tbuckley/cabot-search huggingface dataset:
A randomized phase 2 study of the Bruton tyrosine kinase (Btk) inhibitor acalabrutinib alone or with pembrolizumab for metastatic pancreatic cancer (mPC).
Authors: Michael J. Overman, Charles D. Lopez, Al Bowen Benson, Sattva Swarup Neelapu, Niharika B. Mettu, Andrew H. Ko, Vincent M. Chung, John J. Nemunaitis, James Andrew Reeves, Johanna C. Bendell, Philip Agop Philip, Rita Dalal, Maria Fardis, Joy Greer, Xiaolin Wang, Sandeep Inamdar, Brian Joseph Lannutti, Wayne Rothbaum, Raquel Izumi, Milind M. Javle
Journal: Journal of Clinical Oncology (2016)

4130 Background: The importance of the tumor microenvironment in the biology of mPC has been increasingly recognized. However, immune checkpoint blockade has previously shown limited clinical responses in mPC. Preclinical studies in PC indicate promising anti-tumor effect from acalabrutinib alone and in combination with pembrolizumab. Methods: This was a Phase 2, multicenter, open-label, randomized (1:1; n = 38/arm) study (NCT02362048) evaluating the Btk inhibitor, acalabrutinib (ACP-196) alone (mono) or in combination (combo) with pembrolizumab. This study included a safety run-in that assessed the first 6 patients (pts) enrolled in the combo arm for dose-limiting toxicity (DLT). Adults with histologically confirmed pancreatic ductal adenocarcinoma who had received ≥ 1 prior systemic therapy for mPC were eligible. Acalabrutinib 100 mg PO BID was administered days 1-21 and pembrolizumab 200 mg IV day 1 of each 3-week cycle. Response was assessed every 2 cycles using RECIST 1.1. Blood was collected for exploratory correlative analyses. Results: Preliminary results are provided for the first 58 treated pts (26 mono arm, 32 combo arm). The median number of prior treatments was 2. No DLTs occurred. Grade 3-4 events that occurred in ≥ 2 pts were dehydration (12%), anemia (12%) and hypotension (8%) on the mono arm and were anemia (9%) and abdominal pain (9%) on the combo arm. No Grade 5 treatment-related events were reported. 44 pts (21 mono arm, 23 combo arm) were evaluable for response. In the mono arm, 4 stable disease (SD) were reported. In the combo arm, 3 partial responses (2 PR, 1 PRu), including 1 pt with near resolution of bulky peritoneal disease, and 5 SD were reported. All 3 PRs occurred in pts with a strong family history of pancreatic or breast cancer. Germline testing identified BRCA2VUS in one responder. At the time of the data cut, the median time on study for pts with responses was 3.7 months (range 1.4-4.1). Conclusions: The combination of acalabrutinib and pembrolizumab has a favorable benefit/risk profile and encouraging preliminary antitumor activity in pretreated mPC, particularly in a subpopulation of pts with familial mPC. Clinical trial information: NCT02362048.
The Predictive Value of the Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (CI) in Recipients of Umbilical Cord Blood (UCB) Transplantation.
Authors: Claudio G. Brunstein, Navneet Majhail, Daniela C. Setubal, Todd E. DeFor, Jeffrey S. Miller, Philip B. McGlave, Bruce R. Blazar, Daniel J. Weisdorf, John E. Wagner
Journal: Blood (2007)
Evolutionary Dynamics of Abundant Stop Codon Readthrough
Authors: Irwin Jungreis, Clara S. Chan, Robert M. Waterhouse, Gabriel Fields, Michael F. Lin, Manolis Kellis
Journal: Molecular Biology and Evolution (2016)

Translational stop codon readthrough emerged as a major regulatory mechanism affecting hundreds of genes in animal genomes, based on recent comparative genomics and ribosomal profiling evidence, but its evolutionary properties remain unknown. Here, we leverage comparative genomic evidence across 21 Anopheles mosquitoes to systematically annotate readthrough genes in the malaria vector Anopheles gambiae, and to provide the first study of abundant readthrough evolution, by comparison with 20 Drosophila species. Using improved comparative genomics methods for detecting readthrough, we identify evolutionary signatures of conserved, functional readthrough of 353 stop codons in the malaria vector, Anopheles gambiae, and of 51 additional Drosophila melanogaster stop codons, including several cases of double and triple readthrough and of readthrough of two adjacent stop codons. We find that most differences between the readthrough repertoires of the two species arose from readthrough gain or loss in existing genes, rather than birth of new genes or gene death; that readthrough-associated RNA structures are sometimes gained or lost while readthrough persists; that readthrough is more likely to be lost at TAA and TAG stop codons; and that readthrough is under continued purifying evolutionary selection in mosquito, based on population genetic evidence. We also determine readthrough-associated gene properties that predate readthrough, and identify differences in the characteristic properties of readthrough genes between clades. We estimate more than 600 functional readthrough stop codons in mosquito and 900 in fruit fly, provide evidence of readthrough control of peroxisomal targeting, and refine the phylogenetic extent of abundant readthrough as following divergence from centipede.
A Single Centre Analysis of Spectra Optia Stem Cell Collection Data from Multiple Myeloma and Lymphoma Patients, with and without Plerixafor
Authors: Joy Buckley, Janusz Krawczyk, Fionnuala Ni Chonchubhair, Nelly Besson, Margaret Tarpey, Margaret Murray, Michael C O'Dwyer, Amjad Hayat
Journal: Blood (2014)
Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary
Authors: Didier Dewailly, Geoffroy Robin, Maëliss Peigne, Christine Decanter, Pascal Pigny, Sophie Catteau-Jonard
Journal: Human Reproduction Update (2016)

Androgens, FSH, anti-Müllerian hormone (AMH) and estradiol (E2) are essential in human ovarian folliculogenesis. However, the interactions between these four players is not fully understood. The purpose of this review is to highlight the chronological sequence of the appearance and function of androgens, FSH, AMH and E2 and to discuss controversies in the relationship between FSH and AMH. A better understanding of this interaction could supplement our current knowledge about the pathophysiology of the polycystic ovary syndrome (PCOS). A literature review was performed using the following search terms: androgens, FSH, FSH receptor, anti-Mullerian hormone, AMHRII, estradiol, follicle, ovary, PCOS, aromatase, granulosa cell, oocyte. The time period searched was 1980–2015 and the databases interrogated were PubMed and Web of Science. During the pre-antral ('gonadotropin-independent') follicle growth, FSH is already active and promotes follicle growth in synergy with theca cell-derived androgens. Conversely, AMH is inhibitory by counteracting FSH. We challenge the hypothesis that AMH is regulated by androgens and propose rather an indirect effect through an androgen-dependent amplification of FSH action on granulosa cells (GCs) from small growing follicles. This hypothesis implies that FSH stimulates AMH expression. During the antral ('gonadotropin-dependent') follicle growth, E2 production results from FSH-dependent activation of aromatase. Conversely, AMH is inhibitory but the decline of its expression, amplified by E2, allows full expression of aromatase, characteristic of the large antral follicles. We propose a theoretical scheme made up of two triangles that follow each other chronologically. In PCOS, pre-antral follicle growth is excessive (triangle 1) because of intrinsic androgen excess that renders GCs hypersensitive to FSH, with consequently excessive AMH expression. Antral follicle growth and differentiation are disturbed (triangle 2) because of the abnormally persisting inhibition of FSH effects by AMH that blocks aromatase. Beside anovulation, this scenario may also serve to explain the higher receptiveness to gonadotropin therapy and the increased risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS. Within GCs, the balance between FSH and AMH effects is pivotal in the shift from androgen- to oestrogen-driven follicles. Our two triangles hypothesis, based on updated data from the literature, offers a pedagogic template for the understanding of folliculogenesis in the normal and polycystic ovary. It opens new avenues for the treatment of anovulation due to PCOS.
Perspectives on psychological distress in cancer patients: Comparison between expected, perceived and actual disturbances in a clinic from Argentina
Authors: F. Torrente, D. Gercovich, H. Hirsch, P. Margiolakis, E. Gil Deza, E. Morgenfeld, J. Pollola, B. Rolnik, F. G. Gercovich
Journal: Journal of Clinical Oncology (2006)

18515 Background: Psychological distress is a widespread phenomenon in cancer patients (pts.) Notwithstanding, its recognition and the threshold criteria for referral to a specialized unit are still problematic in clinical practice. Correspondingly, the aim of this study was to explore how much psychological distress (PD) is expected by the oncologists, how much distress is actually present in these pts., and finally how many of them are detected as having significant problems and referred to the mental health unit (MHU). Methods: Three sources of data were compared for the purpose of this study. Firstly, a survey to the practicing oncologists (n =18) was carried out in order to establish the rate of PD expected by them. Secondly, a consecutive sample of 259 pts. was evaluated in the waiting room with the Hospital Anxiety and Depression Scale (HADS) for establishing an estimation of the actual rate of PD in this population. Finally, 115 pts. from the MHU were studied for determining the rate and the accuracy of the referral made by the oncologists. Results: Sixty one percent of the surveyed oncologists considered that 75% or more of their pts would need psychological assistance. The waiting room sample evaluated with the HADS showed that 74.9% of patients surpassed the cutoff score (11 points) for either anxiety or depression, or both. Despite this, less than 5% of the total population of the clinic was referred to the MHU. From this sample, 38.3% of the pts. scored below the cutoff line. The proportion of pts. who exceeded the cutoff score for depression was significantly higher in the MHU sample. Conclusions: Most of the oncologists expect a high rate of PD in their patients, and even overestimate it. Actual rates of anxiety and depression were also high. On the contrary, the rate of referral to specialized mental health treatment was extremely low and the pts. referred were not necessarily highly disturbed. Depression is probably better recognized than anxiety by oncologists. In conclusion, both quantitative and qualitative problems were detected in the referral to the MHU, regardless the awareness of the oncologists about PD. No significant financial relationships to disclose.
Between Death and Hope After Out-of-Hospital Cardiac Arrest
Authors: Luigi M. Biasucci, Giovanna Liuzzo
Journal: Journal of the American College of Cardiology (2015)

“Lasciate ogni speranza di riveder lo cielo o voi che entrate.” —Dante Alighieri’s Divina Commedia [(1)][1]

These words, on the entrance of the “Inferno” in the Divina Commedia , translate as “Abandon all hope you who enter here.” Fortunately, these words are inappropriate in
The Simultaneous Accumulation of the Extremely Cytotoxic Interstrand Cross-Links and Double-Strand Breaks Contributes to the Successful Anti-Myeloma Therapy; The Effect of DNA Repair Inhibitors
Authors: Maria Gkotzamanidou, Evangelos Terpos, Nikhil C. Munshi, Vassilis L. Souliotis, Meletios A. Dimopoulos
Journal: Blood (2015)
Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway
Authors: Qian Mei, Xiang Li, Kang Zhang, Zhiqiang Wu, Xiaolei Li, Yuanguang Meng, Mingzhou Guo, Guangbin Luo, Xiaobing Fu, Weidong Han
Journal: Clinical Cancer Research (2016)

Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented.The loss of heterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-PCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analyses were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation-specific PCR. The tumor-suppressing effects of miR-181a2/181b2 were determined in vitro and in vivo The target gene and signaling pathway that mediated the function of miR-181a2/181b2 were also identified.Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Underexpression of miR-181a2/181b2 was detected in 46% of cervical cancer and was induced by the LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro They also effectively impeded tumor formation and growth in vivo miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55γ) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway.We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the underexpression of miR-181a2/181b2, leading to the elevated activation of the PI3K pathway. Clin Cancer Res; 23(2); 575-86. ©2016 AACR.
Effect of syk inhibition by TAK659 on proliferative, survival, and migratory signals from the microenvironment in chronic lymphocytic leukemia.
Authors: Noelia Purroy, Pau Abrisqueta, Julia Carabia, Eva Calpe, Cecilia Carpio, Carles Palacio, Marta Crespo, Francesc Bosch
Journal: Journal of Clinical Oncology (2014)

7058 Background: Chronic lymphocytic leukemia (CLL) is characterized by the accumulation and proliferation of monoclonal CD5+ mature B-cells in peripheral blood, lymph nodes (LN), and bone marrow (BM). The microenvironment in BM and LN induces proliferation of CLL cells and protects them from spontaneous and chemotherapy-induced apoptosis. Syk is a tyrosine kinase essential for the BCR signaling pathway that also participates in signaling from chemokine receptors and has been shown to be deregulated in CLL. Therefore Syk has been hypothesized to be a rational candidate for targeted therapy in CLL and its inhibition has been tested with the non-specific Syk inhibitor fostamatinib (R406). Against this background we tested the effectiveness of the highly specific Syk inhibitor TAK-659 in suppressing the induction of survival, proliferation and migration of CLL cells by the microenvironment. Methods: To mimic the microenvironment of the proliferative centers ex vivo, we co-cultured primary CLL cells with BM stromal cells (BMSC), CD40L, and CpG ODN along with anti-IgM (BCR stimulation). We evaluated the effects of TAK-659 on BCR signaling, proliferation, apoptosis and chemotaxis. Results: The co-culture system with BMSC and different stimuli induced survival and proliferation of primary CLL cells. Moreover, in this system CLL cells became chemoresistant to fludarabine and bendamustine. TAK-659 inhibited the phosphorylation of Syk, Akt, and ERK1/2 after BCR stimulation. TAK-659 induced apoptosis of co-cultured CLL cells at lower doses than R406. In addition, combination of TAK659 and fludarabine showed a synergistic effect in inducing apoptosis. TAK-659 also inhibited co-culture-induced proliferation, as assessed by Ki-67 expression, and significantly decreased chemotaxis of CLL cells toward CXCL12, CXCL13 and BMSCs. Conclusions: These findings demonstrate that, in this ex-vivo system, the specific inhibition of Syk by TAK-659 effectively overcomes the microenvironment signals that promote proliferation, survival and chemoresistance of primary CLL cells. Altogether, this study provides a rationale for the clinical development of TAK-659 in CLL.
Development and internal validation of a clinical rule to improve antibiotic use in children presenting to primary care with acute respiratory tract infection and cough: a prognostic cohort study
Authors: Alastair D Hay, Niamh M Redmond, Sophie Turnbull, Hannah Christensen, Hannah Thornton, Paul Little, Matthew Thompson, Brendan Delaney, Andrew M Lovering, Peter Muir, John P Leeming, Barry Vipond, Beth Stuart, Tim J Peters, Peter S Blair
Journal: The Lancet Respiratory Medicine (2016)

Antimicrobial resistance is a serious threat to public health, with most antibiotics prescribed in primary care. General practitioners (GPs) report defensive antibiotic prescribing to mitigate perceived risk of future hospital admission in children with respiratory tract infections. We developed a clinical rule aimed to reduce clinical uncertainty by stratifying risk of future hospital admission.8394 children aged between 3 months and 16 years presenting with acute cough (for ≤28 days) and respiratory tract infection were recruited to a prognostic cohort study from 247 general practitioner practices in England. Exposure variables included demographic characteristics, parent-reported symptoms, and physical examination signs. The outcome was hospital admission for respiratory tract infection within 30 days, collected using a structured, blinded review of medical records.8394 (100%) children were included in the analysis, with 78 (0·9%, 95% CI 0·7%-1·2%) admitted to hospital: 15 (19%) were admitted on the day of recruitment (day 1), 33 (42%) on days 2-7; and 30 (39%) on days 8-30. Seven characteristics were independently associated (p<0·01) with hospital admission: age <2 years, current asthma, illness duration of 3 days or less, parent-reported moderate or severe vomiting in the previous 24 h, parent-reported severe fever in the previous 24 h or a body temperature of 37·8°C or more at presentation, clinician-reported intercostal or subcostal recession, and clinician-reported wheeze on auscultation. The area under the receiver operating characteristic (AUROC) curve for the coefficient-based clinical rule was 0·82 (95% CI 0·77-0·87, bootstrap validated 0·81). Assigning one point per characteristic, a points-based clinical rule consisting of short illness, temperature, age, recession, wheeze, asthma, and vomiting (mnemonic STARWAVe; AUROC 0·81, 0·76-0·85) distinguished three hospital admission risk strata: very low (0·3%, 0·2-0·4%) with 1 point or less, normal (1·5%, 1·0-1·9%) with 2 or 3 points, and high (11·8%, 7·3-16·2%) with 4 points or more.Clinical characteristics can distinguish children at very low, normal, and high risk of future hospital admission for respiratory tract infection and could be used to reduce antibiotic prescriptions in primary care for children at very low risk.National Institute for Health Research (NIHR).
Docetaxel (D) plus gemcitabine (G) compared with G in elderly patients with advanced non-small cell lung cancer (NSCLC): Preliminary results of a randomized phase III Hellenic Oncology Research Group trial.
Authors: A. Karampeazis, L. Vamvakas, A. G. Pallis, C. Christophyllakis, N. K. Kentepozidis, V. Chandrinos, A. Polyzos, A. Athanasiadis, G. Milaki, V. Georgoulias
Journal: Journal of Clinical Oncology (2010)

7605 Background: To compare the docetaxel/gemcitabine (DG) combination versus gemcitabine (G) as first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC). Methods: Chemotherapy-naïve patients >70y old with stage IIIB/IV NSCLC and performance status (PS) 0-2 were stratified according to stage and PS and randomized to either D 30 mg/m2 plus G 900mg/m2 (days 1 and 8) or G 1,200mg/m2 (days 1 and 8) every 21 days. A comprehensive geriatric assessment (CGA) was also performed. Results: From 3/2006 to 12/2009, 94 patients (DG n=49; G n=45) were enrolled onto the study. Median age was 74 (range, 70 to 84) and 78 years (range, 70 to 92) in the DG and D arm respectively (p<0.001). Sixty-five (69%) patients had stage IV disease and 16 (17%) a PS of 2. With a median follow-up of 10.27 months, there was no difference in terms of median OS (15.9 vs. 12.2 months; p=0.072), median TTP (3.17 vs. 2.53 months; p=0.227) and ORR (28.3% vs. 11.6%; p=0.066). Patients with an Instrumental Activities of Daily Living (IADL) score <7 had a significantly lower median OS (10.13 vs. 17.3 months; p=0.025) and median TTP (2.13 vs. 4.7 months; p=0.023) than patients with an IALD score of 7-8. The most common toxicity was grade 3/4 neutropenia (8.1% and 6.6% for DG and G, respectively; p=0.545). Conclusions: The DG regimen did not improve OS and TTP in elderly patients with NSCLC; however, patients with high IADL score have a significantly better clinical outcome than patients with low IADL score. No significant financial relationships to disclose.
Digitally deconvolving the tumor microenvironment
Authors: Dvir Aran, Atul J. Butte
Journal: Genome biology (2016)

Understanding a tumor's complex cellular heterogeneity will be crucial for the development of better treatment strategies. A new study suggests a novel method for the in silico dissociation of solid tumors and presents novel insights that have implications for immunotherapy in cancer. Please see the related Research article: www.dx.doi.org/10.1186/s13059-016-1028-7 .
Use of Antipsychotics During Pregnancy
Authors: Katherine L. Wisner, Hyunyoung Jeong, Christina Chambers
Journal: JAMA Psychiatry (2016)

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Different measles outbreaks in Belgium, January to June 2016 – a challenge for public health
Authors: Tine Grammens, Virginie Maes, Veronik Hutse, Valeska Laisnez, Carole Schirvel, Jean Marie Trémérie, Martine Sabbe
Journal: Eurosurveillance (2016)

During the first half of 2016, several outbreaks of measles were reported in the three regions of Belgium. Main challenges for public health were severe complications occurring in adults, nosocomial transmission and infection in healthcare workers. Here, we describe those outbreaks and lessons learnt for public health.