tbuckley/cabot-search huggingface dataset:
Effects of cIAP-1, cIAP-2 and XIAP triple knockdown on prostate cancer cell susceptibility to apoptosis, cell survival and proliferation
Authors: Catherine Gill, Catherine Dowling, Amanda J O'Neill, R William G Watson
Journal: Molecular Cancer (2009)

Abstract Background Manipulating apoptotic resistance represents an important strategy for the treatment of hormone refractory prostate cancer. We hypothesised that the Inhibitor of Apoptosis (IAP) Proteins may be mediating this resistance and knockdown of cIAP-1, cIAP-2 and XIAP would increase sensitivity to apoptosis. Methods cIAP-1, cIAP-2 and XIAP where knocked down either individually or in combination using siRNA in androgen independent prostate cancer PC-3 cells as confirmed by real-time PCR and western blotting. Cells were then treated with TRAIL, Etoposide, or Tunicamycin, and apoptosis assessed by PI DNA staining. Apoptosis was confirmed with Annexin V labelling and measurement of PARP cleavage, and was inhibited using the pan-caspase inhibitor, zVAD.fmk. Clonogenic assays and assessment of ID-1 expression by western blotting were used to measure recovery and proliferation. Results PC-3 are resistant to TRAIL induced apoptosis and have elevated expression of cIAP-1, cIAP-2 and XIAP. Combined knockdown sensitised PC-3 to TRAIL induced apoptosis, but not to Etoposide or Tunicmycin, with corresponding increases in caspase activity and PARP cleavage which was inhibited by ZVAD.fmk. Triple knock down decreased proliferation which was confirmed by decreased ID-1 expression. Conclusion Simultaneous knock down of the IAPs not only sensitised the PC-3 to TRAIL but also inhibited their proliferation rates and clonogenic survival. The inability to alter sensitivity to other triggers of apoptosis suggests that this effect is specific for death receptor pathways and knock down might facilitate immune-surveillance mechanisms to counter cancer progression and, in combination with therapeutic approaches using TRAIL, could represent an important treatment strategy.
NY-ESO-1 Expression and Immunogenicity in Esophageal Cancer
Authors: Shoichiro Fujita, Hisashi Wada, Achim A. Jungbluth, Shuichiro Sato, Tetsuya Nakata, Yuji Noguchi, Yuichiro Doki, Masayoshi Yasui, Yurika Sugita, Takushi Yasuda, Masahiko Yano, Toshiro Ono, Yao-Tseng Chen, Masahiko Higashiyama, Sacha Gnjatic, Lloyd J. Old, Eiichi Nakayama, Morito Monden
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Although NY-ESO-1 was isolated from an esophageal carcinoma patient, its expression in this type of cancer and its immunogenicity in esophageal cancer patients have not yet been fully elucidated. We report here the frequency of NY-ESO-1 mRNA and protein expression in esophageal cancer and the presence of NY-ESO-1-specific immune response in patients. Experimental Design: One hundred twenty three esophageal squamous cell carcinoma specimens were analyzed for the expression of NY-ESO-1 mRNA by conventional and real-time reverse transcription-PCR and the expression of protein by immunohistochemistry and Western blot. Sera and peripheral blood lymphocytes from 51 patients were analyzed for the NY-ESO-1 antibody production by enzyme-linked immunosorbent assay and NY-ESO-1 T cell response by enzyme-linked immunospot assay. Survival analyses were also performed. Results: NY-ESO-1 mRNA was expressed in 41 of 123 (33%) esophageal squamous cell carcinoma specimens, and its expression was found at higher frequency in well-differentiated and moderately differentiated type of cancer. No mRNA copy was detected in any of the adjacent normal tissues. Twenty-one of 24 (87.5%) NY-ESO-1 mRNA-positive tumors were stained positively by immunohistochemistry. Correlation between the level of NY-ESO-1 mRNA expression and the degree of immunohistochemistry positivity was observed. Antibody production was observed in 2 patients with tumors that showed protein expression. Furthermore, a CD8 T-cell response against NY-ESO-1 was observed in 1 of the 2 seropositive patients. Conclusions: The high expression frequency of NY-ESO-1 mRNA and protein indicates NY-ESO-1 as a feasible vaccine target in esophageal cancer.
Risk factors for meningioma in postmenopausal women: results from the Iowa Women's Health Study
Authors: D. R. Johnson, J. E. Olson, R. A. Vierkant, J. E. Hammack, A. H. Wang, A. R. Folsom, B. A. Virnig, J. R. Cerhan
Journal: Neuro-Oncology (2011)

Few risk factors for meningioma, aside from increasing age and female sex, have been identified. We investigated risk factors for meningioma in elderly women, a group with a high incidence. We evaluated associations of demographic, lifestyle, medical history, and anthropometric variables with risk of meningioma in the Iowa Women's Health Study (IWHS), a population-based, prospective cohort study. Risk factors were collected via questionnaires mailed in 1986 and 1992. Incident meningiomas were identified via linkages to Medicare. Cox regression models were used to examine the association of risk factors with meningioma incidence. The mean age at baseline of the 27,791 women in the analysis cohort was 69.3 years (range, 65.0–84.6 years). During 291,021 person-years of follow-up, 125 incident meningiomas were identified. After adjusting for age, lower levels of physical activity (relative risk [RR] , 0.68 for high versus low; P for trend = .039), greater body mass index (BMI; RR, 2.14 for ≥35 versus 19.5–24.9 kg/m2; P for trend = .0019), greater height (RR, 2.04 for >66 versus ≤62 inches; P for trend = .013), and a history of uterine fibroids (RR, 1.72; 95% confidence interval, 1.19, 2.50) were positively associated with meningioma risk in multivariate analysis. BMI at age 18 and 30 years were not associated with risk. There were no associations with menstrual or reproductive factors or other medical history and lifestyle factors. Physical activity, BMI, height, and history of uterine fibroids were associated with meningioma risk in older women. The positive association with height suggests a role for early life influences on risk, whereas the associations with BMI and physical activity suggest a role for modifiable factors later in life.
THE CONDITIONS AND CHARACTERS OF THE IMMUNITY PRODUCED IN THE GUINEA PIG BY INSTILLATION OF HORSE SERUM INTO THE NOSE
Authors: Henry Sewall, Cuthbert Powell
Journal: The Journal of Experimental Medicine (1916)

1. Normal guinea pigs treated by four to six instillations of horse serum into the nose on alternate days become either hypersensitive or refractory to an intravenous injection of 0.38 cc. of serum given 16 days after the last instillation. If the amount of serum in each instillation is as much as 0.2 cc., anaphylactic death is caused by the toxic injection. If the amount of serum in each instillation is reduced to 0.04 cc. the first intravenous injection is without marked effect, and a second injection and subsequent injections of the same amount of antigen are well tolerated in about half the cases. 2. The effect produced by a given dose of serum, whether protective or anaphylactic, depends probably upon the extent of contact with the mucous membrane of the nose. 3. Guinea pigs which, after nasal treatment, have become tolerant to a definite maximum intravenous injection of the antigen appear to increase the degree of their tolerance, at least up to a resting period of more than 4 months. The same does not hold in animals immunized by the peritoneal route. 4. The first two or three instillations of a series probably determine the biologic character, whether of hypersensitiveness or hyposensitiveness, of reaction towards the serum. 5. It is probable that, contrary to the case in parenteral sensitization, hypersensitiveness and protection, respectively, set up by nasal instillations and not followed by parenteral injections, gradually disappear in about 50 to 100 days. 6. We have failed in attempts to eliminate hypersensitiveness, due to subcutaneous injection of serum, by nasal instillations which would protect the normal animal from the development of anaphylaxis. 7. It is suggested that the principles of prophylaxis evolved under these relatively simple conditions should be applied in the study of infectious disease.
Expression and insulin-like growth factor-dependent proteolysis of insulin-like growth factor-binding protein-4 are regulated by cell confluence in vascular smooth muscle cells.
Authors: A Kamyar, C J Pirola, H M Wang, B Sharifi, S Mohan, J S Forrester, J A Fagin
Journal: Circulation Research (1994)

Insulin-like growth factor (IGF)-I is markedly induced after balloon injury in the rat aorta, where it may serve to mediate vascular repair. Because the bioavailability of IGF-I is modulated by IGF-binding proteins (IGFBPs), we examined the regulation of IGFBPs by IGFs in primary cultures of rat aortic smooth muscle cells (SMCs). Serum-deprived SMC-conditioned medium contains IGFBPs of 38 to 45 kD (only in confluent cultures), 30 kD (possibly IGFBP-2), 28 kD, and 24 kD (IGFBP-4), the latter being the most abundant. IGF-I and IGF-II but not insulin evoked a marked decrease of IGFBP-4 as early as 4 hours after treatment. IGFBP-4 mRNA abundance, however, was entirely unaffected by IGF-I for up to 48 hours. IGF-I analogues with high affinity for the IGF-I receptor and weak affinity for IGFBP paradoxically evoked a small increase in IGFBP-4, probably through a general increase in protein synthesis. IGF-I only minimally decreased IGFBP-4 content in medium of sparse cultures, whereas it completely abolished IGFBP-4 content in conditioned medium of superconfluent SMCs. IGF-I also evoked a concentration-dependent increase in the abundance of IGFBP-3 in confluent, but not sparse, SMCs without affecting IGFBP-3 mRNA. Addition of IGF-I to cell-free medium conditioned by confluent, but not by sparsely cultured, SMCs led to rapid degradation of IGFBP-4. Interestingly, IGFBP-4 mRNA was markedly induced in confluent relative to sparsely grown SMCs in an IGF-I independent fashion. Thus, both biosynthesis and IGF-dependent proteolysis of IGFBP-4 are increased in confluent SMCs. Proteolysis was maximal at 37 degrees C and was abrogated by EDTA and by benzamidine. Phenylmethylsulfonyl fluoride and the plasmin inhibitor bdellin had minor inhibitory activity, whereas aprotinin, angiotensin-converting enzyme inhibitors, and N-ethylmaleimide were without effect. The protease does not affect the structure of IGF-I as determined by reverse-phase high-performance liquid chromatography and size-exclusion chromatography of 125I-IGF-I incubated for up to 24 hours with SMC-conditioned medium containing IGFBP-4. In summary, SMCs elaborate a cation-dependent protease in a confluence-dependent fashion, which degrades bound IGFBP-4 and likely releases free structurally intact IGF-I, presumably to interact with the cell surface receptor and/or other IGFBPs.
Dynamic intracoronary thrombosis does not cause significant downstream platelet embolization
Authors: J Barrabés
Journal: Cardiovascular Research (2000)

Objective: A mural intracoronary thrombus is a potential source of platelet emboli that may obstruct downstream microvessels, but this phenomenon has not been characterized. The present study aimed to assess the magnitude of myocardial platelet accumulation downstream of a mural intracoronary thrombus and its modification by a concomitant transient coronary occlusion (OC) or by treatment with aspirin. Methods: The myocardial content of 99mTc-labelled platelets was analyzed in 26 pigs submitted to intimal injury of the left anterior descending coronary artery (LAD) followed by no intervention (n=6), 25-min OC (n=6), or 48-min OC preceded (n=8) or not (n=6) by intravenous administration of 250 mg aspirin. Results: After 2 h, 24 animals had had 12±1 cyclic flow reductions (CFRs) reflecting dynamic LAD thrombosis. Myocardial platelet content in the inferior region was similar among groups. Platelet content in the LAD region was not significantly different to that in the inferior region (129±19%, P=NS) in the no intervention group, but was increased following OC (172±20 and 312±71% after 25- and 48-min OC, respectively, P<0.05). Pre-treatment with aspirin lessened the number of CFRs but did not reduce platelet accumulation in LAD myocardium (483±148%). Myocardial platelet accumulation was not associated with the magnitude of platelet deposition in the LAD nor with the number of CFRs, but was correlated with myeloperoxidase activity (r=0.91, P<0.001) and with infarct size (r=0.52, P=0.05). Histological analysis frequently showed sparse platelets or small platelet or leukoplatelet aggregates in small vessels, but arteriolar emboli were rare. In none of seven additional experiments coronary angiography showed obstructions of arterial branches during CFRs. Conclusion: The magnitude of platelet embolization from a mural intracoronary thrombus into downstream myocardium is small despite the presence of repetitive CFRs.
Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor expression
Authors: A. R. Moschen, C. Molnar, S. Geiger, I. Graziadei, C. F. Ebenbichler, H. Weiss, S. Kaser, A. Kaser, H. Tilg
Journal: Gut (2010)

<h3>Objective</h3> Severe obesity is a chronic inflammatory disease where various cytokines/adipocytokines play a key role. Pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumour necrosis factor-α (TNFα) are produced by human adipose tissue dependent on the degree of obesity. Mouse studies suggest a key role of adipose tissue-derived IL-6 in hepatic insulin resistance via modification of liver suppressor of cytokine signalling 3 (SOCS-3) expression. <h3>Design and methods</h3> We examined the effect of excessive weight loss on systemic levels, subcutaneous and visceral adipose tissue and liver expression of IL-6 and TNFα in 20 severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB). Furthermore, we studied liver expression of SOCS3, an important regulator of insulin resistance, and fat tissue expression of the anti-inflammatory adipocytokine adiponectin and its receptors. Serum and tissue samples were collected before and 6 months after LAGB surgery. <h3>Results</h3> IL-6/TNFα mRNA expression before weight loss were similar in subcutaneous and visceral adipose tissue and much higher compared to hepatic expression. Subcutaneous adipose tissue mRNA expression of both pro-inflammatory cytokines, but especially of IL-6 decreased dramatically after extensive weight loss whereas expression of adiponectin and its receptors increased. Weight loss also led to a significant reduction in liver IL-6 expression, whereas liver TNFα mRNA expression did not change. IL-6 and C-reactive protein serum levels decreased after weight loss whereas TNFα serum levels were below the detection limit before and after surgery. These effects were paralleled by reduced hepatic SOCS3 expression and improved insulin resistance 6 months after LAGB surgery. <h3>Conclusion</h3> Expression of IL-6 and TNFα mRNA is more pronounced in adipose compared to liver tissue in patients with severe obesity. Our results highlight excessive weight loss as a successful anti-inflammatory strategy.
Heart rate variability modifications following exercise training in type 2 diabetic patients with definite cardiac autonomic neuropathy
Authors: M Pagkalos, N Koutlianos, E Kouidi, E Pagkalos, K Mandroukas, A Deligiannis
Journal: British Journal of Sports Medicine (2007)

Cardiac autonomic neuropathy (CAN) as a result of diabetic autonomic neuropathy is positively related to a poor prognosis in diabetic patients. The measurement of heart rate variability (HRV) is a remarkable index of cardiac autonomic dysfunction. The aim of this study was to examine the effects of long-term exercise training on HRV in type 2 diabetic patients with definite CAN.Seventeen type 2 diabetic patients with definite CAN (group A: 56.2 years (SD 5.8)) and 15 without CAN (group B: 55.8 years (SD 5.6)) participated in the study. All patients followed an aerobic exercise training programme three times a week for 6 months; the intensity of the session was 70% to 85% of heart rate reserve. At the beginning and end of the study all subjects underwent graded maximal exercise testing with spiroergometry for the evaluation of their aerobic capacity (VO(2)peak). Moreover, time and frequency domain indices of HRV were obtained from 24 h ambulatory continuous ECG Holter recordings.At baseline, all measurements of HRV indices were significantly reduced in group A compared with group B (p<0.05). Moreover, group A reached a significantly lower VO(2)peak by 14.8% compared with group B (p<0.05). Following the exercise training programme, the SD of all normal-to-normal RR intervals in the entire recording (SDNN) was increased by 18.8% (p<0.05) and 13.8% (p<0.05), the square root of the average of sum of squares of difference between adjacent filtered RR intervals (rMSSd) was increased by 35% (p<0.05) and 15.2% (p<0.05), and the percentage of differences between adjacent filtered RR intervals which was greater than 50 ms for the entire analysis (pNN50) was increased by 400% (p<0.05) and 67.9% (p<0.05) in groups A and B, respectively. Regarding the frequency domain indices, only the high frequency power (HF) was found to be significantly increased in group A. At the end of the exercise training programme, SDNN, rMSSd and low frequency power (LF) were significantly lower (24.3% (p<0.05), 20.3% (p<0.05) and 40% (p<0.05), respectively) in group A compared with group B. Also, VO(2)peak increased by 17.8% (p<0.05) in group A and by 11% (p<0.05) in group B. Furthermore, the exercise training programme had significant effects on blood lipid and glucose levels and glycosylated haemoglobin (HbA(1c)) in both groups.The results indicate that 6-month aerobic exercise training improves the cardiac autonomic nervous system function in type 2 diabetic patients. However, more favourable effects are found in type 2 diabetic patients with definite CAN.
Compelling evidence linking sugary drinks with diabetes
Authors: Edward W Gregg, Ann Albright
Journal: BMJ (2015)

It’s not just about obesity any more

Global estimates of diabetes prevalence continue to outpace previous projections, as virtually all regions of the world continue to see a large and growing prevalence.1 Proposals by diabetes prevention experts for how to change these trends have included both structured programmes for adults at high risk for type 2 diabetes (the “high risk approach”) and environmental and food policies to help change risk factors in the whole population (the “population approach”).1 Promising programmes for those at high risk are already underway and need to be expanded,2 but complementary shifts in underlying risk factors in the broader population are also needed. The list of risk factors for type 2 diabetes is long, with dozens of demographic, behavioural, and genetic risk factors now identified.3 Unfortunately the list of simple, consensus based levers to change population risk factors and substantially influence the risk for type 2 diabetes remains short.

In a linked paper (doi:10.1136/bmj.h3576) Imamura and colleagues present a compelling case that beverages sweetened with sugar should be a major target for policies aimed at reducing the risk of diabetes.4 A systematic review of 17 prospective studies reported three findings; a higher intake of sugar sweetened …
Cell adhesion molecules in oesophageal epithelium.
Authors: H Dobson, M Pignatelli, D Hopwood, C D'Arrigo
Journal: Gut (1994)

The distribution of a range of integrins, E-cadherin, and carcino-embryonic antigen (CEA) like molecules in normal human oesophageal epithelium was investigated immunohistochemically on frozen sections of endoscopic biopsy specimens. The integrin subunits alpha 2, alpha 3, alpha 6, alpha v, beta 1, and beta 5 were expressed throughout the epithelium. There was strong expression of alpha 2, alpha 3, and beta 1 subunits in the basal cell layer and for all the subunits studied the intensity of the staining decreased as cells moved towards the lumen. The heterodimer alpha v beta 3 was expressed weakly in the basal aspect of the basal cell layer only. The CEA molecules were not present in the basal cells layer but there was weak expression in the prickle cell layer and strong positivity in the mature functional layer. E-cadherin was found throughout the epithelium but was weakly expressed at the basal aspect of the basal cells layer and showed strong positivity in the prickle cell and squamous cell layers. These results indicate that cell-cell (E-cadherin, CEA) and cell-matrix (integrins) adhesion molecules show a well defined spatial pattern of immunoreactivity in the oesophageal mucosa and may play a part in the maintenance of normal tissue architecture and physiological homeostasis.
American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer
Authors: Gary H. Lyman, Armando E. Giuliano, Mark R. Somerfield, Al B. Benson, Diane C. Bodurka, Harold J. Burstein, Alistair J. Cochran, Hiram S. Cody, Stephen B. Edge, Sharon Galper, James A. Hayman, Theodore Y. Kim, Cheryl L. Perkins, Donald A. Podoloff, Visa Haran Sivasubramaniam, Roderick R. Turner, Richard Wahl, Donald L. Weaver, Antonio C. Wolff, Eric P. Winer
Journal: Journal of Clinical Oncology (2005)

To develop a guideline for the use of sentinel node biopsy (SNB) in early stage breast cancer.An American Society of Clinical Oncology (ASCO) Expert Panel conducted a systematic review of the literature available through February 2004 on the use of SNB in early-stage breast cancer. The panel developed a guideline for clinicians and patients regarding the appropriate use of a sentinel lymph node identification and sampling procedure from hereon referred to as SNB. The guideline was reviewed by selected experts in the field and the ASCO Health Services Committee and was approved by the ASCO Board of Directors.The literature review identified one published prospective randomized controlled trial in which SNB was compared with axillary lymph node dissection (ALND), four limited meta-analyses, and 69 published single-institution and multicenter trials in which the test performance of SNB was evaluated with respect to the results of ALND (completion axillary dissection). There are currently no data on the effect of SLN biopsy on long-term survival of patients with breast cancer. However, a review of the available evidence demonstrates that, when performed by experienced clinicians, SNB appears to be a safe and acceptably accurate method for identifying early-stage breast cancer without involvement of the axillary lymph nodes.SNB is an appropriate initial alternative to routine staging ALND for patients with early-stage breast cancer with clinically negative axillary nodes. Completion ALND remains standard treatment for patients with axillary metastases identified on SNB. Appropriately identified patients with negative results of SNB, when done under the direction of an experienced surgeon, need not have completion ALND. Isolated cancer cells detected by pathologic examination of the SLN with use of specialized techniques are currently of unknown clinical significance. Although such specialized techniques are often used, they are not a required part of SLN evaluation for breast cancer at this time. Data suggest that SNB is associated with less morbidity than ALND, but the comparative effects of these two approaches on tumor recurrence or patient survival are unknown.