tbuckley/cabot-search huggingface dataset:
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora A kinase (AAK) inhibitor MLN8054 in patients (pts) with advanced solid tumors
Authors: T. Macarulla, E. Rodríguez-Braun, J. Tabernero, S. Roselló, J. Baselga, Y. Lee, M. Manfredi, H. Liu, H. Fingert, A. Cervantes
Journal: Journal of Clinical Oncology (2009)

2578 Background: MLN8054, a first-generation, selective AAK inhibitor, induces chromosome alignment and segregation defects during mitosis, leading to cell death (Hoar et al, MolCellBio 2007;27:4513). This phase I trial examined the safety, PK, and PD of MLN8054 administered orally to adult pts with advanced solid tumors. Methods: Pts received increasing oral doses of MLN8054 until dose-limiting toxicity (DLT) in the first cycle was seen in ≥2 of 3–6 pts in a cohort. Two cohorts received 10 and 20 mg once daily (QD) on d1–5 and d8–12 of 28d cycles. Benzodiazepine-like adverse effects (somnolence) associated with chemical structure and presumably unrelated to AAK inhibition were observed with QD dosing in another Phase 1 study (Dees et al, EJC Suppl 2008;6[12]:91), so subsequent cohorts in this trial were treated with 25, 35, 45, 55, 60, 70, and 80 mg/d in four divided doses (QID) on d1–14, with the largest dose at night. To manage somnolence, methylphenidate 5–15 mg was permitted with daytime doses in the 45–80 mg cohorts. Results: 43 pts received MLN8054 (median 1 cycle [range 1–10]). Dose escalation stopped at 80 mg/d due to DLTs including G3 somnolence (n=1) and G3 transaminitis (n=1). G2 oral mucositis (n=1), which may signal target-related toxicity, was observed first at 80 mg/d, a dose considered to be above the MTD. In PK analyses, MLN8054 was absorbed rapidly (T max = 1–2h) and terminal half-life was 30–40h, presenting a linear exposure-dose profile. In PD analyses, MLN8054 at higher doses increased mitotic count in skin and tumor biopsies and reduced chromosome alignment and spindle bipolarity in the mitotic cells in tumor biopsies, outcomes consistent with AAK inhibition. Stable disease (range 4–9 cycles) was observed in 3 pts (colorectal, non-small cell lung, and melanoma). Conclusions: MLN8054 was absorbed rapidly with a long half-life; PD findings supported MLN8054 inhibition of AAK at higher doses. Dosing for 14d of a 28-d cycle was feasible, but off-target DLTs limited dose escalation before mechanism-based toxicity was seen. MLN8237, a second-generation AAK inhibitor designed with greater mechanistic potency and to minimize benzodiazepine effects, is now in clinical trials. [Table: see text]
ヒト多能性幹細胞の効率的な肝仕様のためのラミニン511とラミニン521ベースマトリックス【Powered by NICT】
Authors: K Kanninen Liisa, Harjumaeki Riina, Peltoniemi Pasi, S Bogacheva Mariia, Salmi Tuuli, Porola Pauliina, Niklander Johanna, Smutny Tomas, Urtti Arto, L Yliperttula Marjo, Lou Yan-Ru
Journal: Biomaterials (2016)
Midostaurin: a magic bullet that blocks mast cell expansion and activation
Authors: P. Valent, C. Akin, K. Hartmann, T.I. George, K. Sotlar, B. Peter, K.V. Gleixner, K. Blatt, W.R. Sperr, P.W. Manley, O. Hermine, H.C. Kluin-Nelemans, M. Arock, H.-P. Horny, A. Reiter, J. Gotlib
Journal: Annals of Oncology (2017)
C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation
Authors: A E Marneth, K H M Prange, A S A Al Hinai, S M Bergevoet, N Tesi, E M Janssen-Megens, B Kim, N Sharifi, M L Yaspo, J Kuster, M A Sanders, E C G Stoetman, J Knijnenburg, T C J M Arentsen-Peters, C M Zwaan, H G Stunnenberg, M M van den Heuvel-Eibrink, T Haferlach, M Fornerod, J H Jansen, P J M Valk, B A van der Reijden, J H A Martens
Journal: Leukemia (2017)
PTH-079 Disease related concerns are strongly associated with disability and quality of life in inflammatory bowel diseasein remission
Authors: K Argyriou, A Kapsoritakis, E Tsakiridou, S Potamianos
Journal: Gut (2017)

Introduction  Patients’ concerns have been negatively associated with adaptation and outcomes in inflammatory bowel diseases (IBD). Disease severity has been shown to be an important predictor for increased concerns and disability as well as for poor quality of life (QoL). However, recent studies reported significant concerns even when patients are in remission.  Our primary aim was to investigate the association among disease related concerns, disability and QoL in IBD in remission. Secondarily, we aimed to find possible associations between concerns and population characteristics.  Method  The study lasted two years (2014–2016). 200 consecutive adult IBD patients from the outpatient clinic of a tertiary referral centre were screened for eligibility. Patients with psychiatric and other commorbidities were excluded. 67 patients were in remission and recruited. Patients‘ concerns were assessed with the rating form of IBD patients’ concerns (RFIPC). For disability and QoL, the 36-item version of WHODAS 2.0 and the inflammatory bowel disease questionnaire were used respectively. Factors significantly associated with RFIPC total and dimentional scores were entered in linear regression analysis.  Results  55.2% of the population had ulcerative colitis (UC) while the rest Crohn’s disease (CD). Mean disease duration was 7.73 years. The mean RFIPC score was 38.63 (sd: 10.3). No significant differences recorded per disease type (p>0.05). Worries about the unknown nature of the disease, feeling out of control, having access to quality medical care, the fear of side effects and the energy level prevailed in our population. Increased level of concerns was strongly associated with increased perceived disability (r=0.716–0.895, p=0.001) and low QoL (r=–0.6–0.7,p=0.001). Full-time employment was the only factor that was independently associated with increased level of concerns among IBD patients in remission in all 4 RFIPC domains. (b=0.509–0.573, p=0.018–0.001) In addition, celibacy (b=0.264, p=0.007) and male sex (b=0.244,p=0.001) were found to be independently related with higher scores in the domains of disease impact and complications respectively.  Conclusion  In remission, the level of patients’ concerns is strongly associated with increased perceived disability and low QoL. Full time employment, celibacy and male gender were associated with increased level of concerns indicating specific targets for future interventions.  References  . Keeton RL, et al. Concerns and worries in people living with inflammatory bowel disease (IBD): A mixed methods study.J Psychosom Res. 2015Jun;78(6):573–8  . Soares JB, et al.The Inflammatory Bowel Disease-Disability Index: validation of the Portuguese version according to the COSMIN checklist.Eur J Gastroenterol Hepatol. 2016Oct;28(10):1151–60  Disclosure of Interest  None Declared
Zoonotic <i>Chlamydia caviae</i> Presenting as Community-Acquired Pneumonia
Authors: Bart P Ramakers, Marloes Heijne, Natascha Lie, Thuy-Nga Le, Monique van Vliet, Vivian P J Claessen, Paulien J P Tolsma, Mauro De Rosa, Hendrik I J Roest, Daisy Vanrompay, Edou R Heddema, Peter Schneeberger, Mirjam H A Hermans
Journal: New England Journal of Medicine (2017)

Zoonotic Chlamydia caviae Presenting as Community-Acquired PneumoniaTo the Editor: Chlamydia caviae is a member of the family of gram-negative intracellular bacteria Chlamydiaceae.Bacteria of this family cause a broad spectrum of diseases in animals and humans and are currently subdivided into a single genus and 11 species. 1 Among these species, C. psittaci and C. abortus are known for their zoonotic potential, causing psittacosis and abortion, respectively, in humans. 2,3In contrast, only one case of mild conjunctivitis has previously been documented in association with C. caviae. 4e describe three unrelated cases of infection in otherwise healthy adults in their early 30s who had respiratory failure caused by severe community-acquired pneumonia (see chest radiographs in Section S1 of the Supplementary Appendix, available with the full text of this letter at NEJM.org) after exposure to ill guinea pigs (Table 1).The three cases, which appeared over a period of approximately 3 years, occurred in persons from different families, at different hospitals, and in different geographic areas.Two patients were treated with mechanical ventilation in the intensive care unit for several days.Chlamydia DNA was detected in specimens obtained from the respiratory tract, serum, or both in all three patients, and the species was identified as C. caviae by means of the Dutch
ビタミンE α‐トコトリエノール封入標的化小胞の静脈投与後の腫瘍退縮
Authors: Karim Reatul, Somani Sukrut, Al Robaian Majed, Mullin Margaret, Amor Rumelo, McConnell Gail, Dufes Christine
Journal: Journal of Controlled Release (2017)
Abstract 113: Regulation Of Aortic Vasodilation By Sigma-1 Receptor Stimulation In Ovariectomized And Pressure Overloaded Rats.
Authors: Hideaki Tagashira, Takayuki Matsumoto, Kumiko Taguchi, Tsuneo Kobayashi, Kohji Fukunaga
Journal: Circulation Research (2013)

Objective: We previously reported that sigma-1 receptor ( σ 1 R ) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ 1 R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. Methods: SA4503 (0.3-1.0 mg kg -1 ) and NE-100 (an σ 1 R antagonist, 1.0 mg kg -1 ) were administered orally for 4 weeks (once daily) to OVX-PO rats, starting from the onset of aortic banding. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. Results: σ 1 R expression in aortic smooth muscle and endothelial cells decreased significantly 4 weeks after PO in OVX rats (vs. Sham or OVX only group). SA4503 administration rescued PO-induced σ 1 R decreases in the descending aorta. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. Conclusions: σ 1 R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ 1 R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ 1 R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ 1 R to prevent vascular endothelial injury in postmenopausal woman.
Arm Swelling Following Attempted Peripherally Inserted Central Catheter
Authors: Sachinder Singh Hans, David Siegel, Carrie Nielsen
Journal: JAMA Surgery (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Intestinal Adenocarcinoma and Intra-Abdominal Hemangio-Endothelioma in Mice Ingesting Methylcholanthrene
Authors: Julius White, Harold L. Stewart
Journal: JNCI Journal of the National Cancer Institute (1942)

Intestinal Adenocarcinoma and Intra-Abdominal Hemangio-Endothelioma in Mice Ingesting Methylcholanthrene Get access Julius White, Julius White senior biochemist Search for other works by this author on: Oxford Academic PubMed Google Scholar Harold L. Stewart Harold L. Stewart senior pathologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 3, Issue 3, December 1942, Pages 331–347, https://doi.org/10.1093/jnci/3.3.331 Published: 01 December 1942
Cgnl1, an endothelial junction complex protein, regulates GTPase mediated angiogenesis
Authors: Ihsan Chrifi, Dorien Hermkens, Maarten M Brandt, Christian G M van Dijk, Petra E Bürgisser, Remco Haasdijk, Jiayi Pei, Esther H M van de Kamp, Changbin Zhu, Lau Blonden, Johan M Kros, Dirk J Duncker, Henricus J Duckers, Caroline Cheng
Journal: Cardiovascular Research (2017)

The formation of cell-cell and cell-extra cellular matrix (ECM) contacts by endothelial cells (ECs) is crucial for the stability and integrity of a vascular network. We previously identified cingulin-like 1 (Cgnl1) in a transcriptomic screen for new angiogenic modulators. Here we aim to study the function of the cell-cell junction associated protein Cgnl1 during vessel formation.Unlike family member cingulin, Cgnl1 expression is enriched in ECs during vascular growth. Cgnl1 is important for the formation of multicellular tubule structures, as shown in vitro using loss-of function assays in a 3D matrix co-culture system that uses primary human ECs and supporting mural cells. Further studies revealed that Cgnl1 regulates vascular growth by promoting Ve-cadherin association with the actin cytoskeleton, thereby stabilizing adherens junctions. Cgnl1 also regulates focal adhesion assembly in response to ECM contact, promoting vinculin and paxillin recruitment and focal adhesion kinase signalling. In vivo, we demonstrate in a postnatal retinal vascular development model in mice that Cgnl1 function is crucial for sustaining neovascular growth and stability.Our data demonstrate a functional relevance for Cgnl1 as a defining factor in new vessel formation both in vitro and in vivo.
Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure
Authors: Filipe S. Cardoso, Michelle Gottfried, Shannan Tujios, Jody C. Olson, Constantine J. Karvellas
Journal: Hepatology (2017)

Hyperammonemia has been associated with intracranial hypertension and mortality in patients with acute liver failure (ALF). We evaluated the effect of renal replacement therapy (RRT) on serum ammonia level and outcomes in ALF. This was a multicenter cohort study of consecutive ALF patients from the United States ALF Study Group registry between January 1998 and December 2016. First, we studied the association of ammonia with hepatic encephalopathy (HE) and 21‐day transplant‐free survival (TFS; n = 1,186). Second, we studied the effect of RRT on ammonia for the first 3 days post study admission (n = 340) and on 21‐day TFS (n = 1,186). Higher admission (n = 1,186) median ammonia level was associated with grade 3‐4 HE (116 vs. 83 μmol/L) and mortality at day 21 attributed to neurological (181 vs. 90 μmol/L) and all causes (114 vs. 83 μmol/L; P &lt; 0.001 for all). Among 340 patients with serial ammonia levels, 61 (18%) were on continuous RRT (CRRT), 59 (17%) were on intermittent RRT (IRRT), and 220 (65%) received no RRT for the first 2 days. From days 1 to 3, median ammonia decreased by 38%, 23%, and 19% with CRRT, IRRT, and no RRT, respectively. Comparing to no RRT use, whereas ammonia reduction with CRRT was significant ( P = 0.007), with IRRT it was not ( P = 0.75). After adjusting for year of enrollment, age, etiology, and disease severity, whereas CRRT (odds ratio [OR], 0.47 [95% confidence interval {CI}, 0.26‐0.82]) was associated with reduction in 21‐day transplant‐free all‐cause mortality, IRRT (OR, 1.68 [95% CI, 1.04‐2.72]) was associated with an increase. Conclusion: In a large cohort of ALF patients, hyperammonemia was associated with high‐grade HE and worse 21‐day TFS. CRRT was associated with a reduction in serum ammonia level and improvement of 21‐day TFS. (H epatology 2018;67:711‐720).
同所性肺腫瘍における沈黙遺伝子発現への安定化ポリエステルsiRNAナノ粒子のエーロゾルデリバリー【Powered by NICT】
Authors: Yan Yunfeng, Zhou Kejin, Xiong Hu, B Miller Jason, A Motea Edward, A Boothman David, Liu Li, J Siegwart Daniel
Journal: Biomaterials (2017)
術前MRIと術中画像誘導のための標的多モードナノレポーター【Powered by NICT】
Authors: Lee Joonseok, C Gordon Andrew, Kim Hacksung, Park Wooram, Cho Soojeong, Lee Byeongdu, C Larson Andrew, A Rozhkova Elena, Kim Dong-Hyun
Journal: Biomaterials (2016)
Pembrolizumab in Programmed Death Ligand 1–Positive Endometrial Cancer
Authors: Federica Tomao, Pierluigi Benedetti Panici, Silverio Tomao
Journal: Journal of Clinical Oncology (2017)

In the article by Ott et al, 1 the aim of the study, KEYNOTE-028 (NCT02054806), was to evaluate the activity and safety profile of pembrolizumab in patients with heavily pretreated advanced endometrial cancer (EC), a subgroup with a poor prognosis.This article deserves some consideration to give the study proper meaning.Unfortunately, it is a small study, as are others that explore the activity of different agents in advanced and metastatic EC.Of the 75 patients evaluated for programmed death ligand 1 expression, 36 (48%) had positive tumors.According to eligibility criteria, up to 12 patients were excluded; moreover, another woman was excluded for lack of post-baseline assessment, and three received no assessment at the time of the data cutoff.The study design stated that sarcomas should be excluded; in our opinion, even a patient with a carcinosarcoma should have been excluded to have a more homogeneous group for this investigation.For the same reason, the two patients who received adjuvant radiotherapy should have been excluded.Therefore, only 17 patients were eligible by clinical assessment-certainly too few to answer to the question about clinical activity of pembrolizumab in patients with programmed death ligand 1-positive EC.In this article, the authors reported the promising role of bevacizumab in EC according to available scientific data. 1,24][5][6] In the trial reported by Aghajanian et al, 2 56 patients were recruited to evaluate the activity of bevacizumab in recurrent or persistent EC.Of 55 patients, 52 were eligible and evaluable.In the study, one complete and six partial responses were observed (together, 13.5% response rate); the median response duration reported was 6 months.Moreover, 21 patients (40.4%) were progression free for at least 6 months.The median progression-free survival and overall survival (OS) times were 4.2 and 10.5 months, respectively.According to these data, bevacizumab use was proposed as singleagent therapy for patients with EC who experienced progression after standard chemotherapy. 3In the study by Ott et al, 1 the 6-and
Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap
Authors: Aparna Lakshmanan, John C. Byrd
Journal: Cancer Discovery (2017)

Abstract Summary: In this issue Grommes and colleagues elegantly show that the irreversible inhibitor of Bruton tyrosine kinase, ibrutinib, promotes a high proportion of durable responses in primary central nervous system lymphoma, a type of diffuse large B-cell lymphoma (DLBCL), and also in secondary DLBCL relapsing to the central nervous system. Mutations in the B-cell antigen receptor–associated protein CD79B with upregulation of the MTOR pathway were associated with diminished response, but preclinical combination of PIK3CA and PIK3CD inhibitors synergized with ibrutinib to overcome this resistance mechanism, providing opportunity for further targeted therapy of this difficult-to-treat disease. Cancer Discov; 7(9); 940–2. ©2017 AACR. See related article by Grommes et al., p. 1018.
To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis – Author's reply
Authors: R.B. Dessau, A.P. van Dam, V. Fingerle, J. Gray, J.W. Hovius, K.-P. Hunfeld, B. Jaulhac, O. Kahl, W. Kristoferitsch, P.-E. Lindgren, M. Markowicz, S. Mavin, K. Ornstein, T. Rupprecht, G. Stanek, F. Strle
Journal: Clinical Microbiology and Infection (2017)
Awareness, Beliefs, and Actions Concerning Zika Virus Among Pregnant Women and Community Members — U.S. Virgin Islands, November–December 2016
Authors: Christine E. Prue, Joseph N. Roth, Amanda Garcia-Williams, Alison Yoos, Lena Camperlengo, Leah DeWilde, Mohammed Lamtahri, Andra Prosper, Cosme Harrison, Lauren Witbart, Irene Guendel, Douglas M. Wiegand, Natasha R. Lamens, Braeanna Hillman, Michelle S. Davis, Esther M. Ellis
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

These cases include immunoglobulin M-probable and polymerase chain reaction/ plaque-reduction neutralization testing confirmed cases of Zika virus disease among symptomatic persons; asymptomatic pregnant women are not included.† The Zika prevention kit included the following items: insect repellent, permethrin, condoms, a mosquito bed net, mosquito dunks (a larvicide used to treat standing water), and educational materials.
Programmed death-1 blockade in mismatch repair deficient cancer independent of tumor histology.
Authors: Luis A. Diaz, Jennifer N. Uram, Hao Wang, Bjarne Bartlett, Holly Kemberling, Aleksandra Eyring, Nilofer Saba Azad, Tianna Dauses, Dan Laheru, James J. Lee, Todd S. Crocenzi, Richard M. Goldberg, George A. Fisher, Tim F. Greten, Christian Frederick Meyer, Amanda Nickles Fader, Deborah Kay Armstrong, Minori Koshiji, Bert Vogelstein, Dung T. Le
Journal: Journal of Clinical Oncology (2016)

3003 Background: Mismatch repair deficiency (MRD) is feature of many cancers at a frequency of approximately 1 in 30 patients independent of tumor histology. Tumors with MRD are deficient in the repair of specific DNA replication errors and as a result accumulate hundreds to thousands of mutations per tumor genome. The high number of somatic mutations increase the chances for at least one of these mutations to result in a highly immunogenic neo-antigenic protein that can trigger a potent anti-tumor immune response in the presence of PD-1 blockade. Methods: To further test this hypothesis, we conducted a phase 2 study to evaluate the activity of pembrolizumab (pembro), a programmed death-1 (PD-1) antibody in MRD tumors independent of tumor histology using a basket design. Pembro was administered at 10 mg/kg every 14 days in patients with > 1 prior therapy. The co-primary endpoints were response and progression-free survival rate at 20 weeks. Secondary endpoints included disease control rate (DCR = CR+PR+SD), PFS, overall survival (OS) and safety. Results: A total of 29 patients were enrolled and treated on this study, including the following histologies: (endometrial: 9; pancreatic: 4; ampullary: 4; biliary: 3; small bowel: 3; gastric: 3; thyroid: 1; prostate: 1; sarcoma: 1). Median follow up time is 8.1 mos. Objective response and disease control rates were 48% (14/29, 95% confidence interval: 29-67%) and 72% (21/29), respectively. Twenty of 29 patients remain on treatment due to clinical benefit. Median overall Survival (OS) and progression-free survival (PFS) were 21 months and not reached (NR). The OS and PFS rates at 12 months were 79% and 54%, respectively, which support the durability of clinical benefit. Among the patients with an objective response, only 3 have developed secondary resistance to pembro with a median time to progression of 5 months. Conclusions: Independent of tumor histology, patients with advanced MRD cancers receive durable clinical benefit with Pembro. Clinical trial information: NCT01876511.