tbuckley/cabot-search huggingface dataset:
Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic Patients
Authors: Wenhui Zhao, Peter T. Katzmarzyk, Ronald Horswell, Yujie Wang, Wei Li, Jolene Johnson, Steven B. Heymsfield, William T. Cefalu, Donna H. Ryan, Gang Hu
Journal: Diabetes Care (2013)

Blood pressure control can reduce the risk of coronary heart disease (CHD) among diabetic patients; however, it is not known whether the lowest risk of CHD is among diabetic patients with the lowest blood pressure level.We performed a prospective cohort study (2000-2009) on diabetic patients including 17,536 African Americans and 12,618 whites. Cox proportional hazards regression models were used to estimate the association of blood pressure with CHD risk.During a mean follow-up of 6.0 years, 7,260 CHD incident cases were identified. The multivariable-adjusted hazard ratios of CHD associated with different levels of systolic/diastolic blood pressure at baseline (<110/65, 110-119/65-69, 120-129/70-80, and 130-139/80-90 mmHg [reference group]; 140-159/90-100; and ≥160/100 mmHg) were 1.73, 1.16, 1.04, 1.00, 1.06, and 1.11 (P trend<0.001), respectively, for African American diabetic patients, and 1.60, 1.27, 1.08, 1.00, 0.95, and 0.99 (P trend<0.001) for white diabetic patients, respectively. A U-shaped association of isolated systolic and diastolic blood pressure at baseline as well as blood pressure during follow-up with CHD risk was observed among both African American and white diabetic patients (all Ptrend<0.001). The U-shaped association was present in the younger age-group (30-49 years), and this U-shaped association changed to an inverse association in the older age-group (≥60 years).Our study suggests that there is a U-shaped or inverse association between blood pressure and the risk of CHD, and aggressive blood pressure control (blood pressure<120/70 mmHg) is associated with an increased risk of CHD among both African American and white patients with diabetes.
Sensitivity of Glioblastomas to Clinically Available MEK Inhibitors Is Defined by Neurofibromin 1 Deficiency
Authors: Wendy L. See, I-Li Tan, Joydeep Mukherjee, Theodore Nicolaides, Russell O. Pieper
Journal: Cancer Research (2012)

Abstract Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor–sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor–sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials. Cancer Res; 72(13); 3350–9. ©2012 AACR.
Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease
Authors: MG Matera, MA Tufano, M Polverino, F Rossi, M Cazzola
Journal: European Respiratory Journal (1997)

We compared the concentrations of dirithromycin and erythromycin at steady state in serum and the intrapulmonary region in patients suffering from acute exacerbation of mild chronic obstructive pulmonary disease. Twenty patients received dirithromycin, 500 mg given orally once daily for five consecutive days. The other 20 patients were treated with erythromycin base, which was administered orally four times daily at a total daily dose of 1000 mg for seven days. All patients were divided into eight groups, with five subjects in each group, according to sampling times (2, 4, 8, and hrs after the last dose) and treatment. After the erythromycin treatment mean serum concentrations were higher than those of dirithromycin treatment mean serum concentrations were higher than those of dirithromycin for upto 4 hours, but they were undetectable 24 hours after the last dose. At all time periods, the concentrations of dirithromycin in bronchial secretion, bronchial mucosa and epithelial lining fluid were greater than the concentration in serum. Concentrations of erythromycin were always lower than those of dirithromycin in the explored pulmonary sites. Our data demonstrated that a five day course of 500 mg of dirithromycin once daily induced higher concentrations and longer persistence in the various potential sites of pulmonary infection than a seven day course of 250 mg of erythromycin every 6 hrs. The shorter duration of therapy and the once daily dosing with good efficacy against common respiratory pathogens would be advantageous for patients and would be likely to promote better patient compliance and acceptability.
Changes in Regional Cerebral Blood Flow With Venlafaxine in the Treatment of Major Depression
Authors: Julia Davies, Keith R. Lloyd, Ivor K. Jones, Anna Barnes, Lyn S. Pilowsky
Journal: American Journal of Psychiatry (2003)

Neuroimaging studies reveal abnormalities of regional cerebral blood flow (rCBF) in major depression. In this study the authors prospectively investigated rCBF and clinical response to venlafaxine, a novel antidepressant.A trial of venlafaxine was performed with seven patients referred with ICD-10 major depression. At entry and 6-week follow-up, the Beck Depression Inventory and Hamilton Depression Rating Scale were administered and rCBF was measured by means of single photon emission computed tomography with [(99m)Tc]hexamethylpropyleneamine oxime. Blood flow changes were explored with statistical parametric mapping.The subjects showed significant improvement after treatment. Statistical parametric mapping analysis revealed increased rCBF bilaterally in the thalamus and decreased rCBF in the left occipital lobe, right cerebellum, and temporal cortex bilaterally.These data confirm limbic cortical rCBF changes associated with effective antidepressant treatment.
Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer
Authors: J R Ross
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To review the evidence for the use of bisphosphonates to reduce skeletalmorbidity in cancer patients with bone metastases. <b>Data sources</b> Electronic databases, scanning reference lists, and consultation withexperts and pharmaceutical companies. Foreign language papers were included. <b>Study selection</b> Included trials were randomised controlled trials of patients withmalignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity. <b>Results</b> 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted ≥ 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P &lt; 0.0001; non-vertebral 0.65, 0.54 to 0.79, P &lt; 0.0001; combined 0.65, 0.55 to 0.78, P &lt; 0.0001), radiotherapy (0.67, 0.57 to 0.79, P &lt; 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates. <b>Conclusions</b> In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.
Subclinical Peripheral Neuropathy Is a Common Finding in Colorectal Cancer Patients Prior to Chemotherapy
Authors: Jessica A. Boyette-Davis, Cathy Eng, Xin S. Wang, Charles S. Cleeland, Gwen Wendelschafer-Crabb, William R. Kennedy, Donald A. Simone, Haijun Zhang, Patrick M. Dougherty
Journal: Clinical Cancer Research (2012)

Of the numerous complications associated with cancer and cancer treatment, peripheral neuropathy is a deleterious and persistent patient complaint commonly attributed to chemotherapy. The present study investigated the occurrence of subclinical peripheral neuropathy in patients with colorectal cancer before the initiation of chemotherapy.Fifty-two patients underwent extensive quantitative sensory testing (QST) before receiving chemotherapy. Changes in multiple functions of primary afferent fibers were assessed and compared with a group of healthy control subjects. Skin temperature, sensorimotor function, sharpness detection, and thermal detection were measured, as was touch detection, using both conventional (von Frey monofilaments) and novel (Bumps detection test) methodology.Patients had subclinical deficits, especially in sensorimotor function, detection of thermal stimuli, and touch detection that were present before the initiation of chemotherapy. The measured impairment in touch sensation was especially pronounced when using the Bumps detection test.The patients with colorectal cancer in this study exhibited deficits in sensory function before undergoing chemotherapy treatment, implicating the disease itself as a contributing factor in chemotherapy-induced peripheral neuropathy. The widespread nature of the observed deficits further indicated that cancer is affecting multiple primary afferent subtypes. Specific to the finding of impaired touch sensation, results from this study highlight the use of newly used methodology, the Bumps detection test, as a sensitive and useful tool in the early detection of peripheral neuropathy.
Neuralgic amyotrophy with bilateral diaphragmatic palsy.
Authors: A Graham, P D Martin, L F Haas
Journal: Thorax (1985)

Neuralgic amyotrophy is a well recognised condition of unknown aetiology with characteristic clinical features.'These include severe pain in the shoulder region, followed within hours or weeks by motor or sensory abnormalities, or both, in the distribution of the cervical roots or nerves.Unilateral disease is more common clinically but if elec- tromyographic (EMG) studies are performed bilateral dis- ease is often found.2 Case reportIn late 1981 a previously well 35 year old man presented with two weeks' orthopnoea and increasing exertional breathlessness such that he became breathless after walk- ing 50 m on the level.Four days before the onset of breath- lessness severe persisting pain in the right shoulder region occurred.This had developed four days after unaccus- tomed physical activity.There was no relevant past history, preceding viral illness, recent vaccination, or systemic upset.When he was examined in the supine position the respiratory rate was 40 per minute but it decreased to 24 per minute after he stood up.Breath sounds at the left lung base were decreased.Sensation was diminished on the lat- eral border of the right upper limb, from shoulder to thumb (corresponding to C5-6 dermatomes).Both triceps, left supinator, and right biceps jerks were diminished.Chest radiography showed collapse and consolidation in the left lower zone.This did not improve with antibiotics and physiotherapy.Bronchoscopy and cervical spine radiographs were normal.Over the next few weeks the dyspnoea remained stable, but the patient became aware of weakness of right shoulder abduction and elbow flexion.During this period paradoxical inspiratory abdominal movement was noted.Diaphragmatic function was evaluated: vital capacity (VC) was 1.0 1 supine and 2.1 1 erect (predicted 4.3 1).The change in transdiaphragmatic pres- sure measured by oesophageal manometry during a max- imum inspiration was zero (predicted >25 mm Hg).Per- cutaneous stimulation of left and right phrenic nerves3 produced no electrical response from the diaphragm.Right sural, lateral popiteal nerve motor, median, ulnar, and radial nerve motor and sensory conduction studies all gave normal results.Neither clinical improvement nor change in the VC supine-erect gradient occurred with aminophylline or oral theophylline despite maintenance of serum con- centrations of the drug within the therapeutic range for six weeks.The right shoulder pain persisted, but was absent three months later.Five months after the onset of symp-
A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma
Authors: Güllü Görgün, Elisabetta Calabrese, Teru Hideshima, Jeffrey Ecsedy, Giulia Perrone, Mala Mani, Hiroshi Ikeda, Giada Bianchi, Yiguo Hu, Diana Cirstea, Loredana Santo, Yu-Tzu Tai, Sabikun Nahar, Mei Zheng, Madhavi Bandi, Ruben D. Carrasco, Noopur Raje, Nikhil Munshi, Paul Richardson, Kenneth C. Anderson
Journal: Blood (2010)
European Development of Clofarabine as Treatment for Older Patients With Acute Myeloid Leukemia Considered Unsuitable for Intensive Chemotherapy
Authors: Alan K. Burnett, Nigel H. Russell, Jonathan Kell, Michael Dennis, Donald Milligan, Stefania Paolini, John Yin, Dominic Culligan, Peter Johnston, John Murphy, Mary-Frances McMullin, Ann Hunter, Emma Das-Gupta, Richard Clark, Robert Carr, Robert K. Hills
Journal: Journal of Clinical Oncology (2010)

Purpose Treatment options for older patients with acute myeloid leukemia (AML) who are not considered suitable for intensive chemotherapy are limited. We assessed the second-generation purine nucleoside analog, clofarabine, in two similar phase II studies in this group of patients. Patients and Methods Two consecutive studies, UWCM-001 and BIOV-121, recruited untreated older patients with AML to receive up to four or six 5-day courses of clofarabine. Patients in UWCM-001 were either older than 70 years or 60 to 69 years of age with poor performance status (WHO &gt; 2) or with cardiac comorbidity. Patients in BIOV-121 were ≥ 65 years of age and deemed unsuitable for intensive chemotherapy. Results A total of 106 patients were treated in the two monotherapy studies. Median age was 71 years (range, 60 to 84 years), 30% had adverse-risk cytogenetics, and 36% had a WHO performance score ≥ 2. Forty-eight percent had a complete response (32% complete remission, 16% complete remission with incomplete peripheral blood count recovery), and 18% died within 30 days. Interestingly, response and overall survival were not inferior in the adverse cytogenetic risk group. The safety profile of clofarabine in these elderly patients with AML who were unsuitable for intensive chemotherapy was manageable and typical of a cytotoxic agent in patients with acute leukemia. Patients had similar prognostic characteristics to matched patients treated with low-dose cytarabine in the United Kingdom AML14 trial, but had significantly superior response and overall survival. Conclusion Clofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics.
Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5
Authors: Hao Shi, Mayank Verma, Lei Zhang, Chen Dong, Richard A. Flavell, Anton M. Bennett
Journal: Journal of Clinical Investigation (2013)

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in dystrophin. The degree of functional deterioration in muscle stem cells determines the severity of DMD. The mitogen-activated protein kinases (MAPKs), which are inactivated by MAPK phosphatases (MKPs), represent a central signaling node in the regulation of muscle stem cell function. Here we show that the dual-specificity protein phosphatase DUSP10/MKP-5 negatively regulates muscle stem cell function in mice. MKP-5 controlled JNK to coordinate muscle stem cell proliferation and p38 MAPK to control differentiation. Genetic loss of Mkp5 in mice improved regenerative myogenesis and dystrophin-deficient mdx mice lacking Mkp5 exhibited an attenuated dystrophic muscle phenotype. Hence, enhanced promyogenic MAPK activity preserved muscle stem cell function even in the absence of dystrophin and ultimately curtailed the pathogenesis associated with DMD. These results identify MKP-5 as an essential negative regulator of the promyogenic actions of the MAPKs and suggest that MKP-5 may serve as a target to promote muscle stem cell function in the treatment of degenerative skeletal muscle diseases.
Role of Ras Isoforms in the Stimulated Proliferation of Human Renal Fibroblasts in Primary Culture
Authors: CLAIRE C. SHARPE, MARK E. C. DOCKRELL, MAZHAR I. NOOR, BRETT P. MONIA, BRUCE M. HENDRY
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The proliferation of renal fibroblasts is implicated in the pathophysiologic processes of renal fibrosis. Many of the growth factors involved in proliferation are known to activate intracellular signaling pathways that converge on Ras monomeric GTPases. Although three ras family genes exist, their functional specificity is not yet known. Using antisense oligonucleotides, a role for Kirsten (Ki)-Ras in the stimulated proliferation of a primate renal fibroblast cell line was previously demonstrated. This study examines Ras in primary cultures of adult human renal fibroblasts. Using reverse transcription-PCR, mRNA for Harvey (Ha)- ras , Ki(4B)- ras , and neural (N)- ras , but not Ki(4A)- ras , were detected. Antisense oligonucleotides targeting Ha-, Ki-, and N- ras mRNA, which were used for liposomal transfection at 100 to 200 nM, were demonstrated to be active and isoform-specific in quantitative reverse transcription-PCR assays. Cellular Ras protein levels, as estimated using isoform-specific monoclonal antibodies, indicated that Ki-Ras was the predominantly expressed isoform (&gt;95% of total Ras protein) under both serum-containing and serum-free conditions, with N- and Ha-Ras being detected in small amounts. Consistent with this finding, the antisense oligonucleotide directed against Ki-Ras reduced total cellular Ras levels by &gt;70%, whereas Ha-Ras, N-Ras, and control oligonucleotides had no significant effect. Proliferation of oligonucleotide-transfected cells was measured using epidermal growth factor (EGF) and serum stimulation. The Ki-Ras oligonucleotide at 100 nM reduced serum-stimulated proliferation by &gt;50% and EGF-stimulated proliferation by 25%, compared with data obtained with the control oligonucleotide ( P &lt; 0.01). The N-Ras oligonucleotide was not active, compared with the control oligonucleotide. The Ha-Ras oligonucleotide was not significantly active at 100 nM but reduced serum-stimulated proliferation by 13% and EGF-stimulated growth by 40% at 200 nM ( P &lt; 0.01). These results demonstrate that Ki-Ras(4B) is the predominantly expressed Ras isoform in human renal fibroblasts in primary culture and is important for both serum- and EGF-stimulated proliferation. Ha-Ras appears to be expressed at low levels but may also play a distinct role in stimulated proliferation.
A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial
Authors: H. Hagman, J.-E. Frödin, Å. Berglund, J. Sundberg, L.W. Vestermark, M. Albertsson, E. Fernebro, A. Johnsson
Journal: Annals of Oncology (2015)
Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis
Authors: Kassandra L. Munger, Lynn I. Levin, Bruce W. Hollis, Noel S. Howard, Alberto Ascherio
Journal: JAMA (2006)

Epidemiological and experimental evidence suggests that high levels of vitamin D, a potent immunomodulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis.To examine whether levels of 25-hydroxyvitamin D are associated with risk of multiple sclerosis.Prospective, nested case-control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy physical disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms.Odds ratios of multiple sclerosis associated with continuous or categorical levels (quantiles or a priori-defined categories) of serum 25-hydroxyvitamin D within each racial/ethnic group.Among whites (148 cases, 296 controls), the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-nmol/L increase in 25-hydroxyvitamin D, 0.59; 95% confidence interval, 0.36-0.97). In categorical analyses using the lowest quintile (<63.3 nmol/L) as the reference, the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P = .02 for trend across quintiles). Only the OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR, 0.38; 95% confidence interval, 0.19-0.75; P = .006). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics (109 cases, 218 controls), who had lower 25-hydroxyvitamin D levels than whites, no significant associations between vitamin D and multiple sclerosis risk were found.The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis.