tbuckley/cabot-search huggingface dataset:
A prospective randomized trial comparing 5-fluorouracil (5-FU), mitomycin-C (MMC), and polysaccharide-K (PSK) versus UFT and PSK as adjuvant chemoimmunotherapy (CITX) for patients with locally advanced gastric cancer with curative resection
Authors: J. Choi, S. Kang, J. Park, H. Lee, Y. Cho, S. Han, H. Lim
Journal: Journal of Clinical Oncology (2007)

15074 Background: Adjuvant chemotherapy has demonstrated small but significant survival benefit in locally advanced gastric cancer in several meta-analyses, while adjuvant CITX showed improved outcome of patients (pts) compared to chemotherapy alone in a few trials. However, optimal chemotherapy regimen remains to be determined. We conducted a randomized trial comparing oral (PO) CITX with intravenous (IV) CITX in gastric cancer pts with curative resection. Methods: All enrolled pts underwent radical surgery with at least D2 dissection. After stratification for pathologic stage (IB or II vs. III) and primary tumor size (=5 cm vs. &gt;5 cm), pts were randomized to IV CITX (5-FU 500 mg/m 2 weekly for 24 weeks, MMC 8 mg/m 2 every 6 weeks x 4) or PO CITX (UFT 400–600 mg/day for 12 months). Pts in both arms received PSK 3 g/day PO for 4 months. The planned target number of pts was 368 to prove the non-inferiority of PO CITX compared to IV CITX in overall survival. Results: A total of 82 pts (stage IB: 6, II: 29, IIIA: 30, IIIB: 17; 44 in IV arm, 38 in PO arm) were enrolled between May 2002 and October 2005, when the trial was closed due to poor accrual. Pts characteristics were well balanced. With a median follow-up of 39 months (14–55 months) in survivors, there were no significant differences in 3-year disease-free survival (82% vs. 61%, p=0.302) and overall survival (84% vs. 79%, p=0.838) between IV and PO arms. No grade 4 toxicity was observed in both arms. IV arm demonstrated higher incidence of grade 2 or 3 neutropenia (79% vs. 52%, p=0.025), thrombocytopenia (19% vs. 0%, p=0.008), and vomiting (36% vs. 9%, p=0.013). Conclusions: Although accrual was well below that planned, the results of this trial suggest that PO CITX with UFT might have similar efficacy with lower toxicity profile compared with 5-FU and MMC CITX in adjuvant treatment for gastric cancer. No significant financial relationships to disclose.
Expansion and characterization of tumor-infiltrating lymphocytes from human sarcoma
Authors: MacLean Hall, John Mullinax, Erica Royster, Angela Reagan, Ricardo Gonzalez, Jose Pimiento, Shari Pilon-Thomas, Amod Sarnaik
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Adoptive Cell Transfer (ACT) using Tumor Infiltrating Lymphocytes (TIL) has previously been shown at our institution and others to be an effective treatment for metastatic melanoma, resulting in a 38% response rate [[1][1]]. We applied this therapy to other solid tumors that have
Natural toll-like receptor agonists in prophylactic vaccines for dendritic cell activation
Authors: Paul Peng, Linda Hammerich, Joshua Brody
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts There is an unmet need for novel and effective treatments for lymphoma, the fifth most common malignancy in the US. In situ vaccination—an immunotherapeutic maneuver involving local irradiation, intratumoral (i.t.) injections of Flt3L and Toll-like receptor (TLR) agonist—has
Immunogenicity of recurrent mutations in MYD88 and EZH2 in non-Hodgkin lymphomas
Authors: Julie S Nielsen, Andrew R Chang, Darin A Wick, Colin G Sedgwick, Zusheng Zong, Andrew J Mungall, Bemuluyigza Baraki, Natalie Kinloch, Zabrina L Brumme, Steven P Treon, Joseph M Connors, Randy D Gascoyne, John R Webb, Brian R Berry, Ryan D Morin, Nicol Macpherson, Brad H Nelson
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts A fundamental challenge in cancer genomics is to design effective, personalized treatments based on the mutational profiles of tumors. Pharmacological targeting of the numerous aberrant pathways found in individual tumors remains exceedingly challenging, but T cell-based therapies
Abstract #5667: ADAMTS1 and MMP1 promote breast cancer bone metastasis through a bone stromal cell-mediated osteolytic signaling cascade
Authors: Xin Lu, Qiongqing Wang, Catherine Van Poznak, Martin Fleisher, Michael Reiss, Joan Massagué, Yibin Kang
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in bone-specific metastasis remain poorly defined despite their well-appreciated role in matrix degradation, tumor invasion and tumor-stroma interaction. Here, we show that two distinct metalloproteinases, ADAMTS1 and MMP1, synergistically promote breast cancer bone metastasis by modulating the bone microenvironment to favor osteoclastogenesis. ADAMTS1 and MMP1 proteolytically release EGF-like growth factors, including Amphiregulin, HB-EGF and TGFa, from tumor cells. The released EGF-like growth factors suppress the expression of Osteoprotegerin in osteoblasts and subsequently potentiate osteoclast differentiation. Activated osteoclasts process the bone matrix and release various growth factors which further support the proliferation of the tumor cells in the bone. Simultaneous gene silencing of ADAMTS1 and MMP1 by short-hairpin RNA in highly bone-metastatic variants of the human breast cancer cell MDA-MB-231 inhibits the progression of osteolytic bone metastasis in the mouse model, whereas co-overexpression of ADAMTS1 and MMP1 in the lowly metastatic variants of MDA-MB-231 promotes bone metastasis. Targeting EGFR signaling in bone stromal cells with EGFR inhibitors also blocks osteolytic bone metastasis by the strong bone-metastatic variants of MDA-MB-231, even though the orthotopic tumor growth is unaffected. Besides in MDA-MB-231, ADAMTS1 and MMP1 were found to be overexpressed in the in vivo selected variants of primary breast tumor cells which preferentially colonize the bone. Elevated MMP1 and ADAMTS1 expression was significantly associated with increased risk of bone metastasis in breast cancer patients. Our study presents, for the first time, a mechanism whereby two distinct metalloproteinases orchestrate a paracrine signaling cascade to promote bone metastasis. This study established ADAMTS1 and MMP1, as well as EGFR signaling in osteoblasts, as promising therapeutic targets for inhibiting bone metastasis of breast cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5667.
General practice will get increased funding from next April
Authors: Gareth Iacobucci
Journal: BMJ (2015)

General practice will receive “disproportionately” higher funding increases than other healthcare services over the next five years as part of a drive to invest more in primary care and ease workload pressures on GPs, NHS England has announced.

GPs and primary medical care will receive an extra 4.0-5.4% cash funding every year for five years, and the formula for allocating primary care funding will be updated to account for “changes in GP workload,” the national body said. The announcement follows a pledge made in the NHS’s Five Year Forward View 1 to increase funding for general practice in recognition that primary care has been under-resourced when compared with hospitals.

The settlement was agreed at …
Effects of steady-state female hormones on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide
Authors: Nassr Nassr, Andreas Hünnemeyer, Rolf Herzog, Joachim Scholpp, Gezim Lahu
Journal: European Respiratory Journal (2011)

Background/Rationale: Roflumilast (ROF) is an oral, selective phosphodiesterase 4 (PDE4) inhibitor licensed for the treatment of severe COPD. It is mainly metabolised by cytochrome P450 (CYP) 1A2 and 3A4 to roflumilast N-oxide (RNO), which mediates >90% of ROF total PDE4 inhibitory activity (tPDE4i), and is then mainly cleared by CYP3A4. Female hormones such as ethinyloestradiol and gestodene can inhibit the metabolism of CYP1A2 and 3A4 substrates; the pharmacokinetic (PK) effects, safety and tolerability of their coadministration with ROF were therefore investigated.

Methods: In a phase I, open-label, two-period PK study, 20 women received a single dose of ROF 500μg with/without concomitant oral administration of a daily fixed dosing to steady state of gestodene 0.075mg plus ethinyloestradiol 0.03mg. Blood samples were taken for the analysis of ROF and RNO over 120 hours after ROF dosing.

Results: After coadministration, total systemic exposure for ROF (AUCinf) increased to 151% (90% CI 122, 187%) of reference, and peak concentration (Cmax) increased to 138% (90% CI 121, 158%). For RNO, the AUCinf was 114% (90% CI 96.6, 134%) after coadministration, while Cmax decreased to 87.6% (90% CI 80.4, 95.5%). The tPDE4i rose to 117% (90% CI 98.8, 138%). The combination of ROF and female hormones was well tolerated and there were no safety concerns.

Conclusions: No clinically relevant interaction between ROF/RNO and gestodene plus ethinyloestradiol was observed. These results suggest that ROF may be used without dose adjustments with other exogenous female hormones, including those used in hormone replacement therapy.
Chronobiological Patterns of Onset of Tako-Tsubo Cardiomyopathy
Authors: Rodolfo Citro, Mario Previtali, Daniella Bovelli, Olga Vriz, Costantino Astarita, Marco Mariano Patella, Gennaro Provenza, Corinna Armentano, Quirino Ciampi, Giovanni Gregorio, Massimo Piepoli, Eduardo Bossone, Roberto Manfredini
Journal: Journal of the American College of Cardiology (2009)
Venous Thromboembolism in Children with Acute Lymphoblastic Leukemia in Northern Europe
Authors: Nadine Gretenkort Andersson, Susanna Ranta, Tony Frisk, Maria Winther Gunnes, Jon Helgestad, Ólafur G Jónsson, Mats Heyman, Birgitte Klug Albertsen, Anne Mäkipernaa, Kaie Pruunsild, Thomas Leth Frandsen, Sonata Saulyte Trakymiene, Ulf R. Tedgard, Ellen Ruud, Ruta Tuckuviene
Journal: Blood (2014)
Gene expression profiling identifies genes associated with liver metastasis of human colonic carcinoma using a novel metastasis model with NOD/SCID/γcnull (NOG) mice.
Authors: Hiroshi Suemizu, Kenji Kawai, Makoto Monnai, Norikazu Tamaoki, Yasuyuki Ohnishi, Masato Nakamura
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3849 

Liver metastases frequently develop in patients with aggressive colon cancer. Therefore, an animal model of liver metastasis for elucidation of the molecular mechanisms and evaluation of antitumor agents is especially important for drug development. Previous in vivo human colon cancer metastasis models using nude mice or SCID mice have been unsatisfactory due to bias of residual immunity in recipient animals. Therefore, we developed a more reliable assay model for liver metastasis using NOD/SCID/γcnull (NOG) mice. We evaluated liver metastasis capabilities of human colon cancer cell lines using this xeno-transplantation model. Liver metastases were examined at autopsy within 6 weeks after 10^4 cells were transplanted intrasplenically. Twelve human colon cancer cell lines (COLO320DM, HCT 116, SW480, HT-29, WiDr, LoVo, LS174T, SW1417, SW48, LS123, COLO201 and CaCo2) formed diverse metastatic foci in the liver of the NOG mice. SW1417, SW48, LS123, COLO201 and CaCo2 showed no metastasis with 10^4 cells. On the other hand, COLO320DM, HCT 116 and SW480 metastasized in 100% (6/6) of the mice. HT-29, WiDr, LoVo and LS174T metastasized in 88.9% (8/9), 87.5% (7/8), 83.3% (5/6) and 50.0% (3/6) of the mice, respectively. Using this metastasis model, we established progressively more metastatic human colon cancer cell lines. Cells from a few liver metastatic foci of the mice injected with 10^5 of SW48 were expanded in vitro and subsequently injected into spleens of NOG mice. By repeating these procedures, we were able to obtain a cell line, designated LM2-SW48. To identify genes involved in liver metastasis of colon cancer cells, the gene expression profiles of over 47,000 transcripts (Affymetrix, Human Genome U133 Plus 2.0 Array) were compared in these cell lines. Statistically significant differences in gene expression (4-fold or greater) were observed for 52 gene sets. We found 41 genes to be progressively down-regulated during the transition from SW40 parental line to LM2-SW48 line, whereas 11 genes were progressively up-regulated. We have already identified 45 genes involved in liver metastasis of pancreatic cancer cells by comparing the gene expression with the highly metastatic LM-BxPC-3 and parental BxPC-3 lines. However, no gene identified in colon cancer was also found in pancreatic cancer. This result suggested the existence of an organ specific liver metastatic process. The majority of genes identified in this study are new candidates as encoding proteins relevant to the liver metastatic process.
2008 Stroke Council Award and Lecture—Brain and Heart: The Good, the Bad, and the Different
Authors: Vladimir Hachinski
Journal: Circulation (2008)

The brain and the heart are unique and essential organs, with autoregulated blood supplies and sophisticated electrical systems, functioning with harmonious complementarity in health; however, disease of one organ can threaten the other. Cardiac valvular disease, atrial fibrillation, and acute myocardial infarction carry a risk of stroke, and both ischemic and hemorrhagic strokes can lead to cardiac abnormalities and sudden death. Heart disease and stroke share most of the same risk factors, but not to the same degree, nor necessarily with the same consequences. For example, hypertension represents the single most powerful risk factor for stroke and can result in a major intracerebral hemorrhage, a condition without equivalent in any other organ. Despite the superficial resemblance between angina and transient ischemic attack, the mechanisms differ. Angina can be brought on by exercise, but no amount of mental exercise will lead to “brain angina.” Most cardiac patients can maintain a reasonable quality of life on half of their cardiac output. No meaningful quality of life is likely with half of brain output. Stroke recovery is complex. The brain is the only organ with which one can communicate directly and whose feelings have to be considered in recovery. Although stroke and heart disease prevention have much in common, puzzling differences remain. In primary prevention, aspirin prevents heart attacks in men but not in women, and strokes in women but not in men. Given the great commonalities and interrelationships between vascular brain and heart disease, it has been sensible and successful to have one organization encompassing cerebrovascular and cardiovascular health and diseases. To continue to progress at an accelerated pace, we need to become more familiar with the mutual relationship between cerebrovascular and cardiovascular disease, work together where we can, and separately where we must, but with the common aim of vanquishing both.
It's Totally Tubular…Riding The New Wave of Ovarian Cancer Research
Authors: Ruth Perets, Ronny Drapkin
Journal: Cancer Research (2015)

Abstract Hereditary breast and ovarian cancer syndrome carries significant mortality for young women if effective preventive and screening measures are not taken. Preventive salpingo-oophorectomy is currently the only method known to reduce the risk of ovarian cancer-related death. Histopathological analyses of these surgical specimens indicate that a high proportion of ovarian cancers in women at high risk and in the general population arise from the fallopian tube. This paradigm shift concerning the cell of origin for the most common subtype of ovarian cancer, high-grade serous carcinoma, has sparked a major effort within the research community to develop new and robust model systems to study the fallopian tube epithelium as the cell of origin of “ovarian” cancer. In this review, evidence supporting the fallopian tube as the origin of ovarian cancer is presented as are novel experimental model systems for studying the fallopian tube epithelium in high-risk women as well as in the general population. This review also addresses the clinical implications of the newly proposed cell of origin, the clinical questions that arise, and novel strategies for ovarian cancer prevention. Cancer Res; 76(1); 10–17. ©2015 AACR.
Nischarin inhibits LIMK to regulate cofilin phosphorylation and tumor cell invasion
Authors: Yuemin Ding, Suresh Alahari
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2182 

Nischarin is a novel protein that regulates cell migration by inhibiting p21 activated kinase (PAK). Previously we have shown that Nischarin regulates cell invasion. To understand the mechanism of regulation of cell invasion by Nischarin, we have searched for proteins that associate with Nischarin. We show that Nischarin interacts with LIM Kinase (LIMK), more specifically to the kinase as well as the PDZ domains of LIMK. Both Nischarin and LIMK co-precipitated from cell lysates of overexpressed cells as well as from endogenous proteins. Activated Rac enhances association of LIMK and Nischarin. By association of Nischarin with LIMK, Nischarin inhibits LIMK activation, Cofilin phosphorylation as well as PAK-LIMK mediated cell invasion of breast cancer cells. Inhibition of Nischarin expression by RNA interference stimulates breast cancer cell invasion. Although PAK, Nischarin and LIMK exist in tripartite complex, a strong interaction between Nischarin and LIMK exist only when PAK is inactive. Also we confirmed that PAK and Nischarin compete for interaction with LIMK by using PAK1 inhibitor, the autoinhibitory domain of PAK. These data suggest that Nischarin regulates cell invasion through LIMK1-Cofilin signaling cascade. This study identifies a novel function of Nischarin demonstrating the disruption of complexes between LIMK and PAK, and leading to inhibitory effects on LIMK signaling.
Abstract 15782: Hypertrophic Cardiomyopathy-causing Mutations in Human Beta-Cardiac Myosin Converter Domain Alter Power Output of Sarcomere Function in Vitro
Authors: Masataka Kawana, Tural Aksel, Suman Nag, Shirley Sutton, Kathleen Ruppel, James Spudich
Journal: Circulation (2014)

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 in the general population and is an important cause of arrhythmias, heart failure, and sudden cardiac death. beta-cardiac myosin comprises 1/3 of genetic mutations associated with HCM, while the underlying primary effects of these mutations on the biomechanical function of myosin remain elusive. In particular, the converter domain of myosin has been known to be a hot spot for HCM-causing mutations. However, how alterations in this region affect its ability to transduce small changes in the catalytic domain to the lever arm to accomplish the power stroke is unclear. We hypothesize that these mutations affect the biomechanics of human beta-cardiac myosin in different ways (e.g. changing the spring constant of the elastic element of the motor resulting in altered intrinsic force, changing the duty ratio of the myosin and therefore the ensemble force produced, or altering the stroke size of myosin upon interaction with actin), all of which result in changes in the power output of the myosin power stroke. To date, much important biochemical work has involved use of mouse and other non-human cardiac myosin isoforms, as well as skeletal muscle biopsy studies, but these studies have produced mixed results due to isoform differences and lack of homology in amino acid sequence between species. Here we used a recently reported in vitro system to express human beta-cardiac myosin using an adenoviral based expression in a mouse myoblast cell line, and characterized the molecular effects of severe HCM-causing converter domain mutations, R719W and R723G. We also studied HCM-causing mutations at the same amino acid positions which result in more benign clinical phenotypes (normal life span), R719Q and R723C. Using ATPase and in vitro motility assays, we found that severe HCM mutations caused 10~15% increases in actin gliding velocity, no change in ATPase, and loaded in vitro motility assays showed altered power output, while benign mutations showed no significant differences compared to wild type. These observations support the view of altered power output as the primary effect of HCM mutations. Further analysis at the single molecule level is underway to elucidate the precise mechanisms underlying these biomechanical changes.
Adolescents with adversity related injury are more at risk of death than those with accidental injuries, finds study
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

Adolescents in England who are treated in hospital for injuries related to violence or drug or alcohol use or that are self inflicted should be offered psychological and social support, researchers have said, after finding that these youngsters are at increased risk of death or further injury in the next 10 years.1

Currently national guidance in England stipulates that only young people who present with self inflicted injuries should be given psychosocial assessment. To find out …
Evidence-based management of vitiligo: summary of a Cochrane systematic review
Authors: M. Whitton, M. Pinart, J.M. Batchelor, J. Leonardi-Bee, U. Gonzalez, Z. Jiyad, V. Eleftheriadou, K. Ezzedine
Journal: British Journal of Dermatology (2015)

Vitiligo affects around 1% of the world's population. Despite it being relatively common, there is still no effective treatment. The objective of this study was to update the Cochrane systematic review of randomized clinical trials (RCTs) to evaluate the efficacy of treatments for vitiligo. We carried out searches of a range of databases to October 2013 for RCTs of interventions for vitiligo regardless of language or publication status. At least two reviewers independently assessed study eligibility and methodological quality and extracted data using data extraction forms approved by the Cochrane Skin Group. Our primary outcomes of interest were quality of life, > 75% repigmentation and adverse effects. We retrieved 96 studies, of which 39 were new studies, with an overall total of 4512 participants. Repigmentation was assessed in all studies, although only five reported on all three of our primary outcomes. Regarding our two secondary outcomes, six studies measured cessation of spread but none assessed long‐term permanence of repigmentation at 2 years' follow‐up. Most of the studies evaluated combination treatments, which generally showed better repigmentation than monotherapies. Of the new studies, seven were surgical interventions. The majority of the studies had fewer than 50 participants. The quality of the studies was poor to moderate at best. Very few studies specifically included children or participants with segmental vitiligo. Five years after the last update of this review, there are still important variations in study design and outcome measures in clinical trials for vitiligo, limiting the evidence for the efficacy of different therapeutic options. The best evidence from individual trials showed short‐term benefit from topical corticosteroids and various forms of ultraviolet radiation combined with topical preparations. Long‐term follow‐up and patient‐rated outcomes should be incorporated into study design, and more studies should assess psychological interventions.
Peptide libraries for comprehensive coverage of the tumor mutanome in immune monitoring and immunotherapy
Authors: Aaron Castro, Maren Eckey, Tobias Knaute, Ulf Reimer
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Many cancers are associated with functional mutations which can be readily identified using new DNA sequencing methods. Sequence information is used for the generation of personalized cancer vaccines with promising clinical benefit. Intelligent ways to select the relevant, tumor-