tbuckley/cabot-search huggingface dataset:
RETRACTED ARTICLE: HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression
Authors: Huajie Song, Dan Li, Xiaojing Wang, Erhu Fang, Feng Yang, Anpei Hu, Jianqun Wang, Yanhua Guo, Yang Liu, Hongjun Li, Yajun Chen, Kai Huang, Liduan Zheng, Qiangsong Tong
Journal: Journal of Hematology & Oncology (2020)

Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to tumor progression. However, the mechanisms regulating expression of glycolytic genes in neuroblastoma (NB), the most common extracranial solid tumor in childhood, still remain elusive.Crucial transcriptional regulators and their downstream glycolytic genes were identified by integrative analysis of a publicly available expression profiling dataset. In vitro and in vivo assays were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. Survival analysis was performed by using Kaplan-Meier method and log-rank test.Hepatocyte nuclear factor 4 alpha (HNF4A) and its derived long noncoding RNA (HNF4A-AS1) promoted aerobic glycolysis and NB progression. Gain- and loss-of-function studies indicated that HNF4A and HNF4A-AS1 facilitated the glycolysis process, glucose uptake, lactate production, and ATP levels of NB cells. Mechanistically, transcription factor HNF4A increased the expression of hexokinase 2 (HK2) and solute carrier family 2 member 1 (SLC2A1), while HNF4A-AS1 bound to heterogeneous nuclear ribonucleoprotein U (hnRNPU) to facilitate its interaction with CCCTC-binding factor (CTCF), resulting in transactivation of CTCF and transcriptional alteration of HNF4A and other genes associated with tumor progression. Administration of a small peptide blocking HNF4A-AS1-hnRNPU interaction or lentivirus-mediated short hairpin RNA targeting HNF4A-AS1 significantly suppressed aerobic glycolysis, tumorigenesis, and aggressiveness of NB cells. In clinical NB cases, high expression of HNF4A-AS1, hnRNPU, CTCF, or HNF4A was associated with poor survival of patients.These findings suggest that therapeutic targeting of HNF4A-AS1/hnRNPU/CTCF axis inhibits aerobic glycolysis and NB progression.
Abstract P6-03-07: NOTCH3 targeting inhibits ALDH1 activity and restores chemosensitivity in metastatic TNBC
Authors: Antonino Bonaventura D'Assoro
Journal: Cancer Research (2020)

Abstract Background: Onset of metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which include dissemination of cancer cells from the primary tumor to secondary organs. NOTCH signaling plays a critical role in promoting Triple Negative Breast Cancer (TNBC) metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We established unique TNBC cells (TNBC-M14, -M25 and -M40), isolated from patient-derived brain metastasis xenografts (PD-BMXs). NOTCH3 genetic targeting was achieved using Lenti-vector shRNAs. Immunoblot analysis was used to assess NOTCH3 expression. ALDH1 activity was established using the ALDEOFLUOR Kit. To assess self-renewal capacity and resistance to docetaxel-based chemotherapy, TNBC cells were cultured under non-adherent conditions to form mammospheres (MPS). A publicly clinical database (http://kmplot.com) was employed to analyze NOTCH3 expression in a selected cohort of 107 lymph- node+ TNBC patients. Results: TNBC-M14, -M25 and -M40 MPS showed NOTCH3 overexpression and higher ALDH1 activity compared to MDA-MB 231 MPS used as control. To investigate the causative role of NOTCH3 in inducing ALDH1 activity, self-renewal capacity and chemoresistance, we infected TNBC MPS with Lenti-vector shRNAs targeting NOTCH3. NOTCH3 geneting targeting induced a significant reduction of ALDH1 activity compared to TNBC MPS infected with scrambled Lenti-shRNAs. Significantly, NOTCH3 geneting targeting significantly impaired MPS formation and restored sensitivity to docetaxel. The correlation between aberrant NOTCH3 expression and poor outcome in patients with advanced TNBC was also investigated in a publicly clinical database. Conclusions: These findings provide a compelling preclinical rationale for the design of novel clinical trials that will selectively target NOTCH3 to delay metastatic growth and to improve the clinical outcome of patients with advanced TNBC. Citation Format: Antonino Bonaventura D'Assoro. NOTCH3 targeting inhibits ALDH1 activity and restores chemosensitivity in metastatic TNBC [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-07.
Abstract P4-05-23: Validation of proteome based molecular stratification of breast cancer using 1,229 patient samples from four independent datasets
Authors: Balazs Gyorffy
Journal: Cancer Research (2020)

Abstract Introduction. In routine diagnostics, four genes are used to determine the molecular subtype and the optimal systemic therapy for breast cancer patients, ESR1, PGR, HER2, and in some cases MKI67. While these can be measured by different molecular genetic methods, immunohistochemistry is still the most widely used technique. The aim of present study was to determine how effective recent proteomic technologies are in measuring the expression of these genes. Methods. A literature search was performed to identify available proteome-level datasets. Differential expression was compared using Mann-Whitney test. Receiver operating characteristics (ROC) was computed to validate discriminative power and to determine the optimal cutoff values. Each dataset was processed separately. Results. All together four datasets with a total of 1,229 specimens with proteome level-data were identified. One dataset was generated using RPPA (reverse phase protein lysate microarray, n=874) and three using LC-MS (liquid chromatography-mass spectrometry, n=355). In all four datasets combined, a total of 7,419 proteins were measured. It was not possible to analyze all combinations because of limited data availability - HER2 data was available in the RPPA study only, and ESR1/PGR in the LC-MS studies only. The determination of HER2 status by IHC and HER2 protein expression by RPPA show very high correlation (p=2.9E-18). ESR1 protein expression determined by LC-MS show a significant correlation to IHC results (p=0.04). The ROC analysis for HER2 delivered an area under the ROC curve (AUC) of 0.74 (p=1.9e-20). For ESR1, the AUC was 0.61 (p=0.03). ESR1 and PGR show a moderate correlation in LC-MS data (correlation coefficient=0.17, p=0.04). Finally, when comparing MKI-67 expression between normal (n=53) and tumor samples (n=65) within one dataset, tumor samples had significantly higher expression (fold change=2.22, p=3.9E-05). Conclusions. The RPPA method achieved high correlation with IHC results. Our results suggest that proteomic technologies will be capable to deliver molecular stratification enabling the discrimination of breast cancer subtypes in the future. Citation Format: Balazs Gyorffy. Validation of proteome based molecular stratification of breast cancer using 1,229 patient samples from four independent datasets [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-23.
Abstract P4-10-16: Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer
Authors: Amir Sonnenblick, Mali Salmon-Divon, Roberto Salgado, Noam Pondé, Sibylle Loibl, Carsten Denkert, Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Amos Azaria, Sherene Loi, Stefan Michiels, Christos Sotiriou
Journal: Cancer Research (2020)

Abstract Purpose We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. Experimental Design The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease-free survival (DDFS). Results Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N=209), were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (HR=1.27 p-interaction=0.014 [DCN], HR=1.58, p-interaction=0.027 [PLAU], HR=1.71, p-interaction=0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER-positive tumors (HR=0.73 p-interaction=0.47 [DCN], HR=0.71, p-interaction=0.73 [PLAU], HR=0.84; p-interaction=0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC &amp;lt;50%). Conclusions Reactive stroma in HER2-positive/ER-negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy. Citation Format: Amir Sonnenblick, Mali Salmon-Divon, Roberto Salgado, Noam Pondé, Sibylle Loibl, Carsten Denkert, Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Amos Azaria, Sherene Loi, Stefan Michiels, Christos Sotiriou. Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-16.
Management of Critically Ill Adults With COVID-19
Authors: Jason T. Poston, Bhakti K. Patel, Andrew M. Davis
Journal: JAMA (2020)

Mervyn Singer, MD, FRCP; Clifford S. Deutschman, MD, MS; Christopher Warren Seymour, MD, MSc; Manu Shankar-Hari, MSc, MD, FFICM; Djillali Annane, MD, PhD; Michael Bauer, MD; Rinaldo Bellomo, MD; Gordon R. Bernard, MD; Jean-Daniel Chiche, MD, PhD; Craig M. Coopersmith, MD; Richard S. Hotchkiss, MD; Mitchell M. Levy, MD; John C. Marshall, MD; Greg S. Martin, MD, MSc; Steven M. Opal, MD; Gordon D. Rubenfeld, MD, MS; Tom van der Poll, MD, PhD; Jean-Louis Vincent, MD, PhD; Derek C. Angus, MD, MPH
Patterns and Characteristics of Methamphetamine Use Among Adults — United States, 2015–2018
Authors: Christopher M. Jones, Wilson M. Compton, Desiree Mustaquim
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Methamphetamine is a highly addictive central nervous system stimulant. Methamphetamine use is associated with a range of health harms, including psychosis and other mental disorders, cardiovascular and renal dysfunction, infectious disease transmission, and overdose (1,2). Although overall population rates of methamphetamine use have remained relatively stable in recent years (3), methamphetamine availability and methamphetamine-related harms (e.g., methamphetamine involvement in overdose deaths and number of treatment admissions) have increased in the United States* (4,5); however, analyses examining methamphetamine use patterns and characteristics associated with its use are limited. This report uses data from the 2015-2018 National Surveys on Drug Use and Health (NSDUHs) to estimate methamphetamine use rates in the United States and to identify characteristics associated with past-year methamphetamine use. Rates (per 1,000 adults aged ≥18 years) for past-year methamphetamine use were estimated overall, by demographic group, and by state. Frequency of past-year use and prevalence of other substance use and mental illness among adults reporting past-year use were assessed. Multivariable logistic regression examined characteristics associated with past-year use. During 2015-2018, the estimated rate of past-year methamphetamine use among adults was 6.6 per 1,000. Among adults reporting past-year methamphetamine use, an estimated 27.3% reported using on ≥200 days, 52.9% had a methamphetamine use disorder, and 22.3% injected methamphetamine. Controlling for other factors, higher adjusted odds ratios for past-year use were found among men; persons aged 26-34, 35-49, and ≥50 years; and those with lower educational attainment, annual household income <$50,000, Medicaid only or no insurance, those living in small metro and nonmetro counties,† and those with co-occurring substance use and co-occurring mental illness. Additional efforts to build state and local prevention and response capacity, expand linkages to care, and enhance public health and public safety collaborations are needed to combat increasing methamphetamine harms.
Abstract P4-02-08: What happened to clinically node positive breast cancer patients who showed conversion into pN0 after neoadjuvant chemotherapy?: Single center for 10 years
Authors: Joo Hwa Kwak, Heein Jo, Eun-Gyeong Lee, Eun Jin Song, Jai Hong Han, So-Youn Jung, Han-Sung Kang, Eun Sook Lee, Seeyoun Lee
Journal: Cancer Research (2020)

Abstract Objective: This study aimed to evaluate the outcomes between sentinel lymph node biopsy (SLNB) and axillar lymph node dissection (ALND) on recurrence and survival in clinically node positive breast cancer patients who showed conversion into pN0 after neoadjuvant chemotherapy (NAC) from 10 years cohort in single center. Materials &amp; Method: This study enrolled total 225 patients, from January 2006 to December 2015 who underwent breast cancer surgery and axillar lymph node approach in clinically axillar lymph node metastasis with conversion into node negative after neoadjuvant chemotherapy. One hundred patients had only SLNB and 125 patients had ALND finally. Results: The median follow-up time was 58 months (range, 12-147 months) in only SLNB group and 103 months (range 9-174 months) in ALND group and the median number of retrieved SLNs was 2 (range, 1-6) and 11 (2-31). The 5 years overall survival rate of SLNB and ALND group is 94%, 95.7% (P=0.786), disease free survival rate 91.9%, 91.6%, (p=0.753) which was not statistically significant. Three patients (3%) and 6 patients (4.8%) showed loco-regional recurrence respectively. All they showed ipsilateral axillary lymph node recurrence. Seven patients (7%) and 6 patients (4.8%) in SLNB group and ALND group showed distant metastasis. However, there were more complications in the ALND group than in the SLNB group. Among them, ALND group showed the higher rate of shoulder stiffness than SLNB group (7% vs 10.4%, p=0.384, respectively). Especially, the incidence of lymphedema was 6 times higher in ALND group. (4 patients (4%) vs 29 patients (23.2%), p=0.271) Conclusion: We found the SLNB only group did not increase the recurrence or metastatic rate from the patients, but reduced the incidence of complications such as lymphedema from the 10 years single center cohort. Therefore, we suggest SLNB can be considered as a reliable as an alternative to ALND when the complete response is achieved by re-staging with imaging study after neoadjuvant chemotherapy. Keyword: neoadjuvant chemotherapy, sentinel lymph node biopsy, axillar lymph node dissection Citation Format: Joo Hwa Kwak, Heein Jo, Eun-Gyeong Lee, Eun Jin Song, Jai Hong Han, So-Youn Jung, Han-Sung Kang, Eun Sook Lee, Seeyoun Lee. What happened to clinically node positive breast cancer patients who showed conversion into pN0 after neoadjuvant chemotherapy?: Single center for 10 years [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-08.
Covid-19: Researchers launch app to track spread of symptoms in the UK
Authors: Susan Mayor
Journal: BMJ (2020)

Nearly 700 000 people signed up in the first 24 hours of the launch of an app to help track the spread of coronavirus across the UK in real time and collect information on the range of self-reported symptoms and the characteristics of those most at risk.

The Covid Symptom Tracker app (covid.joinzoe.com) enables users to make a daily report of any symptoms. It is available free of charge to members of the public in the UK. The app has also been given to 5000 twins and their families recruited from the ongoing TwinsUK cohort study.1

“The aim of the app is to help slow the outbreak” by understanding what measures work, said the researchers from King’s College London and Guy’s and St Thomas’ Hospitals in partnership with ZOE, a spin-off health data science company from King’s. “It will …
Abstract P5-08-08: Risk reducing mastectomy in average and high risk patients with locally advanced triple negative breast cancer
Authors: Neda Stjepanovic, Danilo Giffoni, Sonal Gandhi, Katarzyna Jerzak, Sharon Lemon, Karen Ott, Rossanna Pezo, Kathleen Pritchard, Samuel Tabbarah, Maureen Trudeau, Ellen Warner, William Tran, Andrea Eisen
Journal: Cancer Research (2020)

Abstract Background: Women with locally advanced triple negative breast cancer (LA-TNBC) have a high risk of disease recurrence and are monitored clinically and with annual mammograms. High risk women, such as BRCA1/2 carriers, are additionally monitored for second primary breast cancers (BC) with annual MRIs and may opt for risk reducing mastectomy (RRM) as a prophylactic measure. Our aim was to explore the clinical outcomes of patients (pts) with average BC risk and high BC risk (known BRCA1/2 carriers) who undergo RRM at the time of LA-TNBC diagnosis. Methods: We included 78 consecutive LA-TNBC pts, stages IIB and III, with resectable unilateral disease, treated at the Sunnybrook Health Sciences Centre from 2009 to 2018. Pts who did not undergo systemic chemotherapy and surgical treatment were excluded, as well as pts with a history of prior BC. Medical records were reviewed for clinical outcomes, pathology and germline BRCA1/2 testing results. Log rank test was used to determine the time to recurrence (TTR) and overall survival (OS) differences among women who underwent RRM and those who did not. Results: Median age at diagnosis of LA-TNBC was 49 years (range 27-82) and 14 (18%) pts were BRCA1/2 carriers. All pts underwent neoadjuvant chemotherapy with 27 (35%) presenting complete pathological response. Fifteen pts underwent RRM, out of which seven were BRCA1/2 carriers. Mean follow up time was 34 (2-86) months, during which 25 pts (32%) were diagnosed with distant disease recurrence and none with second primary BC. Median TTR was 10 months (range 1-48) and median OS was 18 months (range 2-86). RRM was not associated with TTR (p=0.45) and OS (p=0.98). Presence of germline BRCA1/2 also did not correlate with TTR (p=0.16) and OS (p=0.21). Conclusions: In our cohort of pts with LA-TNBC, the prognosis was driven by the risk of recurrence rather than the risk of second primary BCs. RRM was not associated with improved clinical outcomes, regardless the BRCA1/2 status and larger studies are required to support this procedure at the time of diagnosis of LA-TNBC. Citation Format: Neda Stjepanovic, Danilo Giffoni, Sonal Gandhi, Katarzyna Jerzak, Sharon Lemon, Karen Ott, Rossanna Pezo, Kathleen Pritchard, Samuel Tabbarah, Maureen Trudeau, Ellen Warner, William Tran, Andrea Eisen. Risk reducing mastectomy in average and high risk patients with locally advanced triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-08.
Doctors as leaders: be honest about continued underfunding
Authors: John Puntis
Journal: BMJ (2020)

The Academy of Medical Royal Colleges recognises that the past decade has been difficult for healthcare with “insufficient resources, increased demand, and damage by the wrong drivers.” It suggests that “recognition of these issues alongside an increased funding package provides an opportunity for change. Workforce issues are now being taken seriously” and there is “a move from competition to collaboration.” …
Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival
Authors: Mary A. Wood, Benjamin R. Weeder, Julianne K. David, Abhinav Nellore, Reid F. Thompson
Journal: Genome Medicine (2020)

Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized.Using a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential.We find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes.We find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.
Balancing Risk and Reward: Greater Research Oversight Is Appropriate for Novel Therapies for Children With Life-Limiting Illness
Authors: Yoram Unguru
Journal: The American Journal of Bioethics (2020)

"Balancing Risk and Reward: Greater Research Oversight Is Appropriate for Novel Therapies for Children With Life-Limiting Illness." The American Journal of Bioethics, 20(4), pp. 104–105
Covid-19: healthcare staff in hotspot areas are prioritised as testing expands
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The BMJ Medical leaders have welcomed the government's "belated" decision to expand covid-19 testing capacity but said it has taken too long to commence and is still far too limited.On 27 March the government announced it was opening three new laboratories in England to focus on processing covid-19 testing samples from healthcare staff.Staff in the worst affected parts of the country, such as London, are being prioritised, especially in areas of highest impact, such as intensive care, with all health and care staff following as capacity increases.