tbuckley/cabot-search huggingface dataset:
Adrenergic Control of the Peripheral Circulation in Cardiomyopathic Hamsters with Heart Failure
Authors: ALLYN L. MARK, HOWARD E. MAYER, PHILLIP G. SCHMID, DONALD D. HEISTAD, FRANCOIS M. ABBOUD
Journal: Circulation Research (1973)

Adrenergic control of the peripheral circulation was studied in cardiomyopathic hamsters to determine if the functional status of terminal vascular sympathetic nerve endings is augmented in heart failure. Four groups of hamsters were studied: myopathic hamsters with heart failure (average age 296 days), myopathic hamsters without heart failure (average age 171 days), and two corresponding control groups of randomly bred hamsters matched for age. In hamsters with heart failure, the concentration of catecholamines in hearts, aortas, and femoral arteries was reduced compared with that in corresponding control hamsters. In myopathic hamsters without heart failure, the concentration of catecholamines was reduced in femoral arteries, but it was not reduced in hearts or aortas. Resting vascular resistance and vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, and angiotensin in the perfused hindquarters was reduced in hamsters with heart failure but not in myopathic hamsters without heart failure. These studies suggest that the functional status of terminal sympathetic nerve endings in blood vessels of the extremities is not augmented and may be reduced in this model of heart failure. Studies on other models of heart failure are needed to determine whether the absence of increased vascular catecholamines and the absence of augmented responses to sympathetic nerve stimulation are characteristic of heart failure in general or are unique to this model that has characteristics of highoutput failure.
Results of the Dutch National Study of the Palliative Effect of Irradiation Using Two Different Treatment Schemes for Non–Small-Cell Lung Cancer
Authors: Gijsbert W.P.M. Kramer, Stofferinus L. Wanders, Ed M. Noordijk, Ernest J.A. Vonk, Hans C. van Houwelingen, Wilbert B. van den Hout, Ronald B. Geskus, Mirjam Scholten, Jan-Willem H. Leer
Journal: Journal of Clinical Oncology (2005)

Purpose A national multicenter randomized study compared the efficacy of 2 × 8 Gy versus our standard 10 × 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non–small-cell lung cancer. Patients and Methods Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 × 3 Gy or 2 × 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival. Results Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P &lt; .001). Palliation in the 10 × 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 × 8-Gy. Survival in the 10 × 3-Gy arm was significantly (P = .03) better than in the 2 × 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%). Conclusion The 10 × 3-Gy radiotherapy schedule is preferred over the 2 × 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.
The Mitogen-Activated Protein Kinase Kinase 4 Has a Pro-Oncogenic Role in Skin Cancer
Authors: Katherine G. Finegan, Cathy Tournier
Journal: Cancer Research (2010)

The mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a nonredundant component of stress-activated MAPK signaling modules. Its function in tumorigenesis remains highly controversial with some studies indicating that MKK4 is a tumor suppressor, whereas others have reported a pro-oncogenic role. To clarify the role of MKK4 in cancer, we have created a novel mouse model to test the effect of the specific loss of MKK4 in the epidermis on the formation of papillomas caused by activated ras mutation. We have discovered that skin-specific MKK4-deficient mice are resistant to carcinogen-induced tumorigenesis. One mechanism by which MKK4 promotes cell proliferation and the formation of tumors is by increasing epidermal growth factor receptor expression through the c-Jun NH(2)-terminal protein kinase/c-Jun signaling pathway. Together, our results provide the first genetic demonstration that MKK4 is essential to mediate the oncogenic effect of Ras in vivo, thereby validating MKK4 as a potential drug target for cancer therapy.
Metastatic Cutaneous Apocrine Adenocarcinoma Treated With a Combination of Pertuzumab-Based Targeted Therapy and Taxane Chemotherapy
Authors: Masaki Otsuka, Osamu Yamasaki, Tatsuya Kaji, Tadahiko Shien, Keiji Iwatsuki
Journal: JAMA Dermatology (2015)

This case report suggests that the combination of pertuzumab-based targeted therapy with taxane chemotherapy may develop into a new treatment option for patients with HER2-positive metastatic cutaneous apocrine carcinoma.
Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation
Authors: Emanuele Angelucci, Pietro Muretto, Antonio Nicolucci, Donatella Baronciani, Buket Erer, Javid Gaziev, Marta Ripalti, Pietro Sodani, Silvia Tomassoni, Giuseppe Visani, Guido Lucarelli
Journal: Blood (2002)
Wireless capsule endoscopy and Crohn's disease
Authors: P Swain
Journal: Gut (2005)

Wireless capsule endoscopy appears to be superior to all current forms of radiological investigation of the small intestine in detecting the mucosal abnormalities of Crohn’s disease

When the wireless capsule endoscope (WCE) was introduced,1 fears that the capsule might become impacted caused early clinical protocols to exclude any patients with a hint of previous subacute obstruction or symptoms suggestive of Crohn’s disease.2–6 In fact a few patients with Crohn’s disease were inadvertently included in these early studies3–6 as the symptoms of this disease are often subtle and other investigations are sometimes inconclusive. WCE in a short time has acquired a well established role in the investigation of patients with recurrent gastrointestinal bleeding of obscure origin when gastroscopy and colonoscopy fail to reveal the source.2–6 Occult Crohn’s disease was found to be a cause of bleeding or anaemia in several of these series. Capsule endoscopy has been used in more than 100 000 patients worldwide.

Several comparative studies have shown that WCE could outperform push enteroscopy in finding clinical causes of bleeding. Although the image quality of push enteroscopy is superior in the area it reached, WCE did not miss much that push enteroscopy saw and provided images from the large percentage of the small intestine that could not be reached by push enteroscopy. In five comparisons the capsule found more small intestinal pathology than push enteroscopy (66%, 68%, 69%, 55%, 66% v 19%, 32%, 36%, 38%, 28%)3–5,7,8 and four of these studies showed statistically significant differences in favour of capsule endoscopy.4,5,7,8

WCE has also performed well in comparisons with small bowel radiology. Just as the numbers of barium meal and barium enemas have atrophied with the widespread availability of gastroscopy and colonoscopy, radiological investigations of …
Early G1 Cyclin-Dependent Kinases as Prognostic Markers and Potential Therapeutic Targets in Esophageal Adenocarcinoma
Authors: Amin Ismail, Santhoshi Bandla, Marie Reveiller, Liana Toia, Zhongren Zhou, William E. Gooding, Irina Kalatskaya, Lincoln Stein, Mary D'Souza, Virginia R. Litle, Jeffrey H. Peters, Arjun Pennathur, James D. Luketich, Tony E. Godfrey
Journal: Clinical Cancer Research (2011)

Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort, and its association with clinical endpoints and functional relevance are unclear.We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored.Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing six genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified cyclin-dependent kinase 6 (CDK6) as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low-level amplification (10%) was observed at the 12q13 region containing the CDK6 homologue cyclin-dependent kinase 4 (CDK4). Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expressions is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage independence of EAC cells through activation of the pRB pathway.We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease.
ITPR1 Protects Renal Cancer Cells against Natural Killer Cells by Inducing Autophagy
Authors: Yosra Messai, Muhammad Zaeem Noman, Meriem Hasmim, Bassam Janji, Andrés Tittarelli, Marie Boutet, Véronique Baud, Elodie Viry, Katy Billot, Arash Nanbakhsh, Thouraya Ben Safta, Catherine Richon, Sophie Ferlicot, Emmanuel Donnadieu, Sophie Couve, Betty Gardie, Florence Orlanducci, Laurence Albiges, Jerome Thiery, Daniel Olive, Bernard Escudier, Salem Chouaib
Journal: Cancer Research (2014)

Abstract Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia-inducible factors (HIF). In this study, we investigated the potential role of HIF2α in regulating RCC susceptibility to natural killer (NK) cell–mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared with the VHL-corrected cell line (WT7). This resistance was found to require HIF2α stabilization. On the basis of global gene expression profiling and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2α and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK-mediated killing through the activation of autophagy in target cells by NK-derived signal. Interestingly, both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Our data provide insight into the link between HIF2α, the ITPR1-related pathway, and natural immunity and strongly suggest a role for the HIF2α/ITPR1 axis in regulating RCC cell survival. Cancer Res; 74(23); 6820–32. ©2014 AACR.
Antibodies binding to citrullinated telopeptides of type I and type II collagens and to mutated citrullinated vimentin synergistically predict the development of seropositive rheumatoid arthritis
Authors: Marja-Kaisa Koivula, Markku Heliövaara, Harri Rissanen, Timo Palosuo, Paul Knekt, Heikki Immonen, Juha Risteli
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To assess whether antibodies binding to citrullinated carboxy-terminal telopeptides of type I and type II collagens (TELO-I and TELO-II, respectively), mutated citrullinated vimentin (MCV) and cyclic citrullinated peptides (CCP) predict the development of rheumatoid arthritis (RA). <h3>Methods</h3> A case–control study was nested within a Finnish cohort of 36 000 adults who had neither arthritis nor a history of arthritis at baseline examination in 1966–1972. Among them, 151 subjects developed seropositive (ie, positive for rheumatoid factor) RA, and 67 subjects developed seronegative RA by late 1989. One or two control subjects were chosen for every case. Preillness serum specimens were analysed for antibodies against synthetic TELO-I, TELO-II, MCV and CCP. <h3>Results</h3> The mean levels of anti-TELO-I, anti-TELO-II, anti-CCP and anti-MCV antibodies were higher in subjects who later developed seropositive or seronegative RA than in controls. In subjects who later developed seronegative RA, anti-TELO-I and anti-TELO-II antibodies were statistically significantly higher compared with controls (p=0.005 and p=0.013). In the highest tertiles of anti-MCVs and anti-TELO-I levels, the OR for rheumatoid-factor-positive RA were 2.66 (95% CI 1.48 to 4.77) or 2.51 (CI 1.48 - 4.28), respectively. The subjects ranked into the highest tertiles of both anti-TELO-I and anti-MCV antibodies had a 4.56 OR (95% CI 1.82 to 11.46) of developing seropositive RA compared with those in the lowest tertiles of these antibodies. For the co-occurrence for high anti-TELO-II and anti-MCV antibodies, the corresponding OR was 3.62 (95% CI 1.37 to 9.54). <h3>Conclusion</h3> Antibodies to TELO-I or TELO-II and MCV exert a synergistic effect on the risk of developing seropositive RA.
Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers
Authors: Thomas Reinert, Charlotte Modin, Francisco M. Castano, Philippe Lamy, Tomasz K. Wojdacz, Lise Lotte Hansen, Carsten Wiuf, Michael Borre, Lars Dyrskjøt, Torben F. Ørntoft
Journal: Clinical Cancer Research (2011)

Epigenetic alterations are common and can now be addressed in a parallel fashion. We investigated the methylation in bladder cancer with respect to location in genome, consistency, variation in metachronous tumors, impact on transcripts, chromosomal location, and usefulness as urinary markers.A microarray assay was utilized to analyze methylation in 56 samples. Independent validation was conducted in 63 samples by a PCR-based method and bisulfite sequencing. The methylation levels in 174 urine specimens were quantified. Transcript levels were analyzed using expression microarrays and pathways were analyzed using dedicated software.Global methylation patterns were established within and outside CpG islands. We validated methylation of the eight tumor markers genes ZNF154 (P < 0.0001), HOXA9 (P < 0.0001), POU4F2 (P < 0.0001), EOMES (P = 0.0005), ACOT11 (P = 0.0001), PCDHGA12 (P = 0.0001), CA3 (P = 0.0002), and PTGDR (P = 0.0110), the candidate marker of disease progression TBX4 (P < 0.04), and other genes with stage-specific methylation. The methylation of metachronous tumors was stable and targeted to certain pathways. The correlation to expression was not stringent. Chromosome 21 showed most differential methylation (P < 0.0001) and specifically hypomethylation of keratins, which together with keratin-like proteins were epigenetically regulated. In DNA from voided urine, we detected differential methylation of ZNF154 (P < 0.0001), POU4F2 (P < 0.0001), HOXA9 (P < 0.0001), and EOMES (P < 0.0001), achieving 84% sensitivity and 96% specificity.We initiated a detailed mapping of the methylome in metachronous bladder cancer. Novel genes with tumor, chromosome, as well as pathway-specific differential methylation in bladder cancer were identified. The methylated genes were promising cancer markers for early detection of bladder cancer.
Macrophage Migration Inhibitory Factor Is a Determinant of Hypoxia-Induced Apoptosis in Colon Cancer Cell Lines
Authors: Kangshen Yao, Seiichiro Shida, Muthu Selvakumaran, Robert Zimmerman, Ephraim Simon, Jonathan Schick, Naomi B. Haas, Marge Balke, Howard Ross, Steven W. Johnson, Peter J. O'Dwyer
Journal: Clinical Cancer Research (2005)

Abstract Hypoxia contributes to cytotoxic chemotherapy and radiation resistance and may play a role in the efficacy of antiangiogenesis cancer therapy. We have generated a series of cell lines derived from the colon adenocarcinoma models HT29 and HCT116 by exposing cells in vitro to repeated sublethal periods of profound hypoxia. These cell lines have altered sensitivity to hypoxia-induced apoptosis: those derived from HT29 are resistant, whereas those from HCT116 are more susceptible. We used cDNA selected subtractive hybridization to identify novel genes mediating sensitivity to hypoxia-induced apoptosis and isolated macrophage migration inhibitory factor (MIF) from the hypoxia-conditioned cell lines. MIF expression correlates with susceptibility of the cell lines to apoptosis. In hypoxia-resistant cells, the induction of apoptosis by hypoxia can be restored by the addition of exogenous recombinant MIF protein, suggesting that resistance may result in part from down-regulation of MIF production possibly through an autocrine loop. Inhibition of MIF using small interfering RNA in the susceptible lines conferred resistance to hypoxia-induced cell death. The relative expression of MIF in the hypoxia-conditioned cells implanted s.c. in severe combined immunodeficient mice in vivo was similar to that observed in vitro. In an analysis of 12 unrelated colon tumor cell lines, MIF expression and response to hypoxia varied widely. Cell lines in which MIF was inducible by hypoxia were more sensitive to oxaliplatin. In human colon tumor specimens analyzed by immunohistochemistry, MIF expression was similarly variable. There was no detectable expression of MIF in normal colon mucosa or adenoma but positive staining in all carcinomas tested. Taken together, these data indicate that MIF may be a determinant of hypoxia-induced apoptosis in vitro and that its variable expression in human colon cancers may indicate a functional role in vivo. We suggest that MIF expression in colorectal cancer may be a marker of susceptibility to therapies that may depend on induction of hypoxia, possibly including antiangiogenic therapy.
CULTIVATION OF PSEUDORABIES VIRUS
Authors: Erich Traub
Journal: The Journal of Experimental Medicine (1933)

Pseudorabies virus has been cultivated in series in rabbit testicle, guinea pig testicle, and chick embryo media, and its growth requirements have been studied. Intranuclear inclusions, similar to those produced by pseudorabies virus in vivo, have been found in rabbit testicle cultures. The virus has not changed its pathogenic properties for rabbits, guinea pigs, or mice during the course of cultivation.
Suppression of Proximal T Cell Receptor Signaling and Lytic Function in CD8+ Tumor-Infiltrating T Cells
Authors: Ngozi Monu, Alan B. Frey
Journal: Cancer Research (2007)

Abstract CD8+ tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity upon contact with cognate tumor cells. Although CD3ζ is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLCγ-1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56lck is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting “switch”. Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56lck (∼10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56lck in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56lck in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56lck activation motif (Y394), thus inhibiting effector phase functions. [Cancer Res 2007;67(23):11447–54]
Interleukin-1 receptor antagonist in refractory haemochromatosis-related arthritis of the hands
Authors: Augustin Latourte, Aline Frazier, Claire Brière, Hang-Korng Ea, Pascal Richette
Journal: Annals of the Rheumatic Diseases (2013)

Patients with hereditary haemochromatosis (HH) may present arthralgia in the hands and large joints or severe arthropathy mimicking osteoarthritis typically involving metacarpophalangeal (MCP) joints 2 and 3.1–3 This arthropathy, which may seriously affect quality of life, was reported to occur in 20%–50% of HH patients with articular complaints and can coexist with calcium pyrophosphate deposition.4–6

Hand arthropathy is not alleviated by phlebotomy, and in a few patients, disease is refractory or intolerant to standard treatments such as non-steroidal anti-inflammatory drugs (NSAIDs), low-dose colchicine or analgesics. Thus, these patients remain without adequate treatment.

Given the frequent presence of local inflammatory symptoms in MCP joints and the discovery that interleukin 1β (IL-1β) plays a key role in the pathogenesis of arthritis due to …
Heteroplasmy in mice with deletion of a large coding region of mitochondrial DNA.
Authors: P Boursot, H Yonekawa, F Bonhomme
Journal: Molecular Biology and Evolution (1987)

Polymorphism of animal mitochondrial DNA (mtDNA) has been shown to involve point mutations and limited length variations affecting essentially noncoding regions. In two wild mice of the European subspecies Mus mus musculus we found a mitochondrial mutant with a very large deletion in a coding region. The deletion is 5 kbp long (31% of the mitochondrial chromosome) and encompasses six tRNA genes and seven protein genes. The two mice were heteroplasmic: they contained a mixture of normal mtDNA and the deletion mutant. Although the latter is functionally defective, it represents 78%-79% of the mtDNA molecules in our preparations from each animal.