tbuckley/cabot-search huggingface dataset:
Testosterone suppression: Impact of testosterone level on disease progression in advanced prostate cancer.
Authors: Shawn Dason, Justin Tong, Christopher Brian Allard, Bobby Shayegan
Journal: Journal of Clinical Oncology (2012)

46 Background: In patients with advanced prostate cancer, medical castration remains a mainstay of treatment. A testosterone level below 50 ng/dL has been previously accepted as an adequate level of androgen suppression and remains the benchmark level for clinical trials. However, there is mounting evidence that lower testosterone levels may be associated with improved clinical outcomes. We evaluated our cohort of patients with advanced prostate cancer to assess the impact of testosterone suppression on progression to castrate resistant prostate cancer (CRPC). Methods: Patient data was obtained from a prospective database of patients undergoing androgen deprivation therapy (ADT) at a tertiary centre from 2006-2011. A total of 39 patients were eligible for inclusion with at least 12 months follow-up. Patients were administered LHRH agonists or antagonist with testosterone and PSA assessments every 3 months. Patients were considered to have progressed to CRPC when there were at least 2 consecutive rises in PSA above nadir, clinical progression, or death from disease. Patients were stratified into two risk groups based on 6-month absolute and 1-year mean testosterone levels following initiation of ADT. Baseline characteristics between risk groups were compared using the Student’s t-test and chi-squared test. Probability of disease progression was assessed using the Kaplan-Meier method and compared using the log-rank test. Results: Median patient follow up was 2.3 years with 38% free of disease at last follow up. Patients with 6-month absolute testosterone less than 32 ng/dL had an increased time to CRPC (log rank p=0.06). Patients with 1-year mean testosterone less than 32 ng/dl had a significantly increased time to CRPC (log rank p=0.005). Patients did not differ significantly in their baseline characteristics. Conclusions: Adequate testosterone suppression during ADT may play a clinically significant role in delaying CRPC. While PSA levels are often used to assess for response to ADT, the current study suggests testosterone level in the first year following initiation of ADT may serve as an early predictor of disease progression.
Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study
Authors: S. Nilsson, P. Cislo, O. Sartor, N.J. Vogelzang, R.E. Coleman, J.M. O'Sullivan, J. Reuning-Scherer, M. Shan, L. Zhan, C. Parker
Journal: Annals of Oncology (2016)

BackgroundRadium-223 dichloride (radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P).Patients and methodsAnalyses were conducted to determine treatment effects of radium-223 plus standard of care (SOC) versus placebo plus SOC on QOL using FACT-P and EQ-5D. Outcomes assessed were percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores during the study.ResultsAnalyses were carried out on the intent-to-treat population of patients randomized to receive radium-223 (n = 614) or placebo (n = 307). The mean baseline EQ-5D utility and FACT-P total scores were similar between treatment groups. A significantly higher percentage of patients receiving radium-223 experienced meaningful improvement in EQ-5D utility score on treatment versus placebo {29.2% versus 18.5%, respectively; P = 0.004; odds ratio (OR) = 1.82 [95% confidence interval (CI) 1.21–2.74]}. Findings were similar for FACT-P total score [24.6% versus 16.1%, respectively; P = 0.020; OR = 1.70 (95% CI 1.08–2.65)]. A lower percentage of patients receiving radium-223 experienced meaningful worsening versus placebo measured by EQ-5D utility score and FACT-P total score. Prior docetaxel use and current bisphosphonate use did not affect these findings. Treatment was a significant predictor of EQ-5D utility score, with radium-223 associated with higher scores versus placebo (0.56 versus 0.50, respectively; P = 0.002). Findings were similar for FACT-P total score (99.08 versus 95.22, respectively; P = 0.004).ConclusionsQOL data from ALSYMPCA demonstrated that improved survival with radium-223 is accompanied by significant QOL benefits, including a higher percentage of patients with meaningful QOL improvement and a slower decline in QOL over time in patients with CRPC.
Correlation of molecular effects and pathologic complete response to preoperative lapatinib and trastuzumab, separately and combined prior to neoadjuvant breast cancer chemotherapy.
Authors: F. A. Holmes, Y. M. Nagarwala, V. A. Espina, L. A. Liotta, M. A. Danso, R. I. Gallagher, K. McIntyre, C. R. C. Osborne, J. M. Mahoney, A. M. Florance, T. C. Anderson, J. O'Shaughnessy
Journal: Journal of Clinical Oncology (2011)

506 Background: Extinction of HER2 signaling in HER2 driven BC may be curative. Alternative activation pathways (HER1, HER3) & mutated downstream signal transducers allow resistance to therapy. Study aim: molecularly characterize HER2+ BC before & after 2 wks anti-HER2 therapy (AHT) with T, L, or T+L & to correlate these with pCR to continuation of same AHT with neoadjuvant chemo (FEC75 x 4 Q3W–>Paclitaxel x 12W). pCR is absence of all invasive cancer in breast & lymph nodes. pCR-Breast used for molecular analysis. Methods: 100 consenting patients (pts) with stage II/III, HER2+ BC, normal cardiac function were randomized to T, L or T+L. Before & after AHT, all pts had core needle biopsies for tissue microarray, stem cell analysis & reverse phase protein microarrays, measuring 60 different phosphoprotein/post-translationally modified protein signaling & gene expression analysis endpoints. Results: pCR in the ITT-E (ITT-E: Pts who had surgery, ≥75% compliant to chemo and took no prohibited meds.) pts: 54%, 45%, 74% for T, L, T+L arms. Analysis by response: 1) Responders (R) have altered HER2 downstream interconnections with PI3K (Spearman rho correlation [rho] 0.5, p=0.12) vs the non-responders [NR] (rho 0.9, p=0.037) & HER3Y1289 correlated (p<0.001 for all endpoints) with EGFRy1173, mTOR 2448, & Beta Catenin 33. 2) NR have a) intact signaling with PI3K (rho 0.9, p=0.037); b) intact interactions with autophagy (PI3K - LC3B rho 0.83, p=0.04); c) intact stem cell – proliferation signaling (Musashi - p70S6 Kinase T389 (p=0.007, rho 0.89), CD44 - PTEN S380 (p<0.001, rho 0.92) were not significant in R. Analysis by AHT, prior to AHT R vs. NR: 1) TRZ MMP-14, 2) LAP EGFRtyr1068 & Fox01/03T24/32 were statistically different. Conclusions: Our study provides a unique in vivo snapshot of molecular changes in signaling pathways of microdissected tumor cells before & after anti-HER2 therapy. Molecular profiles suggest NR use autophagy & stem cell related pathways to evade therapy, while R have disruption of HER2-HER3 linkages & known downstream regulators of growth & transcription. These results provide insights into novel candidate "drugable" targets.
Mucosal inflammation and bronchial hyperreactivity
Authors: L A Laitinen, A Laitinen
Journal: European Respiratory Journal (1988)

Asthma is a chronic disease characterized by increased bronchial responsiveness ranging in degree from mild ~o severe. AU:Way inflammation has been receiving 1ncrcased auenuon as the major mechanism in bronchial hypcrrcsponsiveness. Many stimuli known to induce airwa~ inflam~ation ~lso i.ncrease bronchial reactivity, e.g. v~ral rcsp1ratory mfectJOns, ozone, antigens and chem1ca ls such as toluene diisocyanate (TDI). ~nflamma~ion should be understood not only as an mcrease m the number of inflammatory cells, but also as including an increase in the bronchial blood flow and vascular permeability leading to mucosal oedema and epithelial shedding. The time sequence and severity of this inflammatory process in the pathogenesis of asthma is not known, although some information of the separate events has been obtained in recent studies (LAITINEN et al. [1]; BARNES [2]· PERssoN [3)) •
Long‐term outcomes of thrombotic microangiopathy treated with plasma exchange: A systematic review
Authors: Bashiar Thejeel, Amit X. Garg, William F. Clark, Aiden R. Liu, Arthur V. Iansavichus, Ainslie M. Hildebrand
Journal: American Journal of Hematology (2016)

With the adoption of plasma exchange as standard treatment for thrombotic microangiopathy (TMA), more patients are surviving and long-term outcomes have greater relevance. We conducted a systematic review to synthesize and evaluate the quality of evidence on long-term outcomes of TMA among adults treated with plasma exchange and to identify factors that may be associated with a worse long-term prognosis. We searched databases from 1980 to 2013 for eligible articles published in any language. We included studies that reported outcomes in at least ten adults with a history of TMA treated with plasma exchange and at least 6 months of follow-up. We abstracted data in duplicate and assessed the methodological quality of each study using an assessment tool developed based on recommended validity criteria. We screened 6672 articles, reviewed 213, and included 34 studies totaling 1182 patients (study median [range], 24 [10-118]). The mean (or median) follow-up ranged from 6 months to 13 years. The cumulative incidence of relapse and mortality was highly variable and ranged from 3 to 84 and 0 to 61%, respectively. The incidence of other outcomes across 10 studies also varied (outcomes included hypertension, kidney disease, preeclampsia, stroke, seizure, severe cognitive impairment, and depression); in three other studies, long-term neurocognitive function and health-related quality of life were significantly lower than in the general population. Patients who survive an episode of TMA may be susceptible to long-term vascular complications, but the magnitude of this risk and how to mitigate it remains unclear. Am. J. Hematol. 91:623-630, 2016. © 2016 Wiley Periodicals, Inc.
“Real-Time” Monitoring of Under-Five Mortality: Lessons for Strengthened Vital Statistics Systems
Authors: Jennifer Bryce, Agbessi Amouzou, Cesar G. Victora, Gareth Jones, Romesh Silva, Kenneth Hill, Robert E. Black
Journal: PLoS Medicine (2016)

Civil registration and vital statistics systems are increasingly recognized as drivers of human rights, health, and development programs—especially for women and children [1]. Vital statistics systems are weak in most low-income countries [2,3], precisely where the burden of maternal and child deaths is highest and, therefore, the need for up-to-date, high-quality estimates of levels and trends in maternal and child mortality is greatest [4]. The UN Commission on Information and Accountability for Women’s and Children’s Health identified the reporting of births and deaths as a cornerstone for vital statistics systems in low-income countries [5]. This has led to intensified efforts to support and strengthen the routine reporting of vital events [6].

In this paper, we synthesize results generated by the Real-Time Monitoring of Under-Five Mortality (RMM) project, and highlight aspects that can inform efforts to strengthen vital statistics systems in low-income countries. Table 1 provides an overview of the methods tested by the RMM project in Ethiopia, Ghana, Malawi, Mali, and Niger. Full details on the design and implementation of RMM methods, the accuracy of the mortality estimates they produce, and their running costs are reported in the papers that form the Collection.

Table 1
Real-time mortality monitoring (RMM) approaches tested, by country.

		Community-based reporting on vital events	Adjusted health facility data	Rapid household survey methods
		Paid worker 	Unpaid worker 		Repeated 	Imputed 
Ethiopia	✓			✓	✓	
Ghana		✓			✓	
Malawi	✓		✓	✓	✓	
Mali		✓			✓	
Niger				✓	✓	


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The RMM project produced two sets of overarching findings: 1) quantitative results on the accuracy of under-five mortality estimates produced by various methodological approaches; and 2) experiential findings on the challenges of generating vital statistics for recent periods in real-world settings.
Tackling the crisis in general practice
Authors: Martin Roland, Sam Everington
Journal: BMJ (2016)

<h3>Introduction</h3> Neurocritical care is a rapidly developing subspecialty within intensive care medicine which aims to improve outcomes of critically ill neurological patients. This has inspired the formation of specialised intensive care units or services to provide dedicated care of brain-injured patients, as well as new training pathways for physicians. However, expansion has been variable worldwide and it is yet to be determined if there are clear benefits in regard to patient outcomes. We are planning a systematic review with meta-analysis to assess whether the introduction of neurocritical care units or services, or neurointensivists have favourable effects on survival. <h3>Methods and analysis</h3> We will include all observational and interventional studies comparing specialised neurocritical care units or services with general or non-specialised units in the care of acutely brain-injured adults. The primary outcome will be all-cause mortality at the longest follow-up, and secondary outcomes will be intensive care unit and hospital length of stay, and functional outcomes. All relevant studies will be identified through database searches. All study selection and data extraction will be conducted by two independent reviewers. We will conduct a random-effects meta-analysis to synthesise evidence for all outcomes. In addition, we will perform a subgroup analysis by disease process. We will assess confidence in the cumulative evidence using the Grading of Recommendations, Assessment, Development and Evaluations framework. <h3>Ethics and dissemination</h3> This systematic review and meta-analysis does not require ethical approval. We will publish findings from this systematic review in a peer-reviewed scientific journal and present these at conferences. It will be included in the primary author's higher degree research thesis. <h3>PROSPERO registration number</h3> CRD42020177190.
Does First-Line Therapy Affect the Outcome of Patients with Pancreatic Cancer?
Authors: M. Santoni, A. Bittoni, K. Andrikou, A. Lanese, C. Pellei, A. Conti, P. Bertocchi, A.E. Brunetti, M. Russano, V. Vaccaro, N. Silvestris, M. Milella, D. Santini, A. Zaniboni, S. Cascinu
Journal: Annals of Oncology (2014)
Nonproliferating Neoplastic Cells in Culture: Behavior of the Adenine Nucleotides
Authors: A D Glinos, K R Warren
Journal: JNCI Journal of the National Cancer Institute (1979)

The intracellular concentrations of the adenine nucleotides were determined in suspension cultures of WRL-10A cells, a subline of the L-929 mouse fibroblasts, during the progression of the cells from exponential growth to high-density, nonproliferating populations. The development of the nonproliferating state was associated with a 50% reduction of the adenine nucleotide pool, whereas the energy charge remained at values above 0.90. This change was also observed in the early phase of starvation of low-density cultures and could be reproduced by selective simultaneous withdrawal of glucose and glutamine, which indicated interference with the de novo synthesis of purines. In this respect, therefore, nonproliferating populations of WRL-10A cells resemble purine-limited bacterial systems but not density-inhibited normal fibroblasts in which the size of the adenine nucleotide pool is known to remain unchanged. This difference in the physiologic state of nonproliferating normal and neoplastic cells is potentially significant for tumor chemotherapy.
Abstract 14690: Tnf-a Overproduction in Post-Ischemic Hearts Abolishes the Cardioprotection of Late Insulin Treatment
Authors: Feng Fu, Jie Xu, Haifeng Zhang, Jia Li, Feng Gao
Journal: Circulation (2013)

Background:  Previous studies from our lab and others have demonstrated that early insulin treatment protects the heart against acute myocardial ischemia (AMI) injury. However, early insulin treatment is not always available for all the AMI patients. In this study we thus compared the effects of early and late insulin treatment on post-ischemic cardiac funtion and remodeling and the underlying mechanisms.   Methods and Results:  Ischemic heart failure was induced by left anterior descending coronary artery occlusion in male SD rats. Early insulin treatment (20 min after MI) improved cardiac function and retarded ventricular remodeling, as evidenced by increased ejection fraction (58.4 ± 3.2% vs. 40.1 ± 2.0% of saline, n=11,  P  P  P    Conclusions:  These data demonstrate that early insulin treatment improves cardiac function and retards ventricular remodeling in the MI rats. While late insulin treatment at 1 week after MI fails to exert the protective effects due to myocardial insulin resistance induced by TNF-α overproduction.
Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy
Authors: Khurrum Shahzad, Fabian Bock, Moh’d Mohanad Al-Dabet, Ihsan Gadi, Shrey Kohli, Sumra Nazir, Sanchita Ghosh, Satish Ranjan, Hongjie Wang, Thati Madhusudhan, Peter P. Nawroth, Berend Isermann
Journal: Journal of the American Society of Nephrology (2016)

Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1β), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucose-stressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.
Detection of circulating tumor cells in peripheral blood of patients who underwent lung cancer surgery
Authors: T. Hirata, K. Takenaka, E. Nakayama, M. Sonobe, F. Chen, T. Shoji, T. Fujinaga, H. Sakai, K. Sato, R. Miyahara, H. Date
Journal: Journal of Clinical Oncology (2008)

7564 Background: We tested the hypothesis that circulating tumor cells (CTCs) are detected in patients who underwent lung cancer surgery using the CellSearch system (Veridex LLC, Warren, NJ). Methods: Blood was drawn from 27 patients who received lung cancer surgery and 42 healthy volunteers. In total, eighty-one blood samples were collected from each donor who underwent lung cancer surgery just before starting operation, immediately after tumor resection, and about one hour after operation. Eighty-two samples were collected from 42 healthy volunteers. CTCs were enumerated using the CellSearch system. Results: In 42 healthy volunteers, 4.9% (4 of 82 samples) had one detectable CTC in 7.5 mL of blood, but no sample had more than one detectable CTC. Thus, we established 2 detectable CTCs as the cutoff level of CTC-positivity. In 27 patients who received lung cancer surgery, 25.9% (21 of 81 samples) had one detectable CTC and 16.0% (13 of 81 samples) had two or more detectable CTCs. Four of 6 CTC-positive cases before surgery were in I pathologic stages. Three of 4 cases who were CTC-negative before surgery, but CTC-positive during or after surgery, were T2 or T3 in TNM classification. Conclusions: CTCs were detected in the peripheral blood of patients with lung cancer, before, during, and after surgery. The results of this study may suggest the possibility of micrometastasis in blood in early-stage lung cancer and of blood dissemination during lung cancer surgery. No significant financial relationships to disclose.
Abstract P5-03-04: Effect of aging on the function and transformation of murine mammary stem cells
Authors: A Bandyopadhyay, Q Dong, D Wang, H Gao, A Wu, I-T Yeh, L Sun
Journal: Cancer Research (2012)

Abstract Epidemiological studies have shown that the risk of getting breast cancer progressively increases with age. A woman is 100 times more susceptible to develop breast cancer in her 60s than in her 20s. A better understanding of altered cellular and molecular mechanisms leading to the development of sporadic breast cancers as a result of aging are urgently needed for its prevention and treatment in growing population of older women. Recent research implicated that adult mammary stem cells (MaSCs) might be responsible for the initiation and progression of certain types of breast cancer. But no studies have been reported on how lifelong exposure of MaSCs to endogenous and environmental stresses during aging compromises their self-renewal and differentiation function and predispose them to neoplastic transformation either spontaneously or after carcinogen exposure. In our study, we have investigated the effect of progressive aging and carcinogen exposure on MaSC number and function in a murine model. The FACS isolated MaSC enriched basal cells, characterized by their immunophenotype (Lin−CD49fhighCD24med) were utilized to evaluate MaSC frequency and function during aging by in vitro mammosphere formation and 3D-ECM sphere differentiation assay as well as by in vivo cleared mammary fat pad transplantation (IVT). The results of our study showed that the percentage of MaSCs analyzed by both FACS profile and in vitro assays, increased steadily with increasing age observed at 2, 7, 17 and 25 month-old C57BL/6 mice. Subsequent IVT using mammosphers or 3D structures formed by young (4 months) and old MaSCs (28 months) derived from C57BL/6 mice showed similar in vivo functional mammary gland regenerative capacity indicating similar self-renewal/differentiation ability between young and old MaSCs. However, we found that the regenerated glands from old MaSCs had significantly higher number of spontaneous pre-neoplastic lesions (52.0%) than those from young MaSCs (18.3%). Significantly, MaSC frequency was also increased by the in vivo exposure of a carcinogen, N-Methyl-N-Nitrosourea (MNU, 25 mg/kg body weight, once a week for three consecutive weeks), in old mice with no effect on total mammary cell number. Furthermore, the old MaSCs expanded by MNU treatment were still capable of in vivo regeneration with similar success rate as that of normal old MaSCs. But, we observed increased frequency of hyperplasia and dysplasia in the regenerated glands initiated by MNU treated old MaSC. Our results indicate that MaSCs might be the precursors of preneoplastic lesions and old MaSCs appear to be predisposed to premalignant transformation, which is enhanced by the exposure to a DNA damaging agent. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-04.