tbuckley/cabot-search huggingface dataset:
BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM).
Authors: Jeffrey Alan Sosman, Adil Daud, Jeffrey S. Weber, Kevin Kim, Richard Kefford, Keith Flaherty, Jeffrey R. Infante, Omid Hamid, Jonathan S. Cebon, Lynn Mara Schuchter, Robert R. McWilliams, Mario Sznol, William Howard Sharfman, Alain Patrick Algazi, Karl D. Lewis, Shonda M Little, Peng Sun, Georgina Long, Kiran Patel, Rene Gonzalez
Journal: Journal of Clinical Oncology (2013)

9005 Background: Dual inhibition of the MAP kinase (MAPK) pathway with dabrafenib (D) and trametinib (T) in combination has demonstrated clinical benefit compared to D alone in a randomized Phase II trial in V600 BRAF-mutant MM pts, thus delaying the development of BRAFi resistance. Little is known about the efficacy of D + T after BRAFi resistance has been acquired. This analysis evaluates the ability of D + T combination to treat acquired resistance compared to the D + T combination as first-line treatment. Methods: These data from a phase I/II study include 1. BRAFi-resistant group: pts who received 150/2 D+T in Part B (n=26) and Part C (n=43) following progression on BRAFi monotherapy (mono); 2. BRAFi-naïve group: pts who received initial 150/2 D+T in Part B (n=24) and Part C (n=54). Results: Baseline characteristics (ECOG PS, M staging, LDH) were similar across all groups.In the Part B BRAFi-resistant group, 93% of pts previously received D or vemurafenib and all pts received D prior to D+T in Part C. In BRAFi-resistant group, prior best response of CR/PR (38%, 56%), SD (35%, 27%), PD (27%, 7%) was observed in Parts B and C respectively. In BRAFi-resistant group, the ORR and PFS with D+T was lower than initial D+T in BRAFi-naive group. Median duration of response (DoR) in BRAFi-resistant group cannot be calculated due to small no. of pts responding. Median DoR for BRAFi-naïve pts was 11.3 mo and 10.5 mo in Parts B and C respectively. In Part C, the 12-mo overall survival rates in BRAFi-naïve (150/2) pts was 79% vs 70% for pts initially on D mono, despite 80% pts crossing over to D+T combination. Conclusions: The clinical activity for 150/2 D+T combination is consistently superior in BRAFi-naive group vs BRAFi-resistant group in both Parts B and C. Dual MAPK blockade can delay clinical resistance to BRAF inhibition. However, once BRAFi resistance has occurred, the combination of BRAFi + MEKi is far less effective. Clinical trial information: NCT01072175. [Table: see text]
T-Cell-Mediated Antitumor Immune Response Induced by Oncofetal Antigens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: S Gautam, S D Deodhar
Journal: JNCI Journal of the National Cancer Institute (1981)

The possibility that fetal antigens take part in tumor immunity has been investigated to a limited extent, but the results of these studies have been controversial. It is not clear that tumor inhibition shown in some systems is due to an immune reaction. In the present study, performed in a weakly immunogenic tumor system (Lewis T241 fibrosarcoma in inbred C57BL/6J mice), immunization of mice with syngeneic fetal cells resulted in striking inhibition of growth and metastases of tumors. Mice that had gone through single pregnancies also showed a decreased rate of tumor growth and tumor metastases. Further studies have shown that the tumor inhibitory response evoked by fetal cell immunization is due to fetal antigens, and the male specific HY antigen is not responsible for antitumor response. Injection of tumor cells mixed with spleen cells from mice immunized with syngeneic fetal cells into normal mice resulted in significant inhibition of tumor growth and metastases in the Winn neutralization assay. Syngeneic fetal cells, normal adult spleen cells, or spleen cells from C57BL/6 mice immunized with allogeneic fetal cells did not inhibit tumor growth or metastases. These results show that tumor inhibition following fetal cell immunization is due to an immune reaction and is not due to a nonimmune physiologic process. Further analysis of effector cells showed them to be of the T-cell type.
NIH plans to be more nimble and innovative
Authors: Michael McCarthy
Journal: BMJ (2015)

To realize the promise of new biomedical technologies and meet new challenges to human health, the US National Institutes of Health will seek to create a more nimble, innovative, and efficient organization, says a five year plan released by the agency on 16 December and mandated by Congress.1

The director of the NIH, Francis S Collins, said that the plan “will guide our efforts to turn scientific discoveries into better health, while upholding our responsibility to be wise stewards of the resources provided by the American people.”

With a budget of $30bn (£20m; €28m), the NIH is the largest source of biomedical research funding in the world, supporting the work of more than 300 000 researchers in the United States and abroad. However, for more than a decade the NIH’s funding has …
Pre-clinical evaluation of bortezomib, doxorubicin, dexamethasone, and lenalidomide in multiple myeloma (MM)
Authors: M. Hari, Z. Hector-Word, D. Lebovic, M. Soengas, A. Jakubowiak
Journal: Journal of Clinical Oncology (2008)

19513 Background: Treatment with bortezomib combinations have shown to improve efficacy in MM. In clinical studies, among the most active are 3-drug combinations of bortezomib, liposomal doxorubicin and dexamethasone (VDD), with 93% patients achieving at least 50% disease reduction (PR), and lenalidomide, bortezomib, Dexamethasone (RVD) with 89% PR rate. However, > 90% reduction of the disease (VGPR) associated with longer survival was seen in only 63% and 35% patients, respectively. In this study, we evaluated whether combining 4- drugs (VDDR) can further improve elimination of myeloma cells. In addition to cytotoxicity, we investigated the effects of bortezomib combinations on Noxa and c-myc as markers of activity of bortezomib combinations. Methods: MM cell lines MM1.S, NCI H929 and RPMI 8226 were treated with combinations of bortezomib (Vel), doxorubicin (Dox), dexamethasone (Dex) and lenalidomide (Rev) and cytotoxicity was measured by MTT assays. Noxa and c-myc induction, and caspase-3,-8 and -9 activation were evaluated by immunoblotting after treatment with drugs in MM cells and normal PBMCs. Results: VDDR showed 2–4 fold higher cytotoxicity than Vel/Dox, Vel/Dex and Vel/Rev, and comparable toxicity to VDD in NCI H929 cells. In cells sensitive to Rev (MM1.S), VDDR showed higher cytotoxicity than VDD. Vel selectively increased Noxa levels in MM cell lines but not in normal PBMCs. In studies to date, the combination of VDD resulted in higher levels and faster kinetics of Noxa induction than Vel alone and leads to more potent caspase activation observed within 16hrs of treatment. Neither Dox nor Dex had any effect on Noxa levels. Noxa induction correlated with higher c-myc levels upon Vel treatment in RPMI 8226 cells. Knocking down c-myc with shRNA resulted in partial loss of Noxa suggesting that c-myc is required for Noxa induction. Conclusions: VDDR shows higher efficacy in preclinical models providing a rationale for a phase I/II clinical trial in newly diagnosed MM to be activated in the MMRC. Based on the preliminary results, tumor specific Noxa induction can be used as a biomarker for pre-clinical evaluation of the efficacy of Velcade-based regimens in myeloma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene, Millennium Celgene, Millennium
Physical medicine and rehabilitation
Authors: M. E. Brandstater
Journal: JAMA (1995)

Restorative care has always been the central focus of physical medicine and rehabilitation (physiatry). Beginning in the acute phase of trauma or illness, restoration of patients with physical impairments and disabilities encompasses a continuum of services required throughout the postacute and chronic phases of care. Physiatrists provide restorative care to patients with a wide range of disabling illnesses or injuries, including such disorders as spinal cord injury, brain injury, and stroke, and musculoskeletal disorders, such as back pain.  Recognition of the efficacy and cost-benefit of rehabilitation led to a major expansion of hospital-based rehabilitation services in the 1980s and early 1990s. Many patients with complex disabilities, such as those after acute spinal cord injury, require acute inpatient rehabilitation. They need close medical monitoring, frequent changes in care plans, intensive rehabilitation nursing, and comprehensive care provided by an interdisciplinary health care team. However, not all rehabilitation patients need such a comprehensive
Respiratory mechanics characterization in a mouse model of house dust mite allergy
Authors: Camille Doras, Yves Donati, Philippe Eigenmann, Ferenc Peták, Walid Habre
Journal: European Respiratory Journal (2014)

Background-  While ovalbumin (OVA) sensitization is an often used asthma model in mice, house dust mite (HDM) sensitization is of the most relevant clinically. However the respective role of lung compartments in the occurrence of HDM-induced bronchospasm is poorly understood.   Objectives-  To evaluate the respiratory impedance during the early phase of allergic response in mice sensitized to HDM compared to OVA.   Methods-  BALB/c mice were randomized into naive or sensitized groups (OVA: 50µg+2mg alum/200µL intraperitoneal injection on days 0 and 7, 60µg/20µL intranasal instillations on days 14-17; HDM: 6x 25µg/20µL intranasal instillations over 2 weeks). After sensitization, mice were anesthetized and mechanically ventilated. Forced oscillatory respiratory mechanics (airway resistance (Raw), tissue damping (G) and elastance (H)) were assessed before and over 15 minutes (159) following allergen challenge.   Preliminary results-  After OVA challenge in OVA sensitized mice, the marked Raw response peaking at 159 (% baseline 128±48 p   Conclusions-  Mice sensitized with OVA or HDM presented different patterns of allergic lung response. While OVA challenge led primarily to airway response with subsequent development of ventilation heterogeneities, HDM challenge compromised predominantly the viscoelastic properties of the lung.   Supported by SNSF grant 332003B-143331/1 .
Pharmacology of Heparin and Related Drugs
Authors: Barbara Mulloy, John Hogwood, Elaine Gray, Rebecca Lever, Clive P. Page
Journal: Pharmacological Reviews (2015)

Heparin has been recognized as a valuable anticoagulant and antithrombotic for several decades and is still widely used in clinical practice for a variety of indications. The anticoagulant activity of heparin is mainly attributable to the action of a specific pentasaccharide sequence that acts in concert with antithrombin, a plasma coagulation factor inhibitor. This observation has led to the development of synthetic heparin mimetics for clinical use. However, it is increasingly recognized that heparin has many other pharmacological properties, including but not limited to antiviral, anti-inflammatory, and antimetastatic actions. Many of these activities are independent of its anticoagulant activity, although the mechanisms of these other activities are currently less well defined. Nonetheless, heparin is being exploited for clinical uses beyond anticoagulation and developed for a wide range of clinical disorders. This article provides a "state of the art" review of our current understanding of the pharmacology of heparin and related drugs and an overview of the status of development of such drugs.
P1288 : Budd chiari syndrome (BCS) in France from a large national cohort
Authors: M. Allaire, I. Ollivier-Hourmand, R. Morello, C. Chagneau-Derrode, J. Dumortier, O. Goria, N. Ganne-Carrié, N. Carbonell, J.-P. Cervoni, V. De Ledinghen, S. Dharancy, C. Bureau, A. Abergel, F. Oberti, A. Minello, M.-P. Ripault, R. Anty, J.-B. Nousbaum, M. Ecochard, J.-P. Becquart, H. Barraud, I. Archambeaud, A. Guillygomarc’h, V. Ozenne, M.-N. Hilleret, S. Radenne, E. Nguyen-Khac, J.-M. Perarnau, P. Le Filliatre, B. Dauvois, M. Doffoel, J.-J. Raabe, E. Saillard, G. Delaval, D. Valla, T. Dao, A. Plessier
Journal: Journal of Hepatology (2015)
Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial
Authors: Carmen J. Allegra, Greg Yothers, Michael J. O’Connell, Robert W. Beart, Timothy F. Wozniak, Henry C. Pitot, Anthony F. Shields, Jerome C. Landry, David P. Ryan, Amit Arora, Lisa S. Evans, Nathan Bahary, Gamini Soori, Janice F. Eakle, John M. Robertson, Dennis F. Moore, Michael R. Mullane, Benjamin T. Marchello, Patrick J. Ward, Saima Sharif, Mark S. Roh, Norman Wolmark
Journal: JNCI Journal of the National Cancer Institute (2015)

National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3–4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.
A phase I pharmacokinetic (PK) study of MBP-426, a novel liposome encapsulated oxaliplatin
Authors: K. K. Sankhala, A. C. Mita, R. Adinin, L. Wood, M. Beeram, S. Bullock, N. Yamagata, K. Matsuno, T. Fujisawa, A. Phan
Journal: Journal of Clinical Oncology (2009)

2535 Background: MBP-426 is a novel liposome encapsulated oxaliplatin (L-OHP) formulation bound to human transferrin, developed to improve the safety and efficacy of L -OHP through the prolongation of circulation time and by targeting transferrin receptors on tumor cells. In vitro, MBP-426 is effective against various human cancer cell lines. This study assessed the toxicity and safety of intravenously (IV) administered MBP-426, including defining the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). Methods: Patients (pts) with advanced/ metastatic solid tumors refractory to conventional therapy received MBP-426 as 2–4 hrs IV infusion every 3 weeks in cohorts of 3 to 6 pts. Enrollment required age &gt; 18 yrs, ECOG Performance Status 0–2 and adequate organ functions. Tumor response was assessed by RECIST. Plasma was sampled for PK. Results: 39 pts were dosed, median age 59 (range 27–79), 25 (64%) male. The common tumor types were colorectal 23 (60%), pancreas 3 (8%), and neuroendocrine 3 (8%). Most pts were heavily pretreated with chemotherapy or chemoradiation. 77% pts had received oxaliplatin or cisplatin. Eleven dose levels ranging from 6 to 400 mg/m 2 were evaluated. At 400 mg/m 2 , 2/3 pts had DLT as grade 4 thrombocytopenia and prolonged thrombocytopenia (1 pt each). The recommended phase II dose is 226 mg/m 2 where 1/6 pts had grade 4 thrombocytopenia. Grade 3–4 toxicities included fatigue (3 pts), hypercholesterolemia (3 pts), anemia (2 pts) and constipation (1 pt). Common grade 1–2 toxicities were nausea and/or vomiting (59%), fatigue (43%), infusion reaction (15%), thrombocytopenia (15%), anemia (13%) and peripheral neuropathy (13%). 15 pts had stable disease after 2 cycles. 3 pts with colon carcinoma refractory to conventional oxaliplatin had stable disease for 4, 5 and 6 cycles respectively, one of them had 25% decrease in target lesions. PKs of MBP-426 were dose-proportional. Main PK parameters at 226 mg/m 2 were AUC 2141+419 μg.hr/ml, and t½ 89+92 hr, comparing favorably with intact L-OHP. Conclusions: MBP-426 has a favorable safety profile with thrombocytopenia as main DLT. The PK target concentration of L-OHP was exceeded at higher doses. Based on PK and toxicity profiles, the recommended dose is 226 mg/m 2 . [Table: see text]
Imaging techniques in the evaluation of solitary pulmonary nodules (SPNs)
Authors: Marta Dabrowska, Rafal Krenke, Piotr Korczynski, Marta Maskey-Warzechowska, Malgorzata Zukowska, Jolanta Kunikowska, Wlodzimierz Kupis, Ryszarda Chazan
Journal: European Respiratory Journal (2011)

Despite new imaging techniques such as contrast enhanced computed tomography (CECT) or positron emission tomography with 18-fluorodeoxyglucose (FDG-PET/CT), non-invasive diagnosis of SPN etiology still remains a problem.   Aim:  1. to assess the incidence of maligancy in newly diagnosed SPNs  2. to evaluate utility of CECT and FDG-PET/CT in SPN diagnosis   Methods:  85 patients with newly diagnosed SPNs were observed on an ambulatory basis between 2008 and 2010.  The diagnosis of malignant etiology of SPNs was based on pathological examination.  The benign etiology was proved based on either:  1. pathological examination  2. lack of growth for at least 2 years or resolution in radiological follow-up  3. central/total calcification in CT  The result of FDG PET/CT was suggestive for benign etiology of SPN if uptake of FDG was like background (SUV    Results:  The SPN etiology was determined in 60 patients. 12 nodules (14%) were malignant. 48 nodules (56.5%) were benign. 17 patients are still under observation; 8 were lost to follow up.  FDG-PET/CT was performed in 32 patients. In 16 cases the result was negative, 12 had an increased FDG uptake, 4 were inconclusive. The sensitivity, specificity, positive (PPV)and negative predicative value (NPV) and diagnostic accuracy of FDG-PET/CT were 91%, 87%, 83%, 93% and 88%, respectively.  CECT was performed in 26 patients. In 10 cases the result was suggestive for benign SPN. The sensitivity, specificity, PPV, NPV and diagnostic accuracy of CECT were 100%, 48%, 69%, 100%, and 58% respectively.   Conclusions:  The diagnostic accuracy of FDG-PET/CT is higher than that of CECT. The advantage of CECT is its high sensitivity and NPV.
Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus
Authors: Mykola Mamenko, Isha Dhande, Viktor Tomilin, Oleg Zaika, Nabila Boukelmoune, Yaming Zhu, Manuel L. Gonzalez-Garay, Oleh Pochynyuk, Peter A. Doris
Journal: Journal of the American Society of Nephrology (2015)

Store-operated calcium entry (SOCE) is the mechanism by which extracellular signals elicit prolonged intracellular calcium elevation to drive changes in fundamental cellular processes. Here, we investigated the role of SOCE in the regulation of renal water reabsorption, using the inbred rat strain SHR-A3 as an animal model with disrupted SOCE. We found that SHR-A3, but not SHR-B2, have a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), the endoplasmic reticulum calcium (Ca(2+)) sensor that triggers SOCE. Balance studies revealed increased urine volume, hypertonic plasma, polydipsia, and impaired urinary concentrating ability accompanied by elevated circulating arginine vasopressin (AVP) levels in SHR-A3 compared with SHR-B2. Isolated, split-open collecting ducts (CD) from SHR-A3 displayed decreased basal intracellular Ca(2+) levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca(2+) mobilization that requires SOCE in CD cells from SHR-A3. This effect decreased the abundance of aquaporin 2 and enhanced its intracellular retention, suggesting impaired sensitivity of the CD to AVP in SHR-A3. Stim1 knockdown in cultured mpkCCDc14 cells reduced SOCE and basal intracellular Ca(2+) levels and prevented AVP-induced translocation of aquaporin 2, further suggesting the effects in SHR-A3 result from the expression of truncated STIM1. Overall, these results identify a novel mechanism of nephrogenic diabetes insipidus and uncover a role of SOCE in renal water handling.
South Africa's Health: Impressions of health in the new South Africa: a period of convalescence
Authors: R. Kale
Journal: BMJ (1995)

South Africa is a fledgling democracy.With a fair, and generally peaceful, first election in April 1994 it has shown the world that its people can make decisions that would do credit to a more mature democracy.Fears that the end of apartheid would be accompanied by a bloodbath were proved wrong.South Africa is an extreme example of inequity in every sphere of life including health care.This series of five articles tries to capture a picture of the health of South Africa.I spent three weeks in South Africa and met doctors, administrators, politicians, and others who could enlighten me.In Cape Town, Johannesburg, Pretoria, Durban, and Kwazulu I visited hospitals, townships, and shanty towns that I was told were representative-and safe to visit.This first article looks at the period after the elections and describes immediate gains and losses.The next three articles discuss the role of the traditional healers of South Africa, the country's mental health profile, and its medical workforce.The last article considers the South African government's plans and the dilemmas faced by its health planners while restructuring health care and undoing the ills of apartheid.Inequity in health care and apartheid Apartheid made South Africa unique.Racial dis- crimination exists in every country where people from different racial groups live together, but in South Profile ofhealth and disease in South Africa Asians Blacks "Coloureds" Whites Population
Meningeal Carcinomatosis in Lung Cancer
Authors: Eric T. Wong, Jeffrey T. Joseph
Journal: Journal of Clinical Oncology (2000)

Article Tools Meningeal Carcinomatosis in Lung Cancer Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.15.2926 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10920141 Meningeal Carcinomatosis in Lung Cancer Eric T. WongxEric T. WongSearch for articles by this author , Jeffrey T. JosephxJeffrey T. JosephSearch for articles by this author Show More Beth Israel Deaconess Medical Center, Boston, MA https://doi.org/10.1200/JCO.2000.18.15.2926 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical Oncology