tbuckley/cabot-search huggingface dataset:
rHuKGF optimistically attenuates MAPK/ERK mediated cell proliferation pathway in emphysematous lungs
Authors: Sudhir Kotnala, Harsh Bhardwaj, Amit Tyagi, Jai Prakash Muyal
Journal: European Respiratory Journal (2013)

Background: Pulmonary emphysema is a chronic lung disease marked by destruction of the lung9s gas-exchange structures and is so far irreversible. Recently, it has been reported that an exogenous rHuKGF has the potential to induce alveolar epithelium proliferation in emphysematous lungs of mice. Objective: The aim of the present study was to investigate the effect of rHuKGF in the lungs of emphysema challenged mice on MAPK/ERK mediated signalling pathway that regulates alveolar epithelial cell proliferation. Methods: Three experimental groups [i.e., emphysema (ES), therapy model for emphysema (EK) and control (SS)] were prepared. Subsequently, lungs from each mouse were collected for histopathology & QPCR based analyses. Results: Histopathology-based photomicrographs clearly represented that the rHuKGF treated emphysematous lungs reversed the loss of alveolar septa, which were lost in elastase treated lungs compared to healthy lungs. Upon validation on molecular level, QPCR studies revealed that the mRNA levels of FGF7, FGFR2, Ras, c-Raf, Erk1, Erk2, c-Myc and CREBBP were significantly increased while Elk-1 was notably decreased in therapy group when compared with emphysema group and were well comparable with the control group. Conclusion: Therapeutic supplementation of rHuKGF ameliorates the deregulated MAPK/ERK pathway in emphysema condition, resulting in alveolar epithelium regeneration. Hence rHuKGF may prove to be a potential drug in the treatment of emphysema; however, further elaborated studies are to be conducted.
Comparison of Three Isotopic Assays of Cell-Mediated Cytotoxicity Against Mouse Tumor Cells. II. Sensitivity and Specificity of the Assays and Characteristics of Effector and Sensitizing Cells
Authors: Chou-Chik Ting, Myrthel E. Nunn, Joseph Y. Park, Ronald B. Herberman
Journal: JNCI Journal of the National Cancer Institute (1977)

Three assays of cell-mediated cytotoxicity in mice, involving release of either 51Cr (CRA), 125iododeoxyuridine (IRA), or [3H]proline (PRA), were compared under identical test conditions. Experiments were performed with effector cells from mice immunized with FBL-3 tumor cells, a syngeneic Friend virus-induced leukemia, or with allogeneic normal spleen cells. With established tissue culture cells as targets, similar results were obtained in all three assays. The cytotoxicity produced by cells from in vivo-immunized mice and the induction of cytotoxicity in vitro were T-cell-dependent. When short-term culture target cells were used, the IRA gave a more selective pattern of cytotoxicity than did the other two assays. However, when remaining target cells at the end of the assay were treated with trypsin, higher levels of 125iododeoxyuridine (125IUDR) release were seen, and the results were then comparable to those in the CRA and PRA. These results indicated that 125IUDR, a nuclear label, could only be released after lysis of cells. In contrast, 51Cr or [3H]proline, which are cytoplasmic labels, could also be released from damaged but unlysed cells. These fundamental differences could give different results in these assays, which could determine their correlation with in vivo transplantation immunity.
Comparative Growth of SJL/J Lymphomas in Irradiated and Normal SJL/J Mice: Cell Cycle Distribution and Tumor Cell Quantification2
Authors: Edward F. Rosloniec, Cary Gottlieb, Anthony W. Butch, Stephen P. Lerman
Journal: JNCI Journal of the National Cancer Institute (1985)

Flow cytometric and biological quantification of tumor cells revealed that 650 rad gamma-radiation 1 day prior to iv injection of H-2DS negative lymphoma cells into SJL/J mice resulted in approximately a fourfold (day 3) to twelvefold (day 7) decrease in the tumor cell content of lymphoid organs as compared to that in unirradiated mice. Approximately 1.6-fold less tumor growth was noted (day 7) in 700-rad gamma-irradiated as compared to growth in unirradiated (SJL/J × CBA/J)F1 mice. Distributions of tumor cells in S-phase of the cell cycle were comparable at days 3, 5, and 7 in irradiated and unirradiated mice. Although approximately 26% of splenic tumor cells were in S-phase at days 5 and 7 in irradiated SJL/J mice, splenic tumor cell content did not increase during this time period. The data indicate that early (prior to day 3) and late (after day 5) events are responsible for decreased tumor growth in irradiated mice.
Overnight fasting serum cholesterol, HDL, LDL and triglycerides levels and bone mineral density (BMD) values during adjuvant letrozole in daily practice.
Authors: C. Fontaine, M. Huizing, A. Dewaele, K. Vandenbossche, J. Vermey, D. Schallier, F. Geurs, B. Neyns, J. Degreve
Journal: Journal of Clinical Oncology (2007)

11040 Background: Background: Randomized clinical trials (RCT’s) have demonstrated a superiority of adjuvant aromatase inhibitors (AI’s) over tamoxifen (TAM) in disease free survival and overall survival, immediately postoperatively, in cross-over or extended setting in hormone receptor positive BC. In these studies AI’s were associated with increased bone demineralization and a rise in non- fasting serum cholesterol. Patients and methods: The tolerance for adjuvant letrozole was reviewed in 185 postmenopausal women with hormone receptor-positive early BC including fasting cholesterol levels and bone mineral density (BMD) values. Results: 121 patients (pts) received first-line adjuvant letrozole and 64 pts were crossed over from TAM. Median follow-up was 26 months (15–63 mths). Median age was 56 yrs (37–85y). Median time on letrozole was 23 months. Forty three of the 185 (24 %) of the pts discontinued the adjuvant therapy with letrozole (after a median duration of treatment of 5 months (1wk-30mths)), because of intolerance (83.7%)and PD in 16.3%. Median overnight fasting serum cholesterol levels did not change significantly (p=0.4) over a 2 year observation period from (203.5 mg/dl (131–342)) baseline to (205.5 mg/dl (151–330)) follow-up in 32 evaluable (14/32 pts prior TAM) pts. Median HDL levels rose from 65.5 mg/dl (38–107) to 70 mg/dl (38–103) (p=0.03) after 2 years, but LDL levels did not rise significantly. In the contrary triglycerides levels decreased from 122.5 mg/dl (48–238) to 105 mg/dl (47–285) (p=0.01). Despite the use of upfront biphosphonates in 1/3 of the pts, loss of BMD was significant for the lumbar spine after 2 years in 22 evaluable (8/22 prior TAM) pts (median T-score decreased from minus 0.3 to -0. 45, p=0.02), but not for the hip. Conclusion: Adjuvant letrozole did not significantly increase overnight fasting serum cholesterol levels in daily practice. Adjuvant letrozole was associated with a significant rise in HDL levels and a significant decrease in triglycerides levels after 2 years of therapy. Loss of BMD was observed in concordance with results from RCT’s. Adjuvant letrozole had to be discontinued prematurely because of tolerance issues in 20 % of the pts. No significant financial relationships to disclose.
Effects of riociguat in severe experimental pulmonary hypertension
Authors: Baktybek Kojonazarov, Michaela Lang, Norbert Weissmann, Friedrich Grimminger, Johannes-Peter Stasch, Werner Seeger, Hossein Ardeschir Ghofrani, Ralph Schermuly
Journal: European Respiratory Journal (2011)

Introduction: The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including pulmonary hypertension (PH). Riociguat is the first of a new class of drugs, the sGC stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body's own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects.

Aim: The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on pulmonary vascular remodeling in severe experimental PH.

Methods: Angioproliferative PH was induced in rats by combined exposure to the VEGFr antagonist SU5416 and hypoxia. 21 days thereafter, rats were randomized for treatment with riociguat (10 mg/kg), sildenafil (50 mg/kg) or vehicle for the next 14 days. Echocardiography and invasive hemodynamic measurements were performed. Pulmonary vascular remodeling was assessed by histomorphomety.

Results: In rats with established PH, RVSP was significantly decreased by treatment with riociguat to 73±4 mmHg (p<0.01) and sildenafil to 80±3 mmHg (p<0.05) as compared to placebo (89±3 mmHg). No significant difference in systemic arterial pressure was detected between placebo and treated animals. Both compounds significantly decreased RV hypertrophy and improved RV function by normalization of TAPSE and Tei index, but effects of riociguat were more pronounced. Riociguat significantly reduced the proportion of occluded arteries, increased proportion of opened arteries and decreased neointima/media ratio.

Conclusion: We demonstrated that riociguat effectively suppresses pulmonary vascular remodeling and significantly improves RV function in an experimental model of PH.
The Need for Further Preventive Measures for Occupational Bladder Cancer
Authors: Elisabete Vainio Weiderpass, Harri Vainio
Journal: JAMA Oncology (2015)

In this issue of JAMA Oncology, Cumberbatch and colleagues1 present a systematic review of the evidence of contemporary occupational exposure to carcinogens and bladder cancer incidence and mortality risk, as well as a meta-analysis of risk estimates.
Clinical significance of ventilation heterogeneity in adult patients with asthma
Authors: Sherif Gonem, Sushiladevi Natarajan, Dhananjay Desai, Christopher Newby, Steven Corkill, Amisha Singapuri, Per Gustafsson, Christopher Brightling, Salman Siddiqui
Journal: European Respiratory Journal (2013)

Background   Ventilation heterogeneity (VH), measured using multiple breath inert gas washout (MBW), is thought to be a sensitive marker of small airway obstruction. We hypothesised that VH would be (i) associated with impaired asthma control and reduced quality of life in patients with normal spirometry, (ii) related to asthma severity, and (iii) differentially expressed across clinical asthma phenotypes.   Methods   Ninety-one patients with asthma and eighteen healthy control subjects attended a single visit and underwent clinical and physiological characterisation, including spirometry, body plethysmography, impulse oscillometry, MBW and induced sputum cell count. Patients completed the six-point Asthma Control Questionnaire (ACQ-6), Asthma Quality of Life Questionnaire (AQLQ) and visual analogue scores for cough, breathlessness and wheeze.   Results   Among those with normal spirometry, asthma patients with increased VH manifested increased ACQ-6 scores (1.48 vs 1.03, p  acin(corr)  = 0.211 vs 0.114, p    Conclusions   VH is associated with impaired asthma control and reduced quality of life in patients with normal spirometry. Further studies are required to determine whether VH parameters may be utilised to predict the risk of fixed airflow obstruction in asthma and stratify the response to small particle inhaled and systemic asthma therapies.
Cocaine-Associated Myocardial Infarction
Authors: Judd E Hollander
Journal: Journal of the Royal Society of Medicine (1996)

Myocardial ischaemia and infarction has become a well-recognized sequelae of cocaine use. The possibility of recent cocaine use should be assessed in patients with potential myocardial ischaemia because the treatment of patients with myocardial ischaemia related to cocaine differs from that of patients with myocardial ischaemia unrelated to cocaine. Patients with cocaine-associated myocardial ischaemia should receive initial treatment with benzodiazepines to decrease central adrenergic stimulation. Aspirin should be used to reduce thrombus formation, and nitroglycerin to reverse coronary vasoconstriction. Patients with continued ischaemia can be treated with either low doses of phentolamine, or verapamil. If ischaemia continues after treatment with these agents mechanical reperfusion or thrombolytic therapy should be considered depending upon the clinical circumstances. Patients with myocardial ischaemia secondary to cocaine should not receive treatment with beta adrenergic antagonists as these agents enhance coronary vasoconstriction thereby worsening ischaemia.
Risk of Demyelinating Diseases in the Central Nervous System in Patients With Inflammatory Bowel Disease Treated With Tumor Necrosis Factor Inhibitors
Authors: Nynne Nyboe Andersen, Björn Pasternak, Mikael Andersson, Nete Munk Nielsen, Tine Jess
Journal: JAMA Internal Medicine (2015)

This population-based cohort study suggests a possible 2-fold increased relative risk but a low absolute risk of central demyelinating diseases associated with anti-TNF exposure in patients with irritable bowel syndrome.
Treatment of Waldenstrom’s Macroglobulinemia With Thalidomide
Authors: Meletios A. Dimopoulos, Athanassios Zomas, Nora A. Viniou, Vassiliki Grigoraki, Eleni Galani, Charis Matsouka, Olga Economou, Nikolaos Anagnostopoulos, Panayiotis Panayiotidis
Journal: Journal of Clinical Oncology (2001)

PURPOSE: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom’s macroglobulinemia (WM). PATIENTS AND METHODS: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. RESULTS: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. CONCLUSION: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.
Congenital Heart Disease in Adults: Joseph K. Perloff, MD and John S. Child, MD. 406 pp. Philadelphia, Pa: WB Saunders; 1997. $110.00. ISBN 0-7216-2998-9.
Authors: Ariane Marelli
Journal: Circulation (1998)

“… it is the past that is in front of us; it is the future that lies behind us.” —James Downy



The diagnosis and treatment of congenital heart disease is one of the greatest medical success stories witnessed in the latter half of the 20th century. An estimated 32 000 infants with newly diagnosed congenital cardiovascular lesions are born in the United States each year. First-year mortality rates have dropped 50% since the l960s. Currently, ≈80% of first-year survivors live to reach adulthood. By the year 2000, the estimated prevalence of adults with congenital heart disease in the United States alone is expected to approach 1 million.1 

The result of converging advances in medicine, pediatrics, and cardiovascular surgery, this achievement highlights the impact of a well-crafted multidisciplinary collaborative effort. In that spirit, Perloff and Child have published …
Is farnesyltransferase inhibitor effective as adjuvant or neoadjuvant therapy in orthotopic implantation of hamster pancreatic cancer
Authors: E. M. Lima, C. Y. Morioka, F. P. Costa, S. Saito, C. C. Huang, A. Watanabe
Journal: Journal of Clinical Oncology (2007)

14153 Background: p21-Ras participates in signalling events from membrane tyrosine kinase receptors and a variety of intracellular biochemical pathways to downstream therapeutic strategy.Farnesyl transferase inhibitors (FTI) block the main post-translational plasma membrane and subsequent activation of downstream effector.A curative resection model in Syrian golden hamsters has been developed previously. Aim: To evaluate the effectiveness of FTI as adjuvant or neoadjuvant therapy in hamster experimental pancreatic cancer model. Materials and Methods: HaPT-1,a cell line derived from nitrosamine induced pancreatic cancer was used in these experiments.MTT and MTT agarose were performed.Subcutaneous implanted tumor was resected in exponential phase and tissue was implanted into the pancreas.At Day 7 or Day 14, partial pancreatectomy and splenectomy were performed.Hamsters were divided in 7 groups:1.Positive control (PC,n=5),2.Only FTI (FT,n=5),3.Neodjuvant therapy after surgical resection at Day 7 (NT-R7,n=10),4.Adjuvant therapy after resection at Day 7 (AT-S7,n=10),5.Neoadjuvant therapy after resection at Day 7 (NT-S14,n=10),6.Adjuvant therapy after resection at Day 14 (AT-S14,n=10), and 7.Only surgery at Day 14 (SR,n=5).FTI was administered for one week. In FT and NT groups, drug was administered 3 days after orthotopic implantation.Body weight and side effects were recorded.Fourteen days after the surgical resection, sacrifice was done.Four animals of each group were left to study the survival.After 180 days, living hamsters were sacrificed. Resected and necropsied specimens were sent to histopathological analysis. Results: Successful rate of implantation was 100%.PC,FT,NT-S7,AT-S7,NT-S14,AT-S14,and SR survived in average 82,103,119,134,123,132,and 139 days.Two hamsters of AT-S7 (20%),two of AT-S14 (20%),and two of SR (40%) were alive until 180 days.Intra operatory bleeding was higher in NT groups.Loss of body weight was present in all FTI treated groups. Conclusions: Farnesyltransferase inhibitor showed not to be effective in the curative treatment of orthotopically implanted tumors. It may be used to increase the survival time as adjuvant therapy. No significant financial relationships to disclose.
Combined Inhibitors of Carcinogenesis: Effect on Azoxymethane-Induced Intestinal Cancer in Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Norman D. Nigro, Arthur W. Bull, Paulette S. Wilson, Barbara K. Soullier, Majid A. Alousi
Journal: JNCI Journal of the National Cancer Institute (1982)

Outbred male Sprague-Dawley CD rats were fed a complete semisynthetic diet and were given supplemental low doses (2 ppm) of selenium as H2SeO3 in their drinking water or 50 mg 13-cis-retinoic acid (13-cis-RA) and 2 g beta-sitosterol/kg diet either singly, in combinations of two, or in combinations of all three. Intestinal tumors were induced with eight weekly sc injections of 8 mg azoxymethane (AOM)/kg body weight, and inhibition of tumor formation was determined by tumor counts after 26 weeks. Noncarcinogen controls for each dietary group received eight injections of sterile water. Tumor inhibition was statistically significant in 2 groups of animals: Dietary control animals had a tumor frequency of 5.07 tumors/rat, rats receiving selenium- plus 13-cis-RA supplementation had a tumor frequency of 3.77, and those being given the combination of all three inhibitors had 2.75 tumors/rat. Analysis of fecal steroids from 3 AOM groups (dietary controls, the beta-sitosterol plus 13-cis-RA-supplemented group, and the group receiving all three additives) after 4 months of supplementation showed that the addition of beta-sitosterol to the diet had no effect on acidic or neutral steroids, regardless of the observed difference in tumor frequency. These results suggest that subpharmacologic doses of inhibitors, particularly those that inhibit the process by different mechanisms, while ineffective alone, may provide significant inhibition of tumorigenesis when used in combination.
Decreased Interleukin‐20 Expression in Scleroderma Skin Contributes to Cutaneous Fibrosis
Authors: Hideo Kudo, Masatoshi Jinnin, Yoshihide Asano, Maria Trojanowska, Wakana Nakayama, Kuniko Inoue, Noritoshi Honda, Ikko Kajihara, Katsunari Makino, Satoshi Fukushima, Hironobu Ihn
Journal: Arthritis & Rheumatology (2014)

To clarify the role of interleukin-20 (IL-20) in the regulatory mechanism of extracellular matrix expression and to determine the contribution of IL-20 to the phenotype of systemic sclerosis (SSc).Protein and messenger RNA (mRNA) levels of collagen, Fli-1, IL-20, and IL-20 receptor (IL-20R) were analyzed using polymerase chain reaction (PCR) array, immunoblotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and real-time PCR.PCR array revealed that IL-20 decreased gene expression of α2(I) collagen (0.03-fold), Smad3 (0.02-fold), and endoglin (0.05-fold) in cultured normal dermal fibroblasts. Fli-1 protein expression was induced by IL-20 (~2-fold). The inhibition of collagen by IL-20, the induction of Fli-1 by IL-20, and the reduction of Smad3 and endoglin by IL-20 were also observed in SSc fibroblasts. Serum IL-20 levels were reduced only slightly in SSc patients but were significantly decreased in patients with scleroderma spectrum disorders (the prodromal stage of SSc) compared with those in normal subjects (111.3 pg/ml versus 180.4 pg/ml; P < 0.05). On the other hand, IL-20 mRNA expression in SSc skin was decreased compared with that in normal skin (P < 0.05), which may result in the induction of collagen synthesis in SSc dermal fibroblasts. IL-20R was expressed in normal and SSc fibroblasts. Moreover, IL-20 supplementation by injection into the skin reversed skin fibrosis induced by bleomycin in mice (~0.5-fold).IL-20 reduces basal collagen transcription via Fli-1 induction, while down-regulation of Smad3 and endoglin may cancel the effect of transforming growth factor β in SSc fibroblasts. To confirm the therapeutic value of IL-20 and IL-20R, their function and expression in vivo should be further studied.
Antitumor Activity of Bacterial Infection. I. Effect of &lt;italic&gt;Listeria monocytogenes&lt;/italic&gt; on Growth of a Murine Fibrosarcoma
Authors: Robert C Bast, B. Zbar, G. B. Mackaness, H. J. Rapp
Journal: JNCI Journal of the National Cancer Institute (1975)

Growth of a murine fibrosarcoma was suppressed when tumor cells were mixed with viable Listeria monocytogenes (LM) before intradermal injection into nonimmune syngeneic recepients. Immunization of recipients, by intravenous injection of LM 11 days before transplantation of LM-tumor cell mixtures, eliminated the mortality associated with large doses of LM but did not alter the antitumor activity of the microorganisms. Simultaneous injection of LM and tumor cells at separate sites failed to affect tumor growth, which suggested that contact between LM and tumor cells was required for tumor suppression. Tumor-specific immunity was not observed; mice surviving injection of LM and tumor cells did not resist a second tumor-cell challenge. At least 100 times more heat-killed LM was required to produce the antitumor effect of viable organisms. The ability of heat-killed LM to suppress tumor growth was abolished by treatment of recipients with rabbit antiserum to mouse thymocytes, which was consistent with a requirement for a host response to the LM. Regression of established fibrosarcoma transplants was produced by the intratumor injection of viable LM 5 days after injection of tumor cells. Intratumor injection of BCG at this interval was not effective. The incidence of tumor regression was not increased by multiple intratumor injections of LM, by intratumor injection of a combination of LM and BCG, or by preimmunization with LM prior to the intratumor injection of the same organism.