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Recruitment of RNA polymerase II to hypoxia-inducible factor (HIF) target genes under normoxia is a prerequisite for HIF-mediated transactivation. However, the underlying mechanism of this recruitment remains unknown. Here we report that chromodomain helicase DNA-binding protein 4 (CHD4) physically interacts with α and β subunits of HIF1 and HIF2 and enhances HIF-driven transcriptional programs to promote breast cancer progression. Loss of HIF1/2α abolished CHD4-mediated breast tumor growth in mice. In breast cancer cells under normoxia, CHD4 enrichment at HIF target gene promoters increased RNA polymerase II loading through p300. Hypoxia further promoted CHD4 binding to the chromatin via HIF1/2α, where CHD4 in turn enhanced recruitment of HIF1α, leading to HIF target gene transcription. CHD4 was upregulated and correlated with HIF target gene expression in human breast tumors; upregulation of CHD4 and other known HIF coactivators in human breast tumors was mutually exclusive. Furthermore, CHD4 was associated with poor overall survival of patients with breast cancer. Collectively, these findings reveal a new fundamental mechanism of HIF regulation in breast cancer, which has clinical relevance.Significance:This study identifies CHD4 as a HIF coactivator and elucidates the fundamental mechanism underlying CHD4-mediated HIF transactivation in breast tumors.

Purpose: To develop a standardized approach for molecular diagnostics, we used the gene expression ratio bioinformatic technique to design a molecular signature to diagnose malignant pleural mesothelioma (MPM) from among other potentially confounding diagnoses and differentiate the epithelioid from the sarcomatoid histologic subtype of MPM. In addition, we searched for pathways relevant in MPM in comparison with other related cancers to identify unique molecular features in MPM.Experimental Design: We conducted microarray analysis on 113 specimens including MPMs and a spectrum of tumors and benign tissues comprising the differential diagnosis of MPM. We generated a sequential combination of binary gene expression ratio tests able to discriminate MPM from other thoracic malignancies. We compared this method with other bioinformatic tools and validated this signature in an independent set of 170 samples. Functional enrichment analysis was conducted to identify differentially expressed probes.Results: A sequential combination of gene expression ratio tests was the best molecular approach to distinguish MPM from all the other samples. Bioinformatic and molecular validations showed that the sequential gene ratio tests were able to identify the MPM samples with high sensitivity and specificity. In addition, the gene ratio technique was able to differentiate the epithelioid from the sarcomatoid type of MPM. Novel genes and pathways specifically activated in MPM were identified.Conclusions: New clinically relevant molecular tests have been generated using a small number of genes to accurately distinguish MPMs from other thoracic samples, supporting our hypothesis that the gene expression ratio approach could be a useful tool in the differential diagnosis of cancers. Clin Cancer Res; 19(9); 2493–502. ©2013 AACR.

Table S3 shows unique mutations in A375 VCR cells compared to parental using exome sequencing

Supplementary Data from Targeting BCAT1 Combined with α-Ketoglutarate Triggers Metabolic Synthetic Lethality in Glioblastoma

Purpose:Combined MAPK pathway inhibition using dual BRAF and MEK inhibitors has prolonged the duration of clinical response in patients with BRAFV600E-driven tumors compared with either agent alone. However, resistance frequently arises.Experimental Design:We generated cell lines resistant to dual BRAF/MEK inhibition and utilized a pharmacologic synthetic lethal approach to identify a novel, adaptive resistance mechanism mediated through the fibroblast growth factor receptor (FGFR) pathway.Results:In response to drug treatment, transcriptional upregulation of FGF1 results in autocrine activation of FGFR, which potentiates extracellular signal-regulated kinases (ERK) activation. FGFR inhibition overcomes resistance to dual BRAF/MEK inhibitors in both cell lines and patient-derived xenograft (PDX) models. Abrogation of this bypass mechanism in the first-line setting enhances tumor killing and prevents the emergence of drug-resistant cells. Moreover, clinical data implicate serum FGF1 levels in disease prognosis.Conclusions:Taken together, these results describe a new, adaptive resistance mechanism that is more commonly observed in the context of dual BRAF/MEK blockade as opposed to single-agent treatment and reveal the potential clinical utility of FGFR-targeting agents in combination with BRAF and MEK inhibitors as a promising strategy to forestall resistance in a subset of BRAF-driven cancers.

Hypoxia induces a vast array of long noncoding RNAs (lncRNA) in breast cancer cells, but their biological functions remain largely unknown. Here, we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF2), but not HIF1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells in vitro. Gain- and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion in vitro and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis.Significance:This study reveals the molecular mechanism by which the lncRNA RAB11B-AS1 regulates hypoxia-induced angiogenesis and breast cancer metastasis, and provides new insights into the functional interaction between a lncRNA and tumor microenvironment.

Table S1 shows mutations in A375 VemR cells compared to the parental using exome sequencing.

Table S2 shows mutations in A375 CobiR cells compared to the parental using exome sequencing

List of the Tumor types having mutations in both MYH9 and RHOA genes in the cBioPortal for Cancer Genomics database

List of the tumor specific mutations identified by whole-genome sequencing and validated in the 10 pairs of MPM tumor and germline DNA samples

Expression levels of candidate genes in 151 patients by gender and histology

List of SNVs identified in the analyzed genes

Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (P < 0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that nonepitheliod histology (P = 0.037), whereas CDKN2A deletions occurred more frequently in nonepithelioid subtypes among men (P = 0.021) and were correlated with shorter overall survival for the entire cohort (P = 0.002) and for men (P = 0.012). Furthermore, women were more likely to harbor TP53 mutations (P = 0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in nonepithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM. Cancer Res; 76(2); 319–28. ©2015 AACR.

List of the 51 canonical pathways significantly enriched (p

Schematic representation of the SNVs and/or chromosomal aberrations identified in BAP1, NF2, TP53, MYH9, RHOA, MYH6, MYH10, PIK3C2A, TNFRSF1A, and 22q and 9p in a panel of 147 MPM tumors.

Expression levels for BAP1, NF2, TP53, MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A detected by Affymetrix® Human Gene 1.1 ST Array in 151 MPM

Whole genome sequencing data analysis of 10 MPM tumor and matched DNA generated by Complete Genomics platform

BackgroundPancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest cancers, with few modern tools to inform patient prognosis and help guide treatment options. Transcriptome-based molecular subtyping is one emerging technology that has been employed to help patients optimize available therapeutic approaches. Here we retrospectively demonstrate the clinical validity of PurIST (Purity Independent Subtyping of Tumors), an RNA-based classifier that divides PDAC patients into two subtypes with differential prognoses, as a validated laboratory-developed test (LDT) on the Tempus Labs sequencing platform.MethodsA cohort comprising 258 late-stage PDAC patients with available transcriptomic and outcomes data was drawn from the Tempus clinicogenomic database and classified using PurIST into one of two subtypes (“Basal” or “Classical”). Differences in patient survival from the date of diagnosis were compared between subtypes, and between two common first-line treatment regimens, FOLFIRINOX, and gemcitabine + nab-paclitaxel.ResultsOf the 258 PDAC patients in the validation cohort, PurIST classified 173 as classical subtype, 59 as basal subtype, and 26 as no-calls. Reinforcing previous findings, patients of the basal subtype had significantly lower overall survival than those of the classical subtype. Notably, differential survival by subtype was significant among the subset of patients on FOLFIRINOX, but not those on gemcitabine + nab-paclitaxel.ConclusionsThe implementation of PurIST on a high-throughput clinical laboratory RNA-Seq platform and the demonstration of the model’s clinical utility in a real-world cohort together show that PurIST can be used at scale to refine PDAC prognosis and thereby inform treatment selection to improve outcomes for advanced-stage PDAC patients.

Background The COVID-19 pandemic has disproportionately impacted racial and ethnic minorities in the United States, including Asian Americans, Native Hawaiians and Pacific Islanders (Asian Americans and NH/PIs). However, few studies have highlighted nor disaggregated these disparities by Asian Americans and NH/PIs ethnic subgroups. Methods This retrospective, cross-sectional observational study aimed to assess variation of Asian Americans and NH/PIs COVID-19 testing and outcomes compared to non-Hispanic Whites (NHW). The study utilized data from the electronic health records (EHR) and the COVID-19 Universal Registry for Vital Evaluations (CURVE) from all patients tested for SARS-CoV-2 (n = 556,690) at a large, health system in Northern and Central California between February 20, 2020 and March 31, 2021. Chi-square tests were used for testing differences in the severity of COVID-19 (hospitalization, ICU admission, death) and patient demographic and clinical characteristics across the Asian Americans and NH/PIs subgroups and NHW. Unadjusted and adjusted Odds Ratios (ORs) were estimated for measuring effect of race ethnicity on severity of COVID-19 using multivariable logistic regression. Results Of the entire tested population, 70,564/556,690 (12.7%) tested positive for SARS-CoV-2. SARS-CoV-2 positivity of Asian subgroups varied from 4% in the Chinese and Korean populations, to 11.2%, 13.5%, and 12.5% for Asian Indian, Filipino, and “other Asian” populations respectively. Pacific Islanders had the greatest subgroup test positivity at 20.1%. Among Asian Americans and NH/PIs patients with COVID-19 disease, Vietnamese (OR = 2.06, 95% CI = 1.30–3.25), “Other Asian” (OR = 2.13, 95% CI = 1.79–2.54), Filipino (OR = 1.78, 95% CI = 1.34–2.23), Japanese (OR = 1.78, 95% CI = 1.10–2.88), and Chinese (OR = 1.73, 95% CI = 1.34–2.23) subgroups had almost double the odds of hospitalization compared to NHW. Pacific Islander (OR = 1.58, 95% CI = 1.19–2.10) and mixed race subgroups (OR = 1.55, 95% CI = 1.10–2.20) had more than one and a half times odds of hospitalization compared to NHW. Adjusted odds of ICU admission or death among hospitalized patients by different Asian subgroups varied but were not statistically significant. Conclusions Variation of COVID-19 testing and hospitalization by Asian subgroups was striking in our study. A focus on the Asian Americans and NH/PIs population with disaggregation of subgroups is crucial to understand nuances of health access, utilization, and outcomes among subgroups to create health equity for these underrepresented populations.

Purpose Breast cancer outcomes are impaired by both delays and disparities in treatment. This study was performed to assess their relationship and to provide a tool to predict patient socioeconomic factors associated with risk for delay. Methods The National Cancer Database was reviewed between 2004 and 2017 for patients with non-metastatic breast cancer managed with upfront surgery. Times to treatment were measured from the date of diagnosis. Patient, tumor, and treatment factors were assessed with attention paid to sociodemographic variables. Results 514,187 patients remained after exclusions, with 84.3% White, 10.8% Black, 3.7% Asian, and Hispanics comprising 5.6% of the cohort. Medicaid and uninsured patients had longer mean adjusted time to surgery (≥ 46 days) versus private (36.7 days), Medicare (35.9 days), or other governmental insurance (39.8 days). After adjustment, Black race and Hispanic ethnicity were most impactful, adding 6.0 and 6.4 preoperative days, 10.9 and 11.5 days to chemotherapy, 11.1 and 9.1 days to radiation, and 12.5 and 8.9 days to endocrine therapy, respectively. Income, education, and insurance, among other factors, also affected delay. A nomogram, including race and sociodemographic factors, was created to predict the risk of preoperative delay. Conclusion Significant disparities exist in timeliness of care for factors, including but not limited to, race and ethnicity. Although exact causes cannot be discerned, these data indicate population subsets whose intervals of care risk being longer than those specified by national quality standards. The nomogram created here may help direct resources to those at highest risk of incurring a treatment delay. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-021-06460-9.

INTRODUCTION: Previous studies have shown racial disparities in outcomes after out-of-hospital cardiac arrest. Although several treatment factors may account for these differences, there is limited information regarding differences in CPR quality and its effect on survival in underrepresented racial populations. METHODS: We conducted a secondary analysis of data from patients enrolled in the Pragmatic Airway Resuscitation Trial (PART). We calculated compliance rates with AHA 2015 high quality CPR metrics as well as compliance to intended CPR strategy (30:2 or continuous chest compression) based on the protocol in place for the first responding EMS agency. The primary analysis used general estimating equations logistic regression to examine differences between black and white patients based on EMS-assessed race after adjustment for potential confounders. Sensitivity analyses examined differences using alternate race definitions. RESULTS: There were 3004 patients enrolled in PART of which 1734 had >2 minutes of recorded CPR data and an EMS-assessed race (1003 white, 555 black, 176 other). Black patients had higher adjusted odds of compression rate compliance (OR: 1.36, 95% CI: 1.02-1.81) and lower adjusted odds of intended CPR strategy compliance (OR: 0.78, 95% CI: 0.63-0.98) compared to white patients. Of 974 transported to the hospital, there was no difference in compliance metric estimates based on ED-reported race. CONCLUSION: Compression rate compliance was higher in black patients however compliance with intended strategy was lower based on EMS-assessed race. The remaining metrics showed no difference suggesting that CPR quality differences are not important contributors to the observed outcome disparities by race.

(a) Schematic illustration for the preparation of iRGD-R7-LAHP-M NPs. (b) The prepared NPs penetrated into the deep tumor, and released LAHP and metal ions in acid pH, inducing singlet oxygen-mediated cell death and evoking immunogenic cell death.

A new 2D fluorescent organic-metal chalcogenide (OMC), CdClHT (HT = 4-hydroxythiophenol), evenly covered with phenol groups is reported. CdClHT represents unparalleled selectivity and the highest sensitivity towards 2,4,6-trinitrophenol (TNP) (

Organic small molecule semiconductor (OSMS) microporous crystals with strong π–π interactions are rare but have great potential in applications requiring both excellent mass and charge transport.

We report the discovery of a facile peptide macrocyclization and stapling strategy based on a fluorine thiol displacement reaction (FTDR), which renders a class of peptide analogues with enhanced stability, affinity, cellular uptake, and inhibition of cancer cells. This approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides in the presence of intrinsic cysteines. The identified benzenedimethanethiol linker greatly promoted the alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations. The cellular uptake of benzenedimethanethiol stapled peptides appeared to be universally enhanced compared to the classic ring-closing metathesis (RCM) stapled peptides. Pilot mechanism studies suggested that the uptake of FTDR-stapled peptides may involve multiple endocytosis pathways in a distinct pattern in comparison to peptides stapled by RCM. Consistent with the improved cell permeability, the FTDR-stapled lead Axin and p53 peptide analogues demonstrated enhanced inhibition of cancer cells over the RCM-stapled analogues and the unstapled peptides., Strategies capable of stapling unprotected peptides in a straightforward, chemoselective, and clean manner, as well as promoting cellular uptake are of great interest. Here the authors report a peptide macrocyclization and stapling strategy which satisfies those criteria, based on a fluorine thiol displacement reaction.

We demonstrated here a series of Aspidosperma terpenoid alkaloids can be quickly prepared using semisynthesis from naturally sourced tabersonine, featuring multiple oxygen-based substituents on the indole ring such as hydroxy and methoxy groups. This panel of complex compounds enabled the exploration of indole modifications to optimize the indole alkaloids’ anticancer activity, generating lead compounds (e.g., with C15-hydroxy, C16-methoxy, and/or C17-methoxy derivatizations) that potently inhibit cancer cell line growth in the single-digit micromolar range. These results can help guide the development of Aspidosperma terpenoid alkaloid therapeutics. Furthermore, this synthetic approach features late-stage facile derivatization on complex natural product molecules, providing a versatile path to indole derivatization of this family of alkaloids with diverse chemical functionalities for future medicinal chemistry and chemical biology discoveries.

We conducted a national survey of pediatric infectious diseases (ID) clinicians on outpatient parenteral antibiotic therapy (OPAT) practices and post-discharge ID follow-up. Only 15% of sites required ID consultation for all OPAT. ID division resources for post-discharge care varied. Opportunities exist to increase ID involvement in post-discharge management of serious infections.

Pressure and temperature are two important indicators for human skin perception. Electronic skin (E-skin) that mimics human skin within one single flexible sensor is beneficial for detecting and differentiating pressure and temperature and showing immunity from tensile strain disruptions. However, few studies have simultaneously realized these conditions. Herein, a flexible and strain-suppressed pressure-temperature dual-modal sensor based on conductive and microstructured metal-organic framework (MOF) films was reported and mainly prepared by

Emergency Medical Services personnel are often the first to intervene in the care of critically ill children. Airway management is a fundamental step in prehospital resuscitation, yet there is significant variation in current prehospital airway management practices. Our objective is to present a methodologic approach to determine the optimal strategy for prehospital pediatric airway management. We describe the conceptual premise for the Pediatric Prehospital Airway Resuscitation Trial, a novel Bayesian adaptive sequential platform trial. We developed an innovative design to enable comparison of the three predominant prehospital pediatric airway techniques (bag-mask-ventilation, supraglottic airway insertion, and endotracheal intubation) in three distinct disease groups (cardiac arrest, major trauma, and other respiratory failure). We used a Bayesian statistical approach to provide flexible modeling that can adapt based on prespecified rules according to accumulating trial data with patient enrollment continuing until stopping rules are met. The approach also allows the comparison of multiple interventions in sequence across the different disease states. This Bayesian hierarchical model will be the primary analysis method for the Pediatric Prehospital Airway Resuscitation Trial. The model integrates information across subgroups, a technique known as “borrowing” to generate accurate global and subgroup-specific estimates of treatment effects and enables comparisons of airway intervention arms within the overarching trial. We will use this Bayesian hierarchical linear model that adjusts for subgroup to estimate treatment effects within each subgroup. The model will predict a patient-centered score of 30-day intensive care unit-free survival using arm, subgroup, and emergency medical services agency as predictors. The novel approach of Pediatric Prehospital Airway Resuscitation Trial will provide a feasible method to determine the optimal strategy for prehospital pediatric airway management and may transform the design of future prehospital resuscitation trials.

A DNA G-quadruplex (G4) is a non-canonical four-stranded nucleic acid structure involved in many biological processes in mammals. The current knowledge on plant DNA G4s, however, is limited; whether and how DNA G4s impact gene expression in plants is still largely unknown. Here, we applied a protocol referred to as BG4-DNA-IP-seq followed by a comprehensive characterization of DNA G4s in rice (Oryza sativa L.); we next integrated dG4s (experimentally detectable G4s) with existing omics data and found that dG4s exhibited differential DNA methylation between transposable element (TE) and non-TE genes. dG4 regions displayed genic-dependent enrichment of epigenomic signatures; finally, we showed that these sites displayed a positive association with expression of DNA G4-containing genes when located at promoters, and a negative association when located in the gene body, suggesting localization-dependent promotional/repressive roles of DNA G4s in regulating gene transcription. This study reveals interrelations between DNA G4s and epigenomic signatures, as well as implicates DNA G4s in modulating gene transcription in rice. Our study provides valuable resources for the functional characterization or bioengineering of some of key DNA G4s in rice.

PURPOSE: Gastric cancers are classified as diffuse-type (DTGC) or intestinal-type (ITGC). DTGCs have distinct clinical and histopathologic features, and carry a worse overall prognosis compared to ITGCs. Atrophic gastritis (AG) and intestinal metaplasia (IM) are known precursors to ITGC. It is unknown if AG and IM increase risk for DTGC. METHODS: We performed a systematic review to identify studies reporting on the association of AG/IM and DTGC. We extracted the odds ratio (OR) of the association from studies, and performed pool analysis. Subgroup analysis was performed on studies reporting histologic severity (using operative link systems) to assess if histologic severity of AG/IM was associated with higher risk. RESULTS: We identified six case-control and eight cohort studies for inclusion. Both AG (pooled OR=1.9, 95% CI 1.5 to 2.4, p

Importance Emergency research is challenging to do well as it involves time sensitive interventions in unstable patients. There is limited time to obtain informed consent from the patient or their legally authorized representative (LAR). Such research is permitted under exception from informed consent (EFIC) if specific criteria are met, including notification after enrollment. Some question whether the risks of EFIC outweighs its benefits. To date, there is limited empiric information about time to notification (TTN) and rates of withdrawal in such trials. Objective To describe variation in TTN and rates of withdrawal among that patients enrolled in EFIC trials over a twelve-year period. Design We performed post hoc descriptive analyses of data from five trials conducted under EFIC. Setting Emergency medical services and receiving hospitals participating in the Resuscitation Outcomes Consortium in the United States and Canada. Participants Patients with out-of-hospital cardiac arrest or life-threatening traumatic injury. Exposures Notification strategies were specified at each site before initiation of enrollment by a local institutional review board. We monitored TTN within each site centrally throughout each study’s enrollment period. Outcomes TTN was defined as time from randomization to first-reported notification of patient or LAR of enrollment. Withdrawal was defined as patient or LAR opt out of ongoing participation at the time of notification. Results Of 35,442 patients enrolled in five trials, 33,805 had cardiac arrest; and 1636 had traumatic injury. TTN varied overall and by patient outcome. Among those with cardiac arrest, TTN ranged from median (5%ile, 95%ile) of 6 (1,27) days to 28 (2, 53) days across sites. 0.3% of notified patients with cardiac arrest withdrew. Among those with traumatic injury, TTN ranged from 0 (0, 5) days to 36 (5, 68) days across sites. 7.7% of notified patients with traumatic injury withdrew. Conclusions and Relevance There is large variation in TTN in trials conducted under EFIC for emergency research. This may be due to several factors. It may or may not be modifiable. Overall rates of withdrawal are low, which suggests current practices related to EFIC are acceptable to those who have participated in emergency research.

Simultaneous multitarget vital signs measurement has become a hot issue for noncontact vital signs perception. However, there is still challenge in the multitarget heartbeat measurement due to the weakness of heartbeat signal and interference from complex environment. In this article, a new multiple-input–multiple-output (MIMO) continuous-wave (CW) radar system equipped with 2-D digital beamforming (DBF) is presented to measure the respiration and heartbeat of multiple human subjects at unknown positions simultaneously. Through 2-D beam scanning of the whole scene, a 2-D radar image is generated. From the image, the chest motion of multiple targets is accurately located. Then, the vital signs of targets are obtained through forming individual beams focusing on the chests of targets. Moreover, the low intermediate frequency (low-IF) architecture is adopted to minimize the impact of flicker noise in low-frequency amplifier stages. The experimental results demonstrate that the proposed MIMO 2-D imaging radar system can locate chest areas of multiple targets, suppress the clutters, and make vital signs measurement, heartbeat measurement in particular, more robust compared with single-input–multiple-output (SIMO) radar system in complex environment.