tbuckley/cabot-search huggingface dataset:
Abstract 332: Controlling the Heart Rate After Resuscitation Decreases Duration of Survival in a Rat Model of Cardiac Arrest
Authors: Zhangle Hu, Jin Yang, Qinyue Guo, Xiaobo Wu, Jennifer Bradley, Mary Ann Peberdy, Joseph Ornato, Wanchun Tang
Journal: Circulation (2018)

Introduction: A high heart rate (HR) after return of spontaneous circulation (ROSC) due to increased sympathetic drive is a compensatory mechanism of postresuscitation myocardial dysfunction. However, it increases myocardial oxygen demand and impairs oxygen supply, and may increase the severity of myocardial ischemia. Hypothesis: Reduction of HR would improve postresuscitation myocardial dysfunction. Methods: Thirty-two male Sprague-Dawley rats weighing 450-550g were randomized into 2 groups: 1) Saline group: Ventricular fibrillation was induced and untreated for 6 min followed by 8 min of CPR. Rats received 0.9% NaCl solution administered from the femoral artery at 1h after return of spontaneous circulation (ROSC). 2) Drug group: Ventricular fibrillation was induced and untreated for 6 min followed by 8 min of CPR. Rats received Ivabradine (0.5ml/kg) solution administered from the femoral artery at 1h after ROSC. All catheters including the endotracheal tube were removed at PR 5h and animals were returned to their cages and closely monitored for the duration of survival. Results: For both groups, postresuscitation myocardial function as expressed by CO, EF, MPI was impaired compared to baseline values. However, the IVA group was significantly inferior to the SAL group with myocardial function index from PR 120’ to PR 300 (*p&lt;0.01) (Figure 1).A significantly shortened duration of survival was observed in the IVA group compared to the SAL group (p&lt;0.01) (Figure 2). Conclusions: Lowering HR significantly reduces myocardial function the duration of survival following successful resuscitation.
State Smoking Restrictions for Private-Sector Worksites, Restaurants, and Bars—United States, 2004 and 2007
Journal: JAMA (2008)

Secondhand smoke is a known carcinogen. Exposure to secondhand smoke causes approximately 35,000 heart disease deaths and 3,000 lung cancer deaths among nonsmokers in the United States every year. Implementing policies that establish smoke-free environments is the most effective approach to reducing secondhand smoke exposure among nonsmokers. Smoking restrictions and smoke-free policies can take the form of laws or regulations implemented at the state or local level or of voluntary policies implemented by private employers and businesses. Smoking restrictions limit smoking to certain areas within a venue; smoke-free policies ban smoking within the entire venue. One of the national health objectives for 2010 is to establish laws in all 50 states and the District of Columbia (DC) that prohibit or restrict smoking in public places and worksites. A related objective calls for all worksites to voluntarily implement policies that prohibit or restrict smoking. To assess progress toward meeting the first objective, CDC reviewed the status of state laws restricting smoking as of December 31, 2004, updating a 1999 study that reported on such laws as of December 31, 1998. This report summarizes the changes in state smoking restrictions for private-sector worksites, restaurants, and bars that occurred during 1999-2004. The findings indicate an increase in the number and restrictiveness of state laws regulating smoking in private-sector worksites, restaurants, and bars from 1999 through 2004. At the end of 2004, however, 16 states still had no restrictions on smoking in any of the three settings considered. Although secondhand smoke exposure among U.S. nonsmokers has decreased sharply in recent years, a substantial portion of nonsmokers continue to be exposed to secondhand smoke.
ECT and the media.
Authors: K Sabbagh
Journal: BMJ (1977)

incorrectly diagnosed until necropsy and the overall mortality was 25 %.Trapnell5 reported that in 6% of his series of 590 patients with acute pancreatitis the diagnosis was made only at necropsy and the overall series mortality was more than 20 %.Thus in any analysis of mortality in primary acute pancreatitis it is important to differentiate between patients in whom the diagnosis is made at necropsy and those in whom it is made during life.Mr Imrie:' and others' have shown that in trials of various therapeutic regimens there is a mortality of about 1000, but these patients are only those who had the diagnosis made in life.Mortality from acute pancreatitis will always be higher than people think is acceptable clinical practice until we can diagnose all cases in life and undertake appropriate early treatment.This distinction is important and must be fully appreciated and acknowledged when making comparisons between different series.Alas, this distinction is not always appreciated, which may explain some of the confusion about mortality in acute pancreatitis.
Substances Added to List of Human Carcinogens
Authors: Melissa Suran
Journal: JAMA (2022)

The National Toxicology Program (NTP) has added 8 substances to its Report on Carcinogens. The report now lists 256 factors that are known or “reasonably anticipated” to cause cancer in humans. Collectively referred to as substances, they range from chemicals and viruses to agents such as x-rays.
Immune profiling of advanced prostate cancer harboring homologous recombination deficiency.
Authors: Maryam Soleimani, Sonia H.Y. Kung, Neetu Saxena, Marisa Thi, Ladan Fazli, Lucia Nappi
Journal: Journal of Clinical Oncology (2022)

163 Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumour microenvironment (TME) associated with HRD is poorly understood. We used mPCa tumours of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumour immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n = 13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumour cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n = 104), and neoadjuvant hormone therapy treated (NHT) (n = 16) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations, BRCA1/2 were the most frequently identified ( BRCA1/2 n = 6, FANCC n = 1, FANCD2 n = 2, PALB2 n = 1, CDK12 n = 1, ATR n = 2). CD8 + cells were primarily localized in the stroma of HRD cohort specimens rather than in the glandular epithelia. The HRD cohort had higher levels of A2aR, in TC and SL (p≤0.0001 for both). When compared to the untreated cohort, PD-L2 levels were higher in SL of the HRD cohort (p≤0.05) while lower in the TC (p≤0.01). Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort (p≤0.01). There were significantly lower levels of GAL9 in the TC of the HRD cohort compared to untreated (p &lt; 0.0001) tumours. There were no differences in TIM-3 levels between the cohorts. Conclusions: Evaluation of stromal and tumour cell immune profiling indicates that compared to other subtypes, mPCa with HRD alteration have a unique immune profile abundant in CD8 + cell, and high in PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable pathways which may render clinical benefit in this patient population.
Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling
Authors: Niraj Kumar Jha, Saniya Arfin, Saurabh Kumar Jha, Rohan Kar, Abhijit Dey, Rohit Gundamaraju, Ghulam Md. Ashraf, Piyush Kumar Gupta, Sugapriya Dhanasekaran, Mosleh Mohammad Abomughaid, Sabya Sachi Das, Sachin Kumar Singh, Kamal Dua, Shubhadeep Roychoudhury, Dhruv Kumar, Janne Ruokolainen, Shreesh Ojha, Kavindra Kumar Kesari
Journal: Seminars in Cancer Biology (2022)

Recent mounting evidence has revealed extensive genetic heterogeneity within tumors that drive phenotypic variation affecting key cancer pathways, making cancer treatment extremely challenging. Diverse cancer types display resistance to treatment and show patterns of relapse following therapy. Therefore, efforts are required to address tumor heterogeneity by developing a broad-spectrum therapeutic approach that combines targeted therapies. Inflammation has been progressively documented as a vital factor in tumor advancement and has consequences in epigenetic variations that support tumor instigation, encouraging all the tumorigenesis phases. Increased DNA damage, disrupted DNA repair mechanisms, cellular proliferation, apoptosis, angiogenesis, and its incursion are a few pro-cancerous outcomes of chronic inflammation. A clear understanding of the cellular and molecular signaling mechanisms of tumor-endorsing inflammation is necessary for further expansion of anti-cancer therapeutics targeting the crosstalk between tumor development and inflammatory processes. Multiple inflammatory signaling pathways, such as the NF-κB signaling pathway, JAK-STAT signaling pathway, MAPK signaling, PI3K/AKT/mTOR signaling, Wnt signaling cascade, and TGF-β/Smad signaling, have been found to regulate inflammation, which can be modulated using various factors such as small molecule inhibitors, phytochemicals, recombinant cytokines, and nanoparticles (NPs) in conjugation to phytochemicals to treat cancer. Researchers have identified multiple targets to specifically alter inflammation in cancer therapy to restrict malignant progression and improve the efficacy of cancer therapy. siRNA-and shRNA-loaded NPs have been observed to downregulate STAT3 signaling pathways and have been employed in studies to target tumor malignancies. This review highlights the pathways involved in the interaction between tumor advancement and inflammatory progression, along with the novel approaches of nanotechnology-based drug delivery systems currently used to target inflammatory signaling pathways to combat cancer.
Artificial Patient Planned; Will Train Anesthesiologists
Journal: JAMA (1966)

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Abstract 291: Galectin-3 as a Risk Predictor of Short-Term Mortality in the Resuscitated Cohorts of Out-of-Hospital Cardiac Arrest
Authors: Zaid Al Jebaje, Umesh C Sharma, Wassim Mosleh, Milind Chaudhari
Journal: Circulation (2018)

Introduction: Out of Hospital Cardiac Arrest (OHCA) is a common and catastrophic manifestation of multiple cardiac and non-cardiac illnesses. Recent studies showed increase in survival rate, reaching to about one third of those who suffer a bystander witnessed OHCA with a shockable rhythm; yet biomarkers to predict outcomes in this group is still missing. Hypothesis: We tested the hypothesis that serum galectin-3, alone or together with galectin-3 binding protein (G3BP),brain natriuretic peptide (BNP) and troponin, can predict the risk of early (30-day) mortality in ResCOHS. Methods: ResCOHS prospective multicenter pilot study enrolled 117 patients with aborted out-of-hospital cardiac arrest, and 10 healthy volunteers. Transthoracic Echocardiogram was performed for cardiac morphology and function. Serum levels of galectin-3, G3BP, BNP and peak troponin were analyzed. Patients were prospectively followed up for 30-days to determine all-cause in-hospital mortality. Results: Among the ResCOHS, patients who died within 30-days had higher BNP and galectin-3 levels, with no differences in the G3BP, peak troponin, CK and CK-MB levels. Receiver operating characteristic analysis for mortality prediction showed that, for 30-day prognosis, galectin-3 had the greatest area under the curve (AUC) at 0.764 (p = 0.001), whereas G3BP, BNP and troponin had an AUC of 0.518 (p = 0.735), 0.759 (p = 0.001)and 0.540 (p=0.460) respectively. In a multivariate logistic regression analysis, an elevated level of galectin-3 was the strongest independent predictor of 30-day mortality (odds ratio 1.04, p = 0.002). The Kaplan-Meier analyses showed that the combination of an elevated galectin-3 with NT-proBNP was a better predictor of mortality than either of the 2 markers alone. Conclusions: In the ResCOHS, higher serum galectin-3 levels are associated with increased chances of death within 30-days of the first episode of cardiac arrest. These findings have implications to target specific therapies to those at the greatest risk of mortality after OHCA.
Cleaved CDCP1 marks the spot: a neoepitope for RAS-driven cancers
Authors: Katelyn L Donahue, Marina Pasca di Magliano
Journal: Journal of Clinical Investigation (2022)

A challenge in cancer treatment is targeting cancer cells while sparing normal cells. Thus, identifying cancer-specific neoepitopes is an active research area. Neoepitopes are generated by the accumulation of mutations; however, deadly cancer types, including pancreatic cancer, have a low mutational burden and, consequently, a paucity of neoantigens. In this issue of the JCI, Lim, Zhou, and colleagues describe a neoepitope generated upon proteolytic cleavage of the transmembrane CUB domain containing protein 1 (CDCP1). CDCP1 is overexpressed in cancer and portends a worse prognosis; previous attempts to target CDCP1 reduced cancer growth, but adversely affected the host. Here, the authors generated an antibody that specifically targeted cleaved CDCP1 (c-CDCP1) and developed a drug conjugate, a vector for radioactive ions, and a mediator of T cell activation. The therapeutics inhibited pancreatic cancer cell growth in vitro and in vivo. Exploiting proteolytic cleavage-derived neoantigens opens an attractive way for specifically targeting cancer cells.
PSA-progression only in high-risk, metastatatic hormone-sensitive prostate cancer patients treated with abiraterone in the LATITUDE trial.
Authors: David Lorente, Nuria Romero, Rebeca Lozano, Silvia Rubio Novella, Angela Montes, Joaquin Mateo, Elena Castro, Alfredo Sanchez, David Olmos
Journal: Journal of Clinical Oncology (2022)

102 Background: The LATITUDE (NCT01715285) trial established the survival benefit of abiraterone (AA) over placebo (PBO) in combination with ADT as first-line therapy in high-risk mHSPC patients. By PCWG3 guidelines, pts with PSA progression and no clinical or radiographic progression should not discontinue therapy. We aimed to evaluate the proportion of patients experiencing PSA progression only in the LATITUDE trial and its prognostic significance. Methods: We performed a retrospective, post-hoc analysis of pts treated in the LATITUDE trial (YODA project #2020-4298). Confirmed PSA progression (PSAProg) and radiographic progression (RadProg) were defined by PCWG2 criteria. Patients with PSA progression with a coinciding radiographic evaluation showing no radiographic progression were defined as progressing by PSA only. In these patients, time from PSA to radiographic progression was defined as the time (months) from the date of confirmed PSAProg to the date of RadProg. Kaplan-meier and Cox models were used to define median survival times and comparison of outcomes in the AA vs PBO groups. Results: 771 patients (63.7%) experienced PSAProg; AA: 302 pts (49.9%); PBO: 469 pts (77.6%). In 501 pts (64.5%) there was no RadProg on the coinciding radiographic evaluation (PSA only progression), 187 (61.9%) in the AA and 314 (67%) in the PBO arm (p = 0.153). 207 (41.3%) pts had measurable disease at baseline, a similar proportion to that in the overall study population (43.8%). 315 (62.9%) of pts with PSA progression only developed subsequent radiographic progression, 105 (56.1%) in the AA and 210 (66.9%) in the PBO arm (p = 0.017). Median time from PSAProg to RadProg was 8.4 months (95%CI: 8.1-9.2); no significant difference was observed in pts in the AA vs PBO arm (9.2 vs 8.3 months; HR: 0.88 [95%CI: 0.7-1.1]; p = 0.287). Median OS from the time of PSAProg was 19.8 months (95%CI:17.2-24) in AA-treated pts. OS from time to PSAProg was longer in AA-treated pts with PSAonly progression than those with simultaneous PSAProg &amp; RadProg (24 vs 15.3 months; HR: 0.62; p = 0.007). Conclusions: A significant proportion of high-risk mHSPC patients experience a PSA rise as the only initial feature of disease progression. In these patients, there appears to be no significant difference in time from PSA to radiographic progression in AA vs PBO treated-patients. These results highlight the need to ensure an appropriate follow-up in pts progressing by PSA, in order to identify radiographic or clinical progression and initiate subsequent therapy early, thereby maximizing benefit from the treatment sequence.
The BARCODE1 study in primary care: Early results targeting men with increased genetic risk of developing prostate cancer—Examining the interim data from a community-based screening program using polygenic risk score to target screening.
Authors: Jana Kathlyn McHugh, Holly ni Raghallaigh, Elizabeth Bancroft, Zsofia Kote-Jarai, Sarah Benafif, Ros A. Eeles
Journal: Journal of Clinical Oncology (2022)

231 Background: A significant proportion of Prostate cancer (PrCa) risk is attributable to heritable risk factors of which only a minority are high risk Mendelian traits. A greater proportion of PrCa is due to the combined effect of multiple low risk variants. There have been approximately 170 single nucleotide polymorphisms (SNPs) identified that are associated with PrCa risk in Europeans. Although each of these confer a low to moderate risk of PrCa, the cumulative risk (polygenic risk score, PRS) of increasing numbers of these risk alleles may confer a substantial relative risk. In PrCa genetic profiling, using PRS, could be used to target population screening to those at highest risk. BARCODE1 is the first study to prospectively review the use of a genetic profile in PrCa screening in the general population in the UK. Methods: Our study invited healthy males aged 55-69 to participate through their Primary Care physicians. Collection kits were mailed to retrieve saliva samples. Genotyping was carried out after DNA extraction using a study specific assay and the PRS was calculated for each participant using the sum of weighted alleles for 130 risk loci. Prostate MRI and Biopsy were then offered to men in the top 10% of the genetic risk profile. Results: 40,292 men were invited by letter to participate. The uptake was 22%, of whom 91% of men were eligible for inclusion. Following DNA extraction, genotyping, and quality control checks, data were available for 5008 men. 573 participants had PRS in the top 10% and were invited for screening; 180 underwent a prostate MRI, and 100 went on to have a systematic +/- targeted prostate biopsy. There were 42 diagnoses of PrCa (42%). 52% of cancers detected were low-risk and are being managed with Active Surveillance (AS). Conclusions: The early data from BARCODE1 have shown the feasibility of this population-based study, with an overall uptake of 22% and a cancer incidence of 42% of men in the top decile of PRS. We have identified clinically significant PrCa in 48%. The BARCODE1 study results will be important in defining the role of PRS genetic profiling in targeted PrCa population screening. Clinical trial information: NCT03857477.
Entrectinib OK'd for Cancers with <i>NTRK</i> Fusions, NSCLC
Journal: Cancer Discovery (2019)

The FDA has approved entrectinib for patients with any solid tumor bearing NTRK fusions, making it the second TRK inhibitor to receive a tissue-agnostic approval; larotrectinib was the first. How the drugs compare to each other remains unknown. Entrectinib was also approved to treat metastatic non-small cell lung cancer with ROS1 rearrangements.
A Phase III Multicenter Randomized Clinical Trial of 60 Gy versus 50 Gy Radiation Dose in Concurrent Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma
Authors: Yujin Xu, Baiqiang Dong, Weiguo Zhu, Jiancheng Li, Rong Huang, Zongwen Sun, Xinmei Yang, Liping Liu, Han He, Zhongxing Liao, Ni Guan, Yue Kong, Wanwei Wang, Jianxiang Chen, Huijuan He, Guoqin Qiu, Ming Zeng, Juan Pu, Wangyuan Hu, Yong Bao, Zhigang Liu, Jun Ma, Hao Jiang, Xianghui Du, Jin Hu, Tingting Zhuang, Jing Cai, Jin Huang, Hua Tao, Yuan Liu, Xiaodong Liang, Juying Zhou, Guangzhou Tao, Xiao Zheng, Ming Chen
Journal: Clinical Cancer Research (2022)

Abstract Purpose: In this multicenter phase 3 trial, the efficacy and safety of 60 Gy and 50 Gy doses delivered with modern radiotherapy technology for definitive concurrent chemoradiotherapy (CCRT) in patients with inoperable esophageal squamous cell carcinoma (ESCC) were evaluated. Patients and Methods: Patients with pathologically confirmed stage IIA‒IVA ESCC were randomized 1:1 to receive conventional fractionated 60 Gy or 50 Gy to the tumor and regional lymph nodes. Concurrent weekly chemotherapy (docetaxel 25 mg/m2; cisplatin 25 mg/m2) and two cycles of consolidation chemotherapy (docetaxel 70 mg/m2; cisplatin 25 mg/m2 days 1‒3) were administered. Results: A total of 319 patients were analyzed for survival, and the median follow-up was 34.0 months. The 1- and 3-year locoregional progression-free survival (PFS) rates for the 60 Gy group were 75.6% and 49.5% versus 72.1% and 48.4%, respectively, for the 50 Gy group [HR, 1.00; 95% confidence interval (CI), 0.75‒1.35; P = 0.98]. The overall survival rates were 83.7% and 53.1% versus 84.8% and 52.7%, respectively (HR, 0.99; 95% CI, 0.73‒1.35; P = 0.96), whereas the PFS rates were 71.2% and 46.4% versus 65.2% and 46.1%, respectively (HR, 0.97; 95% CI, 0.73‒1.30; P = 0.86). The incidence of grade 3+ radiotherapy pneumonitis was higher in the 60 Gy group (nominal P = 0.03) than in the 50 Gy group. Conclusions: The 60 Gy arm had similar survival endpoints but a higher severe pneumonitis rate compared with the 50 Gy arm. Fifty Gy should be considered as the recommended dose in CCRT for ESCC.