tbuckley/cabot-search huggingface dataset:
P35 Treatment with an Alpha 2a Adrenoreceptor Antagonist Modulates Hepatic Inflammation, Markedly Reduces Portal Pressure, and Improves Arterial Pressure and Hepatic Blood Flow in Cirrhotic Rats
Authors: N Shah, M Montes de Oca, D Dhar, M Jover-Cobos, N Alun Davies, R Mookerjee, R Jalan
Journal: Gut (2010)

Introduction  Inflammation plays a pivotal role in modulating the severity of intrahepatic resistance in cirrhosis. Our studies have shown a close relationship between the activation of the sympathetic nervous system, inflammatory response and severity of portal hypertension. Stimulation of alpha 2a adrenergic (ADRA2a) receptors results in inflammation and vasodilation in resistance vasculature, and its antagonism has shown benefit in models of sepsis.  Aim  The aim of the study was to test the hypothesis that treating bile duct ligated rats (BDL) with an ADRA2a antagonist reduces hepatic inflammation and improves the haemodynamic abnormalities associated with cirrhosis.  Method   Male Sprague-Dawley rats (N=46) were studied 4-weeks after BDL surgery (N=29) or sham operation (N=17) and randomised to two doses of placebo or ADRA2a antagonist (BRL 44408, Sigma, UK, 10mg/kg s.c 24 hours prior to study). Portal vein and hepatic arterial blood flow, mean arterial (MAP) and portal pressure were measured directly. Plasma biochemistry was measured by colorimetry. ADRA2a and NFkB protein expression were determined by western blotting and immunohistochemistry (ADRA2a).  Results  BDL rats had significantly increased hepatic protein expression of ADRA2a compared with sham operated rats and this was mostly shown to be located on hepatocytes by immunohistochemistry. Following treatment with ADRA2a antagonist there was a significant increase in the MAP (p  Conclusion  The results of this study show for the first time that modulating ADRA2a-mediated sympathetic tone and hepatic inflammation with an ADRA2a antagonist significantly improves systemic haemodynamics and reduces portal pressure, whilst also increasing hepatic blood flow. Our data provide the rationale for evaluating an ADRA2a antagonist in the treatment of portal hypertension.
Metastatic Mucinous Ovarian Cancer and Treatment Decisions Based on Histology and Molecular Markers Rather Than the Primary Location
Authors: Angela Jain, Paula D. Ryan, Michael V. Seiden
Journal: Journal of the National Comprehensive Cancer Network (2012)

Approximately 22,000 cases of ovarian cancer occur each year in the United States, and likely fewer than 2000 cases of mucinous ovarian cancers. Although 90% of patients with mucinous ovarian cancer present with stage I disease and have curative surgeries, advanced-stage disease is known to have a poor response to standard platinum- and taxane-based chemotherapy. Despite limited enthusiasm, standard chemotherapy is still recommended for most patients with advanced-stage mucinous malignancies of the ovary. This report presents an unusual case of a woman with HER2-positive metastatic mucinous carcinoma of the ovary treated with chemotherapy regimens typically used for colorectal malignancies, followed by epidermal growth factor receptor–targeted therapies.
T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330
Authors: G S Laszlo, C J Gudgeon, K H Harrington, R B Walter
Journal: Blood Cancer Journal (2015)

Abstract Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpress individual T-cell ligands, we found that expression of the inhibitory ligands, PD-L1 and PD-L2, reduced the cytolytic activity of the BiTE antibody construct targeting CD33, AMG 330; conversely, expression of the activating ligands, CD80 and CD86, augmented the cytotoxic activity of AMG 330. Consistent with these findings, treatment with an activating antibody directed at the co-stimulatory T-cell receptor, CD28, significantly increased AMG 330-induced cytotoxicity in human AML cell lines. Using specimens from 12 patients with newly diagnosed or relapsed/refractory AML, we found that activation of CD28 also increased the activity of AMG 330 in primary human AML cells ( P =0.023). Together, our findings indicate that T-cell ligands and co-receptors modulate the anti-tumor activity of the CD33/CD3 BiTE antibody construct, AMG 330. These findings suggest that such ligands/co-receptors could serve as biomarkers of response and that co-treatment strategies with pharmacological modulators of T-cell receptor signaling could be utilized to further enhance the activity of this targeted therapeutic.
Potent Inhibitory Effect of a New Antiestrogen (RU 16117) on the Growth of 7,12-Dimethylbenz[ a ]anthracene-lnduced Rat Mammary Tumors
Authors: Paul A. Kelly, Jacques Asselin, Marc G. Caron, Fernand Labrie, Jean-Pierre Raynaud
Journal: JNCI Journal of the National Cancer Institute (1977)

At the daily dose of 24 mug for a period of 4 weeks, RU 16117 (11alpha-methoxyethinyl estradiol), a new antiestrogen, led to 65% reduction of the number of already established dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in female Sprague-Dawley rats. Not only the tumor number but also the tumor size was reduced by RU 16117 in a manner similar to that seen after ovariectomy. The absence of an inhibitory effect of doses of 0.1 to 12.5 mug 17beta-estradiol (E2) per day, a dose-range which covers the low estrogenic activity of the RU 16117 doses used, suggested that the inhibitory effect of RU 16117 was not due to its estrogenic activity. Decreased levels of receptors for E2, progesterone, and prolactin were found in the tumors remaining after ovariectomy; treatment with the dose of RU 16117 sufficient to inhibit tumor growth (24 mug) had a similar inhibitory effect on the levels of E2 and prolactin receptors. These data suggested that a reduction of hormone receptor levels in the tumor tissue could be a mechanism by which RU 16117 acts as a potent inhibitor of the growth of DMBA-induced mammary carcinoma.The new antiestrogen RU 16117, at doses of 8 or 24 mcg daily, had been shown to completely prevent the development of rat mammary cancer when given from the day after 7,12-dimethylbenz(a)anthracene (DMBA) administration. This study was undertaken to investigate the effect of this compound on the growth of DMBA-induced tumors which had already developed in Sprague-Dawley rats. The effect was compared with that of castration. Levels of receptors for 17beta-estradiol (E2), progesterone, and prolactin (PRL) were correlated with the response. At about 3 months after DMBA administration animals with palpable tumors were selected. The rats were then treated daily for 4 weeks with .1, .5, 2.5, or 12.5 mcg E2 or with 2, 8, or 24 mcg RU 16117 injected in .1 ml of 1% gelatin in .9% NaCl. Controls were injected with the vehicle alone. For comparison, a group of rats were ovariectomized. After 4 weeks' treatment rats were killed, blood collected, and a cytosol was prepared from tumor tissues. Binding assays and radioimmunoassays were done. 8 and 24 mcg doses of RU 16117 led to 45 and 65% inhibition of tumor number, respectively, and tumor size was markedly reduced. Lower doses had less effect. Ovariectomy had an effect similar to that of 24 mcg RU 16117. E2 doses did not change the number or size of tumors. Decreased levels of receptors for E2, progesterone, and PRL were found in the tumors remaining after ovariectomy. The 24 mcg dose of RU 16117 had a similar effect on levels of E2 and PRL receptors. It was considered likely that RU 16117 exerts its inhibitory activity at both the hypothalamic-pituitary and tumor levels.
Adrenal Suppression following Low-Dose Topical Clobetasol Propionate
Authors: E M Ohman, S Rogers, F O Meenan, T J McKenna
Journal: Journal of the Royal Society of Medicine (1987)

The use of topical steroids is associated with adverse systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis, and application of more than 50 g per week of clobetasol propionate cream has been shown to cause secondary adrenal failure. We describe 4 patients who used clobetasol propionate cream over a prolonged period; 3 patients used less than 50 g per week (7.5, 25 and 30 g per week) and yet all developed secondary adrenal failure for up to 4 months after cessation of therapy. Adrenal insufficiency following prolonged use of clobetasol propionate in moderate dosages may therefore be more common than previously recognized. It is suggested that the metyrapone test, which conveniently examines the entire HPA axis, should be employed in patients receiving long-term topical clobetasol propionate cream and that glucocorticoid supplementation should be given during episodes of stress, such as infections and surgery, for up to 4 months after cessation of therapy.
Serum cardiac troponin T levels during treatment of early-stage breast cancer.
Authors: L Hughes-Davies, D Sacks, J Rescigno, S Howard, J Harris
Journal: Journal of Clinical Oncology (1995)

PURPOSE To measure serum troponin T concentrations in patients with early-stage left breast cancer during breast-conserving radiation therapy. Troponin T has been introduced recently as a sensitive and specific marker for acute myocardial injury. PATIENTS AND METHODS We compared pretreatment and posttreatment serum troponin T values in 50 patients undergoing radiation therapy to the entire left breast following conservative surgery for stage I and II breast cancer. RESULTS No changes in troponin T concentrations were found after 45 to 46 Gy whole-breast irradiation. All women had undetectable or normal troponin T on the first and last day of treatment. There was no evidence of an upward trend during treatment. CONCLUSION Radiation therapy to the left breast does not affect serum cardiac troponin T levels, despite the fact that a portion of the myocardium lies within the high-dose region. This suggests that the acute effects of radiation on the myocardium are minor. Long-term evaluation of these patients is necessary to rule out the possibility of late cardiac morbidity due to accelerated atherosclerosis. This study also suggests that an elevated troponin T level during or shortly after left breast irradiation should not be attributed to treatment.
Assessment of allergic status of severe asthma with a new component resolved method using micro-array technique
Authors: Claire Mailhol, Pol Andre Apoil, Antoine Blancher, Alain Didier
Journal: European Respiratory Journal (2012)

Immunocap® ISAC biochip is a new biologic test using component micro-array technique for detection of specific IgE (sIgE) toward 103 molecular allergens. We have used this test to screen a group of severe asthmatics.

ISAC was performed in 21 consecutive patients with severe asthma (American Thoracic Society criteria). Lung function, exhaled nitric oxide (NO), blood eosinophilia, serum total IgE and skin prick tests for pneumallergens were systematically collected.

Population included 11 women and 10 men (mean age 52 +/-16), median FEV1 72% predicted normal, mean NO 66 +/- 47 ppb. Seventeen (81%) patients had a negative ISAC and 4 (19%) had sIgE for at least one molecular allergen of the test. Three of the 4 positive patients had sIgE toward several allergenic sources (mites, pollens, animal dander). One patient was exclusively sensitized for Fel d1 (cat major allergen). Skin prick tests and ISAC were concordant in all patients. The other parameters, clinical, lung function and biology were not different in patients with positive ISAC compared to patients negative for the test.

ISAC is useful to confirm the non atopic status of a subgroup of severe asthmatics and to identify precisely the sensitization profile of severe allergic asthmatics.
Combined modality therapy for primary CNS lymphoma.
Authors: L M DeAngelis, J Yahalom, H T Thaler, U Kher
Journal: Journal of Clinical Oncology (1992)

PURPOSE Primary CNS lymphoma (PCNSL), formerly rare, is being seen with increased frequency among apparently immunocompetent patients. Conventional treatment has consisted of whole-brain radiotherapy (RT) and corticosteroids, with a median survival of 15 to 18 months and a 3% to 4% 5-year survival. Chemotherapy has been useful in the treatment of recurrent PCNSL. In 1985 we began a treatment protocol using chemotherapy and cranial irradiation for the initial therapy of non-AIDS PCNSL. PATIENTS AND METHODS Thirty-one patients (group A) completed the combined modality regimen. All had placement of an Ommaya reservoir and received pre-RT systemic methotrexate, 1 g/m2, plus six doses of intra-Ommaya methotrexate at 12 mg per dose. A full course of cranial RT (4,000-cGy whole-brain RT plus a 1,440-cGy boost) was followed by two cycles of high-dose cytarabine (ara-C), with each course consisting of two doses of 3 g/m2 ara-C separated by 24 hours and infused over 3 hours. During this period, 16 additional patients (group R) were treated with RT alone, either because patients refused chemotherapy or RT was initiated before our consultation; all would have been eligible to participate in the protocol. Follow-up extended through April 1, 1991. RESULTS Group A had a significantly prolonged time to recurrence (median, 41 months) compared with group R (median, 10 months; P = .003). Although median survival was doubled from 21.7 months for group R to 42.5 months for group A, this was not statistically significant because of small sample size. More importantly, group R patients received systemic chemotherapy for recurrent PCNSL, which improved survival. CONCLUSION The addition of chemotherapy to cranial RT for initial treatment of PCNSL significantly improved disease-free survival and contributed to overall survival; all non-AIDS patients with newly diagnosed PCNSL should be considered for combined modality therapy.
Posttraumatic stress disorder in survivors of a mass shooting
Authors: Carol S. North, Elizabeth M. Smith, Edward L. Spitznagel
Journal: American Journal of Psychiatry (1994)

Posttraumatic stress disorder (PTSD) has been best studied among combat veterans. Less is known about PTSD among civilian populations exposed to traumatic events. A recent mass murder spree by a gunman in a cafeteria in Killeen, Tex., has provided a unique opportunity to study acute-phase civilian responses to a combat type of experience.Approximately 1 month after the disaster, 136 survivors were interviewed with the Diagnostic Interview Schedule/Disaster Supplement.In the acute postdisaster period, 20% of the men and 36% of the women met criteria for PTSD, which was the most prevalent psychiatric disorder. Most subjects who developed PTSD had no history of psychiatric illness. Rates of preexisting PTSD were relatively high and did not predict the presence of PTSD after the disaster. A history of other predisaster psychiatric disorders predicted postdisaster PTSD in women but not in men. One-half of the women and one-fourth of the men with postdisaster PTSD also met criteria for another postdisaster psychiatric diagnosis, especially major depression. Psychopathology was infrequent in subjects without PTSD.Disaster intervention workers may be able to most effectively use limited mental health provider resources in the acute postdisaster period by focusing on screening for acute PTSD, which will identify the majority of cases with psychiatric disorders following this kind of disaster. Survivors who have no history of psychiatric disorder should be screened along with those who do because in the present study, they represented the majority of the PTSD cases. Subjects with a history of major depression and women with preexisting psychopathology may be especially vulnerable to posttraumatic syndromes. Individuals with PTSD should be further examined for additional psychiatric diagnoses that may complicate recovery, especially major depression. PTSD among survivors of civilian combat-like experiences does not appear to present in the same way that it has been described in Vietnam veterans.
Abnormality of RUNX1 signal transduction in psoriatic CD34+ bone marrow cells
Authors: G. Yin, J. Li, Y. Wan, R. Hou, X. Li, J. Zhang, T. Cheng, K. Zhang
Journal: British Journal of Dermatology (2010)

Although it has been shown that T-cell dysfunction in psoriasis correlates with various endogenous and exogenous stimuli, there are also intensive and complicated genetic background effects indicating that intrinsic abnormalities may play a more predominant role such as in haematopoietic cells, the haematopoietic microenvironment and the development of haematopoietic cells into T cells.To reveal the activity of haematopoietic stem cells from patients with psoriasis.Bone marrow CD34+ cells were isolated and expression levels were tested by reverse transcriptase-polymerase chain reaction and Western blotting. The binding site for RUNX1 located between SLC9A3R1 and NAT9 and the apoptotic index of CD34+ cells were also investigated.We found that the expression of RUNX1, SLC9A3R1, HLA-C and PRKCB mRNA and RUNX1 protein was significantly higher in patients with psoriasis than in the controls, and SLC9A3R1 expression showed a significant positive correlation with the Psoriasis Area and Severity Index score. There was no statistical significance for PDCD1 mRNA and PKC-β I protein expression levels between the patients with psoriasis and controls. Mutation of RUNX1 binding sites between SLC9A3R1 and NAT9 was not detected, and the apoptotic index in patients with psoriasis showed no statistical significance compared with the controls.Expression of the critical transcription factor RUNX1, which regulates CD34+ cell development and differentiation, was abnormal, and augmentation of these expression levels might induce dysfunction of marrow haematopoietic stem cells and the haematopoietic microenvironment and be involved in the progression of psoriasis.
Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancers
Authors: Helena A. Yu, Gregory J. Riely
Journal: Journal of the National Comprehensive Cancer Network (2013)

EGFR mutations identify patients who are more likely to respond to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) than cytotoxic chemotherapy. The distinct success of the first-generation EGFR TKIs erlotinib and gefitinib has been accompanied by the observation that acquired resistance to these treatments develops after a median of 1 year of treatment. Newer, second-generation EGFR TKIs have been developed with the intent to delay or overcome acquired resistance by the broader inhibition of kinases (eg, HER2 and vascular endothelial growth factor receptor) and/or altering the interactions with EGFR through irreversibly binding to the kinase domain. This article discusses many of these agents (including afatinib, dacomitinib, XL647, AP26113, and CO-1686) which have the potential for greater efficacy compared with first-generation EGFR TKIs, and may also have clinical activity against other oncogenic mutations within the EGFR family, including HER2.
Importance of immunostimulation for community acquired pneumonia management
Authors: Usman Farkhutdinov, Albert Mirchaidarov, Rafagat Farkhutdinov
Journal: European Respiratory Journal (2014)

Active oxygen forms (AOF) play an important role in pathogenesis of lung diseases. Excessive generation of AOF may be one of the reasons of immunity disorders in patients with community acquired pneumonia (CAP).  The aim was to study the effect of i.v. immunoglobulin immunovenin (IMV) administration to patients with CAP.  Methods:The study included 35 patients with CAP. Generation of AOF in blood of patients was studied by luminol-dependent chemiluminescence (ChL) registration. The patients blood was tested to estimate the level of CD3+, CD4+, CD8+, CD16+, CD20+ lymphocytes, the content of A,G,M immunoglobulins (Ig), circulating immunocomplexes (CIC), γ-IFN and TNFa. 17 patients were treated with standard therapy. 18 patients received combined treatment with IMV.  Results: ChL intensity of blood in patients was higher by 2.8 times. It indicated increased production of AOF by blood cells. The level of CD3+,CD4+,CD8+, CD16+ lymphocytes was lower by 1.6-1.8 times, the content of IgA, IgG was lower by 1.3 times and the level of γ-IFN was lower by 2.0 times. Conversely, the level of CD20+ lymphocytes, IgM, CIC and TNFa were higher by 1.6 times. The use of IMV has decreased generation of AOF in blood, eliminated immune disorders, resulted in positive dynamics of clinical findings. With the use of standard therapy high ChL intensity of blood and impairment of the immune status persisted for a long time, the inflammatory process acquired a protracted pattern.  Conclusion: In patients with CAP immunovenin improved AOF production and the immunity status, increased the treatment efficacy.
Sequence instability and functional inactivation of murine Y chromosomes can occur on a specific genetic background.
Authors: F S Nallaseth
Journal: Molecular Biology and Evolution (1992)

When the Y chromosome from Mus. poschiavinus (YPos) is backcrossed onto the C57BL/6J laboratory strain, testicular dysfunction occurs at high frequencies. When five different multicopy probes from the recombinationally suppressed region of the Y chromosome were used, genomic DNAs from sibling female progeny of C57BL/6J YPos males were found to contain YPos-specific sequences ranging from trace levels to levels consistent with an intact Y chromosome. Females with a high copy number of YPos-specific sequences had a karyotype of XYPos and were sterile. Females with trace levels of these sequences were XX and fertile. Repeated sequences in the testis-determining-region (Sxr) of inactive YPos chromosomes were unstable relative to sequences in non-Sxr regions. In contrast, the YPos chromosome was stable and functioned normally in other inbred laboratory strains such as 129/Sv. The frequency and extent of YPos chromosome instability increased with successive backcrosses from stable (129/Sv) to unstable (C57BL/6J) genetic backgrounds. Traces of YPos-specific sequences were first detected in N2 female offspring of F1 males. Therefore, sequences were deleted from YPos chromosomes in the F1 male germ line and were transmitted to N2 females; inactive YPos chromosomes (XYPos females) were first detected in the N3 generation. The mouse line being derived by backcrossing the YPos chromosome onto C57BL/6J inbred strains ended in the N7 generation, since all XYPos offspring were sterile. Even stable repeated sequences from the non-Sxr regions of their inactive YPos chromosomes were precisely rearranged in these N7 offspring at high frequencies. These data are consistent with hybrid dysgenesis in mammals.