Citations

Tumor heterogeneity of a target molecule could contribute to failure of the targeted therapy. We investigated the heterogeneity of MET expression within same primary gastric cancer (GC) and between primary and corresponding secondary GC lesions using immunohistochemistry (IHC). Intratumoral heterogeneity was defined as discordant MET status among 3 tissue microarray cores (3 different areas of same tumor). IHC 3+ was considered positive for MET overexpression. MET overexpression was observed in 2.7% (50/1869) of all examined cores and 5.3% (33/623) of primary GCs. When we compared MET IHC results between 3 cores from each tumor, intratumoral heterogeneity was identified (65.0% in total 623 cases; 84.4% in 480 cases with any staining intensity; 84.9% in 251 cases with moderate to strong intensity; 90.9% in 33 cases with strong intensity). Of 33 MET-overexpressed GCs, the average proportion of strongly stained area was 19.6% in the whole sections. Of 269 cases with primary GC and regional lymph node metastasis, 17 (6.3%) showed MET positivity in which 9 (52.9%) were discordant (negative conversion). In 123 cases with primary and corresponding local recurrent/distant metastatic GC, 3 (2.4%) showed MET positivity in which 2 (66.7%) were discordant (positive conversion). In the survival analysis, MET IHC 3+ in lymph node metastases was an independent negative prognostic factor for overall survival. We found that MET overexpression is uncommon and highly heterogeneous in GC. This severe heterogeneity of MET status should be considered in tissue sampling and development of biomarkers for anti-MET therapy.

A simple, and yet robust, high pass filter is designed to remove non-linear background drift in fast scan cyclic voltammetry.

Objective: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. Study Selection: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. Data Sources: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. Data Extraction: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. Data Synthesis: Use of aspirin was associated with a 7% (95% CI, 2–12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I 2 = 61.6%). Conclusions: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.

Abstract Follicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. However, the molecular mechanisms underlying this phenomenon are largely unclear. Here, we show that murine and human Tfh cells have diminished constitutive expression of IFN-stimulated genes (ISGs) inclusive of antiviral resistance factor MX dynamin-like GTPase 2 (MX2) and IFN-induced transmembrane 3 (IFITM3) compared with non-Tfh cells. A lower antiviral resistance in Tfh was consistent with a higher susceptibility to retroviral infections. Mechanistically, we found that BCL6, a master regulator of Tfh cell development, binds to ISG loci and inhibits the expression of MX2 and IFITM3 in Tfh cells. We demonstrate further that inhibition of the BCL6 BR-C, ttk, and bab (BTB) domain function increases the expression of ISGs and suppresses HIV infection and replication in Tfh cells. Our data reveal a regulatory role of BCL6 in inhibiting antiviral resistance factors in Tfh cells, thereby promoting the susceptibility Tfh cells to viral infections. Our results indicate that the modulation of BCL6 function in Tfh cells could be a potential strategy to enhance Tfh cell resistance to retroviral infections and potentially decrease cellular reservoirs of HIV infection.

Abstract This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).

PurposeThe homeostasis of intracranial pressure (ICP) is of paramount importance for maintaining normal brain function. A noninvasive technique capable of making direct measurements of ICP currently does not exist. MR elastography (MRE) is capable of noninvasively measuring brain tissue stiffness in vivo, and may act as a surrogate to measure ICP. The objective of this study was to investigate the impact of changing ICP on brain stiffness using MRE in a swine model.MethodsBaseline MRE measurements were obtained, and then catheters were surgically placed into the left and right lateral ventricles of three animals. ICP was systematically increased over the range of 0 to 55 millimeters mercury (mmHg), and stiffness measurements were made using brain MRE at vibration frequencies of 60 hertz (Hz), 90 Hz, 120 Hz, and 150 Hz.ResultsA significant linear correlation between stiffness and ICP in the cross‐subject comparison was observed for all tested vibrational frequencies (P ≤ 0.01). The 120 Hz (0.030 ± 0.004 kilopascal (kPa)/mmHg, P < 0.0001) and 150 Hz (0.031 ± 0.008 kPa/mmHg, P = 0.01) vibrational frequencies had nearly identical slopes, which were approximately two‐ to three‐fold higher than the 90 Hz (0.017 ± 0.002 kPa/mmHg, P < 0.0001) and 60 Hz (0.009 ± 0.002 kPa/mmHg, P = 0.001) slopes, respectively.ConclusionIn this study, MRE demonstrated the potential for noninvasive measurement of changes in ICP. Magn Reson Med 79:1043–1051, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Single-cell diversity in the brain The cells that make up an organism may all start from one genome, but somatic mutations mean that somewhere along the line of development, an organism's individual cellular genomes diverge. McConnell et al. review the implications and causes of single-cell genomic diversity for brain function. Somatic mutations caused by mobile genetic elements or errors in DNA repair may underlie certain neuropsychiatric disorders. Science , this issue p. eaal1641

AbstractBased on cytoarchitecture, the posterior cingulate cortex (PCC) is thought to be comprised of two distinct functional subregions: the dorsal and ventral PCC (dPCC and vPCC). However, functional subregions do not completely match anatomical boundaries in the human brain. To understand the relationship between the functional organization of regions and anatomical features, it is necessary to apply parcellation algorithms based on functional properties. We therefore defined functionally informed subregions in the human PCC by parcellation of regions with similar patterns of functional connectivity in the resting brain. We used various patterns of functional connectivity, namely local, whole‐brain and diffuse functional connections of the PCC, and various clustering methods, namely hierarchical, spectral, andk‐means clustering to investigate the subregions of the PCC. Overall, the approximate anatomical boundaries and predicted functional regions were highly overlapped to each other. Using hierarchical clustering, the PCC could be clearly separated into two anatomical subregions, namely the dPCC and vPCC, and further divided into four subregions segregated by local functional connectivity patterns. We show that the PCC could be separated into two (dPCC and vPCC) or four subregions based on local functional connections and hierarchical clustering, and that subregions of PCC display differential global functional connectivity, particularly along the dorsal‐ventral axis. These results suggest that differences in functional connectivity between dPCC and vPCC may be due to differences in local connectivity between these functionally hierarchical subregions of the PCC.Hum Brain Mapp 38:2808–2818, 2017. ©2017 Wiley Periodicals, Inc.