tbuckley/cabot-search huggingface dataset:
Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies.
Authors: Anatoly Dritschilo, Chao H Huang, Charles M Rudin, John Marshall, Brian Collins, Jeanne L Dul, Chuanbo Zhang, Deepak Kumar, Prafulla C Gokhale, Ateeq Ahmad, Imran Ahmad, Jeffrey W Sherman, Usha N Kasid
Journal: Clinical Cancer Research (2006)

Abstract PURPOSE: Raf proteins are key elements of growth-related cellular signaling pathways and are a component of cancer cell resistance to radiation therapy. Antisense oligonucleotides to c-raf-1 permit highly selective inhibition of the gene product and offer a strategy for sensitizing cancer cells to radiation therapy. In this dose escalation study, we evaluated the safety of combined liposomal formulation of raf antisense oligonucleotide (LErafAON) and radiation therapy in patients with advanced malignancies. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated with LErafAON in a phase I dose escalation study while receiving palliative radiation therapy. Drug-related and radiation-related toxicities were monitored. Pharmacokinetics and expression of c-raf-1 mRNA and Raf-1 protein were determined in peripheral blood mononuclear cells. RESULTS: Seventeen patients with palliative indications for radiation therapy were entered into this study. Thirteen patients received daily infusions of LErafAON and four received twice-weekly infusions. Radiation therapy was delivered in daily 300-cGy fractions over 2 weeks. Patients tolerated radiation, and no unexpected radiation-related side effects were observed. Drug-related reactions (grade &amp;gt; or =2), such as back pain, chills, dyspnea, fatigue, fever, flushing, and hypertension, were observed in most patients and were managed by premedication with corticosteroids and antihistamines. Serious adverse events occurred in five patients, including acute infusion-related symptoms, abnormal liver function tests, hypoxia, dehydration, diarrhea, esophagitis, fever, hypokalemia, pharyngitis, and tachypnea. Twelve of 17 patients were evaluable for tumor response at completion of treatment; four showed partial response, four showed stable disease, and four experienced progressive disease. The intact rafAON was detected in plasma for 30 minutes to several hours. Six patients with partial response or stable disease were evaluable for c-raf-1 mRNA and/or Raf-1 protein expression. Inhibition of c-raf-1 mRNA was observed in three of five patients. Raf-1 protein was inhibited in four of five patients. CONCLUSION: This is the first report of the combined modality treatment using antisense oligonucleotides with radiation therapy in patients with advanced cancer. A dose of 2.0 mg/kg of LErafAON administered twice weekly is tolerated with premedication and does not enhance radiation toxicity in patients. The observation of dose-dependent, infusion-related reactions has led to further modification of the liposomal composition for use in future clinical trials.
Role of Insulin in Endogenous Hypertriglyceridemia*
Authors: Gerald M. Reaven, Roger L. Lerner, Michael P. Stern, John W. Farquhar
Journal: Journal of Clinical Investigation (1967)

Dietary carbohydrate accentuation of endogenous triglyceride production has been studied in 33 patients. A broad and relatively continuous spectrum of steady-state plasma triglyceride concentrations was produced in 31 of the 33 subjects during 3 wk of a high carbohydrate (fat-free) liquid formula diet. Two patients developed plasma triglyceride concentrations in excess of 2000 mg/100 ml, and these were the only patients we have studied in which carbohydrate induction of hypertriglyceridemia seemed to be associated with a defect in endogenous plasma triglyceride removal mechanisms. In the remaining 31 patients the degree of hypertriglyceridemia was highly correlated with the insulin response elicited by the ingestion of the high carbohydrate formula (P < 0.005). No significant correlation existed between fasting plasma triglyceride concentration and either plasma glucose or free fatty acid concentrations after the high carbohydrate diet, nor was the degree of hypertriglyceridemia related to degree of obesity. It is suggested that hypertriglyceridemia in most subjects results from an increase in hepatic triglyceride secretion rate secondary to exaggerated postprandial increases in plasma insulin concentration.
Safety and efficacy of oral calcitriol (1, 25 -dihydroxyvitamin D<sub>3</sub> ) for the treatment of psoriasis
Authors: A. PEREZ, R. RAAB, T.C. CHEN, A. TURNER, M.F. HOLLCK
Journal: British Journal of Dermatology (1996)

Plaque-type psoriasis has been successfully treated with oral calcitriol, but there has been no long-term follow-up on the safety and efficacy of this calciotropic hormone for psoriasis. In a single centre study, patients were enrolled in an open trial to evaluate the efficacy and safety of oral calcitriol for psoriasis. Of the 85 patients who received oral calcitriol, 88.0% had some improvement in their disease; 26.5, 36.2 and 25.3%, had complete, moderate and slight improvement in their disease, respectively. The mean baseline psoriasis area severity index score (PASI) of 18.4 +/- 1.0 was reduced to 9.7 +/- 0.8 and 7.8 +/- 1.3 after 6 and 24 months on oral calcitriol therapy. Serum calcium concentrations and 24 h urinary calcium excretion increased by 3.9% and 148.2%, respectively, but were not outside the normal range. Bone mineral density remained unchanged. The clearance of creatinine decreased by 13.4% from baseline during the first 6 months of treatment, and thereafter, remained unchanged after 3 years of follow up. An evaluation of creatinine, inulin and paraaminohypurate (PAH) clearance was performed in eight patients. After 6 months on oral calcitriol, there was a 22.5% decline in creatinine clearance but no significant changes were observed in either inulin or PAH clearance, suggesting that calcitriol alters creatinine metabolism or secretion but does not affect renal function. Oral calcitriol is effective and safe for the treatment of psoriasis.
Early Implementation of Palliative Care Can Improve Patient Outcomes
Authors: Paul A Glare
Journal: Journal of the National Comprehensive Cancer Network (2013)

Patients with cancer experience many complex issues throughout the trajectory of the disease. These range from the physical consequences of cancer and treatment to the psychological, social, and spiritual issues associated with living with the disease. An individualized, comprehensive, and interdisciplinary approach is needed to reduce patient suffering and ensure appropriate symptom management and support from the time of first diagnosis to end of life. Data from randomized clinical trials prove that patients provided with early palliative care can experience relief of symptoms and improvements in quality of life, mood, satisfaction, resource use, and advanced care planning. Professional organizations such as ASCO have begun to develop recommendations that integrate palliative care into standard oncologic care from the time a person is diagnosed with metastatic or advanced cancer. NCCN has a palliative care guideline that recommends early and ongoing assessment of palliative care needs and referral to specialist palliative care services in more complex cases. In turn, oncologists need to consider how best to screen patients and integrate early palliative care with routine oncologic care, within the context of their busy clinics, to ensure that patients, families, and caregivers receive timely support.
Prospective Associations of B-Type Natriuretic Peptide With Markers of Left Ventricular Function in Individuals With and Without Type 2 Diabetes
Authors: Maria H. Kroon, Katja van den Hurk, Marjan Alssema, Otto Kamp, Coen D.A. Stehouwer, Ronald M.A. Henry, Michaela Diamant, Frans Boomsma, Giel Nijpels, Walter J. Paulus, Jacqueline M. Dekker
Journal: Diabetes Care (2012)

Heart failure is common in individuals with type 2 diabetes, and early detection of individuals at risk may offer opportunities for prevention. We aimed to explore 1) prospective associations of B-type natriuretic peptide (BNP) levels in a non-heart failure range with changes in markers of left ventricular (LV) function and 2) possible effect modification by type 2 diabetes in a population-based cohort.
IMMUNOCHEMICAL STUDIES ON BLOOD GROUPS
Authors: Ten Feizi, Elvin A. Kabat, Giuseppe Vicari, Byron Anderson, W. Laurence Marsh
Journal: The Journal of Experimental Medicine (1971)

A partially purified blood group-like substance obtained from milk showed I activity with 2 of 21 anti-I sera. With these antisera, certain human ovarian cyst substances considered to be precursors of the A, B, H, Le(a), and Le(b) substances also showed I activity comparable to the milk material. Strong I activity could be produced by one-stage periodate oxidation and Smith degradation of human ovarian cyst A and B substances, or of hog mucin A + H substance, or by mild acid hydrolysis of human saliva or ovarian cyst blood group B substance. The two sera indicate that I specificity appears at intermediate stages in the biosynthesis of the A, B, H, Le(a), and Le(a) substances. Anti-I sera differ strikingly in their specificities, indicating substantial heterogeneity of the I determinants.
Predictors of response to methotrexate in early DMARD naïve rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial
Authors: Saedis Saevarsdottir, Helena Wallin, Maria Seddighzadeh, Sofia Ernestam, Pierre Geborek, Ingemar F Petersson, Johan Bratt, Ronald F van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2010)

Objective To identify predictors of response to methotrexate (MTX) in early rheumatoid arthritis (RA). Methods In the SWEFOT trial, patients with RA with symptom duration &lt;1 year started MTX monotherapy (20 mg/weekly) and 405/487 continued until the 3–4- month visit. The primary outcome measure was the DAS28-based European League against Rheumatism (EULAR) response criteria. Multivariate logistic regression was used to study the association between response and the following baseline characteristics: gender, age, symptom duration, cigarette smoking habits, autoantibody status, Health Assessment Questionnaire (HAQ) score, concurrent prednisolone and treatment with non-steroidal anti-inflammatory drugs. Secondary response and remission measures were the American College of Rheumatology and the Simple Disease Activity Index and Clinical Disease Activity Index (SDAI/CDAI)-derived criteria. Results After 3–4 months of MTX treatment, the frequency of EULAR good/moderate/no response was 34%/41%/25%, respectively. Parameters associated with a decreased likelihood of EULAR response were female gender (adjusted OR (adj OR) 0.50, 95% CI 0.31 to 0.81), symptom duration (adj OR per month increase 0.93, 95% CI 0.88 to 0.99), current smoking (adj OR 0.35, 95% CI 0.20 to 0.63) and higher HAQ (adj OR 0.56, 95% CI 0.40 to 0.80). Parameters associated with an increased likelihood of EULAR response were higher age (adj OR per 10-year increase 1.30, 95% CI 1.11 to 1.51) and prednisolone treatment (adj OR 2.84, 95% CI 1.43 to 5.63). The findings were similar when patients on prednisolone were excluded and other response criteria tested, although current smoking was the only significant predictor using all response criteria, while HAQ was the only significant predictor of all the remission criteria used. A matrix showed up to ninefold differences between subgroups stratified by the main predictors. Conclusion Current smoking, female sex, longer symptom duration and younger age predict a worse response to MTX in patients with new-onset RA. TrialRegNo NCT00764725
Treatment of advanced pancreatic carcinoma with a combination of protracted infusional 5-fluorouracil and weekly carboplatin: A Mid-Atlantic Oncology Program study
Authors: M. Auerbach, G.L. Wampler, J.J. Lokich, D. Fryer, J.G. Fryer, J.D. Ahlgren
Journal: Annals of Oncology (1997)
Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma
Authors: Sean J. Whittaker, Marie-France Demierre, Ellen J. Kim, Alain H. Rook, Adam Lerner, Madeleine Duvic, Julia Scarisbrick, Sunil Reddy, Tadeusz Robak, Jürgen C. Becker, Alexey Samtsov, William McCulloch, Youn H. Kim
Journal: Journal of Clinical Oncology (2010)

The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL).This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells).Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients.Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.
IL-17 in atopic eczema: Linking allergen-specific adaptive and microbial-triggered innate immune response
Authors: Kilian Eyerich, Davide Pennino, Claudia Scarponi, Stefanie Foerster, Francesca Nasorri, Heidrun Behrendt, Johannes Ring, Claudia Traidl-Hoffmann, Cristina Albanesi, Andrea Cavani
Journal: Journal of Allergy and Clinical Immunology (2008)
Nasal continuous positive airway pressure with supplemental oxygen in coexistent sleep apnoea-hypopnoea syndrome and severe chronic obstructive pulmonary disease
Authors: G Sampol, MT Sagales, A Roca, MD de la Calzada, JM Bofill, F Morell
Journal: European Respiratory Journal (1996)

The objective of our study was to assess the application of nasal continuous positive airway pressure (nCPAP) with supplemental oxygen for correction of upper airway obstructive episodes and hypoxaemia during sleep in stable patients with sleep apnoea-hypopnoea syndrome (SAHS) and severe chronic obstructive pulmonary disease (COPD). Ten male patients with symptomatic SAHS and severe COPD (forced expiratory volume in one second &lt; 50% of predicted) were studied for three consecutive nights. Diagnostic polysomnography was performed the first night and repeated with increasing nCPAP levels, with and without supplemental oxygen on the second and third nights, respectively. Diagnostic polysomnography showed: mean (SD) apnoea-hypopnoea index 41 (22) events.h-1; mean arterial oxygen saturation (Sa,O2) was 86 (2)% and mean desaturation nadir was 81 (4)% during non-rapid eye movement (nREM) sleep and 80 (7)% and 73 (9)%, respectively during REM sleep. The application of nCPAP during the second night corrected apnoeas and hypopnoeas, but mean Sa,O2 remained &lt; 90% in all patients. With the addition of oxygen at a flow of 1.5 L.min-1 at suboptimal nCPAP levels, we observed an increase in apnoea frequency, persistence of apnoeas at nCPAP levels which eliminated them when no supplemental oxygen was administered, and longer duration of apnoeas and hypopnoeas. However, when the effective nCPAP level of the second night was reached with supplemental oxygen during the third night, its efficacy in eliminating apnoeas and hypopnoeas was maintained and, furthermore, all patients presented Sa,O2 &gt; 90%, with no greater hypercapnia cardiac arrhythmias. We conclude that nasal continuous positive airway pressure with supplemental oxygen constitutes a practical therapeutic alternative for hypoxic patients with sleep apnoea-hypopnoea syndrome and chronic obstructive pulmonary disease.
Editorial
Authors: R.J. Norman, A.H. MacLennan
Journal: Human Reproduction Update (2005)

This editorial comments on two similar reviews of the literature on breast cancer and post-menopausal hormone therapies (HTs), puts the results in clinical perspective and suggests where they direct future research and clinical management. Although epidemiological studies have suggested increased breast cancer risk for all menopausal HT regimens, unopposed oral estrogen regimens have not been associated with any increased risk in recent randomized placebo controlled trials (RCTs). Added progestogen after 5 years of combined HT in RCTs increases the risk of breast cancer by four cases per 10 000 per annum. As yet there is no evidence of different risk by progestogen type, dose or route. Theoretically local intrauterine progestogen may not give the same risk, but long-term trials are required. The commentary addresses the responsibility of the media in presenting levels of risk to the public, moving towards safer regimens, safer therapies, appropriate patient choice and, in particular, correct timing of HT where it is prescribed around menopause. This is in contrast to many of the trials when HT was administered after the potential climacteric window of therapeutic opportunity. The current main indication for HT remains for menopausal symptom control where it improves quality of life. HT may be required for many years. The informed woman should decide on HT based on her personal benefits and risks, which should include all aspects of her health.
Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease
Authors: R. Akitake, T. Watanabe, C. Zaima, N. Uza, H. Ida, S. Tada, N. Nishida, T. Chiba
Journal: Gut (2010)

We report a case of immunoglobulin G4 (IgG4)-related sclerosing disease involving the pancreas, liver and salivary glands. Massive infiltration of IgG4-expressing plasma cells was seen in the liver and submandibular lymph nodes. Interestingly, accumulation of IgG4-expressing plasma cells was also seen in the colon and terminal ileum. Peripheral blood mononuclear cells (PBMCs) isolated from this patient exhibited enhanced production of IgG4 and interleukin-10 upon stimulation with Toll-like receptor (TLR) ligands as compared with those from a healthy control. In contrast, production of tumour necrosis factor α and interferon γ by PBMCs from this patient was markedly reduced. Since colonic mucosa is always exposed to TLR ligands derived from commensal organisms, the results of immunological studies suggest that enhanced T helper type 2 responses to intestinal microflora may underlie the immunopathogenesis in this patient with IgG4-related sclerosing disease.
STUDIES ON CYCLOPHOSPHAMIDE-INDUCED TOLERANCE TO SHEEP ERYTHROCYTES
Authors: Alan C. Aisenberg
Journal: The Journal of Experimental Medicine (1967)

Complete immunological tolerance to sheep cells can be induced in mice when cyclophosphamide is injected together with sheep cells or up to 72 hr before or 48 hr after the antigen. As is true for radiation-induced immune suppression, the drug is most effective when given in the 24 hr prior to antigen. Complete cyclophosphamide-induced immunological suppression requires large doses of sheep cells (6.2 x 109 cells), presumably to enable antigen to reach sequestered receptor sites. The cyclophosphamide tolerance system has been analyzed with the Jerne technique to determine plaque-forming cells and with isotopic methods to measure rates of nucleic acid synthesis. This drug suppression has been found to consist of two components. The first is nonspecific injury to the lymphoid system caused by the cytotoxic drug and is related to the proportion of spleen cells killed. The second is antigen-specific immunological tolerance and appears to correlate with profound depression of deoxyribonucleic acid synthesis in the surviving cells. This tolerance is thought to be most consistent with a mechanism in which antigenic stimulation in the presence of cyclophosphamide-inhibited DNA synthesis and mitosis leads to the elimination or death of the specific immunological clone. Tolerance induction with cyclophosphamide is associated with loss of the 19S hemolysin plaques which are seen in nonstimulated mouse spleen, implicating these cells in immune responsiveness. The ability to induce tolerance is lost on the 3rd postantigen day at the end of a 24-hr period in which 19S cells have increased 8-fold and 7S cells 200-fold. The data suggest that loss of sensitivity is due to the emergence on day 3 of drug-resistant plaque-forming cells, particularly those of the 19S variety. In the succeeding days after antigen injection there is a progressive increase in the resistance of plaque-forming cells to cyclophosphamide administration.
Pharmacodynamic Effects and Mechanisms of Resistance to Vemurafenib in Patients With Metastatic Melanoma
Authors: Kerstin Trunzer, Anna C. Pavlick, Lynn Schuchter, Rene Gonzalez, Grant A. McArthur, Thomas E. Hutson, Stergios J. Moschos, Keith T. Flaherty, Kevin B. Kim, Jeffrey S. Weber, Peter Hersey, Georgina V. Long, Donald Lawrence, Patrick A. Ott, Ravi K. Amaravadi, Karl D. Lewis, Igor Puzanov, Roger S. Lo, Astrid Koehler, Mark Kockx, Olivia Spleiss, Annette Schell-Steven, Houston N. Gilbert, Louise Cockey, Gideon Bollag, Richard J. Lee, Andrew K. Joe, Jeffrey A. Sosman, Antoni Ribas
Journal: Journal of Clinical Oncology (2013)

PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.