tbuckley/cabot-search huggingface dataset:
Outpatient chemotherapy for non-metastatic Ewing's sarcoma (ES): Pilot experience. Sarcoma Group, King Faisal Specialist Hospital, Saudi Arabia
Authors: M. Memon, M. A. Raja, P. Moreau, A. Allam
Journal: Journal of Clinical Oncology (2004)

9057 Background: Non-metastatic ES is considered curable with combined modality therapy involving surgery (S), chemotherapy (C) ± radiation therapy (RT). C involves prolonged treatment with multiple cycles, thus adding to in-patient cost. We report our experience with combined modality therapy in ES in ambulatory care setting. Methods: Patients (age = 14) with newly diagnosed non-metastatic ES diagnosed between May 1999 –December 2001 included. All had confirmed histology, staging, C, and surgery/RT whenever feasible/indicated. C: vincristine 1.5 mg/m2 on day 1, adriamycin 20 mg/m2 alternating with actinomycin D 0.5 mg/m2 daily days 1–3, all intravenous, and ifosfamide 2000 mg/m2 intravenous infusion days 1–3 with equivalent mesna in 3 divided doses, one pre and 2 post ifosfamide. Dose intensities of all drugs identical to previously used in-patient regime. Standard anti emetics, 1 litre of hydration given daily. Total 14 cycles q 21 days, response evaluation after 4, 8, 12 cycles and end of therapy. S after 4 cycles if feasible, RT if unresectable or margins positive. Results: Total 19 patients, M:F 14:5, median age 18 (14–42). Primary site chest wall 4, ilium, femur, tibia, fibula 2 each, extraskeletal 3, other bones 4. Primary S in 2 extraskeletal cases, S after initial C in 12 (4 had > 90% necrosis), 2 unresectable, 3 refused S. Median C cycles 11. RT in 12 patients (refused S 4, unresectable 2, others margin status positive or unknown). Overall response - complete 16, partial 1, progression 2. Toxicities: febrile neutropenia 2, non neutropenic grade 3 infections 2, grade 3 mucositis 1. No hemorrhagic cystitis, no grade 3/4 hematologic or renal toxicity, no toxic deaths. Of 16 with complete response, 6 relapsed, 1 with partial response progressed. With median follow up 22 months (8–50), 10/19 (53%) alive with no evidence of disease, 6 alive with disease, 3 died of disease. Conclusion: Outpatient chemotherapy for ES is feasible, well tolerated with manageable toxicities, outcome is comparable to in-patient management. More patients being recruited and longer follow-up required. No significant financial relationships to disclose.
Toll-like Receptor 4 Engagement on Dendritic Cells Restrains Phago-Lysosome Fusion and Promotes Cross-Presentation of Antigens
Authors: Andrés Alloatti, Fiorella Kotsias, Anne-Marie Pauwels, Jean-Marie Carpier, Mabel Jouve, Evy Timmerman, Luigia Pace, Pablo Vargas, Mathieu Maurin, Ulf Gehrmann, Leonel Joannas, Omar I. Vivar, Ana-Maria Lennon-Duménil, Ariel Savina, Kris Gevaert, Rudi Beyaert, Eik Hoffmann, Sebastian Amigorena
Journal: Immunity (2015)
Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells
Authors: Claudia U Duerr, Connor D A McCarthy, Barbara C Mindt, Manuel Rubio, Alexandre P Meli, Julien Pothlichet, Megan M Eva, Jean-François Gauchat, Salman T Qureshi, Bruce D Mazer, Karen L Mossman, Danielle Malo, Ana M Gamero, Silvia M Vidal, Irah L King, Marika Sarfati, Jörg H Fritz
Journal: Nature Immunology (2015)
Diffuse LV Myocardial Fibrosis and its Clinical Associations in Adults With Repaired Tetralogy of Fallot
Authors: Craig S. Broberg, Jennifer Huang, Ingrid Hogberg, Joel McLarry, Patricia Woods, Luke J. Burchill, George A. Pantely, David J. Sahn, Michael Jerosch-Herold
Journal: JACC. Cardiovascular imaging (2015)
Margaret McCartney: Hunt’s plan will shame patients who need costly drugs
Authors: Margaret McCartney
Journal: BMJ (2015)

“This will not just reduce waste by reminding people of the cost of medicine but also improve patient care by boosting adherence to drug regimes,” said Jeremy Hunt.1 Our health secretary wants prescriptions for drugs costing more than £20 (€29; $31) to display the price.

Any politician who dreams up an idea in the bath would be irresponsible not to seek answers to these two key questions: (a) will it work; and (b) what are the harms? Hunt has access to skilled doctors and researchers, but he does not seem to have made any use of them. His plan has had no pilots and no trials—but implementation is happening anyway.

Will it work? Plainly, people who do …
Accelerated return to sport after anterior cruciate ligament injury: a risk factor for early knee osteoarthritis?
Authors: Adam G Culvenor, Kay M Crossley
Journal: British Journal of Sports Medicine (2015)

Returning to preinjury level of sports participation is a primary goal of anterior cruciate ligament reconstruction (ACLR). Indeed, surgical success is often judged on return-to-sport rates. While timeframes of 6–12 months postsurgery are typically expected, in reality, fewer than two-thirds of individuals return-to-sport within the first year post-ACLR.1 Conservatively managed individuals have similar clinical outcomes—future knee function relies on optimal rehabilitation, irrespective of surgery.2 Although consensus for the most effective rehabilitation approach is lacking, contemporary treatment programmes worship at the altar of accelerated return-to-sport.

Although the finish line for ACL rehabilitation is often defined as resuming sporting pursuits, consequences of ACL injury, including the high reinjury and contralateral injury risk, extend for many years, possibly a lifetime. Radiographic knee osteoarthritis (OA) is inevitable for 50–60% of individuals ≥10 years post-ACL injury and reconstruction.3 Given that typical ACL injured patients are young, this early-onset OA often engenders considerable morbidity and impact on healthcare resources. Could our short-sighted fixation on a fast-tracked return-to-sport be linked to these alarming premature OA rates?

Post-traumatic …
The Prognostic and Predictive Value of Soluble Type IV Collagen in Colorectal Cancer: A Retrospective Multicenter Study
Authors: Hans Christian Rolff, Ib Jarle Christensen, Ben Vainer, Lars Bo Svendsen, Rikke Løvendahl Eefsen, Michael Wilhelmsen, Ida Katrine Lund, Gunilla Høyer-Hansen, Hans Jørgen Nielsen, Martin Illemann
Journal: Clinical Cancer Research (2015)

Abstract Purpose: To investigate the prognostic and predictive biomarker value of type IV collagen in colorectal cancer. Experimental Design: Retrospective evaluation of two independent cohorts of patients with colorectal cancer included prospectively in 2004–2005 (training set) and 2006–2008 (validation set). Plasma samples were available from 297 (training set) and 482 (validation set) patients. Type IV collagen determinations were performed using an ELISA. From the training set, 222 tumors were available for IHC. Clinical and follow-up data were retrieved from patient files and national registries. Results: High levels of type IV collagen showed independent prognostic significance in both cohorts with hazard ratios (HRs; for a one-unit change on the log base 2 scale) of 2.25 [95% confidence intervals (CIs), 1.78–2.84; P &amp;lt; 0.0001] and 2.24 (95% CI, 1.75–2.86; P &amp;lt; 0.0001) for the training and validation set, respectively. The prognostic impact was present both in patients with metastatic and nonmetastatic disease. The predictive value of the marker was investigated in stage II and III patients. In the training set, type IV collagen was prognostic both in the subsets of patients receiving and not receiving adjuvant antineoplastic therapy. However, in the validation set, the prognostic effect of the marker vanished when looking at patients who received adjuvant antineoplatic therapy (HR 0.90; 95% CI, 0.42–1.93) but was still present in the group not receiving adjuvant chemotherapy (HR 2.88; 95% CI, 1.98–4.21). Conclusions: The results indicate clinical validity of type IV collagen as a prognostic biomarker in colorectal cancer, although the suggested predictive role of the marker should be validated. Clin Cancer Res; 22(10); 2427–34. ©2015 AACR.
Serum vitamin D levels, VDR, and survival from melanoma
Authors: J. A. Newton Bishop, S. Beswick, J. Randerson-Moor, Y. Chang, P. Affleck, F. Elliott, D. Elder, J. Barrett, T. Bishop
Journal: Journal of Clinical Oncology (2009)

9016 Background: Vitamin D has pleiotropic effects, which may moderate the interaction between patients and their tumors. Two studies were carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma. Methods: A pilot retrospective case-control study in 271 melanoma patients suggested that vitamin D may protect against recurrence of melanoma. We then tested these findings in a survival analysis in a cohort of 872 cases recruited to the Leeds Melanoma Cohort (median follow up of 4.7 years). Results: Pilot study Results suggested that taking vitamin D reduced the risk of relapse from melanoma (OR 0.6, 95% CI: 0.4, 1.1). Non-relapsers had higher mean 25-dihydroxyvitamin D3 levels than relapsers (49 nmol/L compared with 46, p=0.3). Cohort study Higher 25-dihydroxyvitamin D3 levels were associated with lower Breslow thickness at diagnosis and were independently protective of relapse and death: hazard ratio (HR) for relapse free survival (RFS) 0.76, 95% CI: (0.64, 0.96), for a 20nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-dihydroxyvitamin D3 levels on RFS. Conclusions: The pilot study provided preliminary evidence for a role for vitamin D in outcome from melanoma. The cohort study provided further evidence that higher 25-dihydroxyvitamin D3 levels, at diagnosis, were associated both with thinner tumors and better survival, independent of Breslow thickness, from melanoma. Melanoma patients should avoid vitamin D deficiency. Further studies are needed to establish optimal serum levels for melanoma patients. No significant financial relationships to disclose.
Abstract 16414: Changes in the Adhesion of the Cardiomyocytes of Patients With Ischemic Cardiomyopathy are Highly Related to Depressed Left Ventricular Function
Authors: Miguel Rivera, Maria Manzanares, Alba Martinez, Ana Ortega, Carolina Gil Cayuela, Estefania Tarazon, Esther Rosello, Manuel Portoles
Journal: Circulation (2014)

Introduction: Cell adhesion is essential for the proper organization and function of tissues, allowing the process of cardiac contraction in the myocardium. Several molecules are involved in cell binding, such as cadherins and connexins in intercellular junctions and integrins in cell-matrix junctions. Although numerous studies have found abnormalities in some of these molecules in the cardiac tissue of patients with heart failure (HF), the molecular details involved in these changes are not known yet.

Methods: We performed an exhaustive analysis of the expression of genes related to cell adhesion using high-throughput RNA sequencing technology (RNA-Seq). Genetic analysis was performed in patients with dilated cardiomyopathy (DCM) (n=13) and ischemic cardiomyopathy (ICM) (n=13) compared with control hearts (CNT) (n=10). To study the behavior of differentially expressed genes we performed a functional analysis using the DAVID bioinformatics v6 0.7 data base. The morphology of the intercalated discs between HF patients and controls using transmission electron microscopy was compared.

Results: The functional analysis of genes related to cell adhesion revealed alterations in the expression (rate of change>1.3 and p<0.05). A total of 24 genes differentially expressed in HF vs CNT, of which 6 encode integrins and 18 encode molecules involved in intercellular junctions, were identified. Different types of cell junctions are represented by at least one protein encoded by the 18 genes with different expression between patients and controls (GJA3, p<0.0001; DSP, p<0.0001; CLDN9, p<0.0001; PVRL3, p<0.01; PCDHGA3, p<0.001; VCL, p<0.0001; ITGA1, p<0.01). We also observed an elevated inverse relationship between the expression of PCDHGA3 and left ventricular end-systolic diameter (r=-0.86, p<0.01) and fractional shortening (r=-0.86, p<0.01) in patients with ICM.

Conclusions: This study reveals altered cell adhesions in patients with HF. The use of RNA-Seq technology allows us to identify new genes involved in the cardiomyocyte binding with aberrant expression in HF. Changes in PCDHGA3 are related to depressed left ventricular function in ICM.
Regulation of Mg2+ Reabsorption and Transient Receptor Potential Melastatin Type 6 Activity by cAMP Signaling
Authors: Maxime G. Blanchard, Wararat Kittikulsuth, Anil V. Nair, Jeroen H.F. de Baaij, Femke Latta, Jonathan R. Genzen, Donald E. Kohan, René J.M. Bindels, Joost G.J. Hoenderop
Journal: Journal of the American Society of Nephrology (2015)

The transient receptor potential melastatin type 6 (TRPM6) epithelial Mg(2+) channels participate in transcellular Mg(2+) transport in the kidney and intestine. Previous reports suggested a hormonal cAMP-dependent regulation of Mg(2+) reabsorption in the kidney. The molecular details of this process are, however, unknown. Adenylate cyclase 3 (Adcy3) has been shown to colocalize with the Na(+)/Cl(-) cotransporter, a marker of the distal convoluted segment of the kidney, the principal site of TRPM6 expression. Given the critical role of TRPM6 in Mg(2+) reabsorption, an inducible kidney-specific Adcy3 deletion mouse model was characterized for blood and urinary electrolyte disturbances under a normal--and low--Mg(2+) diet. Increased urinary Mg(2+) wasting and Trpm6 mRNA levels were observed in the urine and kidney of Adcy3-deleted animals compared with wild-type controls. Serum Mg(2+) concentration was significantly lower in Adcy3-deleted animals at day 7 on the low Mg(2+) diet. Using patch clamp electrophysiology, cell surface biotinylation, and total internal reflection fluorescence live cell imaging of transfected HEK293 cells, we demonstrated that cAMP signaling rapidly potentiates TRPM6 activity by promoting TRPM6 accumulation at the plasma membrane and increasing its single-channel conductance. Comparison of electrophysiological data from cells expressing the phosphorylation-deficient S1252A or phosphomimetic S1252D TRPM6 mutants suggests that phosphorylation at this intracellular residue participates in the observed stimulation of channel activity. Altogether, these data support a physiologically relevant magnesiotropic role of cAMP signaling in the kidney by a direct stimulatory action of protein kinase A on the plasma membrane trafficking and function of TRPM6 ion channels.
VAMP2–NRG1 Fusion Gene is a Novel Oncogenic Driver of Non–Small-Cell Lung Adenocarcinoma
Authors: Yeonjoo Jung, Seunghui Yong, Pora Kim, Hee-Young Lee, Yeonhwa Jung, Juhee Keum, Sanghyuk Lee, Jhingook Kim, Jaesang Kim
Journal: Journal of Thoracic Oncology (2015)
Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015
Authors: Keith Van Haren, Patrick Ayscue, Emmanuelle Waubant, Anna Clayton, Heather Sheriff, Shigeo Yagi, Rose Glenn-Finer, Tasha Padilla, Jonathan B. Strober, Grace Aldrovandi, Debra A. Wadford, Charles Y. Chiu, Dongxiang Xia, Kathleen Harriman, James P. Watt, Carol A. Glaser
Journal: JAMA (2015)

IMPORTANCEThere has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus.In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology.OBJECTIVE To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury.DESIGN, SETTING, AND PARTICIPANTS Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015.Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded.Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing. MAIN OUTCOMES AND MEASURES Case incidence and infectious agent association.RESULTS Fifty-nine cases were identified.Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years).Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41).Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis.During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments.Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months).Two patients, both immunocompromised adults, died within 60 days of symptom onset.Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested).No pathogens were isolated from the cerebrospinal fluid.The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100 000 person-years) compared with other monitoring periods (0.028 cases per 100 000 person-years; P <.001). CONCLUSIONS AND RELEVANCEIn this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement.The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.
Relapse in the central nervous system in melanoma patients successfully treated with biomodulators.
Authors: M S Mitchell
Journal: Journal of Clinical Oncology (1989)

A number of partial or complete remissions have been induced within the past 3 years in patients with metastatic melanoma treated with biomodulators, such as low-dose cyclophosphamide (CY) and interleukin-2 (IL-2), or active specific immunotherapy. Six of the most successfully treated patients, with prolonged remissions in skin, lymph nodes, liver and/or lung, all had relapses in the brain. At the time of relapse in the CNS, remissions were continuing in the other viscera. A large single intracerebral metastasis was found in four of the six patients; the other two patients had three metastases each, one of which also had meningeal seeding. Resection was performed in the four patients with single lesions, without postoperative radiotherapy. Intrathecal IL-2 successfully controlled meningeal disease. To date, the median survival of the group exceeds 7 months, in contrast to the usual reported median of 1 to 4 months, reflecting the predominance of resectable single lesions. Immunological therapy failed to prevent or treat metastases to the CNS, but may have influenced the patients' reactivity to the disease, producing single rather than diffuse metastases. If melanoma is to be cured now by any systemic therapy, particularly biomodulation, new regional strategies must be devised to overcome the blood-brain barrier. By analogy with autoimmune disease of the CNS such as multiple sclerosis, in which excessive cell-mediated immunity is found, several possible immunological maneuvers are suggested.
Priming GM-CSF and low dose cytarabine (LODAC) in the treatment of high risk and elderly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients
Authors: E. S. Winer, K. B. Miller, G. W. Chan
Journal: Journal of Clinical Oncology (2004)

6612 Background: Priming of leukemic cells with cytokines may enhance the efficacy of cell cycle chemotherapy. We attempted to use GM-CSF to enhance the effects of low dose cytarabine to increase cell recruitment, and optimize cell cycle chemotherapy in patients who could not tolerate conventional induction chemotherapy. Methods: We evaluated the efficacy of GM-CSF priming with low-dose cytarabine and concomitant hydroxyurea in high risk, elderly AML and advanced MDS patients. Patients received induction chemotherapy with GM-CSF 250mcg/m2/d by continuous infusion days 1–7, hydroxyurea 500 mg po qid day 1 and 500mg po tid days 2–15, and cytarabine 20mg/m2/d by continuous infusion days 2–15. Results: Forty-nine patients (26F, 23M) were treated, median age 68.5 years (range 48–85); 78% had no previous treatment, and 22% of patients had a median of 2 prior treatments (range 1–7). All patients were not eligible for standard induction chemotherapy. Following treatment, 44% of the assessable patients had documented aplastic bone marrows. The overall response rate was 49%; 33% with CR and 16% with PR. Median duration of CR was 251 days (range 36–842). The CR for secondary AML was 18%, for de novo AML 38%, and for MDS 67%. None of the patients developed mucositis or alopecia, and no patient had greater than grade I nausea and vomiting. The most common adverse effects were neutropenic fever (68%), atrial fibrillation (7%) and congestive heart failure (5%). Five patients died of treatment related toxicity (sepsis). The median survival for all patients was 150 days, for patients achieving CR was 290 days, and the 1 year survival rate was 24%. Conclusions: GM-CSF priming can enhance the cytoreductive effects of low doses of cytarabine. This combination therapy is well tolerated, and should be explored as an alternative regimen for high risk and elderly AML and advanced MDS patients. No significant financial relationships to disclose.
Prevent diabetic cardiomyopathy in diabetic rats by combined therapy of aFGF-loaded nanoparticles and ultrasound-targeted microbubble destruction technique
Authors: Ying-Zheng Zhao, Ming Zhang, Ho Lun Wong, Xin-Qiao Tian, Lei Zheng, Xi-Chong Yu, Fu-Rong Tian, Kai-Li Mao, Zi-Liang Fan, Pian-Pian Chen, Xiao-Kun Li, Cui-Tao Lu
Journal: Journal of Controlled Release (2015)
Met signaling and malignant progression
Authors: George Vande Woude
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

SY28-04 

Chromosome instability and aneuploidy are hallmarks of cancer as much as tumor cell proliferation and invasion are fundamental components of malignant disease, but it is not clear how they are connected. We asked whether changes in chromosomal content of a cell contribute to the malignant phenotype. Highly proliferative and/or highly invasive subclones and their revertants can be readily isolated from glioblastoma or prostate cancer tumor cell populations, showing that such phenotypic variants are resident in the tumor cell population and can contribute to malignant progression. We show that the invasive or proliferative variants display changes in chromosome content that dictate proportional changes in the chromosome transcriptome. Importantly, the transcriptome changes do favor the expression of genes appropriate for the specific tumor phenotype. We conclude that chromosome instability generates the necessary transcriptome diversity in the tumor cell population to allow for environment-facilitated clonal expansion and clonal evolution of malignant tumor cell populations.