tbuckley/cabot-search huggingface dataset:
ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2
Authors: Hiyaa S. Ghosh, Michele Ceribelli, Ines Matos, Allan Lazarovici, Harmen J. Bussemaker, Anna Lasorella, Scott W. Hiebert, Kang Liu, Louis M. Staudt, Boris Reizis
Journal: The Journal of Experimental Medicine (2014)

Dendritic cells (DCs) comprise two major subsets, the interferon (IFN)-producing plasmacytoid DCs (pDCs) and antigen-presenting classical DCs (cDCs). The development of pDCs is promoted by E protein transcription factor E2-2, whereas E protein antagonist Id2 is specifically absent from pDCs. Conversely, Id2 is prominently expressed in cDCs and promotes CD8+ cDC development. The mechanisms that control the balance between E and Id proteins during DC subset specification remain unknown. We found that the loss of Mtg16, a transcriptional cofactor of the ETO protein family, profoundly impaired pDC development and pDC-dependent IFN response. The residual Mtg16-deficient pDCs showed aberrant phenotype, including the expression of myeloid marker CD11b. Conversely, the development of cDC progenitors (pre-DCs) and of CD8+ cDCs was enhanced. Genome-wide expression and DNA-binding analysis identified Id2 as a direct target of Mtg16. Mtg16-deficient cDC progenitors and pDCs showed aberrant induction of Id2, and the deletion of Id2 facilitated the impaired development of Mtg16-deficient pDCs. Thus, Mtg16 promotes pDC differentiation and restricts cDC development in part by repressing Id2, revealing a cell-intrinsic mechanism that controls subset balance during DC development.
Mitomycin C induces bystander killing in homogeneous and heterogeneous hepatoma cellular models
Authors: Ratna Kumari, Aanchal Sharma, Amrendra Kumar Ajay, Manoj Kumar Bhat
Journal: Molecular Cancer (2009)

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide that is particularly refractory to chemotherapy. Several studies have proposed combination chemotherapy regimen for HCC treatment. However, these therapies are not effective in regressing tumor and prolonging survival of patient's suffering from HCC. Therefore, the development of more effective therapeutic tools and new strategies for the treatment of HCC are urgently needed. Over the last decade much attention has been focused on "bystander effect" as a possible therapeutic strategy for the treatment of certain human tumors. Interest in this therapeutic approach originated from numerous reports describing the radiation induced bystander effect. However, the knowledge about chemotherapy induced bystander effect is still limited. Hence, chemotherapy induced bystander phenomenon in hepatoma cells was explored by utilizing Mitomycin C (MMC).MMC induced bystander killing was observed only in hepatoma cells and it did not occur in cervical cancer cells. MMC induced bystander killing was transferable via medium. It occurred in co-cultured cells indicating the involvement of secreted as well as membrane bound factors. FasL and TRAIL were detected in the conditioned medium from treated cells. In medium transfer experiment, pre-treatment with EDTA (a broad range protease inhibitor) diminished MMC induced bystander killing. Following drug exposure, expression of Fas and TRAIL receptors increased and treatment with neutralizing antibodies against FasL and TRAIL inhibited bystander killing.Our results highlight the therapeutic importance of MMC in the treatment of HCC and implicate role of membrane bound and secreted forms of FasL and TRAIL in MMC induced bystander killing.
Evolutionary string theory
Authors: Zen Faulkes, Anita Davelos Baines
Journal: Behavioral and Brain Sciences (2007)

Abstract Evolution in Four Dimensions claims that epigenetic, behavioral, and symbolic inheritance systems should be considered equal partners to genetics in evolutionary biology. The evidence for, and applicable scope of, these additional inheritance systems is limited, particularly with regard to areas involving learning. It is unclear how including these extra dimensions in mainstream evolutionary thinking translates into testable hypotheses for a productive research program.
Pneumococcal sepsis: should we look for asplenia?
Authors: M. Fadel, D. Luyt, H. Pandya, S. Nichani, D. Jenkins
Journal: Journal of the Royal Society of Medicine (2004)

Asplenic individuals are at risk of developing overwhelming bacterial sepsis with capsulated organisms such as Streptococcus pneumoniae, 1 against which pneumococcal vaccination or antibiotic prophylaxis can provide life-saving protection.Opportunities to identify such individuals should thus be vigorously pursued.
Systemic chemotherapy of brain metastases from small-cell lung cancer: a review.
Authors: C A Kristensen, P E Kristjansen, H H Hansen
Journal: Journal of Clinical Oncology (1992)

PURPOSE For decades the treatment of choice in small-cell lung cancer (SCLC) with brain metastases has been corticosteroids and radiotherapy (RT) because of a presumed lack of penetrance of cytostatic agents into parenchymatous brain metastases. In recent years, several reports have appeared on radiologic and clinical responses to systemic chemotherapy without additional RT in patients with metastatic SCLC in the brain. We reviewed the literature and focused on the methodologic aspects in comparison with RT data. DESIGN We reviewed 12 patient series that included 116 patients and were published between 1981 and 1990. RESULTS The overall brain response to chemotherapy without irradiation in patients with intracranial metastases at diagnosis was 76%, whereas the response rate of brain relapses was 43%. CONCLUSIONS We conclude that intracranial metastases from SCLC seem to respond to chemotherapy as readily as other metastatic locations of SCLC do. Thus first-line cranial irradiation probably should be applied routinely only in cases of delayed brain metastases. Whether consolidating cranial RT should be given after a few courses of initial chemotherapy in SCLC patients with brain metastases at diagnosis is unclear and warrants a randomized evaluation.
Pleiotropic Effects of Atorvastatin and Fenofibrate in Metabolic Syndrome and Different Types of Pre-Diabetes
Authors: Robert Krysiak, Anna Gdula-Dymek, Ryszard Bachowski, Bogusław Okopień
Journal: Diabetes Care (2010)

To compare extra-lipid effects of statins and fibrates in relation to the baseline metabolic status of patients.The study involved a group of 242 metabolic syndrome patients with or without pre-diabetes and randomized to atorvastatin, fenofibrate, or placebo.Compared with matched healthy subjects, metabolic syndrome patients exhibited higher plasma levels/activities of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, factor VII, plasminogen activator inhibitor 1, and enhanced monocyte cytokine release. These abnormalities were alleviated by both atorvastatin and fenofibrate treatment. CRP-lowering and monocyte-suppressing actions were more pronounced for atorvastatin in subjects with impaired fasting glucose and for fenofibrate in patients with impaired glucose tolerance.The presence of pre-diabetes potentiates metabolic syndrome-induced abnormalities in plasma markers of inflammation and hemostasis and in monocyte secretory function. Both atorvastatin and fenofibrate exhibit multidirectional pleiotropic effects in subjects with metabolic syndrome, the strength of which seem to be partially determined by the type of pre-diabetes.
Role of diffusion tensor magnetic resonance tractography in predicting the extent of resection in glioma surgery
Authors: Antonella Castellano, Lorenzo Bello, Caterina Michelozzi, Marcello Gallucci, Enrica Fava, Antonella Iadanza, Marco Riva, Giuseppe Casaceli, Andrea Falini
Journal: Neuro-Oncology (2011)

Diffusion tensor imaging (DTI) tractography enables the in vivo visualization of the course of white matter tracts inside or around a tumor, and it provides the surgeon with important information in resection planning. This study is aimed at assessing the ability of preoperative DTI tractography in predicting the extent of the resection achievable in surgical removal of gliomas. Patients with low-grade gliomas (LGGs; 46) and high-grade gliomas (HGGs; 27) were studied using a 3T scanner according to a protocol including a morphological study (T2, fluid-attenuated inversion-recovery, T1 sequences) and DTI acquisitions (b = 1000 s/mm(2), 32 gradient directions). Preoperative tractography was performed off-line on the basis of a streamline algorithm, by reconstructing the inferior fronto-occipital (IFO), the superior longitudinal fascicle (SLF), and the corticospinal tract (CST). For each patient, the relationship between each bundle reconstructed and the lesion was analyzed. Initial and residual tumor volumes were measured on preoperative and postoperative 3D fluid-attenuated inversion-recovery images for LGGs and postcontrast T1-weighted scans for HGGs. The presence of intact fascicles was predictive of a better surgical outcome, because these cases showed a higher probability of total resection than did subtotal and partial resection. The presence of infiltrated or displaced CST or infiltrated IFO was predictive of a lower probability of total resection, especially for tumors with preoperative volume <100 cm(3). DTI tractography can thus be considered to be a promising tool for estimating preoperatively the degree of radicality to be reached by surgical resection. This information will aid clinicians in identifying patients who will mostly benefit from surgery.
Randomized, Placebo-Controlled, Double-Blind, Phase II Study of Axitinib Plus Docetaxel Versus Docetaxel Plus Placebo in Patients With Metastatic Breast Cancer
Authors: Hope S. Rugo, Alison T. Stopeck, Anil A. Joy, Stephen Chan, Shailendra Verma, Anna Lluch, Katherine F. Liau, Sinil Kim, Paul Bycott, Brad Rosbrook, Angel H. Bair, Denis Soulieres
Journal: Journal of Clinical Oncology (2011)

This multicenter, randomized, double-blind, phase II study assessed safety and efficacy of axitinib plus docetaxel in metastatic breast cancer (MBC).Women with MBC were randomly assigned 2:1 to receive docetaxel 80 mg/m2 once every 3 weeks plus axitinib 5 mg twice per day (combination arm) or placebo (placebo arm), following a lead-in phase I trial. The primary end point was time to progression (TTP).In all, 168 patients were enrolled; 112 were randomly assigned to axitinib and 56 to placebo. Median TTP was numerically longer in the combination arm than in the placebo arm (8.1 v 7.1 months), but this difference was not statistically significant (hazard ratio, 1.24; 95% CI, 0.82 to 1.87; one-sided P = .156). The difference in median TTP was greatest among patients who had received prior adjuvant chemotherapy (9.2 v 7.0 months; P = .043, prespecified subgroup analysis). Objective response rate was higher in the combination arm (41.1% v 23.6%; P = .011). The most common grades 3 to 4 treatment-related adverse events (combination/placebo) included diarrhea (10.8%/0%), fatigue (10.8%/5.4%), stomatitis (12.6%/1.8%), mucositis (9.0%/0%), asthenia (7.2%/0%), and hypertension (4.5%/0%). Three patients in the combination arm experienced serious thromboembolic events (one death). Febrile neutropenia was more frequent in the combination arm (15.3% v 7.1%); rates of other hematologic toxicities were comparable. Increased toxicity with axitinib was generally managed by dose reduction and/or growth factor support.The addition of axitinib to docetaxel did not improve TTP in first-line MBC treatment. Combination therapy may be more effective in patients previously exposed to adjuvant chemotherapy.
Pre-treatment with mesenchymal stem cells reduces ventilator-induced lung injury
Authors: Laura Chimenti, Tomás Luque, Maria R. Bonsignore, José Ramírez, Daniel Navajas, Ramon Farré
Journal: European Respiratory Journal (2012)

Bone marrow-derived mesenchymal stem cells (MSCs) reduce acute lung injury in animals challenged by bleomycin or bacterial lipopolysaccaride. It is not known, however, whether MSCs protect from ventilator-induced lung injury (VILI). This study investigated whether MSCs have a potential role in preventing or modulating VILI in healthy rats subjected to high-volume ventilation. 24 Sprague–Dawley rats (250–300 g) were subjected to high-volume mechanical ventilation (25 mL·kg −1 ). MSCs (5×10 6 ) were intravenously or intratracheally administered (n=8 each) 30 min before starting over-ventilation and eight rats were MSC-untreated. Spontaneously breathing anesthetised rats (n=8) served as controls. After 3 h of over-ventilation or control the animals were sacrificed and lung tissue and bronchoalveolar lavage fluid (BALF) were sampled for further analysis. When compared with controls, MSC-untreated over-ventilated rats exhibited typical VILI features. Lung oedema, histological lung injury index, concentrations of total protein, interleukin-1β, macrophage inflammatory protein-2 and number of neutrophils in BALF and vascular cell adhesion protein-1 in lung tissue significantly increased in over-ventilated rats. All these indices of VILI moved significantly towards normalisation in the rats treated with MSCs, whether intravenously or intratracheally. Both local and systemic pre-treatment with MSCs reduced VILI in a rat model.
Evolutionary relationships of human populations on a global scale.
Authors: M Nei, A K Roychoudhury
Journal: Molecular Biology and Evolution (1993)

Using gene frequency data for 29 polymorphic loci (121 alleles), we conducted a phylogenetic analysis of 26 representative populations from around the world by using the neighbor-joining (NJ) method. We also conducted a separate analysis of 15 populations by using data for 33 polymorphic loci. These analyses have shown that the first major split of the phylogenetic tree separates Africans from non-Africans and that this split occurs with a 100% bootstrap probability. The second split separates Caucasian populations from all other non-African populations, and this split is also supported by bootstrap tests. The third major split occurs between Native American populations and the Greater Asians that include East Asians (mongoloids), Pacific Islanders, and Australopapuans (native Australians and Papua New Guineans), but Australopapuans are genetically quite different from the rest of the Greater Asians. The second and third levels of population splitting are quite different from those of the phylogenetic tree obtained by Cavalli-Sforza et al. (1988), where Caucasians, Northeast Asians, and Ameridians from the Northeurasian supercluster and the rest of non-Africans form the Southeast Asian supercluster. One of the major factors that caused the difference between the two trees is that Cavalli-Sforza et al. used unweighted pair-group method with arithmetic mean (UPGMA) in phylogenetic inference, whereas we used the NJ method in which evolutionary rate is allowed to vary among different populations. Bootstrap tests have shown that the UPGMA tree receives poor statistical support whereas the NJ tree is well supported. Implications that the phylogenetic tree obtained has on the current controversy over the out-of-Africa and the multiregional theories of human origins are discussed.
Mechanically dependent changes in action potentials recorded from the intact frog ventricle.
Authors: M J Lab
Journal: Circulation Research (1978)

The wall of the ventricle contracts inhomogeneously during an isovolumic beat of an isolated, intact frog ventricle. Some epicardial segments actually lengthen while the pressure is rising. Almost simultaneously, the early repolarization phase of the monophasic action potential recorded from such a segment is accelerated, compared to the same phase for an isotonic beat in which the segment shortens. Segment lengthening during the isovolumic beat also may be seen during the late repolarization phase when, in contract to the above, it produces an afterdepolarization. These electrical changes disappear when isotonic contraction is restored. Corroborative findings were obtained from microelectrode and insulated gap recordings from isolated frog ventricular strip. Both electrical changes can be seen clearly when the segment is lengthened by intraventricular injections of Ringer's solution. There also is a short transition period toward the end of the action potential plateau when lengthening produces neither depolarization nor repolarization. The accelerated repolarization is manifest as a shortening of the Q-T interval in the ventricular electrogram. In all experimental preparations, the afterdepolarizations reached threshold for a propagated action potential. This mechanism may explain the generation of extrasystoles in myocardial ischemia.
A Human Minor Histocompatibility Antigen Specific for B Cell Acute Lymphoblastic Leukemia
Authors: Harry Dolstra, Hanny Fredrix, Frans Maas, Pierre G. Coulie, Francis Brasseur, Ewald Mensink, Gosse J. Adema, Theo M. de Witte, Carl G. Figdor, Elly van de Wiel-van Kemenade
Journal: The Journal of Experimental Medicine (1999)

Human minor histocompatibility antigens (mHags) play an important role in the induction of cytotoxic T lymphocyte (CTL) reactivity against leukemia after human histocompatibility leukocyte antigen (HLA)-identical allogeneic bone marrow transplantation (BMT). As most mHags are not leukemia specific but are also expressed by normal tissues, antileukemia reactivity is often associated with life-threatening graft-versus-host disease (GVHD). Here, we describe a novel mHag, HB-1, that elicits donor-derived CTL reactivity in a B cell acute lymphoblastic leukemia (B-ALL) patient treated by HLA-matched BMT. We identified the gene encoding the antigenic peptide recognized by HB-1-specific CTLs. Interestingly, expression of the HB-1 gene was only observed in B-ALL cells and Epstein-Barr virus-transformed B cells. The HB-1 gene-encoded peptide EEKRGSLHVW is recognized by the CTL in association with HLA-B44. Further analysis reveals that a polymorphism in the HB-1 gene generates a single amino acid exchange from His to Tyr at position 8 within this peptide. This amino acid substitution is critical for recognition by HB-1-specific CTLs. The restricted expression of the polymorphic HB-1 Ag by B-ALL cells and the ability to generate HB-1-specific CTLs in vitro using peptide-loaded dendritic cells offer novel opportunities to specifically target the immune system against B-ALL without the risk of evoking GVHD.
Relationship Between HbA1c Level and Peripheral Arterial Disease
Authors: Paul Muntner, Rachel P. Wildman, Kristi Reynolds, Karen B. DeSalvo, Jing Chen, Vivian Fonseca
Journal: Diabetes Care (2005)

Homeostatic glucose control may play an important role in the development of peripheral arterial disease among individuals without diabetes. We sought to evaluate the association of HbA(1c) (A1C) with peripheral arterial disease in a representative sample of the U.S. population with and without diabetes.A cross-sectional study was conducted among 4,526 National Health and Nutrition Examination Survey 1999-2002 participants > or = 40 years of age. Peripheral arterial disease was defined as an ankle-brachial index <0.9 (n = 327).Among nondiabetic subjects, the age-standardized prevalence of peripheral arterial disease was 3.1, 4.8, 4.7, and 6.4% for participants with an A1C <5.3, 5.3-5.4, 5.5-5.6, and 5.7-6.0%, respectively (P trend <0.001). The prevalence of peripheral arterial disease was 7.5 and 8.8% for diabetic participants with A1C <7 and > or = 7%, respectively. After multivariable adjustment and compared with nondiabetic participants with A1C <5.3%, the odds ratio (95% CI) of peripheral arterial disease for nondiabetic participants with an A1C of 5.3-5.4, 5.5-5.6, and 5.7-6.0% was 1.41 (0.85-2.32), 1.39 (0.70-2.75), and 1.57 (1.02-2.47), respectively, and it was 2.33 (1.15-4.70) and 2.74 (1.25-6.02) for diabetic participants with A1C <7 and > or = 7%, respectively.An association exists between higher levels of A1C and peripheral arterial disease, even among patients without diabetes. Individuals with A1C levels > or = 5.3% should be targeted for aggressive risk factor reduction, which may reduce the burden of subclinical cardiovascular disease even among those without diabetes.
Control of aldosterone secretion in the spontaneously hypertensive rat.
Authors: R H Freeman, J O Davis, N V Aharon, S Ulick, M H Weinberger
Journal: Circulation Research (1975)

Adrenal secretion rates of aldosterone, corticosterone, and deoxycorticosterone were studied sequentially in the spontaneously hypertensive rat and the normotensive Kyoto Wistar rat. Steroid secretion was studied at three different ages: 7-8, 11-13, and 22-25 weeks. Also, peripheral plasma levels of aldosterone and plasma renin activity were determined in both the spontaneously hypertensive and the normotensive rats at 7-8 weeks of age. Aldosterone secretion was elevated markedly in dexamethasone-morphine-treated spontaneously hypertensive rats at both 7-8 and 11-13 weeks of age but was not significantly different from control in 22-25-week-old spontaneously hypertensive rats. No statistically significant differences in corticosterone or deoxycorticosterone secretion rates were observed between the spontaneously hypertensive rats and the normotensive Kyoto Wistar controls; however, the data suggested that dexamethasone did not suppress adrenocorticotropic hormone in the 7-8- and 11-13-week-old spontaneously hypertensive rats to the same extent that it did in the normotensive Kyoto Wistar rats. Therefore, aldosterone secretion was reexamined in acutely hypophysectomized 7-8-week-old rats to eliminate completely the influence of the anterior pituitary; no differences in aldosterone, corticosterone, or deoxycorticosterone secretion rates were observed between hypophysectomized spontaneously hypertensive rats and normotensive Kyoto Wistar rats. Moreover, aldosterone secretion in the hypophysectomized 7-8-week-old spontaneously hypertensive rats was reduced markedly compared with that in the intact 7-8-week old spontaneously hypertensive rats, thus confirming the importance of the pituitary in these animals. Determinations of peripheral plasma aldosterone concentration and plasma renin activity in unstressed 7-8-week-old spontaneously hypertensive and normotensive rats revealed that both parameters were depressed significantly in the spontaneously hypertensive rats. Thus, the present data indicate that the renin-angiotensin-aldosterone system is suppressed in the spontaneously hypertensive rat but do not suggest that the system is critically involved in the hypertensive process in these animals
Herpes zoster. The treatment and prevention of neuralgia with adenosine monophosphate
Authors: S. H. Sklar
Journal: JAMA (1985)

Thirty-two adults were enrolled in a randomized, placebo-controlled double-blind trial of intramuscular injections of gel-sustained adenosine monophosphate (AMP) given three times a week for up to four weeks for acute herpes zoster. Adenosine monophosphate moderately reduced the pain soon after the start of treatment, decreased desquamation time, and promoted faster healing of the skin than placebo treatment. Adenosine monophosphate treatment reduced virus shedding and cleared the virus faster than in placebo-treated subjects. At the end of the initial four-week treatment period, 88% of AMP-treated patients were pain free, as opposed to only 43% in the placebo group. After four weeks, all patients who had not recovered from pain started receiving AMP treatment without breaking the code. All these patients recovered from pain within three weeks after initiation of treatment. No recurrence of pain or lesions was experienced from three to 18 months after the end of treatment. Adenosine monophosphate, a natural cellular metabolite, showed no side effects or toxicity during and after the treatment.