tbuckley/cabot-search huggingface dataset:
Hospital trust asks High Court to rule whether it can withdraw girl’s life support
Authors: Clare Dyer
Journal: BMJ (2019)

The parents of a 5 year old girl who has been on life support since February after a brain bleed are fighting moves by the NHS trust caring for her to withdraw life sustaining treatment and allow her to die.

In a five day hearing next month Barts Health NHS Trust will ask the High Court to rule that keeping Tafida Raqeeb alive artificially is futile and not in her best interests.

In a case with echoes of the bitter legal battles over the fate of Charlie Gard and Alfie Evans, Tafida’s parents, Shelina Begum and …
Do patients with axial spondyloarthritis with radiographic sacroiliitis fulfil both the modified New York criteria and the ASAS axial spondyloarthritis criteria? Results from eight cohorts
Authors: Anne Boel, Anna Molto, Désirée van der Heijde, Adrian Ciurea, Maxime Dougados, Lianne S Gensler, Maria-José Santos, Eugenio De Miguel, Denis Poddubnyy, Martin Rudwaleit, Astrid van Tubergen, Floris A van Gaalen, Sofia Ramiro
Journal: Annals of the Rheumatic Diseases (2019)

Background Patients with spondyloarthritis with radiographic sacroiliitis are traditionally classified according to the modified New York (mNY) criteria as ankylosing spondylitis (AS) and more recently according to the Assessment of SpondyloArthritis international Society (ASAS) criteria as radiographic axial spondyloarthritis (r-axSpA). Objective To investigate the agreement between the mNY criteria for AS and the ASAS criteria for r-axSpA and reasons for disagreement. Methods Patients with back pain ≥3 months diagnosed as axSpA with radiographic sacroiliitis (mNY radiographic criterion) were selected from eight cohorts (ASAS, Esperanza, GESPIC, OASIS, Reuma.pt, SCQM, SPACE, UCSF). Subsequently, we calculated the percentage of patients who fulfilled the ASAS r-axSpA criteria within the group of patients who fulfilled the mNY criteria and vice versa in six cohorts with complete information. Results Of the 3882 patients fulfilling the mNY criteria, 93% also fulfilled the ASAS r-axSpA criteria. Inversely, of the 3434 patients fulfilling the ASAS r-axSpA criteria, 96% also fulfilled the mNY criteria. The main cause for discrepancy between the two criteria sets was the reported age at onset of back pain. Conclusion Almost all patients with axSpA with radiographic sacroiliitis fulfil both ASAS and mNY criteria, which supports the interchangeable use of the terms AS and r-axSpA.
Evaluation of the prognostic utility of miRNA and multiple genetic markers in stage IIA colon cancer.
Authors: Elizabeth Mambo, Tiffany Sanford, Kalyan Buddavarapu, Alex Adai, Paul A. Lebourgeois, Karen Rasmussan, Lana Garmire
Journal: Journal of Clinical Oncology (2012)

3630 Background: The variable prognoses of stage II colon cancer subjects have provoked a therapeutic dilemma of who should receive adjuvant therapy. Presently, prognosis is evaluated on often subjective histopathological features. Reliable, objective markers that can accurately predict recurrence risk are needed. Using retrospectively collected tumor samples with known clinical outcome, we evaluated the prognostic utility of miRNA together with clinicopathological features and molecular markers with suggestive prognostic value. Methods: We evaluated the expression of miRNA in 118 stage IIA FFPE tumors (73 non-recurrent, NR; 45 recurrent, R) using the Affymetrix Gene Chip V1.0 microarray, and performed RT-qPCR to verify select miRNAs. We also sequenced KRAS codons 12/13, and BRAF codon 600, and assessed MSI status using a fluorescent PCR-based assay. MMR protein expression was determined by IHC. An empirical approach was applied to screen miRNA using combinatorial criteria of microarray 2-way ANOVA analysis, Kaplan-Meier curve logrank, and single and multivariate Cox-regression. miRNA was the most significant predictor among all histopathological and molecular features (FDR&lt;0.05). A miRNA classifier was built with nested two-layer cross-validation. Results: The top miRNA model was selected based on AUC estimates and Cox-regression p-value. This model included 30 miRNAs; 25 of these were common with the empirical approach, confirming the robustness of candidate selection. The miRNA classifier distinguished R from NR cases with an AUC of ~0.74. Among all histopathological and molecular features evaluated, grade was significantly associated with disease-free survival (logrank p&lt;0.05). Both single variate and multivariate Cox analysis revealed that grade and PMS2 status were strongly associated with recurrence (p&lt;0.05). Lastly, lack of expression of PMS2 and MLH1, BRAF V600E and MSI was highly correlated (Φ coefficient &gt; 0.6), and associated with non-recurrent disease. Conclusions: These data provide strong support for miRNAs as independent prognostic biomarkers for stage IIA colon cancer.Validation work is ongoing to demonstrate the potential utility of these miRNAs in patient stratification.
Establishment of a chordoma xenograft and in vivo testing of compounds identified by high-throughput screening.
Authors: Matteo Maria Trucco, Breelyn A. Wilky, Ola Awad, Preeti Shah, Naheed Gul, Menghang Xia, Ruili Huang, David Mark Loeb
Journal: Journal of Clinical Oncology (2012)

10025 Background: Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. Therapy primarily consists of surgical resection and radiation. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents for chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Methods: Primary tumor from a classic sacral chordoma was obtained, immediately processed into a single cell suspension and injected in to the parasacral area of a NOD/SCID/IL-2R gamma-null mouse, and tumor grew after 3 months. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds. Two established chordoma cell lines, U-CH1 and UCH2B, were treated and cell viability measured by CellTiter-Glo assay. Cells were incubated for 48 hours with drug concentrations ranging from 0.5nM to 46uM. The screen yielded several compounds that showed activity and two were tested in the xenograft. Results: We have established a xenograft model of dedifferentiated chordoma. High-throughput screening of compounds identified compounds that show activity against chordoma cell lines. In vivo testing of two identified compounds showed a dramatic reduction of tumor growth. Conclusions: We have established a xenograft model of dedifferentiated chordoma. High-throughput screening of compounds identified compounds that show activity against chordoma cell lines. In vivo testing of two identified compounds showed a dramatic reduction of tumor growth.
Phase I/II study of preoperative concurrent chemoradiotherapy with S-1, irinotecan, and cetuximab for locally advanced rectal adenocarcinoma.
Authors: Mitsuyoshi Ota, Ayumu Goto, Yasushi Ichikawa, Yusuke Suwa, Jun Watanabe, Kazuteru Watanabe, Kuniya Tanaka, Hirotoshi Akiyama, Shoichi Fujii, Itaru Endo
Journal: Journal of Clinical Oncology (2012)

e14050 Background: Recent studies reported that the cetuximab regimen including irinotecan has high tumor-response rates as a neoadjuvant chemotherapy for colorectal cancer patients. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for irinotecan combined use of S-1 and cetuximab as a preoperative chemoradiotherapy and to evaluate the feasibility and effect in patients with locally advanced rectal cancer. Methods: Patient s with adenocarcinoma of the lower rectum were enrolled in a phase I trial. Wild type KRAS was confirmed by biopsy specimen in all eligible patients. Also, UGT1A1 gene polymorphism was examined to avoid irinotecan-induced severe neutropenia and homozygous type (*28/*28, *6/*6, *28/*6) patients were excluded from this study. A total dose of 50.4 Gy was delivered in 28 fractions over 6 weeks, and 80 mg/m 2 of S-1 was orally administered twice a day on days 1–14 and 22–35. Irinotecan was given 125 mg/m 2 (level 1) to 150 mg/m 2 (level 2) on day 1 and 22. Cetuximab was given 400 mg/m 2 on day 7 as a loading and 250 mg/m 2 weekly on day 1 to 35. Surgical resection was scheduled 6–8 weeks after the completion of chemoradiation. Results: Among the 5 patients, who received 125 mg/m 2 irinotecan, dose-limiting toxicity (DLT); perforation occurred in 1 patient. Grade 3 neutoropenia occurred in 2 patients, who recovered within a week. Within grade 2 of anal pain and acne-like erythema was occurred in all patients. A pathological complete response (pCR) was not observed, pathological downstaging was observed in 4/5 patients (80%), and a tumor volume reduction of 68% was obtained. Conclusions: In phase I, the maximum-tolerated dose was not reached, and the recommended dose (RD) of irinotecan was seemed to be 125 mg/m 2 . This new protocol referred to KRAS and UGT1A1 profile is well tolerated, and should proceed to a phase II trial to evaluate the effectiveness.
Preclinical development of an anti-CD30/anti-CD16A bispecific tetravalent TandAb antibody for the treatment of Hodgkin lymphoma.
Authors: Stefan Knackmuss, Uwe Reusch, Carmen Burkhardt, Ivica Fucek, Fabrice Le Gall, Hans-Gerd Pauels, Melvyn Little, Eugene Zhukovsky
Journal: Journal of Clinical Oncology (2012)

e18532 Background: CD30 is a validated tumor target that is expressed on both Hodgkin’s Lymphoma cells and some activated immune cells. To improve antibody-based therapies targeting CD30, Affimed developed an NK cell-recruiting bispecific antibody. Methods: To enhance the recruitment and activation of NK cells for tumor cell lysis, we isolated a human antibody that is highly specific for the A isoform of FcgRIII (CD16A). Its variable domain (Fv) was used to construct a tetravalent bispecific TandAb, consisting of four Fvs linked in tandem, with two binding sites for both the CD16A on NK cell and the CD30 target cell antigens. The resulting anti-CD30/anti-CD16A bispecific tetravalent TandAb AFM13 was compared to both an anti-CD30/anti-CD16A bispecific diabody and an Fc-enhanced anti-CD30 IgG in binding and cytotoxicity assays in vitro. Pharmacokinetics and safety of the TandAb were investigated in Cynomolgus monkeys. Results: AFM13 is retained longer on NK cells than either the anti-CD30 IgG or the bispecific diabody due to its bivalency for CD16A; it binds both CD16A alleles (158F, 158V) equally well indicating the potential for broader patient response than that achieved with current therapeutic mAbs. AFM13 did not induce systemic activation of NK cells. It displays higher potency (EC 50 ) and higher efficacy (maximal lysis) than either the anti-VD30 IgGs or the bispecific diabody in a cytotoxicity assay. The cytotoxic activity of AFM13 is unaffected by physiological concentrations of polyclonal IgG, whereas that of anti-CD30 IgGs is dramatically reduced. Cynomolgus monkeys were identified as the only relevant species for toxicity testing. Pharmacokinetics studies reveal AFM13 half-lives of up to 22.9 h after repeated dosing. MTD was not reached in a single dose escalation study ranging to 100 mg/kg maximum. A 28 days toxicity study, with dosing up to 10 mg/kg every other day, revealed an excellent safety profile. No signs of immunotoxicity or systemic cytokine release were observed. Conclusions: AFM13 may be a more effective treatment for Hodgkin’s Lymphoma that is refractory to treatment with anti-CD30 IgGs and is under evaluation in a Phase I clinical trial.
Benefit of adjuvant chemotherapy for stage I epithelial ovarian cancer according to the histologic type.
Authors: Hiroyuki Fujiwara, Yuji Takei, Yasushi Saga, Shizuo Machida, Naoto Sato, Chikako Yoshida, Suzuyo Takahashi, Akiyo Taneichi, Mitsuaki Suzuki
Journal: Journal of Clinical Oncology (2013)

5552 Background: The benefit of adjuvant chemotherapy in stage I epithelial ovarian cancer (EOC) remains controversial. We retrospectively examined stage I EOC patients to clarify the benefits of adjuvant chemotherapy according to the histological type. Methods: The outcomes of 131 patients with stage I EOC that was diagnosed by exact staging laparotomy at the Jichi Medical University Hospital over a 22-year period from 1988 to 2009 were evaluated. Eighty-seven of the patients had received adjuvant chemotherapy (stage: IA 17, IC(intraoperative rupture;R) 27, IC(other) 43; histological type: clear cell adenocarcinoma(CCC) 38, mucinous adenocarcinoma(MC) 18, endometrioid adenocarcinoma(EC) 18, serous adenocarcinoma(SAC) 13), while 44 had undergone observation alone (stage: IA 31, IC(R) 12, IC(other) 1; histological type: CCC 11, MC 17, EC 11 and SAC 5). Outcomes for patients were compared between the two groups. Results: The overall recurrence rate in the adjuvant chemotherapy group was 18.4% (16/87). The rates of recurrence according to stage were IA 5.9% (1/17), IC(R) 14.8% (4/27), and IC (other) 25.6% (11/43). Recurrence by histological type were CCC 12, SAC 2(G1and G2), and one each for EC and MC. Recurrence was seen in all stages in CCC patients; however, there was no recurrence in stage IA in patients with non-CCC. The overall recurrence rate in the observation group was 11.4% (5/44). All five recurrences occurred in CCC patients, and no recurrence was observed in the 33 non-CCC patients (IA 26, IC(R) 7). In patients with IC(R) CCC, the recurrence rate was significantly higher in the observation group (80%;4/5) than in the adjuvant chemotherapy group (18.8%; 3/16) (p = 0.025). Conclusions: This retrospective study showed that the CCC is associated with recurrence in stage I EOC and adjuvant chemotherapy for these patients may improve outcomes. The recommended states for adjuvant chemotherapy in stage I EOC are as follow: 1) all subtype of stage I for CCC, and 2) IC(other) for non-CCC. Although further prospective studies are required, these results afford useful information with which to determine the adjuvant chemotherapy in stage I EOC.
Evaluation of GPER agonist G-1 combined with navitoclax in platinum-resistant and -sensitive ovarian cancer cells.
Authors: Dennis C. DeSimone, Trung T. Nguyen, Eugen Brailiou, John C. Taylor, Gabriela Cristina Brailoiu, Jeff Boyd, Eric A. Ariazi
Journal: Journal of Clinical Oncology (2013)

e13563 Background: Most ovarian cancer patients are treated with platinum-based chemotherapy but eventually relapse with incurable disease. The G protein-coupled estrogen receptor GPER (GPR30) mediates Ca 2+ mobilization in response to estrogen and G-1, a synthetic agonist. Large and sustained Ca 2+ responses can lead to mitochondrial Ca 2+ overload and apoptosis. Hence, we evaluated whether G-1 could induce apoptosis in cisplatin-sensitive A2780 and isogenic cisplatin–resistant CP70 (14-fold resistant), C30 (70-fold resistant) and C200 (157-fold resistant) human ovarian cancer cells. Bcl-2 and Bcl-xL protect mitochondria from Ca 2+ overload, and were overexpressed in these cisplatin-resistant cells; thus we also examined combining the Bcl-2 family inhibitor navitoclax with G-1. Methods: Cytoplasmic [Ca 2+ ] c and mitochondrial [Ca 2+ ] m were monitored using microscopy and fluorescent Ca 2+ probes. Cell cycle, apoptosis and mitochondrial membrane potential (MMP) were assessed by flow cytometry of propidium iodide, Annexin V and DiIC 1 (5) -stained cells. The intracellular Ca 2+ chelator BAPTA was used to block Ca 2+ mobilization. Results: Expression of the 53kDa GPER but not the 38 kDa isoform progressively increased with increasing cisplatin resistance. G-1 elicited sustained [Ca 2+ ] c rises that correlated with 53 kDa GPER expression, followed by rises in [Ca 2+ ] m . In all cells, 2.5 μM G-1 blocked cell cycle progression at G2/M, inhibited proliferation, and induced apoptosis (A2780 &gt; C30 &gt; CP70 ≥ C200). G-1 induced p53, caspase-3 and PARP cleavage, and MMP loss. BAPTA prevented G-1’s cell cycle and apoptotic effects in cells showing large Ca 2+ mobilization responses but did not in cells with small Ca 2+ responses. Combining navitoclax with G-1 superadditively decreased cell viability and increased apoptosis. Conclusions: G-1 blocked cell cycle progression and induced apoptosis via a Ca 2+ -dependent pathway in cells expressing high 53 kDa GPER levels, but via a Ca 2+ -independent pathway in cells with low 53 kDa GPER expression. G-1 also interacted cooperatively with naviticlax. Therefore, G-1 plus navitoclax shows potential for therapeutic use in platinum-sensitive and -resistant ovarian cancer.
Drug Approved for Inflammatory Nasal Cavity Condition
Authors: Rebecca Voelker
Journal: JAMA (2019)

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Interferon alfa-induced autoimmunity and serum S100 levels as predictive and prognostic biomarkers in high-risk melanoma in the ECOG-intergroup phase II trial E2696
Authors: J. J. Stuckert, A. A. Tarhini, S. Lee, C. Sander, J. M. Kirkwood
Journal: Journal of Clinical Oncology (2007)

8506 Background: Uncontrolled evidence demonstrates that adjuvant high-dose interferon alfa-2b (HDI) benefit in high-risk melanoma patients is predicted by autoimmunity induction, and the prognosis of melanoma has been correlated with levels of S-100 protein. We have evaluated these two serological markers in the context of a completed phase II study E2696. Methods: Patients with resectable AJCC stage IIB, III, and IV melanoma were randomly assigned to receive GM2-KLH/QS-1 (GMK vaccine) plus concurrent HDI (Arm A) or GMK plus sequential HDI (Arm B), or GMK without HDI (Arm C). Sera from 103 patients were banked at baseline and 3 additional time points, and have been tested for serum protein S100, and anti-nuclear, anti-thyroid peroxidase, anti-thyroglobulin, anti-mitochondrial, and total anti-cardiolipin autoantibodies (AA) using ELISA. Results: At a median follow-up of 96.5 mo (range: 17–109), the median relapse-free survival (RFS) was 28.3 mo, 95% CI (18.4, 43.6) (64 /103 patients relapsed). Median survival has not been reached (54/103 alive). AA were induced in 17 subjects (25%; n=69) receiving HDI and GMK versus 2 (6%; n=34) receiving GMK alone (2p-value=0.031). In HDI arms induced AA were detected = 12 weeks after therapy initiation. RFS was improved among HDI recipients with AA, but with the limited numbers in this phase II trial this trend does not achieve significance. In the multivariate (Cox regression model) analysis, adjusting for treatment (HDI vs. no HDI) and baseline S-100 value for later time points, S-100 level ≥0.08 microg/l was an independent prognostic factor for RFS at baseline (HR=1.96; p=0.0273), week 4–6 (HR=1.72; p=0.073), wk 12–14 (HR=1.81; p=0.048) and wk 52 (HR=4.3; p&lt;0.001). The hazard ratio (HR) for OS was 1.86 at wk 12–14 (p=0.061), and 5.7 at wk 52 (p&lt;.001). In the model using wk 52 S-100 value (at completion of HDI), the HR adjusted for treatment was 7.1 p=0.009. Conclusions: Autoimmunity is a predictive biomarker of RFS with HDI in the E2696 trial compared to GMK. Serum protein S-100 level ≥0.08 microg/l is an independent prognostic marker for RFS and OS most significant at baseline and 1 year of followup. Current studies will evaluate these markers in the larger phase III trial E1694 with 880 subjects. [Table: see text]
The RNA-binding protein LARP1 is a cancer therapeutic target
Authors: E A Ghazaly, J Le Quesne, D Jiang, S L Mangala, J Chettle, C Rodriguez-Aguayo, G Lopez-Berestein, C Gnanaranjan, M Mura, C Stavraka, A K Sood, S P Blagden
Journal: Cancer Research (2017)
The gender-based violence and recovery centre at Coast Provincial General Hospital, Mombasa, Kenya: An integrated care model for survivors of sexual violence
Authors: Marleen Temmerman, Emilomo Ogbe, Griffins Manguro, Iqbal Khandwalla, Mary Thiongo, Kishor N. Mandaliya, Lou Dierick, Markus MacGill, Peter Gichangi
Journal: PLoS Medicine (2019)

Sexual violence (SV) is highly prevalent and a major public health problem globally.In Kenya, an estimated 32% of females and 18% of males were reported to have experienced SV before the age of 18 years.• This paper presents a data set collected between 2007 and 2018 and describes the gender-based violence and recovery centre (GBVRC) model under which survivors of SV were cared for at a 24-hour public hospital in Mombasa, Kenya-including its development, implementation, achievements, and challenges.• The GBVRC model is a partnership that provides (in addition to emergency healthcare) mental health support, paralegal services, and integrated cooperation with police, judiciary, local leaders, and the wider community.The Mombasa GBVRC has provided post-SV care to 6,575 people reporting SV, of whom 88% were female and over 50% were younger than 16 years.Over 90% of the perpetrators were family, neighbours, community members, or in some other way known to the survivors.• The low rate (19%) of attendance by survivors for the second counselling visit suggests a more robust strategy is needed for follow-up-for example, by referring people back to smaller, closer health facilities.A second limitation was a lack of trained staff, although this is an expected issue in sub-Saharan Africa.There was also a low rate of legal resolution to the cases.This may be due to the need for education about the standard of evidence required by courts.• The experiences of successful and sustainable implementation of the GBVRC model should strengthen arguments for service delivery for people experiencing SV in this and similar settings.
Abstract 18771: Protease-Activated Receptor Type 4 (PAR-4) Antagonism With BMS-986120 Selectively Inhibits Human Thrombus Formation Under Conditions of High Shear Stress
Authors: Simon J Wilson, Fraz A Ismat, Hafid Narayan, Jennifer Raftis, Timothy J Gray, Michael Cerra, Zhaoqing Wang, Xuewen Ma, Jing Yang, David E Newby
Journal: Circulation (2016)

Introduction: Despite current anti-platelet agents, many individuals continue to experience recurrent ischaemic events. BMS-986120 is a novel anti-platelet agent that antagonises protease-activated...