tbuckley/cabot-search huggingface dataset:
Impact of Comorbidity on Chemotherapy Use and Outcomes in Solid Tumors: A Systematic Review
Authors: Linda Lee, Winson Y. Cheung, Esther Atkinson, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2010)

The treatment of cancer in patients with comorbidities can be challenging as these individuals are underrepresented in clinical trials. We conducted a systematic review to determine the impact of comorbidity on chemotherapy use, delivery, tolerability, and survival among patients with solid tumors to summarize current data and provide recommendations for future research. METHODS All English-language articles from 1990 to 2009 that explored the association between comorbidity and chemotherapy were identified from MEDLINE and EMBASE. Abstracts were reviewed for eligibility, and data on study design and results were extracted.Thirty-four articles met the inclusion criteria. Study populations and design were heterogeneous, and the quality of reporting was generally poor. Most studies were retrospective (76%), were based on a cancer registry linked with administrative data (47%), and assessed the overall effect of comorbidity using an index score (76%). Sixteen studies (47%) investigated chemotherapy use, and 29 (85%) addressed survival. The majority reported decreased chemotherapy use (75%) and inferior survival (69%) for patients with comorbidities compared to those without. In 11 of 14 studies, inferior survival was independent of treatment. Of the few studies that addressed chemotherapy tolerability, seven of 10 reported an increased rate of severe toxicity, and three of five reported increased treatment delays for patients with comorbidity. CONCLUSION Chemotherapy use and outcomes among cancer patients with comorbidities are generally inferior, but the existing evidence is limited and of insufficient quality to determine the relationship between decreased use and inferior survival. Further studies that are prospective and site and stage specific are warranted.
The Fumagillin Analogue TNP-470 Inhibits DNA Synthesis of Vascular Smooth Muscle Cells Stimulated by Platelet-Derived Growth Factor and Insulin-like Growth Factor-I
Authors: Hidenori Koyama, Yoshiki Nishizawa, Masayuki Hosoi, Shinya Fukumoto, Kyoko Kogawa, Atsushi Shioi, Hirotoshi Morii
Journal: Circulation Research (1996)

The effect of an angiogenesis inhibitor, TNP-470, on DNA synthesis and its underlying signaling cascades stimulated by platelet-derived growth factor (PDGF)-BB and insulin-like growth factor (IGF)-I were examined in bovine vascular smooth muscle cells (SMCs). PDGF-BB (10 ng/mL)- and IGF-I (100 ng/mL)-stimulated increase in DNA synthesis was completely abolished by simultaneous treatment with TNP-470 (1.0 ng/mL). TNP-470 had no effects on PDGF receptor autophosphorylation or early signal transduction, such as activation of mitogen-activated protein kinase and immediate early gene expression. PDGF-BB induced an increase in mRNA levels of cyclin D1, cyclin-dependent kinase (cdk) 4, and cdk2, as well as the activity of cdk2, which preceded the G1/S boundary, as estimated by the kinetics of DNA synthesis. The PDGF-BB-induced activation of cdk2 was inhibited by TNP-470, which was correlated with decreased cdk2 mRNA levels. In contrast, TNP-470 had no or less marked effect on cyclin D1 and cdk4 mRNA levels induced by PDGF-BB. TNP-470 also inhibited a much smaller increase in cdk2 mRNA levels and activation stimulated by IGF-I. In conclusion, TNP-470 potently inhibits DNA synthesis of SMCs, and this inhibition is associated with decreased levels of cdk2 mRNA and activity.
Cardiovascular Disease Among American Indians and Alaska Natives
Authors: Thomas K Welty, John L Coulehan
Journal: Diabetes Care (1993)

Objective— To compare the regional differences in cardiovascular disease in AI/AN with the U.S. general population and determine the parity gap and preventable proportion of cardiovascular mortality. Research Design and Methods— Age-adjusted cardiovascular disease mortality rates for 1981–1983 and hospital discharge rates for 1982–1984 reported by the IHS were compared with U.S. data for 1982 and 1983, respectively. Results— Rates of ischemic heart disease and atherosclerosis were found to be generally low among AI/AN although those in the 25- to 44-yr age-group have higher death rates from cardiovascular disease than in the U.S. population. Although the mortality rate from cardiovascular disease in AI/AN is 19% lower than the rate for the general U.S. population, the parity gap in individual regions of the U.S. ranges from favorable to extremely unfavorable. There were also wide variations in the preventable gap theoretically possible by reduction of the three major risk factors. Conclusions— Changing nutrition and exercise patterns and the increasing prevalence of diabetes in many Indian tribes may have adverse effects in the future, possibly increasing the prevalence of heart disease. Regional differences in the prevalence of some major cardiovascular risk factors (smoking, hypertension, hypercholesterolemia, and diabetes) are the probable explanation for these differences in cardiovascular morbidity and mortality rates. Prevention and treatment of these risk factors will have the greatest impact in attempts to reduce cardiovascular disease among AI/AN. In addition, moderation in the use of alcohol, or abstinence, may prevent sudden deaths resulting from acute intoxication.
Anti-oxidized-LDL antibodies as a possible cause of inflammation in unstable angina
Authors: F. Summaria, C. Monaco, G. Niccoll, R. Teoli, G. Bellomo, C. Perugini, M. Bagnati, A. Buffon, G. Liuzzo, G. Caligiuri, F. Croa, A. Masari
Journal: Journal of the American College of Cardiology (1998)
Mammalian Sirtuins: Biological Insights and Disease Relevance
Authors: Marcia C. Haigis, David A. Sinclair
Journal: Annual Review of Pathology Mechanisms of Disease (2010)

Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.
A Polymer-Based Antibody–Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy
Authors: Alexander V. Yurkovetskiy, Mao Yin, Natalya Bodyak, Cheri A. Stevenson, Joshua D. Thomas, Charles E. Hammond, LiuLiang Qin, Bangmin Zhu, Dmitry R. Gumerov, Elena Ter-Ovanesyan, Alex Uttard, Timothy B. Lowinger
Journal: Cancer Research (2015)

Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development.
Intestinal fluid and electrolyte transport in man during reduced circulating blood volume.
Authors: H Sjovall, H Abrahamsson, G Westlander, R Gillberg, S Redfors, M Jodal, O Lundgren
Journal: Gut (1986)

The effect on intestinal net transport of fluid and electrolytes of a reduced circulating blood volume was studied in the human jejunum with the triple lumen perfusion technique. The blood volume was reduced by changing the lower extremities from an elevated to a dependent position combined with a venous stasis. The tilting manoeuvre, probably resembling a bleeding of about 600-800 ml, significantly increased net absorption of fluid, sodium and chloride while glucose transport was unaffected. Concomitantly the blood flow decreased and vascular resistance increased in the forearm vascular bed. The results are consistent with the hypothesis that activity in the sympathetic nervous system initiated from unloading of the cardiopulmonary volume receptors enhances intestinal absorption of fluid and electrolytes. The results also indicate that the human intestines are an important target organ in the compensatory mechanisms activated during hypovolaemia due to - for example, haemorrhage.
Darbepoietin Alfa Potentiates the Efficacy of Radiation Therapy in Mice with Corrected or Uncorrected Anemia
Authors: Shoucheng Ning, Cynthia Hartley, Graham Molineux, Susan J. Knox
Journal: Cancer Research (2005)

Abstract Darbepoietin alfa (DA) is a long-acting analogue of erythropoietin that has reduced receptor affinity and enhanced biological activity. Experiments were done to test the hypothesis that correction of anemia in tumor-bearing mice by DA would increase tumor oxygenation and potentiate radiation-induced tumor cell killing. A SCC VII tumor model was used to study tumor responses to fractionated radiation therapy in mice with anemia induced by total body irradiation. Administration of DA reduced the extent and duration of anemia and associated tumor hypoxia, protected the bone marrow cells and prevented the body weight loss from the effect of irradiation, and facilitated the recovery in a time-dependent manner, with the administration of DA prior to total body irradiation having the greatest protective effect. When combined with fractionated radiation therapy, DA increased the tumor growth delay time from 2.7 days for irradiation alone to 7.3 to 10.6 days for combination of DA and irradiation. The effect of DA on tumor responses to fractionated radiation therapy was observed when DA was given 18 to 4 days before starting radiation therapy, but DA was also equally effective as a radiosensitizer when given only 2 hours before fractionated irradiation therapy. Weekly dosing of DA was as efficacious for the enhancement of radiation responses of tumors as biweekly dosing. Similar results were obtained in the RIF-1 fibrosarcoma tumor model. These studies show that DA can effectively correct anemia in tumor-bearing mice and sensitize tumor cells to fractionated radiation therapy. Importantly, DA was also able to sensitize tumors to radiation in mice with uncorrected anemia and hypoxia, suggesting that the effect of DA on radiosensitivity was independent of these factors and a different mechanism of action may be responsible for this effect.
Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells
Authors: Mirjam Kool, Thomas Soullié, Menno van Nimwegen, Monique A.M. Willart, Femke Muskens, Steffen Jung, Henk C. Hoogsteden, Hamida Hammad, Bart N. Lambrecht
Journal: The Journal of Experimental Medicine (2008)

Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)–resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c+ monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting “nature's adjuvant,” the inflammatory DC through induction of the endogenous danger signal uric acid.
TKANSPORT INTO AND WITHIN THE SKIN
Authors: IRVIN H. BLANK, ROBERT J. SCHEUPLEIN
Journal: British Journal of Dermatology (1969)

SUMMARY.— Developments in recent years permit us to state the following principles which relate to percutaneous absorption. (1) The entire stratum corneum junctions as the rate-limiting barrier in the skin. (2) For penetration from weak solutions, flux is directly proportional to the concentration of the penetrant in the solution which is presented to the cutaneous surface. (3) Flux increases as the solubility of the penetrant in the stratum corneum increases. (4) Flux increases as the mobility of the penetrant in the stratum corneum (diffusion constant) increases. (5) Flux decreases as the thickness of the membrane increases. (6) When concentrations in the presenting solution reach high values, flux is not proportional to concentration. (7) Flux through dermal tissue is much more rapid than flux through the stratum corneum. For substances which penetrate relatively rapidly, the major pathway through the skin for steady-state conditions is directly through the cells of the stratum corneum. For very slowly penetrating substances, shunts, e.g., the appendages, may be the major pathway. Strongly polar and strongly non-polar molecules probably travel via different "molecular" pathways. Even though many of these principles have evolved from in vitro experiments, it is reasonable to expect them to apply equally well to in vivo situations.
Combination chemotherapy with 5-fluorouracil (5FU) and 1,3-bis(2-chloro-ethyl)-1-nitrosourea (BCNU) prolongs survival of rats with dimethylhydrazine-induced colon cancer.
Authors: M Danzi, M R Lewin, J P Cruse, C G Clark
Journal: Gut (1983)

The effects of combination chemotherapy with 5FU and BCNU on rats with dimethylhydrazine (DMH)-induced colon cancer were investigated in a long term survival study. Eighty Wistar rats received a colon cancer producing regimen on DMH (40 mg/kg body weight/week, subcutaneously for 10 weeks). After presenting with signs of colonic disease, all rats underwent diagnostic laparotomy and colonoscopy when colon tumours were located, measured and the extent of the disease staged. Only animals with tumours (n = 63) were included and allocated to one of three tumour stages. Stage A (n = 17), had colonic tumours without serosal involvement; stage B (n = 28) had serosal involvement without metastases; stage C (n = 18) had serosal involvement with lymphadenopathy and/or metastases. Each group was randomly allocated into two subgroups, one serving as untreated controls while the other received 5FU (300 mg/m2 weekly intragastrically for life) together with BCNU (40 mg/m2 intraperitoneally on days 0, 42 and 84). The effect of chemotherapy on tumour growth was measured sequentially by colonoscopy. Animals were observed until death and necropsied, when colon carcinoma was histologically confirmed and survival analysed. The results indicate that chemotherapy significantly prolongs the survival of rats with the least advanced disease (stage A) but was of no benefit to rats with locally advanced or metastatic disease (stages B and C). Furthermore, chemotherapy was associated with a significant reduction in tumour size. Survival analyses in untreated animals show that the laparotomy staging system adopted provides accurate prognostic information. This study shows that DMH-induced colon tumours are chemosensitive, and suggests that this animal model may be a valuable testing ground for new chemotherapeutic agents.
Shifting the Focus: Conflict of Interest and the Food Industry
Authors: Jonathan H. Marks, Donald B. Thompson
Journal: The American Journal of Bioethics (2011)

Click to increase image sizeClick to decrease image size Acknowledgments The authors acknowledge the generous collaborative support of the Edmond J. Safra Center for Ethics at Harvard University (through its Lab on Institutional Corruption) and the Rock Ethics Institute at Penn State for their project on industry-related conflicts of interest in health-related food research and in nutrition education and practice.
Lung function in healthy British women.
Authors: A M Hall, C Heywood, J E Cotes
Journal: Thorax (1979)

The forces expiratory volume, total lung capacity, transfer factor (diffusing capacity), and their subdivisions have been measured in 113 healthy British women aged 27 to 74 years of whom 47 were current smokers and 66 were lifetime non-smokers. The results have been analysed in terms of age, stature, mass, body fat, and smoking. In addition to their relation to stature and to age, the inspiratory capacity was positively correlated with indices of body muscle while the residual volume, expiratory reserve volume, and total lung capacity were inversely correlated with the percentage of body mass that is fat or with mass divided by the square of stature. The inverse correlation between total lung capacity and age was apparently due to the quantity of body fat increasing with age. The transfer factor and its subdivisions were inversely correlated with smoking. In this study the forced expiratory volume and vital capacity were independent of both fat and smoking; the transfer factor was independent of the physiological response to exercise. The results provide reference values for lung function in British women.
The New Weight-Loss Drugs, Lorcaserin and Phentermine-Topiramate
Authors: Steven Woloshin, Lisa M. Schwartz
Journal: JAMA Internal Medicine (2014)

In 2012, the US Food and Drug Administration approved 2 drugs for long-term weight loss: lorcaserin hydrochloride (Belviq; Eisai Inc) and phentermine-topiramate (Qysmia; Vivus Inc). The approvals were based on 1-year trials showing that on top of recommendations to follow a calorie-restricted diet and to increase exercise, patients randomized to either drug lost more weight than patients randomized to placebo (3% [95% CI, 3%-4%] more weight lost with lorcaserin; 7% [95% CI, 3%-4%] more with phentermine /topiramate). The drugs have been associated with serious harms: Both drugs' labels include warnings about memory, attention, or language problems and depression; for lorcaserin, the label also warns of valvular heart disease and euphoria; and for phentermine-topiramate, the label warns of metabolic acidosis, increased heart rate, anxiety, insomnia, and elevated creatinine levels. Neither medication is marketed in Europe because of safety concerns. The manufacturer withdrew its application for lorcaserin in Europe after the European Medicines Agency (EMA) said approval was unlikely, and the EMA rejected phentermine-topiramate. In the United States, the required postmarketing safety trials are behind schedule. Until there is more convincing evidence about the cardiovascular safety of these drugs, physicians and patients should approach them cautiously. Patients who do not lose at least 5% of their body weight within 12 weeks of starting to take either drug should stop taking it, as stated in the prescribing information.
HER3 Is a Determinant for Poor Prognosis in Melanoma
Authors: Markus Reschke, Daniela Mihic-Probst, Edward Htun van der Horst, Pjotr Knyazev, Peter J. Wild, Markus Hutterer, Stefanie Meyer, Reinhard Dummer, Holger Moch, Axel Ullrich
Journal: Clinical Cancer Research (2008)

The epidermal growth factor receptor family member HER3 is overexpressed in diverse human cancers and has been associated with poor prognosis in breast, lung, and ovarian cancer. However, the relevance of HER3 with regard to its prognostic significance and function in primary melanoma and metastases remains largely elusive.HER3 protein expression was analyzed immunohistochemically using tissue microarrays of 130 primary melanoma and 87 metastases relative to established clinical variables. The possibility of an influence of HER3 on melanoma cell proliferation, migration, invasion, and chemotherapy-induced apoptosis was studied in human melanoma cell lines.We show that HER3 is frequently expressed in malignant melanoma and metastases at elevated levels. High HER3 expression may serve as a prognostic marker because it correlates with cell proliferation, tumor progression, and reduced patient survival. Suppression of HER3 expression by RNA interference reduces melanoma cell proliferation, migration, and invasion in vitro. In addition, down-regulation of HER3 synergistically enhances dacarbazine-induced apoptosis. Moreover, monoclonal antibodies specific for the extracellular portion of HER3 efficiently block heregulin-induced proliferation, migration, and invasion of melanoma cell lines.Our results provide novel insights into the role of HER3 in melanoma and point out new possibilities for therapeutic intervention.
Plasma TARC concentration may be a useful marker for asthmatic exacerbation in children
Authors: T.F. Leung, C.K. Wong, C.W.K. Lam, A.M. Li, W.K. Ip, G.W.K. Wong, T.F. Fok
Journal: European Respiratory Journal (2003)

Recent studies suggested the T-helper cells type-2 lymphocytes-specific thymus and activation-regulated chemokine (TARC) and monocyte-derived chemokine (MDC) are useful inflammatory markers for chronic asthma. However, their roles in assessing the severity of acute asthma are unknown. This study aims to evaluate the serial changes of plasma TARC and MDC concentrations in children with asthmatic exacerbation. All patients with acute asthma were treated with systemic corticosteroid for 5 days. The severity of asthmatic exacerbation was classified according to the Global Initiative for Asthma guidelines. Plasma TARC and MDC concentrations were measured by sandwich enzyme immunoassays. Sixteen children, with a median (interquartile range) age of 9.3 (7.2–10.6) yrs and asthmatic exacerbation, were recruited. Plasma TARC concentration showed inverse correlation with peak expiratory flow rate at presentation. The median plasma TARC concentration was highest during the acute attacks (46 pg·mL −1 ) as compared to those levels at 1 (31 pg·mL −1 ) and 5 weeks (32 pg·mL −1 ) following treatment. The median plasma MDC level similarly decreased from 698 pg·mL −1 at baseline to 261 pg·mL −1 1 week later, but increased back to 574 pg·mL −1 at 5 weeks. These results suggest that plasma T-helper cells type-2 lymphocytes-specific thymus and activation-regulated chemokine but not monocyte-derived chemokine concentration may be a useful inflammatory marker in assessing asthmatic exacerbation in children.