tbuckley/cabot-search huggingface dataset:
Evidence for sex-specific genetic architectures across a spectrum of human complex traits
Authors: Konrad Rawlik, Oriol Canela-Xandri, Albert Tenesa
Journal: Genome biology (2016)

Sex differences are a common feature of human traits; however, the role sex determination plays in human genetic variation remains unclear. The presence of gene-by-sex (GxS) interactions implies that trait genetic architecture differs between men and women. Here, we show that GxS interactions and genetic heterogeneity among sexes are small but common features of a range of high-level complex traits. We analyzed 19 complex traits measured in 54,040 unrelated men and 59,820 unrelated women from the UK Biobank cohort to estimate autosomal genetic correlations and heritability differences between men and women. For 13 of the 19 traits examined, there is evidence that the trait measured is genetically different between males and females. We find that estimates of genetic correlations, based on ~114,000 unrelated individuals and ~19,000 related individuals from the same cohort, are largely consistent. Genetic predictors using a sex-specific model that incorporated GxS interactions led to a relative improvement of up to 4 % (mean 1.4 % across all relevant phenotypes) over those provided by a sex-agnostic model. This further supports the hypothesis of the presence of sexual genetic heterogeneity across high-level phenotypes. The sex-specific environment seems to play a role in changing genotype expression across a range of human complex traits. Further studies of GxS interactions for high-level human traits may shed light on the molecular mechanisms that lead to biological differences between men and women. However, this may be a challenging endeavour due to the likely small effects of the interactions at individual loci.
Obstetric anal sphincter injury
Journal: BMJ (2010)

Obstetric trauma following childbirth is the primary cause of faecal incontinence in women. Injury to the anal sphincter complex is common: it has been clinically diagnosed in 0.4‐2.5% of vaginal deliveries involving a mediolateral episiotomy and in up to 19% of cases of midline episiotomy. Studies using endoanal ultrasound have reported occult anal sphincter injury in up to 35% of women after their first delivery. This paper reviews the risk factors for obstetric anal sphincter injury, as well as diagnosis and management of the condition.
Preliminary Experience of the Spanish Compassionate Use Registry of Bendamustine in Patients with Relapsed and/or Refractory Multiple Myeloma
Authors: Beatriz Aguado Bueno, Isabel VicuÑa Andres, Laura Entrena, Felipe De Arriba, Isabel Krisnik, BegoÑa Navas, Marta Callejas, Anabel Teruel, Aurelio Lopez, Tomas Gonzalez Lopez, Inmaculada Castillo, Jaime Perez De Oteyza, Dunia De Miguel, Sara Rivas Calvo, Raquel Rodriguez Posada, Adrian Alegre
Journal: Blood (2012)
Abstract 4673: A novel way to sensitize pancreatic cancer cells for gemcitabine treatment
Authors: Jingwu Xie, Dongsheng Gu, Xiaoli Zhang, Yanfei Jia, Gabi Chiorean
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a dismal median survival of 6 months. While combining albumin-bound paclitaxel with gemcitabine has shown clear therapeutic advantage, numerous attempts using novel targeted therapies did not yield clinical benefits. Gemcitabine is still the first-line treatment for patients with PDAC. We hypothesize that strategies to increase gemcitabine sensitivity may be effective in PDAC treatment. In this study, we report that cancer stem cell regulator Sox2 is highly induced in acquired gemcitabine resistant pancreatic cell lines, and down-regulation of Sox2 sensitizes cancer cells to gemcitabine treatment both in the cultured cells and in mouse models. Down-regulation of Gli1/2 was associated with reduced Sox2 expression, decreased expression of cancer stem cell markers. We found Gli1/2 proteins in association with a Sox2 promoter sequence with a putative Gli binding site, suggesting a direct regulation of Sox2 by Gli1/2. We further showed that down-regulation of Gli1 or Gli2 was as effective as Sox2 knockdown in sensitizing cancer cells to gemcitabine treatment. The relevance of Gli1/2-Sox2 signaling axis to PDAC was suggested by association of high Sox2 expression with poor survival in stage II PDAC patients. Taken together, our data indicate an important role of non-canonical hedgehog signaling in regulation of gemcitabine sensitivity, and down-regulation of Gli1/2 transcription factors, together with gemcitabine, may be effective in pancreatic cancer treatment. Citation Format: Jingwu Xie, Dongsheng Gu, Xiaoli Zhang, Yanfei Jia, Gabi Chiorean. A novel way to sensitize pancreatic cancer cells for gemcitabine treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4673.
Flow-Mediated Vasodilation of a Conduit Artery in Relation to Downstream Peripheral Tissue Blood Flow During Reactive Hyperemia in Humans
Authors: Tetsuya Nakamura, Yuichiro Saito, Tatsuya Kato, Hiroyuki Sumino, Jin Hoshino, Zenpei Ono, Tetsuo Sakamaki, Ryozo Nagai
Journal: Circulation (1997)

Arterial conduit vessels dilate in response to increased blood flow stimuli. Our objective was to determine precisely how a change in large arterial diameter results in a change in peripheral tissue blood flow. Using high-resolution ultrasound Doppler echography, we measured the diameter of the right femoral artery at rest, during reactive hyperemia, and after administration of 2.5 mg of sublingual isosorbide dinitrate in 10 healthy young men. Reactive hyperemia was induced by distal circulatory arrest followed by reperfusion of the leg ipsilateral (right) or contralateral (left) to the side of arterial diameter measurements. Femoral arterial blood flow was calculated by simultaneous measurement of femoral arterial diameter and blood velocity. The change in skin blood flow was also analyzed simultaneously by laser Doppler flowmetry, Reactive hyperemia induced a 2-fold increase in femoral arterial blood velocity 30 sec after cuff release. During this flow augmentation, the femoral artery dilated. The peak of skin blood flow was coincident with the peak of femoral arterial vasodilation. The time required for the return of arterial diameter to baseline was longer than that for blood flow in both the conduit artery and the peripheral skin tissue. Equivalent cuff occlusion and release of the contralateral limb had no effect on ipsilateral arterial diameter. Isosorbide dinitrate induced dilation in all subjects, despite the absence of a significant increase in blood velocity. These results indicate that the human femoral artery dilates in response to increased blood velocity, and that the flow-mediated vasodilation of a large conduit artery is involved in the adjustments of blood flow in the downstream peripheral tissue. (Jpn Circ J 1997; 61: 772 - 780)
The use of one-step nucleic acid amplification (OSNA) and tumor-related factors in the axillary management of breast cancer: A predictive model.
Authors: Shramana Mitul Banerjee, Norman R. Williams, Timothy Ian Davidson, Soha El-Sheikh, My-annh Tran-Dang, Stephen Davison, Mohammed R. Keshtgar
Journal: Journal of Clinical Oncology (2015)

61 Background: Recent trends in surgical practice advocate selective use of axillary nodal clearance (ANC) following sentinel lymph node biopsy (SNB) in the treatment of breast cancer. We aimed to determine the effectiveness of one-step nucleic acid amplification (OSNA) using CK19 mRNA copy number and tumor-related factors in predicting non-sentinel axillary nodal involvement, in order to formulate local guidelines for ANC. Methods: Patients due to have SNB at our institution for invasive breast cancer as well as selected patients with high grade ductal carcinoma in situ with negative assessment of the axilla on pre-operative imaging were included. Alternate slices of each node were sent for assessment by either OSNA or Histopathology. Immediate ANC was performed if OSNA was positive. The CK19 mRNA copy number, the total tumor load (summation of m RNA copy number of positive nodes,TTL), the total nodal status at ANC and tumor characteristics including grade, tumor size and lymphovascular invasion (LVI) for each patient were determined. A model of risk probability was constructed using TTL and tumor related factors. Results: 664 nodes were examined from 425 patients who had SNB performed between 2011 and 2014. After excluding 8 patients who did not meet the study criteria, 648 nodes from 417 patients were included for analysis. The concordance between OSNA and histology was 91.4%; positive predictive value (PPV) and negative predictive value (NPV) was 77% and 97% respectively. Patients with TTL less than 1400 did not have additional non sentinel lymph node involvement. TTL (p&lt;0.01), and presence of LVI (p&lt;0.05) were predictive for additional nodal involvement. The risk model identified all patients with more than 2 positive nodes as requiring ANC. All patients with non-sentinel node metastases at ANC were selected. Conclusions: OSNA is a sensitive and reliable intraoperative method for the detection of sentinel node metastases. Our study has shown it can also be used to predict the presence of non-sentinel metastases. Patients deemed high risk may be offered immediate ANC while axillary surgery in other groups may be omitted or be decision-based on risk stratification.
Antitumor activity and immune reponse in CD40 immunotherapy with gemcitabine and nab-paclitaxel in an orthotopic pancreatic cancer mouse model.
Authors: Despina Siolas, Jane Cullis, Antonina Avanzi, Kate Byrne, Lawrence P. Leichman, Robert H. Vonderheide, Dafna Bar-Sagi
Journal: Journal of Clinical Oncology (2016)

271 Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. A Phase I trial of CD40 immunotherapy in combination with gemcitabine demonstrated the combination was safe and achieves tumor responses in patients with pancreatic ductal adenocarcinoma. We investigated the effectiveness of gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy in an orthotopic pancreatic mouse model. Methods: Pancreatic cells obtained from a Kras G12D ;Trp53 R172H (KPC) genetically engineered mouse were cultivated in cell culture and surgically implanted into the pancreata of immunocompetent syngeneic C57/Bl6 mice allowing for tumor formation in situ. Two weeks after KPC cell implantation, mice were treated with 120 mg/kg gemcitabine and 120 mg/kg nab-paclitaxel by intraperitoneal injection. Forty eight hours after chemotherapy administration, mice were treated with 100 ug of FGK45 CD40 immunotherapy. Mouse tumors and spleens were harvested from euthanized mice ten days after drug treatment. Tumor and spleens were analyzed histologically and by flow cytometry. Results: Mice treated with combination chemotherapy and immunotherapy had a significant reduction in tumor volume in comparison to vehicle treated mice. Combination chemotherapy did not cause a significant decrease in tumor volume. No changes were seen in stromal remodeling using trichrome histological staining. Mice treated with CD40 immunotherapy had an increase in spleen size indicating an immune response. Histological and flow cytometry analysis revealed an increase in CD45+ cells in the tumors of the CD40 immunotherapy treated samples in comparison to chemotherapy alone. Conclusions: CD40 immunotherapy in combination with gemcitabine and albumin-bound paclitaxel has significant antitumor activity in an orthotopic pancreatic cancer mouse model provoking an immune response in the tumors. Future experiments will focus on identifying immune mediators critical for drug efficacy.
Quantitative Effect of Age In Predicting Empirically-Defined Treatment-Related Mortality and Resistance In Newly Diagnosed AML: Case Against Age Alone as Primary Determinant of Treatment Assignment
Authors: Roland B. Walter, Megan Othus, Gautam Borthakur, Farhad Ravandi, Jorge E. Cortes, Sherry A. Pierce, Frederick R. Appelbaum, Hagop Kantarjian, Elihu H. Estey
Journal: Blood (2010)
Abstract 4806: Enhancing the efficacy of tosedostat through carboxylesterase induction
Authors: Priscilla Wei Ling Hong, Amanda Melanie Smith, Lambro Angelo Johnson, Dorothy Loo, Thomas Stoll, Michelle M. Hill, Andrew S. Moore
Journal: Cancer Research (2016)

Abstract Malignant cells, including acute myeloid leukaemia (AML), have high protein turnover to support their accelerated cell growth. Aminopeptidases regulate proteolysis, supplying free amino acids for new protein synthesis. Inhibition of aminopeptidases depletes free amino acids, impairing new protein production, leading to impaired cell growth and proliferation. Hence, aminopeptidase inhibition is of particular interest as a therapeutic strategy for AML. Tosedostat (CHR-2797) is an aminopeptidase inhibitor which is converted to its active metabolite, CHR-79888, by intracellular carboxylesterases (CES). This active metabolite is poorly membrane permeable, resulting in intracellular accumulation. Tosedostat has shown promise as a potential therapeutic strategy for AML and is well-tolerated in adult patients. However, its efficacy in paediatric AML has not been established. We set out to investigate the use of tosedostat for paediatric AML and enhance its efficacy through CES1 induction. It is hypothesised that inducing CES will lead to increased CHR-79888 production and subsequently, increased tosedostat efficacy. The IC50 of tosedostat across 11 AML cell lines (6 paediatric and 5 adult), determined by resazurin reduction assay, was approximately 13μM. Biochemical assays demonstrated that tosedostat inhibited cellular aminopeptidase activity in a concentration-dependent manner. However, this inhibitory effect was reversible with rapid, but incomplete, enzyme activity recovery upon drug withdrawal, irrespective of initial concentration or treatment duration. Quantitative PCR and immunoblotting revealed no correlation between CES expression and sensitivity to tosedostat. Cellular CES1 activity was also measured. Benzil and Bis(4-nitrophenyl)phosphate (BNPP) were used to modulate cellular CES1 activity. Assays of CES1 enzyme kinetics demonstrated that following temporary exposure to the reversible CES inhibitor benzil, there is a rebound in CES1 activity in AML cells. Consistent with this observation, pre-treatment by benzil increased CES1 activity, especially in MV4-11 cells. Moreover, reduced cell viability with tosedostat treatment following benzil pre-treatment correlated with the induction of CES1 activity in AML cell lines. Together, these data suggest that enhanced tosedostat efficacy through induction of CES activity is a novel therapeutic approach to treat AML. Citation Format: Priscilla Wei Ling Hong, Amanda Melanie Smith, Lambro Angelo Johnson, Dorothy Loo, Thomas Stoll, Michelle M. Hill, Andrew S. Moore. Enhancing the efficacy of tosedostat through carboxylesterase induction. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4806.
Refractory Cytokine Release Syndrome in Recipients of Chimeric Antigen Receptor (CAR) T Cells
Authors: Noelle V. Frey, Bruce L. Levine, Simon F. Lacey, Stephan A. Grupp, Shannon L Maude, Stephen J. Schuster, Pamela Shaw, Wei-Ting Hwang, Mariusz A. Wasik, Amrom Obstfeld, Mimi Leung, Angela Shen, Solveig G. Ericson, Jan J Melenhorst, Carl H. June, David Porter
Journal: Blood (2014)
A randomized phase II trial evaluating the performance of genomic expression profiles to direct the use of preoperative chemotherapy for early-stage breast cancer.
Authors: P. K. Marcom, W. Barry, M. B. Datto, J. Geradts, J. A. Olson, J. Marks, G. H. Lyman, A. Potti, G. S. Ginsburg, J. R. Nevins
Journal: Journal of Clinical Oncology (2010)

TPS102 Background: Genomic assays have been shown to provide the potential for personalized approaches to breast cancer therapy. Full-transcriptome assays using microarrays are challenging, but have the advantage of providing multiple prognostic and predictive signatures in one assay. We have developed genomic predictive signatures for various clinically relevant cancer characteristics, including sensitivity to cytotoxic chemotherapies. We have investigated the analytic performance of these signatures in biologic replicates, and begun applying them in this prospective randomized clinical trial. Methods: Eligible patients have intact HER2 negative primary breast cancers with tumor size over 1.5 cm and any clinical lymph node status. A fresh frozen sample of the primary tumor must be obtained. After pathology assessment, RNA is analyzed on an Affymetrix H133 Plus 2.0 microarray. The expression data is used to predict doxorubicin (A) and docetaxel (T) sensitivity using previously defined signatures and analytic techniques developed to make one-at-a-time predictions from microarray data. Patients are then assigned to four cycles of standard doxorubicin/cyclophosphamide (AC) or docetaxel/cyclphosphamide (TC) chemotherapy in a blinded process randomizing in a 1:2 ratio to a control arm (random assignment to either AC or TC) or a genomically guided (GG) chemotherapy arm. In the GG arm, patients are assigned to AC or TC treatment if the predicted sensitivity is over 0.6 for A or T, respectively. If predictions for both agents are over 0.6, the higher score is used; if both scores are below 0.6, patients are randomly assigned to AC or TC. The primary endpoint is pathologic complete response (pCR) in the breast, with the primary objectives: 1) determine whether genomic profiling for drug-sensitivity can improve the pCR rate as compared to randomly assigned therapy; and 2) determine whether genomic profiling can identify drug-sensitive and drug-resistant patients including a comparison of subgroups for the two individual regimens. The accrual goal is 270 patients randomized; currently, 42 patients have been consented and 32 randomized. No significant financial relationships to disclose.
57PD Multicenter observational study of fulvestrant 500 mg in postmenopausal Japanese women with ER positive advanced or recurrent breast cancer after prior endocrine treatment (SBCCSG29 study)
Authors: K. Kimizuka, K. Inoue, S. Nagai, T. Saito, S. Nakano, K. Futsuhara, T. Sakurai, H. Yamada, S. Hata, S. Kaneko, M. Kurosumi
Journal: Annals of Oncology (2015)
Detection of β-D-glucan for the diagnosis of invasive fungal infection in children with hematological malignancy
Authors: Juliette Guitard, Marie-Dominique Tabone, Yaye Senghor, Cyrille Cros, Didier Moissenet, Karine Markowicz, Nadia Valin, Guy Leverger, Christophe Hennequin
Journal: Journal of Infection (2016)
Expression of Four Major WT1 Splicing Variants in AML and CML: Development of Quantitative Real-Time PCRs and Preliminary Results in Patient Samples.
Authors: Tereza Lopotova, Jana Moravcova, Vaclava Polivkova, Jaroslav Polak, Jiri Schwarz, Hana Klamova, Katerina Machova Polakova
Journal: Blood (2009)
Safety and compliance data of the phase III study of adjuvant chemotherapy for patients (pts) with completely resected, pathological (p-) stage I (T1 &gt; 2 cm) non-small cell lung cancer (NSCLC): A Japan Clinical Oncology Group Trial, JCOG0707.
Authors: Hideo Kunitoh, Masahiro Tsuboi, Hiroyuki Sakurai, Masashi Wakabayashi, Morihito Okada, Kenji Suzuki, Norihiko Ikeda, Mitsuhiro Takenoyama, Yasuhisa Ohde, Makoto Takahama, Katsuo Yoshiya, Isao Matsumoto, Motohiro Yamashita, Takashi Marutsuka, Hiroshi Date, Yasuki Saito, Yoshinori Yamashita, Norihito Okumura, Shun-ichi Watanabe, Hisao Asamura
Journal: Journal of Clinical Oncology (2016)

8522 Background: Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese pts with completely resected, p-stage I (T1 > 2 cm) NSCLC. This trial aimed at estimating the efficacy of TS1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population. Methods: Eligible pts had received complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1 > 2 cm, by 5th Edition UICC TNM) NSCLC, within 56 days of enrollment. Pts were randomized to receive: oral UFT 250mg/M2/d for 2 years (Arm A), or oral TS1 80mg/M2/d for 2 weeks and 1 week rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), it was judged to be underpowered. The study protocol was amended so that the primary endpoint is relapse-free survival (RFS). With the calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 79% and one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75. Results: From Nov. 2008 to Dec. 2013, 963 pts were enrolled: median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 received pneumonectomy. At the data cut-off in May 2015, 94% of pts in Arm A and all in Arm B completed protocol therapy. ≥ Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.7 (1.5/14.5) % in Arm A, and in 14.4 (3.4/11.9) % in Arm B, respectively. 65% of the pts in Arm A received UFT for ≥ 1 year, whereas 69% of Arm B received TS1 for ≥ 6 months. There were 4 cases of on-protocol deaths, probably of cardio-vascular origin, 1 in Arm A and 3 in Arm B. Based on the 2nd interim analysis in Sep. 2015, the data and safety monitoring committee recommended follow-up of pts without unmasking of treatment arms. Estimated combined 2-year OS and RFS were 97.3% and 89.6%, respectively. Conclusions: Both post-operative adjuvant therapies were feasible, with similar compliances. Main results will be available in 2019. Clinical trial information: 000001494.