tbuckley/cabot-search huggingface dataset:
A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC)
Authors: R. W. Ross, M. Stein, J. Sarantopoulos, P. Eisenberg, T. Logan, S. Srinivas, J. Rosenberg, U. Vaishampayan
Journal: Journal of Clinical Oncology (2007)

15601 Background: XL880 is a novel inhibitor of receptor tyrosine kinases targeting MET and VEGFR2/KDR. (IC 50 for MET 0.4nM and KDR 0.8 nM). PRC is a rare (10–15%) subtype of kidney cancer which is notoriously resistant to systemic treatment. The familial form of PRC is associated with germline activating mutations of MET, while amplification and overexpression of MET is seen in the sporadic form. In an ongoing phase I dose escalation study of XL880 in forty patients with advanced solid tumors, five partial responses (PRs) were noted in 3 of 4 treated patients with PRC, and in two pts with thyroid cancer. The MTD in this study was 3.6 mg/kg of XL880 administered orally daily for 5 consecutive days every 2 weeks. Methods: In this phase 2 study, XL880 is administered orally as a single agent at a dose of 240 mg on days 1–5 of each 14 day cycle. Previously untreated pts with a histologic diagnosis of metastatic PRC are eligible and are stratified based on the presence or absence of MET germline mutations. Planned enrollment is 15 evaluable pts in each stratum. Inclusion criteria also include ECOG performance status &lt; 3 and absence of brain metastases. Tumor response is assessed every 8 weeks by RECIST criteria. Archival primary tumor and lymph node metastasis were collected for pharmacodynamic assessments. Results: To date, 6 pts have been enrolled and received XL880. Five pts have tested negative for MET germline mutations; results for one pt are pending. Of 3 pts with at least one post baseline tumor assessment, 1 pt has demonstrated a PR and two pts have demonstrated stable disease &gt; 3 months, one of whom has improvement in bone scan and bone pain. Hypertension has been reported in 2 pts who responded to anti- hypertensive treatment. Two SAEs have been reported as unrelated; pulmonary embolism and intratumoral hemorrhage. MET expression was detected in untreated primary and metastatic tumor. Reduction in Ki67, and an increase in TUNEL labeling were observed in the post treatment sample. Conclusions: XL880 is the 1st orally available small molecule inhibitor of MET to enter the clinic and appears to be generally well tolerated. Anti-tumor activity has been observed and XL880 may represent an active treatment option for pts with PRC. Enrollment continues and updated results will be presented. No significant financial relationships to disclose.
Health Education England threatens to cut trusts’ funding for training if they don’t impose junior doctor contract
Authors: Abi Rimmer
Journal: BMJ (2016)

Health Education England (HEE) has told hospital trusts that they could lose funding for training posts if they decide not to impose a new contract on their junior doctors.

In a letter sent to the chief executives of all hospital trusts in England, Ian Cumming, HEE’s chief executive, said, “Implementation of the national contract will be a key criterion for HEE in making its decisions on our investment in training posts.”

Last week the health …
Phase II study of B7–1 gene-modified autologous tumor cell vaccine and subcutaneous IL-2 for patients with stage IV renal cell carcinoma (RCC)
Authors: P. Thompson, M. Fishman, J. Seigne, M. Dunn, W. Janssen, R. Smilee, M. J. Farmelo, D. Noyes, J. Pow Sang, S. Antonia
Journal: Journal of Clinical Oncology (2005)

4502 Background: Since efficacy of subcutaneous interleukin-2 (IL-2) is limited in RCC, novel treatments are needed. The protein B7–1 is normally not expressed by RCC cells, so forced expression could increase tumor cell immunogenicity by providing costimulation (second signal) for tumor-reactive T cells encountering vaccine. Additionally, IL-2 treatment could also expand vaccine-activated, tumor-reactive T cells, thus augmenting the immune response. Previously, our phase I study demonstrated safety and development of detectable immune responses using this combined approach. Methods: In this phase II trial, autologous vaccine was cultured from primary tumor or resected metastasis specimens and transduced (ALVAC vector) with B7–1 gene, resulting in B7–1 protein expression. Eligibility included: no limitations on number of prior treatments; measurable tumor required, ECOG PS 0 or 1; adequate organ function; no active CNS disease; and no steroid use. Vaccines were administered on days 1, 29, and 57. Beginning about day 43, subcutaneous IL-2 was administered at 250,000 IU/kg/day for 5 days of the first week, then at 125,000 IU/kg/day, 5 days a week, for 5 more weeks. Results: Thirty-seven patients were treated. Median age: 59 years (38–82); metastatic sites: lung 22, lymph nodes 10, bone 7, other site 25. Four patients had received prior interferon or IL-2. Response rates: pathologic complete response 3%, partial response 8%, stable disease 40%, progression 40%. Median survival: 22.5 months. Treatment was well tolerated. Observed grade 3 toxicity included: fatigue 29%, anorexia 8%, hyponatremia 5%, dehydration 5%, anemia 5%, tachycardia 5%. One patient had grade 4 diarrhea. All toxicities were observed during IL-2 treatment. Conclusions: (1) Major clinical responses in 11% of patients, and stable disease in 40%. (2) Median survival of 22.5 months; appears better than previously reported in high dose IL-2 series. (3) Acceptable toxicity was observed with the regimen. (4) The regimen may merit further development for RCC immunotherapy. SUPPORTED BY NIH CA082059 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron Chiron Chiron
Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders
Authors: Ashley E. Nordsletten, Henrik Larsson, James J. Crowley, Catarina Almqvist, Paul Lichtenstein, David Mataix-Cols
Journal: JAMA Psychiatry (2016)

<h3>Importance</h3> Psychiatric disorders are heritable, polygenic traits, which often share risk alleles and for which nonrandom mating has been suggested. However, despite the potential etiological implications, the scale of nonrandom mating within and across major psychiatric conditions remains unclear. <h3>Objective</h3> To quantify the nature and extent of nonrandom mating within and across a broad range of psychiatric conditions at the population level. <h3>Design, Setting, and Participants</h3> Population-based cohort using Swedish population registers. Participants were all Swedish residents with a psychiatric diagnosis of interest (attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, bipolar disorder, major depression, generalized anxiety disorder, agoraphobia, social phobia, obsessive-compulsive disorder, anorexia, or substance abuse), along with their mates. Individuals with select nonpsychiatric disorders (Crohn's disease, type 1 and type 2 diabetes mellitus, multiple sclerosis, or rheumatoid arthritis) were included for comparison. General population samples were also derived and matched 1:5 with each case proband. Inpatient and outpatient diagnostic data were derived from the Swedish National Patient Register (1973-2009), with analyses conducted between June 2014 and May 2015. <h3>Main Outcomes and Measures</h3> Correlation in the diagnostic status of mates both within and across disorders. Conditional logistic regression was used to quantify the odds of each diagnosis in the mates of cases relative to matched population controls. <h3>Results</h3> Across cohorts, data corresponded to 707 263 unique case individuals, with women constituting 45.7% of the full population. Positive correlations in diagnostic status were evident between mates. Within-disorder correlations were marginally higher (range, 0.11-0.48) than cross-disorder correlations (range, 0.01-0.42). Relative to matched populations, the odds of psychiatric case probands having an affected mate were significantly elevated. Differences in the magnitude of observed relationships were apparent by disorder (odds ratio range, 0.8-11.4). The number of comorbidities in a case proband was associated with the proportion of affected mates. These relationships were not apparent or weaker in magnitude among nonpsychiatric conditions (correlation range, −0.03 to 0.17). <h3>Conclusions and Relevance</h3> Nonrandom mating is evident in psychiatric populations both within specific disorders and across the spectrum of psychiatric conditions. This phenomenon may hold important implications for how we understand the familial transmission of these disorders and for psychiatric genetic research.
Well-Differentiated Syringofibrocarcinoma in a Patient With Clouston Syndrome
Authors: Ian D. Odell, Evelyn Lilly, Katharine Reeve, Marcus W. Bosenberg, Leonard M. Milstone
Journal: JAMA Dermatology (2016)

From the beginning, the therapy showed remarkable efficacy in both clinical symptoms and laboratory findings, with an almost complete disappearance of pustulation 48 hours after the first injection.Though 3 to 4 days after each injection, the patient developed minor flares of new pustules, he continuously improved.These small recurrences decreased over time and may be attributed to on-off phenomena of the antibody.In conclusion, the patient showed a rapid response to secukinumab with regard to the cutaneous and systemic manifestations of severe GPP, indicating that this new targeted therapy might also be used to treat PP.
Adverse Impact Of Elevated Pretransplantation Serum Ferritin Levels On Survival and Nonrelapse Mortality After Allogeneic Hematopoietic Stem Cell Transplantation In Children
Authors: Osamu Kondo, Kohei Higuchi, Mariko Shimizu, Azusa Mayumi, Kanako Isaka, Akihisa Sawada, Maho Sato, Masahiro Yasui, Masami Inoue
Journal: Blood (2013)
A safety and schedule seeking trial of Bcl-2 inhibitor obatoclax in previously untreated older patients with acute myeloid leukemia (AML)
Authors: A. Raza, N. Galili, G. Borthakur, T. H. Carter, D. F. Claxton, H. P. Erba, D. J. DeAngelo, M. S. Berger, A. Schimmer
Journal: Journal of Clinical Oncology (2009)

3579 Background: Obatoclax (Ob) is a small-molecule inhibitor of all Bcl-2 prosurvival proteins. In a previous study a 70 year old patient with untreated AML had a cytogenetic CR 8 days after receiving 20 mg/m 2 of Ob over 24 hrs. This study evaluated the single-agent response rate in older patients with previously untreated AML. Methods: A Safety phase to evaluate escalating doses of Ob given by 3-hr infusion was performed. Based on previous results, the dose of 60 mg over 24 hrs was used for the 24-hr infusion arm of the Schedule Seeking phase, in which Ob was administered as either a 3-hr or 24-hr infusion for 3 consecutive days every 2 wks. The endpoint of the Schedule Seeking phase was CR after C2 in 16 randomized patients. Eligibility criteria included age ≥ 70, untreated AML (1 prior Rx allowed in Safety phase), ECOG PS ≤2, adequate renal and hepatic function. PK samples were collected during C1. Results: 18 patients (8 male; median age 82) were enrolled. 2/3 patients enrolled into the 1st cohort (30 mg x 3 days) of the Safety phase had DLT events (ataxia and somnolence). 3 patients enrolled into a 20 mg x 3 days cohort had no DLTs; this dose was used for Schedule Seeking patients receiving 3-hr infusions. In the Schedule Seeking phase, 7 patients were randomized to receive 20 mg by 3-hr infusion and 5 were randomized to receive 60 mg by 24-hr infusion. The most common (&gt;25%) AEs were euphoric mood (50%), ataxia (38%), &amp; somnolence (38%). Efficacy data after C2 show that 3 patients in the 20 mg 3-hr infusion cohort in the Safety phase and 1 at the same dose &amp; schedule in the Schedule Seeking phase had ≥50% decrease in BM blasts after C2, which was not seen in the 60 mg 24-hr infusion cohort. There were no CRs. There was a single death by D28 (24-hr infusion). There were significant differences in PK by infusion schedule. Conclusions: MTD for Ob as a 3-hr infusion administered in older patients with AML on 3 consecutive days is 20 mg/day, and both this regimen and 60 mg as a 24-hr infusion x 3 days were well tolerated. Evidence of biological activity was seen with the 3-hr infusion schedule but not with the 24-hr infusion schedule, suggesting that efficacy may be improved with the 3-hr infusion schedule and may be related to PK differences. [Table: see text]
Risk of skeletal-related events (SREs) in patients with breast cancer (BC) and newly diagnosed metastases to bone.
Authors: Charu Taneja, Lois Lamerato, Andrew Glass, Kathryn E. Richert-Boe, John Edelsberg, Greg G. Wolff, Natalie Czapski, Karen Chung, Akshara Richhariya, Gerry Oster
Journal: Journal of Clinical Oncology (2012)

e12024 Background: Bone is a common site of metastatic involvement in patients (pts) with BC. Bony metastases (mets) are often associated with SREs (spinal cord compression [SCC], pathologic fracture [PF], surgery to bone [SB], radiotherapy to bone [RT]). Skeletal complications cause significant morbidity and mortality. Current estimates of SRE risk come principally from randomized clinical trials. Information from routine clinical practice is limited. Methods: Using the tumor registry and electronic data stores at a large US Midwest healthcare system that serves approximately 800,000 persons, we retrospectively identified all pts aged ≥18 yrs with primary BC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Electronic medical records were reviewed by trained abstractors for evidence of SREs between date of bone mets diagnosis and death, loss to follow-up, or end of study. Cumulative incidence of SREs was estimated in the presence of competing risk of death. Results: We identified a total of 378 pts with primary BC and newly diagnosed bone mets; 87 pts had evidence of SREs at initial diagnosis of bone mets and were excluded from the analyses. Among the remaining 291 pts, mean (SD) age was 58.2 yrs (14.3 yrs), and 99% were women; 46% were Caucasian and 48% were African-American. Median duration of follow-up after diagnosis of bone mets was 16.1 months (mos). At 12 mos, cumulative incidence of SREs was 44.5% (SCC, 5.2%; PF, 21.0%; SCC and/or PF, 23.3%; SB, 7.6%; RT, 34.3%) (Table). Corresponding figures at 24 mos were 53.8% (SCC, 7.5%; PF, 29.3%; SCC and/or PF, 32.5%; SB, 9.4%; RT, 41.7%). Approximately one-half (45.0%) of study subjects received intravenous bisphosphonates prior to SRE. Conclusions: Pts with BC in routine clinical practice are at high risk of SREs following initial diagnosis of bone mets. [Table: see text]
Scalp cooler efficacy to reduce anthracycline-induced alopecia and its QOL impact in breast cancer
Authors: R. O. El-saka, G. El-Husseiny, Y. Rostom, A. Salama
Journal: Journal of Clinical Oncology (2009)

e13539 Background: Hair loss is a common, unavoidable, and stressful side effect of chemotherapy. This work was performed to evaluate the role of scalp cooling in reducing anthracycline-induced hair loss and its impact on Quality of life (QOL). Methods: The study was conducted from July 2007 to August 2008. It included 120 females with breast cancer, treated in adjuvant setting. Patients were chosen according to certain criteria (age ≤ 70 years, WHO performance status 0–1, no cardiac disease, no serious psychiatric conditions, no previous chemotherapy). Patients were divided randomly into 2 groups according to whether scalp cooler was used or not during chemotherapy. Chemotherapy consisted of doxorubicin (50 mg/m 2 ), 5-FU (500 mg/m 2 ) and cyclophosphamide (500 mg/m 2 ) for 6 cycles. Paxman Scalp Cooler was used. The cap was applied 20 minutes before, during and 2 hours after infusion. Hair loss was assessed using WHO criteria at each cycle and after 6 cycles of chemotherapy. QOL was assessed using EORTC QLQ-C30 and BR23. Results: After 4 cycle, 61.7 % of patients in scalp cooling group had grade 4 hair loss compared to 81.7 % of patients in control group. After 6 cycles, 85% of patients in scalp cooling group experienced grade 4 hair loss compared to 100% of patients in the control group. Only 9 patients (15%) in the scalp cooling group developed grade 1–2 hair loss. No significant relation was found between the degree of hair loss and the liver function tests. Most patients (73.3%) were comfortable during cooling. QOL scores were comparable between the two groups except for emotional functioning and body image. In the hair loss group, 71.2% of patients showed severe disturbance of emotional functioning and 54.1% of patients had moderate disturbance in body image. In hair preservation group (9 patients), 77.8% developed moderate disturbance of emotional functioning and all patients had mild disturbance in the body image. Conclusions: The role of scalp cooling is limited at the total dose of 300 mg/m 2 doxorubicin. It may be more effective with fewer cycles or less aggressive drug combination. Hair loss affects various aspects of QOL, especially emotional functioning and body image. More time is needed to assess the long term effect of hair loss on QOL and the incidence of scalp metastasis in the two study groups. No significant financial relationships to disclose.
Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer Relapsing on Standard Dose Alectinib
Authors: Justin F. Gainor, Andrew S. Chi, Jennifer Logan, Ranliang Hu, Kevin S. Oh, Priscilla K. Brastianos, Helen A. Shih, Alice T. Shaw
Journal: Journal of Thoracic Oncology (2015)
A Hydrogel Bridge Incorporating Immobilized Growth Factors and Neural Stem/Progenitor Cells to Treat Spinal Cord Injury
Authors: Hang Li, Trevor R. Ham, Nicholas Neill, Mahmoud Farrag, Ashley E. Mohrman, Andrew M. Koenig, Nic D. Leipzig
Journal: Advanced Healthcare Materials (2016)

Spinal cord injury (SCI) causes permanent, often complete disruption of central nervous system (CNS) function below the damaged region, leaving patients without the ability to regenerate lost tissue. To engineer new CNS tissue, a unique spinal cord bridge is created to deliver stem cells and guide their organization and development with site‐specifically immobilized growth factors. In this study, this bridge is tested, consisting of adult neural stem/progenitor cells contained within a methacrylamide chitosan (MAC) hydrogel and protected by a chitosan conduit. Interferon‐γ (IFN‐γ) and platelet‐derived growth factor‐AA (PDGF‐AA) are recombinantly produced and tagged with an N‐terminal biotin. They are immobilized to streptavidin‐functionalized MAC to induce either neuronal or oligodendrocytic lineages, respectively. These bridges are tested in a rat hemisection model of SCI between T8 and T9. After eight weeks treatments including chitosan conduits result in a significant reduction in lesion area and macrophage infiltration around the lesion site ( p &lt; 0.0001). Importantly, neither immobilized IFN‐γ nor PDGF‐AA increased macrophage infiltration. Retrograde tracing demonstrates improved neuronal regeneration through the use of immobilized growth factors. Immunohistochemistry staining demonstrates that immobilized growth factors are effective in differentiating encapsulated cells into their anticipated lineages within the hydrogel, while qualitatively reducing glial fibrillary acid protein expression.
Distinct severity stages of obstructive sleep apnoea are correlated with unique dyslipidaemia: large-scale observational study
Authors: Jian Guan, Hongliang Yi, Jianyin Zou, Lili Meng, Xulan Tang, Huaming Zhu, Dongzhen Yu, Huiqun Zhou, Kaiming Su, Mingpo Yang, Haoyan Chen, Yongyong Shi, Yue Wang, Jian Wang, Shankai Yin
Journal: Thorax (2016)

<h3>Background</h3> Dyslipidaemia is an intermediary exacerbation factor for various diseases but the impact of obstructive sleep apnoea (OSA) on dyslipidaemia remains unclear. <h3>Methods</h3> A total of 3582 subjects with suspected OSA consecutively admitted to our hospital sleep centre were screened and 2983 (2422 with OSA) were included in the Shanghai Sleep Health Study. OSA severity was quantified using the apnoea–hypopnea index (AHI), the oxygen desaturation index and the arousal index. Biochemical indicators and anthropometric data were also collected. The relationship between OSA severity and the risk of dyslipidaemia was evaluated via ordinal logistic regression, restricted cubic spline (RCS) analysis and multivariate linear regressions. <h3>Results</h3> The RCS mapped a nonlinear dose–effect relationship between the risk of dyslipidaemia and OSA severity, and yielded knots of the AHI (9.4, 28.2, 54.4 and 80.2). After integrating the clinical definition and RCS-selected knots, all subjects were regrouped into four AHI severity stages. Following segmented multivariate linear modelling of each stage, distinguishable sets of OSA risk factors were quantified: low-density lipoprotein cholesterol (LDL-C), apolipoprotein E and high-density lipoprotein cholesterol (HDL-C); body mass index and/or waist to hip ratio; and HDL-C, LDL-C and triglycerides were specifically associated with stage I, stages II and III, and stages II–IV with different OSA indices. <h3>Conclusions</h3> Our study revealed the multistage and non-monotonic relationships between OSA and dyslipidaemia and quantified the relationships between OSA severity indexes and distinct risk factors for specific OSA severity stages. Our study suggests that a new interpretive and predictive strategy for dynamic assessment of the risk progression over the clinical course of OSA should be adopted.
Abstract 80: Lay Bystanders Taught With the 2010 CPR Guidelines Perform Deeper Chest Compressions Than Those Taught With the 2005 Guidelines When Tested Longitudinally, A Multicenter Hospital-Based Study
Authors: Audrey L Blewer, David G Buckler, Owen K Beams, Marion Leary, Barbara J Riegel, Lance B Becker, Peter W Groeneveld, Judy Shea, Mary E Putt, Benjamin S Abella
Journal: Circulation (2013)
Dreaming and the place of consciousness in nature
Authors: Antti Revonsuo
Journal: Behavioral and Brain Sciences (2001)

The research program defended by O'Regan &amp; Noë (O&amp;N) cannot give any plausible explanation for the fact that during REM-sleep the brain regularly generates subjective experiences (dreams) where visual phenomenology is especially prominent. This internal experience is almost invariably organized in the form of “being-in-the-world.” Dreaming presents a serious unaccountable anomaly for the sensorimotor research program and reveals that some of its fundamental assumptions about the nature of consciousness are questionable.
Dynamics of IS-related genetic rearrangements in resting Escherichia coli K-12.
Authors: T Naas, M Blot, W M Fitch, W Arber
Journal: Molecular Biology and Evolution (1995)

An analysis of restriction fragment length polymorphism (RFLP) using eight residential insertion sequence (IS) elements as hybridization probes reveals that the genome of resting bacteria is more dynamic than it was long believed. Escherichia coli strains stored in agar stabs for up to 30 yr accumulate a genetic variation which is correlated to time of storage. This spontaneous mutagenesis is often IS-specific, with particularly high activity for IS5, and thus suggests that transpositional DNA rearrangements are a major cause for the observed genetic polymorphism. The RFLP patterns indicate a burst of IS30 transposition to occur occasionally. Mutation rate is estimated by two different methods to roughly 10(-5) IS-related DNA rearrangements per bacterial chromosome per hour of storage for the eight IS elements studied. A pedigree derived from the RFLP data reveals that populations had evolved independently in each stab and showed no signs of convergence. Relics of an assumed ancestral population were still present in the stab cultures, but the elder stabs provided mostly mutants. These results indicate that cells placed under nutritional deprivation might have a highly plastic genome and suggest that such plasticity might play an adaptive role.