tbuckley/cabot-search huggingface dataset:
Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain
Authors: Benedetta Artegiani, Dirk Lindemann, Federico Calegari
Journal: The Journal of Experimental Medicine (2011)

Neural stem cells (NSCs) in the adult mammalian brain generate neurons and glia throughout life. However, the physiological role of adult neurogenesis and the use of NSCs for therapy are highly controversial. One factor hampering the study and manipulation of neurogenesis is that NSCs, like most adult somatic stem cells, are difficult to expand and their switch to differentiation is hard to control. In this study, we show that acute overexpression of the cdk4 (cyclin-dependent kinase 4)–cyclinD1 complex in the adult mouse hippocampus cell-autonomously increases the expansion of neural stem and progenitor cells while inhibiting neurogenesis. Importantly, we developed a system that allows the temporal control of cdk4–cyclinD1 overexpression, which can be used to increase the number of neurons generated from the pool of manipulated precursor cells. Beside providing a proof of principle that expansion versus differentiation of somatic stem cells can be controlled in vivo, our study describes, to the best of our knowledge, the first acute and inducible temporal control of neurogenesis in the mammalian brain, which may be critical for identifying the role of adult neurogenesis, using NSCs for therapy, and, perhaps, extending our findings to other adult somatic stem cells.
αCP-4, Encoded by a Putative Tumor Suppressor Gene at 3p21, But Not Its Alternative Splice Variant αCP-4a, Is Underexpressed in Lung Cancer
Authors: Ruben Pio, Isabel Zudaire, Irene Pino, Zafira Castaño, Natalia Zabalegui, Silvestre Vicent, Fermin Garcia-Amigot, Maria D. Odero, Maria D. Lozano, Jesus Garcia-Foncillas, Maria J. Calasanz, Luis M. Montuenga
Journal: Cancer Research (2004)

Abstract αCP-4 is an RNA-binding protein coded by PCBP4, a gene mapped to 3p21, a common deleted region in lung cancer. In this study we characterized the expression of αCP-4 and αCP-4a, an alternatively spliced variant of αCP-4, in lung cancer cell lines and non-small cell lung cancer (NSCLC) samples from early stage lung cancer patients. In NSCLC biopsies, an immunocytochemical analysis showed cytoplasmic expression of αCP-4 and αCP-4a in normal lung bronchiolar epithelium. In contrast, αCP-4 immunoreactivity was not found in 47% adenocarcinomas and 83% squamous cell carcinomas, whereas all of the tumors expressed αCP-4a. Besides, lack of αCP-4 expression was associated with high proliferation of the tumor (determined by Ki67 expression). By fluorescence in situ hybridization, &amp;gt;30% of NSCLC cell lines and tumors showed allelic losses at PCBP4, correlating with the absence of the protein. On the other hand, no mutations in the coding region of the gene were found in any of the 24 cell lines analyzed. By Northern blotting and real-time reverse transcription-PCR, we detected the expression of αCP-4 and αCP-4a messages in NSCLC and small cell lung cancer cell lines. Our data demonstrate an abnormal expression of αCP-4 in lung cancer, possibly associated with an altered processing of the αCP-4 mRNA leading to a predominant expression of αCP-4a. This may be considered as an example of alternative splicing involved in tumor suppressor gene inactivation. Finally, induction of αCP-4 expression reduced cell growth, in agreement with its proposed role as a tumor suppressor, and suggesting an association of this RNA-binding protein with lung carcinogenesis.
Impaired T lymphocyte trafficking in mice deficient in an actin-nucleating protein, mDia1
Authors: Daiji Sakata, Hiroyuki Taniguchi, Shingo Yasuda, Aki Adachi-Morishima, Yoko Hamazaki, Rika Nakayama, Takashi Miki, Nagahiro Minato, Shuh Narumiya
Journal: The Journal of Experimental Medicine (2007)

Trafficking of immune cells is controlled by directed migration of relevant cells toward chemotactic signals. Actin cytoskeleton undergoes continuous remodeling and serves as machinery for cell migration. The mDia family of formins and the Wiskott-Aldrich syndrome protein (WASP)–Arp2/3 system are two major actin nucleating–polymerizing systems in mammalian cells, with the former producing long straight actin filaments and the latter producing branched actin meshwork. Although much is known about the latter, the physiological functions of mDia proteins are unclear. We generated mice deficient in one mDia isoform, mDia1. Although mDia1−/− mice were born and developed without apparent abnormality, mDia1−/− T lymphocytes exhibited impaired trafficking to secondary lymphoid organs in vivo and showed reduced chemotaxis, little actin filament formation, and impaired polarity in response to chemotactic stimuli in vitro. Similarly, mDia1−/− thymocytes showed reduced chemotaxis and impaired egression from the thymus. These results suggest that mDia1 plays a distinct role in chemotaxis in T lymphocyte trafficking.
Management of Lipids in the Prevention of Cardiovascular Events
Authors: Helene Glassberg, Daniel J. Rader
Journal: Annual Review of Medicine (2007)

Lipid-modifying therapy has been proven to significantly reduce cardiovascular events and total mortality. Most of the data have come from statin trials. Statin therapy is generally well-tolerated and safe, and for patients who are at higher than average risk of cardiovascular disease, the benefit of lipid-modifying therapy far exceeds the risk. Careful risk assessment is a critical component of effective lipid-modifying therapy. In the foreseeable future, low-density lipoprotein cholesterol (LDL-C) will remain the primary therapeutic target, and combination therapy is likely to become the norm. The major questions are how low to treat and how to achieve increasingly aggressive targets in lipid-lowering therapy. Many patients on LDL-lowering therapy continue to have abnormalities of the triglyceride-high-density lipoprotein (TG-HDL) axis, so additional drug therapy is often considered for such patients. In this review, we briefly discuss new developments in cardiovascular risk assessment, then discuss recent developments in treatment to reduce LDL, and finally discuss current concepts regarding therapy targeting the TG-HDL axis.
Targeted Therapies to Improve Tumor Immunotherapy
Authors: Jonathan Begley, Antoni Ribas
Journal: Clinical Cancer Research (2008)

Abstract Durable tumor regression and potential cures of metastatic solid cancers can be achieved by a variety of cellular immunotherapy strategies, including cytokine therapy, dendritic cell–based vaccines, and immune-activating antibodies, when used in so-called immune-sensitive cancers such as melanoma and renal cell carcinoma. However, these immunotherapy strategies have very low tumor response rates, usually in the order of 5% to 10% of treated patients. We propose that the antitumor activity of adequately stimulated tumor antigen–specific T cells is limited by local factors within the tumor milieu and that pharmacologic modulation of this milieu may overcome tumor resistance to immunotherapy. By understanding the mechanisms of cancer cell immune escape, it may be possible to design rational combinatorial approaches of novel therapies able to target immunosuppressive or antiapoptotic molecules in an attempt to reverse resistance to immune system control. We term this mode of treatment “immunosensitization.” Ideal candidates for immunosensitizing drugs would be targeted drugs that block key oncogenic mechanisms in cancer cells resulting in a proapoptotic cancer cell milieu and at the same time do not negatively interfere with critical lymphocyte functions.
Clinical commissioning group asks GPs to scrap procedures in bid to reduce £23m deficit
Authors: Gareth Iacobucci
Journal: BMJ (2015)

A cash strapped clinical commissioning group in southwest England has been forced to implement new policies to ration the availability of medical care, because of its “dire” financial situation.

Wiltshire CCG has implemented a cap on planned care activity at local hospitals and increased the number of procedures that it can no longer fund as a result of “the very serious financial position” it was in.

In a letter to local GPs obtained and published online by the doctor and comedian Phil Hammond the CCG said that it was also considering tightening the criteria for referring patients to hospital and asked GPs to help it review the use of branded generic drugs and the number of repeat prescriptions issued, as part of its urgent cost cutting drive.1

The letter, …
Lung Abnormalities after Dasatinib Treatment for Chronic Myeloid Leukemia
Authors: Anne Bergeron, Delphine Réa, Vincent Levy, Clément Picard, Véronique Meignin, Jérome Tamburini, Heriberto Bruzzoni-Giovanelli, Fabien Calvo, Abdellatif Tazi, Philippe Rousselot
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia and are increasingly used for other indications. Fluid retention, however, including pleural effusions, are a significant side effect of imatinib, the first-line treatment for chronic myeloid leukemia. We investigated pleural and pulmonary complications in patients treated with dasatinib, a novel multitargeted tyrosine kinase inhibitor, as part of clinical trial protocols. Of 40 patients who received dasatinib (70 mg twice daily) for imatinib resistance or intolerance, 9 (22.5%) developed dyspnea, cough, and chest pain. Of these nine patients, six had pleural effusions (all were exudates) and seven had lung parenchyma changes with either ground-glass or alveolar opacities and septal thickening (four patients had both pleural effusions and lung parenchyma changes). Lymphocytic accumulations were detected in pleural and bronchoalveolar lavage fluids in all patients except for one who presented with neutrophilic alveolitis. Pleural biopsies revealed lymphocytic infiltration in one patient and myeloid infiltration in another. After dasatinib interruption, lung manifestations resolved in all cases and did not recur in three of four patients when dasatinib was reintroduced at a lower dose (40 mg twice daily). Thus, lung physicians should be aware that lung manifestations, presumably related to an immune-mediated mechanism rather than fluid retention, may occur with dasatinib treatment.
Determination of anti-CCP antibodies in patients with suspected rheumatoid arthritis: does it help to predict the diagnosis before referral to a rheumatologist?
Authors: I K Gao
Journal: Annals of the Rheumatic Diseases (2005)

Prognosis in rheumatoid arthritis (RA) depends critically on early diagnosis and timely treatment with immune modulating drugs. As a consequence, early referral and access of patients with suspected RA to rheumatologists is mandatory for the establishment of diagnosis and initiation of treatment.

Measurement of antibodies to cyclic citrullinated peptide (CCP) is a new and highly specific test for the diagnosis of RA. Detection of anti-CCP antibodies—in particular, if the second generation of anti-CCP2 tests is used—has been shown to be of prognostic significance and to be helpful in early diagnosis of RA.1–9

The goal of this work was to investigate whether the measurement of anti-CCP antibodies alone or in combination with easily determinable parameters of a patient’s complaints and routine laboratory tests might help to identify prospectively patients with a high probability for RA.

For this …
Rational Combination of a MEK Inhibitor, Selumetinib, and the Wnt/Calcium Pathway Modulator, Cyclosporin A, in Preclinical Models of Colorectal Cancer
Authors: Anna Spreafico, John J. Tentler, Todd M. Pitts, Aik Choon Tan, Mark A. Gregory, John J. Arcaroli, Peter J. Klauck, Martine C. McManus, Ryan J. Hansen, Jihye Kim, Lindsey N. Micel, Heather M. Selby, Timothy P. Newton, Kelly L. McPhillips, Daniel L. Gustafson, James V. DeGregori, Wells A. Messersmith, Robert A. Winn, S. Gail Eckhardt
Journal: Clinical Cancer Research (2013)

The mitogen-activated protein kinase (MAPK) pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS-mutant colorectal cancer who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in colorectal cancer, indicating that rational combination strategies are needed.In this study, we conducted unbiased gene set enrichment analysis and synthetic lethality screens with selumetinib, which identified the noncanonical Wnt/Ca++ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we used shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in colorectal cancer cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and showed synergistic antiproliferative effects in in vitro and in vivo models of colorectal cancer.Importantly, this combination not only showed tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of colorectal cancer. In mechanistic studies, we observed a trend toward increased markers of apoptosis in response to the combination of MEK and WntCa(++) inhibitors, which may explain the observed synergistic antitumor effects.These results strengthen the hypothesis that targeting both the MEK and Wnt pathways may be a clinically effective rational combination strategy for patients with metastatic colorectal cancer.
Failure of pulmonary artery banding due to migration of the band
Authors: D. Verel, D. G. Taylor, J. L. Emery
Journal: Thorax (1970)

Pulmonary artery banding controlled the distal pulmonary artery pressure at operation in a 16-month old infant. When she was reinvestigated over two years later there was no pressure gradient at the site of the band. At operation the band was found to have migrated into the lumen of the artery.
New and Surprising Insights Into Pathogenesis of Multicentric Squamous Cancers in the Female Lower Genital Tract
Authors: Qinghua Feng, Nancy B. Kiviat
Journal: JNCI Journal of the National Cancer Institute (2005)

Infection with high-risk types of human papillomavirus (HR-HPV) is extremely common in the cervix, vagina, and vulva; and women with persistent HR-HPV infections at these sites have been shown to be at increased risk for the development of invasive squamous cell cancers at these locations ( 1 – 3 ) . Prior to the establishment of routine cervical cancer screening, invasive cervical cancer was among the most common causes of cancer mortality in women. Compared with cervical cancer, vaginal and vulvar cancers develop infrequently (current age-adjusted incidences of cervical, vaginal, and vulvar cancers = 8.9/100 000 women per year, 0.7/100 000 women per year, and 2.3/100 000 women per year, respectively) ( 4 ) . Previous studies (e.g., [5,6] ) have shown that a history of a prior cervical neoplasm (cervical intraepithelial neoplasia grade 3 [CIN 3] or invasive cervical cancer) is an important risk factor for the development of vaginal and vulvar cancers. The most likely explanation for this association is that women who develop cervical neoplasia frequently are infected with HR-HPV both at the cervix and in the vagina and vulva, and they occasionally develop a second independent neoplasm at the last two sites. Other explanations for this association between a history of a prior cervical neoplasm and the later development of a vaginal or vulvar cancer include recurrence of the original cervical cancer at the surgical margin after hysterectomy
Histone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide Synthase
Authors: Saet-Byel Jung, Cuk-Seong Kim, Asma Naqvi, Tohru Yamamori, Ilwola Mattagajasingh, Timothy A. Hoffman, Marsha P. Cole, Ajay Kumar, Jeremy S. DeRicco, Byeong-Hwa Jeon, Kaikobad Irani
Journal: Circulation Research (2010)

Low-dose acetylsalicylic acid (aspirin) is widely used in the treatment and prevention of vascular atherothrombosis. Cardiovascular doses of aspirin also reduce systemic blood pressure and improve endothelium-dependent vasorelaxation in patients with atherosclerosis or risk factors for atherosclerosis. Aspirin can acetylate proteins, other than its pharmacological target cyclooxygenase, at lysine residues. The role of lysine acetylation in mediating the effects of low-dose aspirin on the endothelium is not known.To determine the role of lysine acetylation of endothelial nitric oxide synthase (eNOS) in the regulation of endothelial NO production by low-dose aspirin and to examine whether the lysine deacetylase histone deacetylase (HDAC)3 antagonizes the effect of low-dose aspirin on endothelial NO production by reversing acetylation of functionally critical eNOS lysine residues.Low concentrations of aspirin induce lysine acetylation of eNOS, stimulating eNOS enzymatic activity and endothelial NO production in a cyclooxygenase-1-independent fashion. Low-dose aspirin in vivo also increases bioavailable vascular NO in an eNOS-dependent and cyclooxygenase-1-independent manner. Low-dose aspirin promotes the binding of eNOS to calmodulin. Lysine 609 in the calmodulin autoinhibitory domain of bovine eNOS mediates aspirin-stimulated binding of eNOS to calmodulin and eNOS-derived NO production. HDAC3 inhibits aspirin-stimulated (1) lysine acetylation of eNOS, (2) eNOS enzymatic activity, (3) eNOS-derived NO, and (4) binding of eNOS to calmodulin. Conversely, downregulation of HDAC3 promotes lysine acetylation of eNOS and endothelial NO generation.Lysine acetylation of eNOS is a posttranslational protein modification supporting low-dose aspirin-induced vasoprotection. HDAC3, by deacetylating aspirin-acetylated eNOS, antagonizes aspirin-stimulated endothelial production of NO.
Effect of Angiotensin II on the Intact Forearm Veins of Man
Authors: NICHOLAS P. DE PASQUALE, GEORGE E. BURCH
Journal: Circulation Research (1963)

Angiotensin II was injected into an isolated venous segment in eighteen human subjects and administered intravenously into a systemic vein in five other subjects. Injections of angiotensin II into an intact isolated venous segment produced no constriction of the segment. Intravenous systemic infusion of angiotensin II produced a slight constriction of the isolated venous segment in three subjects (mean 44 mm H 2 O) and no constriction of the segment in two subjects. The constriction in the venous segment associated with the systemic intravenous administration of the drug could be interrupted by blocking the nerves supplying the venous segment. Thus, angiotensin II has no direct effect upon the forearm veins of man. The rise in segmental venous pressure following the intravenous infusion of angiotensin II appears to originate from reflexes located outside the venous system which influence tone of the superficial veins of the forearm of man.
Endoscopic submucosal dissection using a thulium laser: preliminary results of a new method for treatment of gastric epithelial neoplasia
Authors: Jun-Hyung Cho, Joo Cho, Mi-Young Kim, Seong Jeon, Tae Lee, Hyun Kim, So Jin, Su Hong
Journal: Endoscopy (2013)

<b>Background and study aim:</b> This study aimed to evaluate the feasibility of a novel laser system for endoscopic submucosal dissection (ESD) of gastric epithelial neoplasia. <b>Patients and methods:</b> A total of 10 patients underwent ESD by a single expert endoscopist. A thulium 2-μm wavelength laser system was used for ESD procedures. Instead of using endoscopy knives, a 550-μm flexible silica fiber was inserted through the working channel of the endoscope. <b>Results:</b> In all patients, ESD was completed using only the thulium laser, without the need for endoscopy knives. The median total procedure time was 49 minutes (range 35 – 203). In 8 /10 patients (80 %), no active bleeding was observed during ESD. The final pathologic mapping revealed low-grade dysplasia (n = 4), differentiated adenocarcinoma (n = 5), and signet ring cell carcinoma (n = 1). Curative resection was achieved in 9 /10 patients (90 %). There were no significant complications, such as delayed bleeding or perforation. <b>Conclusions:</b> The thulium laser system was feasible in ESD of gastric epithelial neoplasia.
Extracapsular Lymph Node Involvement Is a Negative Prognostic Factor After Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Cancer
Authors: Xavier Benoît D'journo, Jean Philippe Avaro, Pierre Michelet, Delphine Trousse, Anne Marie Tasei, Laetitia Dahan, Christophe Doddoli, Roger Guidicelli, Pierre Fuentes, Jean Francois Seitz, Pascal Thomas
Journal: Journal of Thoracic Oncology (2009)
Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency
Authors: Vincent Barlogis, Claire Galambrun, Hervé Chambost, Sylvie Lamoureux-Toth, Philippe Petit, Jean-Louis Stephan, Gérard Michel, Alain Fischer, Capucine Picard
Journal: Journal of Allergy and Clinical Immunology (2011)
EPOX Inhibits Angiogenesis by Degradation of Mcl-1 through ERK Inactivation
Authors: Hui-Lung Sun, An-Chi Tsai, Shiow-Lin Pan, Qingqing Ding, Hirohito Yamaguchi, Chun-Nan Lin, Mien-Chie Hung, Che-Ming Teng
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX), a novel Mcl-1 targeting drug. Experimental Design: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe. Results: EPOX induced endothelial cell apoptosis in association with proteasome-dependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1–free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation of Mcl-1 at T163. Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability. Conclusions: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesis-related pathologies.