tbuckley/cabot-search huggingface dataset:
Information Needed to Conduct First-in-Human Oncology Trials in the United States: A View from a Former FDA Medical Reviewer
Authors: Adrian M. Senderowicz
Journal: Clinical Cancer Research (2010)

Any drug product not previously authorized for marketing in the United States requires the submission of an Investigational New Drug application (IND). Although the IND submission is regulated by law (21CFR 312), there are several issues that are not covered in the law or U.S. Food and Drug Administration (FDA) guidances that are important for a successful IND submission. For oncology products, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 guidance (still in draft) is the most relevant. The most difficult issues to solve in an IND are chemistry, manufacturing and control information, and pharmacology and toxicology. In the United States, pivotal toxicological studies are done in two species: one rodent (i.e., rats) and one nonrodent (i.e., dogs). The safe starting dose is based on toxicological findings observed in the most sensitive species. Most first-in-humans studies in oncology include patients with advanced and/or metastatic disease, as serious to severe side effects of anticancer therapies are often less threatening to advanced cancer patients than their disease, and acceptable levels of toxicity are higher. For other indications (adjuvant therapy, chemoprevention, or healthy volunteers), first-in-human studies need to follow ICH M3 guidelines as the risk to benefit ratio in those subjects and/or patients without evidence of tumor is different. The division welcomes submissions before the IND, also known as pre-INDs, particularly for products with "atypical issues."
The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction
Authors: A. Tivesten, E. Bollano, V. Kujacic, K. Caidahl, X.Y. Sun, T. Hedner, A. Hjalmarson, B.-A. Bengtsson, J. Isgaard
Journal: Journal of the American College of Cardiology (1998)
Four years' experience of intravenous colomycin in an adult cystic fibrosis unit
Authors: MJ Ledson, MJ Gallagher, C Cowperthwaite, RP Convery, MJ Walshaw
Journal: European Respiratory Journal (1998)

Nearly all strains of Pseudomonas aeruginosa are sensitive to colomycin sulphomethate, but studies in the 1970s using large doses demonstrated significant renal and neurotoxic side-effects and it is not now commonly used. In this study colomycin (2 megaunits i.v. t.d.s.) has been used extensively in adult cystic fibrosis (CF) patients and its use reviewed to determine its efficacy and safety profile. Fifty-two CF patients (28 male, 24 female; mean age 26 yrs, range 17-39 yrs) received 135 courses (mean two courses each, range 1-7, median length 14 days) of i.v. colomycin (2,414 patient days in total). It was used in combination with one other i.v. antibiotic in 114 courses (85%) and with two others in 18 (13%). In all cases there was significant improvement in spirometry (pretreatment forced expiratory volume in one second (FEV1) % predicted mean 44.4, range 10-101; post-treatment mean 51.3, range 14-108; p&lt;0.0001). No patient had any neurotoxicity but one developed a skin rash and myositis. There was no change in renal function (urea mean pretreatment 4.1 mmol x L(-1) (sD 1.4), mean post-treatment 43 (2.2), p=NS; creatinine mean pretreatment 77.9 mmol x L(-1) (15.3), mean post-treatment 803 (21.6), p=NS). In the authors' experience intravenous colomycin sulphomethate in moderate doses is an effective and safe antipseudomonal antibiotic which is easy to administer. Other clinicians should consider its use in patients with cystic fibrosis.
Exercise is medicine and physicians need to prescribe it!
Authors: R E Sallis
Journal: British Journal of Sports Medicine (2008)

The three major factors that influence our health and longevity are genetics, the environment and behaviour. Because we have very little control over genetic factors, it is critical that we focus on the environmental and behavioural factors we can control to improve health. Whereas great strides have been made in reducing the environmental factors influencing disease, such as through vaccinations, hygiene and safety regulations, little has been done to target behavioural factors such as physical inactivity. It is tragic that so little has been done to address the one major factor affecting our health and longevity that is almost entirely under our control. At this point in time, I believe physical inactivity has become the greatest public health problem of our time and finding a way to get patients more active is absolutely critical to improving health and longevity in the 21st century.

The beneficial relationship between exercise and health has been well known dating back to the 5th century BC, when Hippocrates said that “Eating alone will not keep a man well; he must also take exercise. For food and exercise… work together to produce health”.1 This relationship has been further defined by years of scientific research that shows a clear correlation between physical activity and health status. That is, those individuals who maintain an active and fit way of life live longer and healthier lives than those who do not. This association between physical activity and health persists in virtually every subgroup of the population, regardless of age, sex, race or environmental condition.2

There is clear scientific evidence proving the benefit of regular physical activity on both the primary and secondary prevention of diabetes, hypertension, cancer (particularly breast and colon cancer), depression, osteoporosis and dementia. Furthermore, regular physical activity has been shown to be essential in …
Significant Differential Effects of Alendronate, Estrogen, or Combination Therapy on the Rate of Bone Loss after Discontinuation of Treatment of Postmenopausal Osteoporosis
Authors: Susan L. Greenspan
Journal: Annals of Internal Medicine (2002)

Background: Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly. Objective: To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued. Design: Double-blind, placebo-controlled discontinuation trial. Setting: 18 U.S. centers. Patients: 244 postmenopausal, hysterectomized women 44 to 77 years of age. Intervention: 2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo. Measurements: Bone mineral density and biochemical markers of bone turnover. Results: Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, −5.0% to −4.0%) and a 2.4% decrease at the trochanter (CI, −2.7% to −2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment. Conclusions: Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.
Dietary Fructose Inhibits Intestinal Calcium Absorption and Induces Vitamin D Insufficiency in CKD
Authors: Veronique Douard, Abbas Asgerally, Yves Sabbagh, Shozo Sugiura, Sue A. Shapses, Donatella Casirola, Ronaldo P. Ferraris
Journal: Journal of the American Society of Nephrology (2009)

Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, despite upregulation of 1alpha-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.
Expression and role of RIP140/NRIP1 in chronic lymphocytic leukemia
Authors: Marion Lapierre, Audrey Castet-Nicolas, Delphine Gitenay, Stéphan Jalaguier, Catherine Teyssier, Caroline Bret, Guillaume Cartron, Jérôme Moreaux, Vincent Cavaillès
Journal: Journal of Hematology & Oncology (2015)

RIP140 is a transcriptional coregulator, (also known as NRIP1), which finely tunes the activity of various transcription factors and plays very important physiological roles. Noticeably, the RIP140 gene has been implicated in the control of energy expenditure, behavior, cognition, mammary gland development and intestinal homeostasis. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. During the past years, several papers have reported evidences linking RIP140 to hematologic malignancies. Among them, two recent studies with correlative data suggested that gene expression signatures including RIP140 can predict survival in chronic lymphocytic leukemia (CLL). This review aims to summarize the literature dealing with the expression of RIP140 in CLL and to explore the potential impact of this factor on transcription pathways which play key roles in this pathology.
Genome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for cancer therapy
Authors: Isabella T. Tai, Meiru Dai, David A. Owen, Lan Bo Chen
Journal: Journal of Clinical Investigation (2005)

Overcoming resistance to chemotherapy and radiation therapy has been a difficult but important goal in the effort to cure cancer. We used gene-expression microarrays to identify differentially expressed genes involved in colorectal cancer resistance to chemotherapy and identified secreted protein, acidic and rich in cysteine (osteonectin) (SPARC) as a putative resistance-reversal gene by demonstrating low SPARC expression in refractory human MIP101 colon cancer cells. We were able to achieve restoration of their radiosensitivity and sensitivity to 5-fluorouracil and irinotecan by reexpression of SPARC in tumor xenografts. Moreover, treatment of mice with SPARC conferred increased sensitivity to chemotherapy and led to significant regression of xenografted tumors. The results show that modulation of SPARC expression affects colorectal cancer sensitivity to radiation and chemotherapy. SPARC-based gene or protein therapy may ameliorate the emergence of resistant clones and eradicate existing refractory clones and offers a novel approach to treating cancer.
Lack of correlation of synovial histology with joint damage in rheumatoid arthritis.
Authors: D R Henderson, M I Jayson, C R Tribe
Journal: Annals of the Rheumatic Diseases (1975)

Twenty-two patients with rheumatoid arthritis (RA) involving the knee were studied. The systemic features of the disease were graded and the extent of knee involvement was quantified in terms of the clinical, radiological, and arthroscopic appearances. Adequate synovial biopsies were obtained from 21 patients. In these patients no correlation could be found between the severity of any of the features on histological examination nor between any of these features and the extent of local joint damage, inflammation, or the severity of the systemic disease.
The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications
Authors: Nicholas Mitsiades, Constantine S. Mitsiades, Paul G. Richardson, Vassiliki Poulaki, Yu-Tzu Tai, Dharminder Chauhan, Galinos Fanourakis, Xuesong Gu, Charles Bailey, Marie Joseph, Towia A. Libermann, Robert Schlossman, Nikhil C. Munshi, Teru Hideshima, Kenneth C. Anderson
Journal: Blood (2003)
Testing the Accelerator Hypothesis
Authors: Dana Dabelea, Ralph B. D’Agostino, Elizabeth J. Mayer-Davis, David J. Pettitt, Giuseppina Imperatore, Larry M. Dolan, Catherine Pihoker, Teresa A. Hillier, Santica M. Marcovina, Barbara Linder, Andrea M. Ruggiero, Richard F. Hamman
Journal: Diabetes Care (2006)

OBJECTIVE—The “accelerator hypothesis” predicts that fatness is associated with an earlier age at onset of type 1 diabetes. We tested the hypothesis using data from the SEARCH for Diabetes in Youth study. RESEARCH DESIGN AND METHODS—Subjects were 449 youth aged &amp;lt;20 years at diagnosis who had positive results for diabetes antibodies measured 3–12 months after diagnosis (mean 7.6 months). The relationships between age at diagnosis and fatness were examined using BMI as measured at the SEARCH visit and reported birth weight, both expressed as SD scores (SDSs). RESULTS—Univariately, BMI SDS was not related to age at diagnosis. In multiple linear regression, adjusted for potential confounders, a significant interaction was found between BMI SDS and fasting C-peptide (FCP) on onset age (P &amp;lt; 0.0001). This interaction remained unchanged after additionally controlling for number and titers of diabetes antibodies. An inverse association between BMI and age at diagnosis was present only among subjects with FCP levels below the median (&amp;lt;0.5 ng/ml) (regression coefficient −7.9, P = 0.003). A decrease of 1 SDS in birth weight (639 g) was also associated with an ∼5-month earlier age at diagnosis (P = 0.008), independent of sex, race/ethnicity, current BMI, FCP, and number of diabetes antibodies. CONCLUSIONS—Increasing BMI is associated with younger age at diagnosis of type 1 diabetes only among those U.S. youth with reduced β-cell function. The intrauterine environment may also be an important determinant of age at onset of type 1 diabetes.
Prognostic Markers of Local Relapse in Rectal Cancer: Are We Any Further Forward?
Authors: Patrick G. Johnston
Journal: Journal of Clinical Oncology (2006)

Rectal cancer is a major health problem affecting more than 100,000 patients in the United States and Europe each year. 1 Although it is a highly treatable and often curable disease when localized to the bowel, the prognosis for locally advanced disease varies, with local recurrence rates ranging from 4% to 40%; local recurrenceoftenisthecauseofseveremorbidityandpoormortalityin this disease. 2 Therefore, clinical approaches to prevent early recurrence are one of the major goals in the treatment of rectal cancer. The treatment for patients with clinically resectable, locally invasive rectal cancer has begun to evolve away from more radical surgical approaches such as abdominoperitoneal resection toward attempts at preservation of the anal sphincter and maintenance of anorectal function. 3 In the postoperative setting, there is clear evidence that adjuvant fluorouracil (FU) -based chemotherapy combined with radiotherapy significantly improves disease-free survival and overall survival in patients with rectal cancer. 4 More recently, several groups clearly have shown the benefit in reducing local recurrence rates and toxicity using neoadjuvant preoperative chemotherapy/radiotherapy combinations as opposed to adjuvant treatment. 5,6 Onesuchstudy,theGermanCAO/ARO/AIO-94rectalcancer group trial, randomly assigned 823 patients with T3/4 and/or node-positive rectal cancer to receive preoperative versus postoperative combined-modality therapy consisting of FU on weeks 1 and 5 and 50.4 Gy of concurrent radiation therapy. 4 There was a significant improvement in local recurrence rates (6% in the preoperative group v 13% in the postoperative group) as well as improvements in acute and long-term toxicity. Moreover, in the preoperative group, 39% of the patients initially requiring an abdominoperitoneal resection were able to undergo a sphinctersparing operation, whereas in the postoperatively treated group only 19% were eligible for a sphincter-sparing procedure. Although there was no difference in overall survival between the two groups, the preoperative combined-modality approach significantlyimprovedthechancesofsphincterpreservationandalsoled
Cardiorespiratory Events Recorded on Home Monitors
Authors: Rangasamy Ramanathan, Michael J. Corwin, Carl E. Hunt, George Lister, Larry R. Tinsley, Terry Baird, Jean M. Silvestri, David H. Crowell, David Hufford, Richard J. Martin, Michael R. Neuman, Debra E. Weese-Mayer, L. Adrienne Cupples, Mark Peucker, Marian Willinger, Thomas G. Keens
Journal: JAMA (2001)

Context Home monitors designed to identify cardiorespiratory events are frequently used in infants at increased risk for sudden infant death syndrome (SIDS), but the efficacy of such devices for this use is unproven. Objective To test the hypothesis that preterm infants, siblings of infants who died of SIDS, and infants who have experienced an idiopathic, apparent life-threatening event have a greater risk of cardiorespiratory events than healthy term infants. Design Longitudinal cohort study conducted from May 1994 through February 1998. Setting Five metropolitan medical centers in the United States. Participants A total of 1079 infants (classified as healthy term infants and 6 groups of those at risk for SIDS) who, during the first 6 months after birth, were observed with home cardiorespiratory monitors using respiratory inductance plethysmography to detect apnea and obstructed breathing. Main Outcome Measures Occurrence of cardiorespiratory events that exceeded predefined conventional and extreme thresholds as recorded by the monitors. Results During 718 358 hours of home monitoring, 6993 events exceeding conventional alarm thresholds occurred in 445 infants (41%). Of these, 653 were extreme events in 116 infants (10%), and of those events with apnea, 70% included at least 3 obstructed breaths. The frequency of at least 1 extreme event was similar in term infants in all groups, but preterm infants were at increased risk of extreme events until 43 weeks' postconceptional age. Conclusions In this study, conventional events are quite common, even in healthy term infants. Extreme events were common only in preterm infants, and their timing suggests that they are not likely to be immediate precursors to SIDS. The high frequency of obstructed breathing in study participants would likely preclude detection of many events by conventional techniques. These data should be important for designing future monitors and determining if an infant is likely to be at risk for a cardiorespiratory event.
Expression of Variant Isoforms of the Tyrosine Kinase SYK Determines the Prognosis of Hepatocellular Carcinoma
Authors: Jian Hong, Yunfei Yuan, Jianping Wang, Yadi Liao, Ruhai Zou, Chuanlong Zhu, Binkui Li, Yi Liang, Pinzhu Huang, Zongwei Wang, Wenyu Lin, Yixin Zeng, Jia Le Dai, Raymond T. Chung
Journal: Cancer Research (2014)

The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal-regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L(+)/S(-)) tumors exhibited longer overall survival and time to recurrence than those with SYK(L(-)/S(-)) or SYK(L(+)/S(+)) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention.
EFFICACY OF HIGH AND LOW DOSE ORAL VITAMIN D REPLACEMENT THERAPY IN INFLAMMATORY BOWEL DISEASE (IBD): SINGLE CENTRE COHORT: Table 1
Authors: H J Hiew, M Naghibi, J Wu, J Saunders, F Cummings, T R Smith
Journal: Gut (2013)

<h3>Introduction</h3> IBD patients are at risk of micronutrient deficiency including vitamin D. There is evidence that vitamin D deficiency is associated with poor disease activity. <h3>Aims/Background</h3> To determine the vitamin D status and evaluate the effectiveness of oral vitamin D treatment in a sub-set of IBD patients at a University Hospital. <h3>Method</h3> All IBD patients with serum vitamin D levels measured in 2011 were identified. Vitamin D deficiency was determined as plasma 25-hydroxyvitamin D levels &lt;52 nmol/L. Oral vitamin D treatment was classified as ‘low dose’ when patients prescribed daily 800 units of vitamin D2/D3 and ‘high dose’ when given either 1009000 units once or 509000 units weekly for 6 weeks. Treatment response was assessed within 6 months of treatment. <h3>Results</h3> 205 IBD patients had their plasma vitamin D measured. 95 (46%) were found to be vitamin D deficient with no significant difference in the prevalence between Crohn9s disease (CD) and ulcerative colitis (UC) patients (p=0.449). 32 treatment episodes had follow up measurement. Those who received ‘high dose’ regimen demonstrated a 150% increase in plasma vitamin D compared to a 34% increase in those put on ‘low dose’ regimen (p=0.001). There was no significant difference in treatment response between CD and UC patients (p=0.874) (table&nbsp;1). <h3>Conclusion</h3> Oral vitamin D replacement is an effective treatment for vitamin D deficiency in IBD patients and appears to be dose responsive, in both UC and CD patients. The optimal dose of oral vitamin D supplementation is yet to be determined, but higher doses are significantly more effective.