tbuckley/cabot-search huggingface dataset:
Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer’s disease
Authors: Syed Faraz Kazim, Khalid Iqbal
Journal: Molecular Neurodegeneration (2016)

Alzheimer's disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology. Synaptic loss is a better correlate of cognitive impairment in AD than Aβ or tau pathologies. Thus a highly promising therapeutic strategy for AD is to shift the balance from neurodegeneration to neuroregeneration and synaptic repair. Neurotrophic factors, by virtue of their neurogenic and neurotrophic activities, have potential for the treatment of AD. However, the clinical therapeutic usage of recombinant neurotrophic factors is limited because of the insurmountable hurdles of unfavorable pharmacokinetic properties, poor blood–brain barrier (BBB) permeability, and severe adverse effects. Neurotrophic factor small-molecule mimetics, in this context, represent a potential strategy to overcome these short comings, and have shown promise in preclinical studies. Neurotrophic factor small-molecule mimetics have been the focus of intense research in recent years for AD drug development. Here, we review the relevant literature regarding the therapeutic beneficial effect of neurotrophic factors in AD, and then discuss the recent status of research regarding the neurotrophic factor small-molecule mimetics as therapeutic candidates for AD. Lastly, we summarize the preclinical studies with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021). P021 is a neurogenic and neurotrophic compound which enhances dentate gyrus neurogenesis and memory processes via inhibiting leukemia inhibitory factor (LIF) signaling pathway and increasing brain-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity. P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule. P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.
Phase III study of Ribociclib (LEE011) in combination with Fulvestrant for the treatment of postmenopausal patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) who have received no or only one line of prior endocrine treatment : MONALEESA-3
Authors: P.A. Fasching, Guy Jerusalem, X. Pivot, M. Martin, M. De Laurentiis, K. Blackwell, F.J. Esteva, T. Paquet-Luzy, Z. Tang, K.R. Lorenc, D.J. Slamon
Journal: Clinical Cancer Research (2016)
Antibiotics for acute respiratory tract infections in primary care
Authors: Chris Del Mar
Journal: BMJ (2016)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Antibiotics for acute respiratory tract infections in primary care Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Effects of Mithramycin on Paget's Disease of Bone.
Authors: Will G. Ryan
Journal: Annals of Internal Medicine (1969)

s1 May 1969Effects of Mithramycin on Paget's Disease of Bone.Will G. Ryan, M.D., Theodore B. Schwartz, M.D., F.A.C.P., Charles P. Perlia, M.D.Will G. Ryan, M.D.Search for more papers by this author, Theodore B. Schwartz, M.D., F.A.C.P.Search for more papers by this author, Charles P. Perlia, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-70-5-1103_3 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptMithramycin, an antibiotic related to actinomyein D and used in the treatment of testicular cancer, has been noted to cause hypocalcemia during its administration. This observation and others led us to believe it might be active against Paget's disease. Treatment with this drug (25 µg/kg/day for 10 days) of two patients who had advanced Paget's disease of bone has apparently induced a prolonged beneficial effect. Studies during treatment revealed a change from negative to positive calcium and phosphate balance. Markedly elevated urinary hydroxyproline excretion (>800 mg/24 hr) was dramatically reduced to near-normal levels (50 mg/24 hr), and elevated isotopically determined... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: Will G. Ryan, M.D.; Theodore B. Schwartz, M.D., F.A.C.P.; Charles P. Perlia, M.D.Affiliations: Chicago, Illinois PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byHypercalcemia and Malignant Disease in the Elderly: Magnesium Sulphate Therapy 1 May 1969Volume 70, Issue 5Page: 1103-1104KeywordsAntibioticsBoneCalciumCancer treatmentDrugsExcretionHypocalcemiaPhosphatesTesticular cancer ePublished: 1 December 2008 Issue Published: 1 May 1969 PDF downloadLoading ...
Do advance directives predict receipt of palliative care? An evaluation of a single-institution in the Veterans Administration health care system.
Authors: Manali I. Patel, Jay Bhattacharya, Steven M Asch, James Kahn
Journal: Journal of Clinical Oncology (2014)

203 Background: Cancer-related deaths are often preceded by high utilization of non-beneficial care that may contribute to poor quality of life, adverse symptoms, and high costs. Over the past several years, there is increased attention on palliative care to limit these challenges. Yet, rates of palliative care referral at the end of life remain low, and there are few studies that evaluate why. Our objective is to study whether one potentially important factor among patients with advanced cancer, advance directives, influence referral to palliative care among patients with advanced cancer. Methods: We conducted a retrospective chart review of all patients diagnosed with Stage III and IV cancers and treated at the Veterans Administration Palo Alto Healthcare System (VAPAHCS) in Fiscal Year 2012-2013. Chi-squared tests estimated differences in receipt of palliative care by individual- and clinical-factors. Logistic regression models estimated odds of receipt of palliative care after adjustment for individual and clinical factors). Results: There were 276 patients diagnosed with Stage III and IV cancer during the years of study. No records were excluded from analysis. Median age at diagnosis was 68; thoracic cancers were the most common (31%, p = 0.001). A minority of patients (45%) received palliative care or hospice. Rates of referral to palliative care and hospice were highest among patients with stage IV disease (p=0.003). In logistic regression models adjusted for individual and clinical factors only stage of disease predicted increased odds of palliative care and hospice referral. We could not reject the null hypothesis that presence of an advance directive increased palliative care or hospice treatment. Conclusions: Advance directives may be a useful tool to help patients transition to palliative care and hospice, however, we found no influence of advance directives on the receipt of these services in our VA facility. Future studies should evaluate other factors that predict receipt of high quality end-of-life care for patients with cancer.
Lessons from the Mammography Wars
Authors: Ismail Jatoi, William F Anderson
Journal: New England Journal of Medicine (2010)

To the Editor: Quanstrum and Hayward (Sept. 9 issue)1 propose that medicine should abandon the use of one threshold for determining treatment. They suggest two thresholds: a lower threshold below which the patient should not receive treatment and an upper threshold above which the patient should receive treatment; between the two thresholds, there is a middle region that is subject to the patient’s discretion (no, yes, and maybe). The authors state that there are methods for determining thresholds. These are the same ones that determine the single threshold that has been called into question. Furthermore, what happens when two organizations pick different lower and upper thresholds? The authors suggest that one group should make the final decision, but which panel will be vested with the ultimate authority to determine who will and will not receive treatment? Will the thresholds be determined by those who have to pay for the treatments? Finally, how will the public deal with an approach that is much more complicated than a simple yes or no? In the end, if patients are confused, everyone will suffer.
S61 Analysis of the efficacy and safety of the combination of tiotropium + olodaterol in patients with COPD by previous usage of inhaled corticosteroids: Abstract S61 Table 1
Authors: S Korn, R Buhl, L Grönke, L Korducki, VC Amato, GT Ferguson, R Abrahams
Journal: Thorax (2015)

<h3>Rationale</h3> Tiotropium (T), a long-acting muscarinic antagonist, and olodaterol (O), a long-acting β<sub>2</sub>-agonist (both administered once daily), have been studied as a once-daily combination. Two Phase III studies have demonstrated that T+O significantly improved lung function and symptoms over T and O monotherapy treatments in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).<sup>1</sup> During these studies, patients were allowed to continue existing treatment with inhaled corticosteroids (ICS); this analysis was conducted to determine the effects of study treatment in patients receiving or not receiving ICS as reported at baseline. <h3>Methods</h3> A total of 5162 patients were randomised to treatment with O 5 µg, T 2.5 µg, T 5 µg, T+O 2.5/5 µg or T+O 5/5 µg (Respimat® inhaler) in two 52-week, double-blind, parallel-group studies (NCT01431274 and NCT01431287). Primary efficacy end points were trough forced expiratory volume in 1 s (FEV<sub>1</sub>) response (ie, change from baseline), FEV<sub>1</sub> area under the curve from 0–3 h (AUC<sub>0–3</sub>) response and St George’s Respiratory Questionnaire (SGRQ) total score after 24 weeks. Pooled data are presented for the patient subgroups either using or not using ICS at baseline. <h3>Results</h3> In the overall population, all treatments resulted in clinically relevant improvements in lung function, with significant increases with both T+O doses over the individual components (p &lt; 0.01).<sup>1</sup> These effects on lung function were observed irrespective of whether or not patients had reported concomitant use of ICS at baseline (see Table 1). In the ‘ICS usage’ and ‘no ICS usage’ subgroups, there were no statistically significant differences between the combinations and monotherapy treatments in changes in SGRQ total scores from baseline to Week 24, although SGRQ total scores were improved during this period with T+O. <h3>Conclusions</h3> In patients with COPD, T+O 5/5 µg significantly improved lung function over T 5 µg and O 5 µg monotherapy, irrespective of whether patients had reported ICS use at baseline. <h3>Funding</h3> Boehringer Ingelheim. <h3>Reference</h3> 1 Buhl R, <i>et al</i>.<i> Eur Respir J</i>. 2015;<b>45</b>:969–979
P0987 : A metabolic definition of NASH and its resolution by S-adenosylmethionine in Mat1a KO mice
Authors: J.M. Mato, D. Fernandez-Ramos, I. Martínez-Arranz, R. Mayo, S.C van Liempd, H. Sann, J. Platon, M. Noureddin, P. Aspichueta, C. Alonso, M.L. Martínez-Chantar, S.C. Lu
Journal: Journal of Hepatology (2015)
PD6-2-4: Combined modality treatment for Malignant Pleural Mesothelioma (MPM)
Authors: Kristiaan Nackaerts, Philippe Nafteux, Yolande Lievens, Johan Vansteenkiste, Maurits Demedts, Walter van den Bogaert, Toni Lerut
Journal: Journal of Thoracic Oncology (2007)
Cochrane systematic review and meta-analysis of adjuvant therapy for stage II colon cancer.
Authors: Brandon Matthew Meyers, Humaid Obaid Al-Shamsi, Alvaro Tell Figueredo
Journal: Journal of Clinical Oncology (2015)

3513 Background: Stage III disease is associated with a high risk of relapse after surgery, and adjuvant 5-fluorouracil chemotherapy (5FUc) has been shown to improve overall (OS) and disease-free survival (DFS). Whether adjuvant 5FUc confers a similar benefit in stage II colon cancer is unclear. A previous Cochrane review demonstrated that adjuvant therapy improved DFS, but not OS. An updated systematic review of the literature was undertaken, including all forms of adjuvant therapy. Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE(R), and EMBASE from 1/1987 - 7/2014. We scanned ASCO and ESMO annual meeting proceedings. Randomized controlled trials (RCTs) containing data on stage II colon cancer patients undergoing adjuvant therapy vs. observation were included. Pooled results were expressed as risk ratios (RR), with 95% confidence intervals using a random effects model. Treatments were evaluated using a priori defined categories, and sub-groups, of systemic chemotherapy, regional chemotherapy, and immunotherapy. Results: 25 RCTs met the inclusion criteria. Overall, adjuvant systemic chemotherapy did not improve OS (RR 0.93; 0.81 - 1.07). Sub-group analysis demonstrated that newer 5FUc improved OS (RR 0.85; 0.75 - 0.96) and DFS (RR 0.82; 0.72 - 0.93). Portal vein infusion (PVI), a sub-group of regional chemotherapy, improved OS (RR 0.74; 0.55 - 0.99) but not DFS (RR 0.93; 0.74 - 1.16). Heterogeneity was low for systemic chemotherapy (I2 = 0% for all analyses), but moderate-high for PVI (I2= 41% for OS). Tumour vaccines and edrecolomab immunotherapy resulted in OS similar to observation (RR 0.94; 0.79 - 1.12). The estimated ‘optimal information size’ was only reached for the category of systemic chemotherapy. Conclusions: 5FUc bolus injections demonstrated an improvement in OS and DFS in stage II colon cancer. Although the PVI sub-group showed a statistical benefit to OS, significant heterogeneity, and a failure to reach ‘optimal information size' indicates these results are not robust. Immunotherapy had no demonstrated benefits. Further investigation is required to determine whether subsets of stage II colon cancer patient might derive additional benefit from adjuvant chemotherapy.
Early CD34high cells can be separated into KIThigh cells in which transforming growth factor-beta (TGF-beta) downmodulates c-kit and KITlow cells in which anti-TGF-beta upmodulates c-kit
Authors: P Sansilvestri, AA Cardoso, P Batard, B Panterne, A Hatzfeld, B Lim, JP Levesque, MN Monier, J Hatzfeld
Journal: Blood (1995)
Chlorthalidone Versus Hydrochlorothiazide for the Treatment of Hypertension in Older Adults
Authors: Irfan A. Dhalla, Tara Gomes, Zhan Yao, Jeff Nagge, Navindra Persaud, Chelsea Hellings, Muhammad M. Mamdani, David N. Juurlink
Journal: Annals of Internal Medicine (2013)

Some evidence suggests that chlorthalidone may be superior to hydrochlorothiazide for treating hypertension. This study of elderly patients found little difference between the 2 treatments in a com...
Late solid tumors after treatment for Hodgkin's disease.
Authors: D L Cooper, E Salloum
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.6.2287 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9626237 Late solid tumors after treatment for Hodgkin's disease. D L CooperxD L CooperSearch for articles by this author , E SalloumxE SalloumSearch for articles by this author https://doi.org/10.1200/JCO.1998.16.6.2287 PDF "Late solid tumors after treatment for Hodgkin's disease.." Journal of Clinical Oncology, 16(6), pp. 2287–2288© 1998 by American Society of Clinical Oncology
Phase I/II: The oral isotype-selective HDAC inhibitor MGCD0103 in combination with gemcitabine (Gem) in patients (pts) with refractory solid tumors
Authors: H. Hurwitz, B. Nelson, P. J. O’Dwyer, E. G. Chiorean, N. Gabrail, Z. Li, E. Laille, M. Drouin, M. L. Rothenberg, E. Chan
Journal: Journal of Clinical Oncology (2008)

4625 Background: MGCD0103 is an oral isotype-selective HDAC inhibitor that in pre-clinical studies demonstrated antitumor synergy with gem. The goals of this Phase I/II study (Trial 006) were to determine the maximum tolerated dose (MTD) of MGCD0103 in combination with gem in pts with solid tumors and to evaluate the efficacy of this combination in pts with pancreatic cancer (ca). Methods: Phase I part of this multicenter, open-label, dose-escalation trial studied adults (≥18 yrs) with refractory solid tumors. Phase II part of the trial was limited to gem naive pts with locally advanced or metastatic pancreatic ca. Pts (3–6 per cohort) received MGCD0103 (3x/week) in 28-day cycles at sequential ascending doses using a 3+3 design targeting a dose-limiting toxicity (DLT) rate of <33%. Gem was administered at 1,000 mg/m2, weekly x 3 per cycle. Results: To date, 29 pts have been enrolled (25 in phase I and 4 in phase II) with a median age of 54 (range 34–79) yrs; M:F, 12:17. Dose levels of MGCD0103 evaluated in combination with gem were 50 mg, 75 mg, 90 mg and 110 mg. The MTD and recommended Phase II dose was 90 mg. Among 14 response-evaluable Phase I pts, there were: 2 partial responses (PR) out of 5 pancreatic ca pts and 2 unconfirmed PR in a pt with nasopharyngeal ca and a pt with cutaneous T- cell lymphoma. Two pts were observed with stable disease >2 cycles (1 lung and 1 pancreatic). At the 110 dose level 3 out of the 4 pts had DLTs: 1) fatigue 2) vomiting and abdominal pain 3) thrombocytopenia and anemia. Inhibition of HDAC activity was observed in pts' peripheral blood mononuclear cells. Conclusions: The MTD of MGCD0103 administered in combination with Gem was 90 mg which is comparable to the MTD of single-agent MGCD0103. The combination may have clinical activity in pts with solid tumors in general, and pancreatic ca in particular. Phase II at 90mg MGCD0103 is ongoing in pts with pancreatic ca. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MethylGene, Pharmion MethylGene, Pharmion MethylGene
Evaluation of the radiolabeled human recombinant mini-antibody 131I-L19SIP in patients (pts) with cancer: Results of a phase I/II study.
Authors: P. A. Erba, M. Sollini, R. Boni, A. Claudio Traino, L. Giovannoni, D. Neri, H. D. Menssen, G. Mariani
Journal: Journal of Clinical Oncology (2010)

e13054 Background: The human recombinant antibody L19 selectively binds to the angiogenesis-related and tumor stroma-associated antigen extradomain B (ED-B) fibronectin. 131I-L19SIP is being investigated in a clinical trial in pts with solid cancer to define the maximum tolerated dose for a single application. Methods: All pts had failed multiple therapies and had recurrent and progressive disease at enrollment. A tracer amount of 131I-L19SIP (185 MBq or 5 mCi) was administered for biodistribution and dosimetry evaluation. Whole-body, spot, and SPECT/CT images were acquired at different time points after 131I-L19SIP injection. Three cohorts of pts were scheduled to receive 4107 MBq/m2(111 mCi/m2), 5143 MBq/m2 (139 mCi/m2), and 6167 MBq/m2 (167 mCi/m2) of 131I-L19SIP. Post-therapy planar whole-body and SPECT/CT images were obtained 8–12 days post- administration of the therapeutic dose to confirm specific tumor targeting. Results: 12 pts (7 men, 5 women; mean age 58.1±7.2 yr) were enrolled: NSCLC (4), mesothelioma (3), thymoma (2), head and neck cancer (1), uveal melanoma (1), ovarian adenocarcinoma (1). Based on selective uptake into tumor lesions (lesion/background ratio ≥4) 10 pts were eligible for the therapeutic 131I-L19SIP dose and 7 pts have received treatment (2 pts excluded because of disease progression between the diagnostic and therapeutic phase; 1 pt awaiting therapy). No dose-limiting toxicity observed so far, with the first dose cohort closed and the second actively recruiting. Transient grade 1–4 thrombocytopenia and grade 2–4 lymphocytopenia were observed in all the cases between weeks 1 and 5, with spontaneous recovery; no other systemic or organ-specific toxicity was observed. Sequential [18F]FDG-PET/CT at 2 months after therapy demonstrated significant reduction in size and intensity of [18F]FDG uptake in 1 pt, stable disease in 5 pts, and progressive disease in 1 pt. Conclusions: Preliminary data indicate that ED-B fibronectin is a promising target for the antibody-based delivery of therapeutic agents in pts with solid cancer. A single 131I-L19SIP administration of up to 5143 MBq/m2 is well tolerated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Schering Pharma, Philogen SpA Philogen SpA Bayer Schering Pharma, Philogen SpA Philogen SpA Bayer Schering Pharma
CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP
Authors: Norbert Schmitz, Samira Zeynalova, Maike Nickelsen, Roopesh Kansara, Diego Villa, Laurie H. Sehn, Bertram Glass, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Marita Ziepert, Michael Pfreundschuh, Markus Loeffler, Kerry J. Savage
Journal: Journal of Clinical Oncology (2016)

To develop and validate a risk score for relapse in the CNS in patients with diffuse large B-cell lymphoma (DLBCL).A total of 2,164 patients (18 to 80 years old) with aggressive B-cell lymphomas (80% DLBCL) treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like chemotherapy, who were enrolled in studies from the German High-Grade Non-Hodgkin Lymphoma Study Group and the MabThera International Trial, were analyzed for occurrence of relapse/progression in the CNS. The resulting risk model was validated in an independent data set of 1,597 patients with DLBCL identified in the British Columbia Cancer Agency Lymphoid Cancer database.The risk model consists of the International Prognostic Index (IPI) factors in addition to involvement of kidneys and/or adrenal glands (CNS-IPI). In a three-risk group model, the low-risk group (46% of all patients analyzed), the intermediate-risk group (41%), and the high-risk group (12%) showed 2-year rates of CNS disease of 0.6% (CI, 0% to 1.2%), 3.4% (CI, 2.2% to 4.4%), and 10.2% (CI, 6.3% to 14.1%), respectively. Patients from the validation British Columbia Cancer Agency data set showed similar rates of CNS disease for low-risk (0.8%; CI, 0.0% to 1.6%), intermediate-risk (3.9%; CI, 2.3% to 5.5%), and high-risk (12.0%; CI, 7.9% to 16.1%) groups.The CNS-IPI is a robust, highly reproducible tool that can be used to estimate the risk of CNS relapse/progression in patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Close to 90% of patients with DLBCL belong to the low- and intermediate-risk groups and have a CNS relapse risk < 5%; they may be spared any diagnostic and therapeutic intervention. In contrast, those in the high-risk group have a > 10% risk of CNS relapse and should be considered for CNS-directed investigations and prophylactic interventions.