tbuckley/cabot-search huggingface dataset:
Structure and Function of Alpha-Fetoprotein
Authors: T B Tomasi
Journal: Annual Review of Medicine (1977)

AFP is one of several oncofetal proteins synthesized in large amounts by the fetus. Although synthesis drops markedly shortly after birth, small amounts of AFP continue to be produced in the adult. The function of AFP is unknown, but recent studies suggest the possibility that it may have immunoregulatory properties and/or may influence cell proliferation and growth. The high affinity of AFP for estrogen could have important biological functions, although the significance of this binding has not yet been clearly defined. Elevated levels of AFP are seen in a variety of clinical situations, including pregnancy; hepatic disorders, especially chronic hepatitis; and various malignancies, particularly hepatomas, teratomas, and those of primitive gut origin. It is also produced in murine GVH reactions and in lymphomas, both in mice and humans. In human and murine lymphomas, and murine GVH reactions, the presence of AFP-positive cells and immune suppression are highly correlated, but the role of these in the pathogenesis of the diseases is as yet unclear. It appears, however, that AFP may be produced locally in lymphoid tissues involved in GVH and lymphomatous disease without elevations in serum AFP levels. It is speculated that the local production of AFP in these situations may result from blastogenesis of lymphoid cells directed against foreign tumor or viral antigens. AFP could promote the development of tumors either by suppressing immune surveillance and/or immunity to oncogenic viruses, although this is speculative. Finally, the AFP elevations in maternal serum and amniotic fluid are valuable diagnostically in the detection of fetal abnormalities, particularly neural-tube defects.
Role of Insulin Resistance in Human Disease (Syndrome X): An Expanded Definition
Authors: Gerald M. Reaven
Journal: Annual Review of Medicine (1993)

Resistance to insulin-mediated glucose uptake is characteristic of individuals with impaired glucose intolerance or non-insulin-dependent diabetes, and it also occurs commonly in patients with high blood pressure. The physiological response to a decrease in insulin-mediated glucose uptake is an increase in insulin secretion, and as long as a state of compensatory hyperinsulinemia can be maintained, frank decompensation of glucose tolerance can be prevented. However, it is likely that the defect in insulin action and/or the associated hyperinsulinemia will lead to an increase in plasma triglyceride and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure. It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease.
P27kip1 as molecular target for colon cancer gene therapy
Authors: Luciana Tessitore, Andrea Casazza, Andrea Rasola, Antonia Follenzi, Francesca Platini, Consuelo Bottini
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4427 

P27Kip1, a cyclin-dependent kinase inhibitor, is a negative regulator of the cell cycle which has been associated with cell cycle arrest and apoptosis. Clinically, a low level of p27Kip1 correlate inversely with the tumour progression and the poor prognosis in a variety of human malignancies, including colon cancer. Previous data from our laboratory have shown that p27Kip1 inactivation in human colorectal cancer resulted by, besides reduced nuclear expression, cytoplasmic mislocalization, which was directly related with poor outcomes of the patients for cancer-related relapse and survival. In this study, we transduced a variety of human colon carcinoma cell lines ( DLD-1, HT-29, SW48, SW480, CaCo e LoVo ) with lentiviral vector bearing various concentrations (1-100 ng) of p27Kip1 cDNA. We found that p27Kip1 overexpression inhibited the monolayer growth as well as the ancorage-independent growth in soft agar in all colon cells tested in a dose-dependent manner. The inhibition of in vitro growth by p27Kip1 overexpression was primary due to induction of apoptosis as shown by flow cytometric assay for sub G1 population, reduced permeability to Tetramethylrhodamine methyl ester, increased binding to annexin V and permeability to propidie iodure, indicating the presence of cells undergoing early, medium and advanced apoptosis, respectively. Cell death was associated with diminished bcl2/bax ratio. P27Kip1 overexpression also triggered cell cycle arrest with accumulation of cells with G0/G1 DNA content, due to reduced expression of the pRb phosphorilated protein. In conclusion, the reversion of the neoplastic phenotype by lentiviral p27Kip1 transduction in colon cell lines may represent a novel therapeutic strategy.
Molecular residual disease status at the end of chemotherapy fails to predict subsequent relapse in children with B-lineage acute lymphoblastic leukemia.
Authors: Y Ito, R Wasserman, N Galili, B A Reichard, S Shane, B Lange, G Rovera
Journal: Journal of Clinical Oncology (1993)

PURPOSE We have investigated whether the extent of residual leukemia in the marrows obtained at the completion of chemotherapy can predict subsequent relapse in children with B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Marrow samples of 24 patients were examined for residual disease at the end of treatment using a quantitative method based on the polymerase chain reaction (PCR) amplification of the complementarity determining region-3 of the immunoglobulin heavy chain. RESULTS Of the 15 patients who remain in continuous bone marrow remission (range, 41 to 98 months), 14 had no detectable leukemic cells; one patient had a very low level (one in approximately 335,000 marrow cells) of residual leukemic cells that underwent clonal evolution. Among the nine patients who had a marrow relapse after the completion of treatment, eight patients whose relapses occurred 4 to 54 months from the end of therapy had no detectable leukemic cells, whereas only the one patient who relapsed 2 months after the completion of therapy had detectable residual disease. CONCLUSION These observations indicate that the absence of detectable residual leukemia by PCR at the end of chemotherapy is not sufficient to assure that the patient is cured and suggest that frequent serial monitoring is required for the early prediction of relapse off therapy.
Secondary neoplasms following treatment of malignant germ cell tumors.
Authors: C Bokemeyer, H J Schmoll
Journal: Journal of Clinical Oncology (1993)

The current study investigates the frequency and outcome of secondary malignancies in patients treated for testicular cancer at Hannover University Medical School between 1970 and 1990.One thousand twenty-five patients with a median follow-up duration of 61 months (range, 12 to 240) were included in the analysis. Follow-up was complete in 1,018 patients (99%). Histology was seminoma in 324 patients (38.7%) and nonseminomatous germ cell tumor in 624 patients (61.3%). At the time of median follow-up, 814 patients (79.9%) were alive.Fourteen patients developed a secondary neoplasm (cumulative incidence, 1.38%; 95% confidence interval [CI], 0.75 to 2.30); 13 patients had solid tumors and one had secondary lymphoblastic leukemia with a t(4; 11) translocation including band 11q23. None of 224 patients on surveillance strategy (with or without retroperitoneal lymph node dissection [RPLND]) developed a second neoplasm, compared with four of 413 patients (0.97%; 95% CI, 0 to 1.9) after cisplatin-based chemotherapy (not significant) and nine of 332 patients (2.7%; 95% CI, 0.9 to 4.5) after radiotherapy (P = .02). The cumulative incidence of a secondary neoplasia of 1.76% (95% CI, 0.97 to 2.94) in patients treated by radiotherapy and/or chemotherapy was significantly higher compared with patients on surveillance protocols (P = .03). Chemotherapy containing standard-dose etoposide did not increase the risk of occurrence of secondary neoplasms. A significantly elevated relative risk of 7.53 (range, 3.4 to 14.3) compared with the male German population was only found for patients treated by radiotherapy.Compared with patients who have other curable malignant tumors, an incidence of 1.38 of secondary neoplasms after a median follow-up duration of 61 months is low. The highest risk for secondary neoplasia after treatment of testicular cancer is associated with the use of radiotherapy. Following chemotherapy, no significantly elevated risk was observed. In conclusion, the benefits of curative treatment far outweigh the risk of secondary cancer in patients with malignant germ cell tumors.
MYC, Metabolism, and Cancer
Authors: Zachary E. Stine, Zandra E. Walton, Brian J. Altman, Annie L. Hsieh, Chi V. Dang
Journal: Cancer Discovery (2015)

Abstract The MYC oncogene encodes a transcription factor, MYC, whose broad effects make its precise oncogenic role enigmatically elusive. The evidence to date suggests that MYC triggers selective gene expression amplification to promote cell growth and proliferation. Through its targets, MYC coordinates nutrient acquisition to produce ATP and key cellular building blocks that increase cell mass and trigger DNA replication and cell division. In cancer, genetic and epigenetic derangements silence checkpoints and unleash MYC's cell growth– and proliferation-promoting metabolic activities. Unbridled growth in response to deregulated MYC expression creates dependence on MYC-driven metabolic pathways, such that reliance on specific metabolic enzymes provides novel targets for cancer therapy. Significance: MYC's expression and activity are tightly regulated in normal cells by multiple mechanisms, including a dependence upon growth factor stimulation and replete nutrient status. In cancer, genetic deregulation of MYC expression and loss of checkpoint components, such as TP53, permit MYC to drive malignant transformation. However, because of the reliance of MYC-driven cancers on specific metabolic pathways, synthetic lethal interactions between MYC overexpression and specific enzyme inhibitors provide novel cancer therapeutic opportunities. Cancer Discov; 5(10); 1024–39. ©2015 AACR.
Pulmonary artery diameter to predict pulmonary hypertension in pulmonary sarcoidosis
Authors: Marloes P. Huitema, Marcela Spee, Veronique M.M. Vorselaars, Sanne Boerman, Repke J. Snijder, Hendrik W. van Es, Herre J. Reesink, Jan C. Grutters, Marco C. Post
Journal: European Respiratory Journal (2015)

Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis with a prevalence ranging from 5% to 74% [1]. The aetiology of PH in sarcoidosis is not fully understood. Usually, it is attributed to the destruction of the distal capillary bed by lung fibrosis and/or chronic hypoxaemia. However, the severity of PH does not correlate consistently with the degree of pulmonary fibrosis, and PH exists in sarcoidosis patients without fibrosis, suggesting a multifactorial mechanism. The presence of PH is associated with a poor prognosis, and early diagnosis and treatment might improve outcome [1]. Echocardiography should always be performed when PH is suspected [2]. However, the accuracy of echocardiography in patients with interstitial lung diseases is often limited due to poor image quality and unreliable tricuspid regurgitation signal to measure the right ventricular systolic pressure (RVSP) [3]. Further invasive investigation with the gold standard, right heart catheterisation (RHC), is often required. In order to optimise the noninvasive diagnostic approach, there is a need for more accurate predictors of PH. Computed tomography (CT) may raise suspicion of PH in symptomatic patients or those examined for unrelated indications by showing an increased pulmonary artery (PA) diameter (≥29 mm) and PA diameter/ascending aorta diameter (AAD) ratio (≥1.0) [2]. Similarly, PA diameter indexed to body surface area (BSA) has been suggested as possible predictor of PH. However, these parameters have never been investigated in pulmonary sarcoidosis specifically. Pulmonary artery indexed for body surface area is the most accurate predictor for PH on CT in pulmonary sarcoidosis <http://ow.ly/T863m>
Oxidative stress in the pathogenesis of thoracic aortic aneurysm Protective role of statin and angiotensin II type 1 receptor blocker
Authors: J Ejiri
Journal: Cardiovascular Research (2003)

Objective: The pathogenesis of thoracic aortic aneurysms (TAA) is still unclear. A recent investigation indicated that angiotensin II, a potent activator of NADH/NADPH oxidase, plays an important role in aneurysmal formation. We investigated the potential role of p22 phox -based NADH/NADPH oxidase in the pathogenesis of TAA. Methods: Human thoracic aneurysmal ( n =40) and non-aneurysmal (control, n =39) aortic sections were examined, and the localization of p22 phox , an essential component of the oxidase, and its expressional differences were investigated by immunohistochemistry and Western blot. In situ reactive oxygen species (ROS) generation was examined by the dihydroethidium method, and the impact of medical treatment on p22 phox expression was investigated by multiple regression analysis. Results: In situ production of ROS and the expression of p22 phox increased markedly in TAA throughout the wall, and Western blot confirmed the enhanced expression of p22 phox . The expression was more intense in the regions where monocytes/macrophages accumulated. In these inflammatory regions, numerous chymase-positive mast cells and angiotensin converting enzyme-positive macrophages were present. Their localization closely overlapped the in situ activity of matrix metalloproteinase and the expression of p22 phox . Multiple regression analysis revealed that medical treatment with statin and angiotensin II type 1 receptor blocker (ARB) suppressed p22 phox expression in TAA. Conclusion: Our findings indicate the role of p22 phox -based NADH/NADPH oxidase and the local renin–angiotensin system in the pathogenesis of TAA. Statin and ARB might have inhibitory effects on the formation of aneurysms via hrough the suppression of NADH/NADPH oxidase.
Activated protein C inhibits neutrophil migration in allergic asthma: a randomised trial
Authors: J. Daan de Boer, Marieke Berger, Christof J. Majoor, Liesbeth M. Kager, Joost C.M. Meijers, Sanne Terpstra, Rienk Nieuwland, Anita N. Boing, René Lutter, Diana Wouters, Gerard J. van Mierlo, Sacha S. Zeerleder, Elisabeth H. Bel, Cornelis van't Veer, Alex F. de Vos, Jaring S. van der Zee, Tom van der Poll
Journal: European Respiratory Journal (2015)

Asthma patients show evidence of a procoagulant state in their airways, accompanied by an impaired function of the anticoagulant protein C system. We aimed to study the effect of recombinant human activated protein C (rhAPC) in allergic asthma patients. We conducted a randomised, double-blind, placebo-controlled, proof-of-concept study in house dust mite (HDM) allergic asthma patients. Patients were randomised to receive intravenous rhAPC (24 µg·kg −1 ·h −1 ; n=12) or placebo (n=12) for 11 h. 4 h after the start of infusion, a first bronchoscopy was performed to challenge one lung segment with saline (control) and a contralateral segment with a combination of HDM extract and lipopolysaccharide (HDM+LPS), thereby mimicking environmental house dust exposure. A second bronchoscopy was conducted 8 h after intrabronchial challenge to obtain bronchoalveolar lavage fluid (BALF). rhAPC did not influence HDM+LPS induced procoagulant changes in the lung. In contrast, rhAPC reduced BALF leukocyte counts by 43% relative to placebo, caused by an inhibitory effect on neutrophil influx (64% reduction), while leaving eosinophil influx unaltered. rhAPC also reduced neutrophil degranulation products in the airways. Intravenous rhAPC attenuates HDM+LPS-induced neutrophil migration and protein release in allergic asthma patients by an effect that does not rely on coagulation inhibition.
Ancient Male Recombination Shaped Genetic Diversity of Neo-Y Chromosome in<i>Drosophila albomicans</i>
Authors: Kazuhiro Satomura, Koichiro Tamura
Journal: Molecular Biology and Evolution (2015)

Researchers studying Y chromosome evolution have drawn attention to neo-Y chromosomes in Drosophila species due to their resembling the initial stage of Y chromosome evolution. In the studies of neo-Y chromosome of Drosophila miranda, the extremely low genetic diversity observed suggested various modes of natural selection acting on the nonrecombining genome. However, alternative possibility may come from its peculiar origin from a single chromosomal fusion event with male achiasmy, which potentially caused and maintained the low genetic diversity of the neo-Y chromosome. Here, we report a real case where a neo-Y chromosome is in transition from an autosome to a typical Y chromosome. The neo-Y chromosome of Drosophila albomicans harbored a rich genetic diversity comparable to its gametologous neo-X chromosome and an autosome in the same genome. Analyzing sequence variations in 53 genes and measuring recombination rates between pairs of loci by cross experiments, we elucidated the evolutionary scenario of the neo-Y chromosome of D. albomicans having high genetic diversity without assuming selective force, i.e., it originated from a single chromosomal fusion event, experienced meiotic recombination during the initial stage of evolution and diverged from neo-X chromosome by the suppression of recombination tens or a few hundreds of thousand years ago. Consequently, the observed high genetic diversity on the neo-Y chromosome suggested a strong effect of meiotic recombination to introduce genetic variations into the newly arisen sex chromosome.
The SIN1-PH Domain Connects mTORC2 to PI3K
Authors: Hai-Xin Yuan, Kun-Liang Guan
Journal: Cancer Discovery (2015)

Abstract Summary: The mTOR complex 2, mTORC2, is a critical downstream effector of PI3K that stimulates AGC kinase members, including AKT, PKC, and SGK. Liu and colleagues reported that the pleckstrin homology domain of SIN1, an essential component of mTORC2, directly binds the PI3K product PtdIns(3,4,5)P3 to promote mTORC2 kinase activation and membrane localization, thereby revealing a mechanistic link between PI3K and mTORC2. Cancer Discov; 5(11); 1127–9. ©2015 AACR. See related article by Liu and colleagues, p. 1194.
Self-induced water intoxication and alcohol abuse
Authors: T L Ripley, R C Millson, A B Koczapski
Journal: American Journal of Psychiatry (1989)

According to Feighner criteria, alcohol abuse was significantly more common among 17 schizophrenic male inpatients with self-induced water intoxication than among 17 matched schizophrenic control inpatients. The alcohol abuse had begun 8-22 years before the diagnosis of water intoxication.
BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia
Authors: S-S Chen, B Y Chang, S Chang, T Tong, S Ham, B Sherry, J A Burger, K R Rai, N Chiorazzi
Journal: Leukemia (2015)

Bruton’s tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCγ2 and PKCμ, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL-cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects.
After revision anterior cruciate ligament reconstruction, who returns to sport? A systematic review and meta-analysis
Authors: Alberto Grassi, Stefano Zaffagnini, Giulio Maria Marcheggiani Muccioli, Maria Pia Neri, Stefano Della Villa, Maurilio Marcacci
Journal: British Journal of Sports Medicine (2015)

Return to sport and to pre-injury level represents an important outcome after both primary and revision anterior cruciate ligament (ACL) reconstructions.The aim of the present meta-analysis was to determine the return to sport rate after revision ACL reconstruction.A systematic search was performed of the MEDLINE, Embase and the Cochrane Central Register of Controlled Trials Databases. All the studies that reported return to sport, return to pre-injury sport level and return to high level/competitive sport was considered for the meta-analysis. The overall pooled mean of post-operative knee laxity and pooled rate of positive pivot-shift and objective International Knee Documentation Committee (IKDC) categories was calculated as well.Overall, 472 abstracts were identified and screened for inclusion and only 16 studies reported the rate of return to any level of sport activity at the final follow-up of 4.7 years (range 1.0-13.2 years), showing a pooled rate of 85.3% (CI 79.7 to 90.2). The return to pre-injury sport level was achieved in 53.4% (CI 37.8 to 68.7) of cases. Normal or quasi-normal objective IKDC, less than 5 mm of side-to-side difference at arthrometric evaluations and grade I-II pivot-shift test were reported in 84%, 88% and 93% patients, respectively.In spite of almost 8 patients out of 10 returning to sport after revision ACL reconstruction and showing good stability, only half of the patients returned to the same pre-injury sport level.
Motor Systems, with Specific Reference to the Control of Locomotion
Authors: P S G Stein
Journal: Annual Review of Neuroscience (1978)

The central nervous system (CNS) must produce specific patterns of motor neuron impulses during a coordinated movement. The desire to understand how these patterns are produced and controlled has led investigators to examine the properties of interneurons within the CNS. A set of theoretical principles has emerged from these studies that are applicable to both invertebrates and vertebrates (Wilson 1967, Evarts et al 1971, Gurfinkel & Shik 1973, R. B. Stein et al 1973, Grillner 1975, Herman et al 1976, Shik&Orlovsky 1976, Wetzel & Stuart 1976, P. S. G. Stein 1977). This review will discuss how these principles apply to locomotion and will demon­ strate that they may also serve as useful working hypotheses in the study of other motor systems. The central hypothesis is that there is a neural pattern generator residing within the CNS that serves to produce the basic motor program (Wilson 1972). Informa­ tion derived from sensory input may modify the output of the pattern generator so that the motor output is adapted to the particular mechanical properties of the organism and its environment. The principles are the following: