDS were not objectively assessed. Conclusions The A-CDS appears to be a valid and reliable instrument to measure depressive symptoms in a representative sample of Arab in-patients with heart disease

AKT/mTOR Signaling Modulates Resistance to Endocrine Therapy and CDK4/6 Inhibition in Metastatic Breast Cancers

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2− metastatic breast cancer (MBC) patients. However, 30–40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients