tbuckley/cabot-search huggingface dataset:
Rational Combinations of Trastuzumab With Chemotherapeutic Drugs Used in the Treatment of Breast Cancer
Authors: M. D. Pegram, G. E. Konecny, C. O'Callaghan, M. Beryt, R. Pietras, D. J. Slamon
Journal: JNCI Journal of the National Cancer Institute (2004)

Trastuzumab, a humanized anti-HER2 antibody, increases the clinical benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress HER2. We characterized interactions between trastuzumab and chemotherapeutic agents commonly used in the treatment of breast cancer.Multiple drug effect/combination index isobologram analysis was used to study the efficacy of chemotherapeutic drug plus trastuzumab combinations tested against four HER2-overexpressing breast cancer cell lines (SK-BR-3, BT-474, MDA-MB-361, and MDA-MB-453). Combination index values were derived from parameters of the median effect plots, and statistical tests were used to determine whether the mean combination index values at multiple effect levels were statistically significantly different from a combination index value of 1.0. Values less than 1.0 indicate synergistic interactions, values greater than 1.0 indicate antagonistic interactions, and values equal to 1.0 indicate additive interactions.At a wide range of clinically achievable drug concentrations, synergistic interactions were observed in all four breast cancer cell lines for trastuzumab plus carboplatin (mean combination index values ranged from 0.32 [P<.001] to 0.53 [P<.001]), 4-hydroxycyclophosphamide (mean combination index values ranged from 0.38 [P<.001] to 0.73 [P =.010]), docetaxel (mean combination index values ranged from 0.30 [P<.001] to 0.62 [P<.001]), and vinorelbine (mean combination index values ranged from 0.24 [P<.001] to 0.78 [P<.034]). Additive interactions were observed in all four cell lines with trastuzumab plus doxorubicin, epirubicin, and paclitaxel. Interactions between trastuzumab and gemcitabine were synergistic at low concentrations of gemcitabine and antagonistic at high concentrations. A synergistic interaction was observed with a three-drug combination of docetaxel plus carboplatin plus trastuzumab in SK-BR-3 cells (mean combination index value = 0.09; P<.001).Consistent synergistic interactions of trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, or vinorelbine across a wide range of clinically relevant concentrations in HER2-overexpressing breast cancer cells indicate that these are rational combinations to test in human clinical trials.
Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts
Authors: D P C de Rooy, J A B van Nies, M C Kapetanovic, H Kristjansdottir, M L E Andersson, K Forslind, D M F M van der Heijde, P K Gregersen, E Lindqvist, T W J Huizinga, G Gröndal, B Svensson, A H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2014)

Smoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not known, since deleterious, protective and neutral observations have been made.To determine the effect of smoking on joint damage progression.Smoking status was assessed in 3158 RA patients included in six cohorts (Leiden Early Arthritis Clinic (Leiden-EAC), BARFOT, Lund, Iceland, NDB and Wichita). In total 9412 radiographs were assessed. Multivariate normal regression and linear regression analyses were performed. Data were summarised in a random effects inverse variance meta-analysis.When comparing radiological progression for RA patients that were never, past and current smokers, smoking was significantly associated with more severe joint damage in Leiden-EAC (p=0.042) and BARFOT (p=0.015) RA patients. No significant associations were found in the other cohorts, though a meta-analysis on the six cohorts showed significantly more severe joint damage progression in smokers (p=0.01). Since smoking predisposes to ACPA, analyses were repeated with ACPA as additional adjustment factor. Then the association was lost (meta-analysis p=0.29).This multi-cohort study indicated that the effect of smoking on joint damage is mediated via ACPA and that smoking is not an independent risk factor for radiological progression in RA.
Hair follicle kinetics in psoriasis
Authors: P. SHAHRAD, R. MARKS
Journal: British Journal of Dermatology (1976)

The rate of epidermal cell production has been measured in the various parts of scalp hair follicles in patients with psoriasis of the scalp, and in controls with normal scalp skin. An in vitro technique was used in which thin tissue slices were exposed to tritiated thymidine enabling cells about to divide to become autoradiographically labelled. Biopsies from thirteen patients with psoriasis and nine controls were examined in this way. The labelling indices of the interfollicular epidermis was 27-5% in the psoriatics and 9-5% in the controls. The upper part of the external root sheath had a labelling index of 28% in the psoriatic group compared to 13-9% for the controls. The labelling indices of the sebaceous glands, matrices and external root sheaths were very similar in the two groups. The findings support the hypothesis for a dermal stimulating influence causing the increased epidermopoiesis seen in psoriasis.
Uremic Thrombocytopathy Is not about Urea
Authors: Gabor E. Linthorst, Hans J. Avis, Marcel Levi
Journal: Journal of the American Society of Nephrology (2010)

<h3>Introduction</h3> Labour pain is among the severest pains primigravidae may experience during pregnancy. Failure to address labour pain and anxiety may lead to abnormal labour. Despite the many complementary non-pharmacological approaches to coping with labour pain, the quality of evidence is low and best approaches are not established. This study protocol describes a proposed investigation of the effects of a combination of breathing exercises, foot reflexology and back massage (BRM) on the labour experiences of primigravidae. <h3>Methods and analysis</h3> This randomised controlled trial will involve an intervention group receiving BRM and standard labour care, and a control group receiving only standard labour care. Primigravidae of 26–34 weeks of gestation without chronic diseases or pregnancy-related complications will be recruited from antenatal clinics. Eligible and consenting patients will be randomly allocated to the intervention or the control group stratified by intramuscular pethidine use. The BRM intervention will be delivered by a trained massage therapist. The primary outcomes of labour pain and anxiety will be measured during and after uterine contractions at baseline (cervical dilatation 6 cm) and post BRM hourly for 2 hours. The secondary outcomes include maternal stress hormone (adrenocorticotropic hormone, cortisol and oxytocin) levels, maternal vital signs (V/S), fetal heart rate, labour duration, Apgar scores and maternal satisfaction. The sample size is estimated based on the between-group difference of 0.6 in anxiety scores, 95% power and 5% α error, which yields a required sample size of 154 (77 in each group) accounting for a 20% attrition rate. The between-group and within-group outcome measures will be examined with mixed-effect regression models, time series analyses and paired t-test or equivalent non-parametric tests, respectively. <h3>Ethics and dissemination</h3> Ethical approval was obtained from the Ethical Committee for Research Involving Human Subjects of the Ministry of Health in the Saudi Arabia (H-02-K-076-0319-109) on 14 April 2019, and from the Ethics Committee for Research Involving Human Subjects (JKEUPM) Universiti Putra Malaysia on 23 October 2019, reference number: JKEUPM-2019–169. Written informed consent will be obtained from all participants. Results from this trial will be presented at regional, national and international conferences and published in indexed journals. <h3>Trial registration number</h3> ISRCTN87414969, registered 3 May 2019.
Gene Silencing of the Mitochondrial Adaptor p66 <sup>Shc</sup> Suppresses Vascular Hyperglycemic Memory in Diabetes
Authors: Francesco Paneni, Pavani Mocharla, Alexander Akhmedov, Sarah Costantino, Elena Osto, Massimo Volpe, Thomas Felix Lüscher, Francesco Cosentino
Journal: Circulation Research (2012)

Rationale: Hyperglycemic memory may explain why intensive glucose control has failed to improve cardiovascular outcomes in patients with diabetes. Indeed, hyperglycemia promotes vascular dysfunction even after glucose normalization. However, the molecular mechanisms of this phenomenon remain to be elucidated. Objective: The present study investigated the role of mitochondrial adaptor p66 Shc in this setting. Methods and Results: In human aortic endothelial cells (HAECs) exposed to high glucose and aortas of diabetic mice, activation of p66 Shc by protein kinase C βII (PKCβII) persisted after returning to normoglycemia. Persistent p66 Shc upregulation and mitochondrial translocation were associated with continued reactive oxygen species (ROS) production, reduced nitric oxide bioavailability, and apoptosis. We show that p66 Shc gene overexpression was epigenetically regulated by promoter CpG hypomethylation and general control nonderepressible 5–induced histone 3 acetylation. Furthermore, p66 Shc -derived ROS production maintained PKCβII upregulation and PKCβII-dependent inhibitory phosphorylation of endothelial nitric oxide synthase at Thr-495, leading to a detrimental vicious cycle despite restoration of normoglycemia. Moreover, p66 Shc activation accounted for the persistent elevation of the advanced glycated end product precursor methylglyoxal. In vitro and in vivo gene silencing of p66 Shc , performed at the time of glucose normalization, blunted ROS production, restored endothelium-dependent vasorelaxation, and attenuated apoptosis by limiting cytochrome c release, caspase 3 activity, and cleavage of poly (ADP-ribose) polymerase. Conclusions: p66 Shc is the key effector driving vascular hyperglycemic memory in diabetes. Our study provides molecular insights for the progression of diabetic vascular complications despite glycemic control and may help to define novel therapeutic targets.
The Impact of Folfirinox Chemotherapy on the Treatment Pattern of Patients with Pancreas Cancer Seen at a Tertiary Referral Centre in the UK
Authors: Chopra Neha, El-Khouly Fatima, Julve Maximilian, Goldstein Robert, Mayer Astrid, Thirlwell Christina, Meyer Tim, Gillmore Roopinder
Journal: Annals of Oncology (2014)
Patients with regular physical activity before onset of rheumatoid arthritis present with milder disease
Authors: Maria E C Sandberg, Sara Wedrén, Lars Klareskog, Ingrid E Lundberg, Christina H Opava, Lars Alfredsson, Saedis Saevarsdottir
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Physical activity has been shown to decrease inflammatory markers; here we investigate the effect on the clinical presentation of rheumatoid arthritis (RA). <h3>Methods</h3> We used the cases from the population-based EIRA study (N=617), followed in the Swedish Rheumatology Quality Register, calculating the odds of having above median level of 28-joint disease activity score (DAS28), physician assessment, pain (visual-analogue scale (VAS), VAS-pain) and activity limitation (health assessment questionnaire (HAQ)) at diagnosis, as an effect of physical activity 5 years before diagnosis, investigated both in categories and dichotomised. <h3>Results</h3> Dose–response relationships were seen for all measures; the higher the level of physical activity, the lower the likelihood of having outcome measure above median. Further, <i>regular</i> physical activity associated with 42% reduced odds of having DAS28 above median (OR=0.58 (95% CI 0.42 to 0.81)). Effects were similar for VAS-pain (OR=0.62 (95%CI 0.45 to 0.86)) and physician assessment (OR=0.67 (95%CI 0.47 to 0.95)) but not for HAQ. Statistically significant effects were also found both for the combined objective components and the combined subjective components of DAS28. <h3>Conclusions</h3> Physically active individuals seem to present with milder RA, which adds to the evidence of beneficial effects of physical activity on inflammatory diseases. The observation should be important for both health professionals and individuals seeking to reduce their risk.
Neostigmine Therapy in Rheumatoid Arthritis
Authors: M. Lucchesi, O. Lucchesi
Journal: Annals of the Rheumatic Diseases (1946)

Aortic valve replacement via open heart surgery, although still the standard treatment for severe symptomatic aortic valve stenosis, is not an option for many patients with severe symptoms, and these patients are often left with suboptimal strategies such as medical management or balloon valvuloplasty. But over the last 5 years improvements in percutaneous approaches to implantation of prosthetic aortic valves have made it a potential therapeutic option for these patients. Technical and device issues are being refined, and percutaneous aortic valve replacement is showing promise in ongoing clinical trials.
Advances in the biological effects of terahertz wave radiation
Authors: Li Zhao, Yan-Hui Hao, Rui-Yun Peng
Journal: Military Medical Research (2014)

The terahertz (THz) band lies between microwave and infrared rays in wavelength and consists of non-ionizing radiation. Both domestic and foreign research institutions, including the army, have attached considerable importance to the research and development of THz technology because this radiation exhibits both photon-like and electron-like properties, which grant it considerable application value and potential. With the rapid development of THz technology and related applications, studies of the biological effects of THz radiation have become a major focus in the field of life sciences. Research in this field has only just begun, both at home and abroad. In this paper, research progress with respect to THz radiation, including its biological effects, mechanisms and methods of protection, will be reviewed.
Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice
Authors: Veerle Compernolle, Koen Brusselmans, Till Acker, Peter Hoet, Marc Tjwa, Heike Beck, Stéphane Plaisance, Yuval Dor, Eli Keshet, Florea Lupu, Benoit Nemery, Mieke Dewerchin, Paul Van Veldhoven, Karl Plate, Lieve Moons, Désiré Collen, Peter Carmeliet
Journal: Nature Medicine (2002)
Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Māori: results from a 28-year follow-up study
Authors: Tien Huey Lim, Edward Gane, Chris Moyes, Barry Borman, Chris Cunningham
Journal: Gut (2014)

<h3>Background</h3> Chronic hepatitis B infection is endemic in New Zealand and has high prevalence in New Zealand Māori. Previous longitudinal studies in populations with predominantly vertically acquired chronic hepatitis B have shown low spontaneous hepatitis B surface-antigen (HBsAg) seroclearance rates: 0.5–1.4% annually (mean age of clearance 48 years). We report the 28-year follow-up data on clinical and serological outcomes in indigenous New Zealand Māori with early horizontally acquired HBV. <h3>Methods</h3> In 1984, community seroprevalence study identified 572 HBsAg-positive individuals, followed for 28 years. Liver-related mortality and hepatocellular carcinoma (HCC) incidence were compared between these 572 HBV carriers and 1140 HBsAg-negative matched case-controls. Surviving HBsAg-positive individuals have been followed up in 2012 with clinical assessment, blood tests and liver transient elastography. Rates of hepatitis B e-antigen (HBeAg) and HBsAg seroconversion were determined. <h3>Results</h3> After total 13 187.4 person-years follow-up, 15 HBsAg-positive patients have developed HCC compared with none of the HBsAg-negative controls (p&lt;0.001). 12 HBsAg-positive patients died from liver-related causes compared with none in the controls (p&lt;0.001). Spontaneous HBeAg-seroconversion occurred in 91% of HBeAg-positive patients. Spontaneous HBsAg loss occurred in 33% overall (annual clearance rate 1.34%), with higher rates at older ages (1.05% in patients&lt;20 years at entry vs 4.3% per annum &gt;40 years at entry, p&lt;0.0001). Median ages of HBeAg loss and HBsAg loss were 23 years (range 6–66 years) and 40 years (range 4–80 years), respectively. <h3>Conclusions</h3> Horizontally transmitted HBV in Maori is similarly associated with increased risk of liver-related mortality and HCC compared with Chinese, although absolute incidence rates are lower. The rates of HBeAg and HBsAg loss are high, and occur at an earlier age than previously reported.
Expression and Gene Amplification of Actinin-4 in Invasive Ductal Carcinoma of the Pancreas
Authors: Satoru Kikuchi, Kazufumi Honda, Hitoshi Tsuda, Nobuyoshi Hiraoka, Issei Imoto, Tomoo Kosuge, Tomoko Umaki, Kaoru Onozato, Miki Shitashige, Umio Yamaguchi, Masaya Ono, Akihiko Tsuchida, Tatsuya Aoki, Johji Inazawa, Setsuo Hirohashi, Tesshi Yamada
Journal: Clinical Cancer Research (2008)

Abstract Purpose: An invasive growth pattern is one of the hallmarks of pancreatic ductal carcinoma. Actinin-4 is an actin-binding protein associated with enhanced cell motility, invasive growth, and lymph node metastasis. Actinin-4 might play an important role in the development and progression of pancreatic cancer. Experimental Design: The expression of actinin-4 was examined immunohistochemically in 173 cases of invasive pancreatic ductal carcinoma. The copy number of the actinin-4 (ACTN4) gene was calculated by fluorescence in situ hybridization. The expression of actinin-4 was stably knocked down by short hairpin RNA, and tumorigenicity was evaluated by orthotopic implantation into mice with severe combined immunodeficiency. Results: The expression level of actinin-4 was increased in 109 (63.0%) of 173 cases of pancreatic cancer. Kaplan-Meier survival curves revealed that patients with increased expression of actinin-4 had a significantly poorer outcome (P = 0.00001, log-rank test). Multivariate analysis by the Cox proportional hazard model showed that high expression of actinin-4 was the most significant independent negative predictor of survival (hazard ratio, 2.33; P = 0.000009). Amplification (defined as more than four copies per interphase nucleus) of the ACTN4 gene was detected in 11 (37.9%) of 29 cases showing increased expression of actinin-4. Knockdown of actinin-4 expression inhibited the destructive growth of cancer cells in the pancreatic parenchyma. Conclusion: Recurrent amplification of chromosome 19q13.1-2 has been reported in pancreatic cancer, but the exact target gene has not been identified. Actinin-4 contributes to the invasive growth of pancreatic ductal carcinoma, and ACTN4 is one of the candidate oncogenes in this chromosome locus.
Explaining Black–White Differences in Receipt of Recommended Colon Cancer Treatment
Authors: Laura-Mae Baldwin, Sharon A. Dobie, Kevin Billingsley, Yong Cai, George E. Wright, Jason A. Dominitz, William Barlow, Joan L. Warren, Stephen H. Taplin
Journal: JNCI Journal of the National Cancer Institute (2005)

Black-white disparities exist in receipt of recommended medical care, including colorectal cancer treatment. This retrospective cohort study examines the degree to which health systems (e.g., physician, hospital) factors explain black-white disparities in colon cancer care.Data from the Surveillance, Epidemiology, and End Results program; Medicare claims; the American Medical Association Masterfile; and hospital surveys were linked to examine chemotherapy receipt after stage III colon cancer resection among 5294 elderly (> or = 66 years of age) black and white Medicare-insured patients. Logistic regression analysis was used to identify factors associated with black-white differences in chemotherapy use. All statistical tests were two-sided.Black and white patients were equally likely to consult with a medical oncologist, but among patients who had such a consultation, black patients were less likely than white patients (59.3% versus 70.4%, difference = 10.9%, 95% confidence interval [CI] = 5.1% to 16.4%, P < .001) to receive chemotherapy. This black-white disparity was highest among patients aged 66-70 years (black patients 65.7%, white patients 86.3%, difference = 20.6%, 95% CI = 10.7% to 30.4%, P < .001) and decreased with age. The disparity among patients aged 66-70 years also remained statistically significant in the regression analysis. Overall, patient, physician, hospital, and environmental factors accounted for approximately 50% of the disparity in chemotherapy receipt among patients aged 66-70 years; surgical length of stay and neighborhood socioeconomic status accounted for approximately 27% of the disparity in this age group, and health systems factors accounted for 12%.Black and white Medicare-insured colon cancer patients have an equal opportunity to learn about adjuvant chemotherapy from a medical oncologist but do not receive chemotherapy equally. Little disparity was explained by health systems; more was explained by illness severity, social support, and environment. Further qualitative research is needed to understand the factors that influence the lower receipt of chemotherapy by black patients.
Targeted Cancer Therapeutics
Authors: William N. Hait
Journal: Cancer Research (2009)

Abstract Targeted therapies can be defined as drugs developed against a specific target based on its important biological function in cancer. In contrast, nontargeted therapies are drugs identified by phenotypic screening of natural products or chemical libraries against established cancer cell lines or preclinical animal models without a priori knowledge of the target. Targeted therapies are designed to selectively inhibit a target that is abnormal in malignant compared with normal tissues; these drugs often affect proximal events in signaling pathways that drive abnormal growth and have relatively low toxicity. In contrast, nontargeted therapies affect proteins or nucleic acids that may or may not be abnormal in malignant compared with normal tissues; these drugs often target the downstream consequences of activated signaling pathways, e.g., DNA synthesis and microtubule assembly, and are toxic. Whereas targeted therapies are highly effective in selected hematopoietic malignancies, most have shown limited efficacy against complex solid tumors. In contrast, nontargeted drugs include some of the most effective yet most toxic drugs in the oncology pharmacopoeia. In the future, advances in genomics, proteomics, biology, biomarkers, chemistry, and protein engineering will coalesce to accelerate the development of increasingly selective and effective targeted therapies. Understanding the target in context will help identify biomarkers predictive of response. Finally, a detailed understanding of the target's structure and function will help anticipate and identify mechanism of drug resistance and help design drugs and combinations of drugs that retain activity. [Cancer Res 2009;69(4):1263–7]