tbuckley/cabot-search huggingface dataset:
Does a family history of RA influence the clinical presentation and treatment response in RA?
Authors: Thomas Frisell, Saedis Saevarsdottir, Johan Askling
Journal: Annals of the Rheumatic Diseases (2015)

Objectives To assess whether family history of rheumatoid arthritis (RA), among the strongest risk factors for developing RA, also carries information on the clinical presentation and treatment response. Methods The prospective Swedish Rheumatology register was linked to family history of RA, defined as diagnosed RA in any first-degree relative, ascertained through the Swedish Multi-Generation and Patient registers. Clinical presentation was examined among patients with early RA 2000–2011 (symptom onset &lt;12 months before inclusion, N=6869), and response to methotrexate (MTX) monotherapy in the subset starting this treatment (N=4630). Response to tumour necrosis factor inhibitors (TNFi) was examined among all patients with RA starting a TNFi as the first biological disease-modifying antirheumatic drug 2000–2011 (N=9249). Association of family history with clinical characteristics, drug survival, European League Against Rheumatism (EULAR) response and change in disease activity at 3 and 6 months was estimated using linear and generalised logistic regression models. Correlation in relatives’ response measures was also assessed. Results Patients with early RA with family history of RA were more often rheumatoid factor positive, but with no other clinically meaningful differences in their clinical presentation. Family history of RA did not predict response to MTX or TNFi, with the possible exception of no versus good EULAR response to TNFi at 6 months (OR=1.4, 95% CI 1.1 to 1.7). Having a relative who discontinued TNFi within a year increased the odds of doing the same (OR=3.7, 95% CI 1.8 to 7.5), although we found no significant familial correlations in change in disease activity measures. Conclusions Family history of RA did not modify the clinical presentation of RA or predict response to standard treatment with MTX or TNFi. Treatment response, particularly drug survival, may itself be familial.
Epidermal Hyperplasia Induced by 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene in Prosimians&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: K. Adachi, S. Yamasawa, W. Montagna
Journal: JNCI Journal of the National Cancer Institute (1969)

The skin of two species of prosimians, Galago crassicaudatus and Perodicticus potto, was painted 3 times weekly with 7,12-dimethylbenz[a]anthracene in acetone and with dodecylbenzene as a cocarcinogen. After 4–5 weeks, these animals developed typical pseudoepitheliomatous (pseudocarcinomatous) hyperplasia. Analysis of 12 enzyme activities in these hyperplasias showed that those enzymes participating in the Embden-Meyerhof pathway were approximately 2–4 times more active than those in normal epidermis, those of the pentose cycle 5–6 times more active, and those of the tricarboxylic acid cycle and glycogen metabolism 1.6–5 times more active. The enzymes that link carbohydrate to amino acid metabolism, however, had an insignificant increase in activities. Carcinogen paintings were stopped at the 9th week when the animals had systemic side effects. Nearly all the P. potto died, whereas all G. crassicaudatus survived. During the 2 years the latter have been under observation, only 3 apparently benign tumors—2 keratoacanthomas and 1 papilloma—have appeared.
An Immunotoxin Composed of a Monoclonal Antitransferrin Receptor Antibody Linked by a Disulfide Bond to the Ribosome-Inactivating Protein Gelonin: Potent In Vitro and In Vivo Effects Against Human Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C F Scott, V S Goldmacher, J M Lambert, J V Jackson, G D McIntyre
Journal: JNCI Journal of the National Cancer Institute (1987)

An immunoconjugate was prepared containing a disulfide linker between a murine monoclonal antibody (5E9), which recognized the human transferrin receptor, and the ribosome-inactivating protein gelonin. This immunoconjugate was found to consist of two major species, 5E9-gelonin2 and 5E9-gelonin1, and a minor species of 5E9-gelonin3 and less than 10% of either free antibody or gelonin. 5E9-gelonin was extremely toxic in vitro to human tumor cell lines expressing the 5E9 antigen, including a Burkitt's lymphoma, an adult T-cell acute lymphocytic leukemia, an acute myelogenous leukemia, a promyelocytic leukemia, and a cervical carcinoma line. A 24-hour exposure to 10(-9) M immunoconjugate killed 90-99.9% of tumor cells, depending on the cell line. A 5E9-negative murine leukemia was not sensitive to this conjugate. Pharmacokinetic analysis of the disappearance of this immunoconjugate from the murine circulation revealed that it had a biphasic clearance, with an initial rapid phase with a half-life (t1/2) of 3 hours and a later, slower phase with a t1/2 of about 1 day. Analysis of blood samples by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis revealed that a substantial degree of disulfide-linker breakdown occurred in vivo and that the 5E9-gelonin2 species was cleared more rapidly than the 5E9-gelonin1. With use of the same clonogenic assays used to measure in vitro toxicity, biologically active immunoconjugate could be detected in murine plasma for up to 24 hours after iv administration, but the concentration of immunoconjugate by this measure was considerably less than that predicted by SDS-gel electrophoresis. The ability to deliver immunoconjugate to tumor cells in vivo was studied with use of the Burkitt's lymphoma Namalwa as a xenograft in nude mice. It was possible to deliver substantial amounts of immunoconjugate to Namalwa cells in xenografted ascites with direct ip inoculation; lower but significant amounts of immunoconjugate could be delivered to this xenograft after systemic iv administration, provided the tumor burden was low. The 5E9-gelonin conjugate, when administered iv at the time of ip tumor inoculation, prolonged survival of nude mice bearing Namalwa or other human tumors as ascites xenografts and delayed or prevented the growth of subcutaneous nodules of Namalwa in an antigen-specific fashion after a single iv injection. Direct intratumoral administration also inhibited the growth of visible subcutaneous nodules of Namalwa. This immunoconjugate may be useful in the treatment of human cancer.
Absorption and tolerability of BEMA (BioErodible MucoAdhesive) fentanyl in cancer subjects with grade 1 mucositis
Authors: O. Dib, R. Kapoor, W. Reid, J. Stark, D. Blum
Journal: Journal of Clinical Oncology (2008)

20559 Background: Oral transmucosal delivery of fentanyl is a rapid and proven route of administration for the management of breakthrough pain in cancer patients. The BEMA drug delivery system was designed for rapid oral transmucosal drug delivery with dose to dose reliability of plasma concentrations and ease of patient use. BEMA fentanyl consists of a small, dissolvable, polymer disc formulated with the opioid narcotic fentanyl for application to the buccal membranes. In subjects with normal intact oral mucosa, fentanyl is rapidly absorbed from BEMA fentanyl. This study was designed to determine if the absorption of fentanyl is more rapid or extensive in the presence of grade 1 mucositis and if the disc causes irritation to the mucosa membrane. Methods: Seven cancer subjects with grade 1 mucositis and seven age- and gender-matched control cancer subjects without mucositis received a single open-label dose of BEMA fentanyl 200 μg applied to the buccal mucosa. Serial blood samples for analysis of fentanyl plasma concentrations were collected immediately prior to application of BEMA fentanyl and for 4 hours post-dosing. All subjects were monitored for safety throughout the study and were serially questioned regarding irritation at the application site. Results: Overall fentanyl exposure following the 200 μg BEMA fentanyl dose was not higher in subjects with mucositis than those without, as assessed by the mean 4-hour AUC (1.14 vs. 1.29 hr*ng/mL, respectively) and mean Cmax values (0.47 vs. 0.69 ng/mL, respectively). All seven subjects with mucositis became mucositis pain-free at one or more time points following BEMA fentanyl application. The only observed adverse event was mild somnolence reported by two subjects with mucositis. There was no evidence of respiratory depression or significant changes in blood pressure. Conclusions: Application of BEMA fentanyl to an area of grade 1 mucositis does not expose cancer patients to a risk of increased fentanyl plasma concentrations compared to cancer patients without mucositis. BEMA fentanyl is well tolerated at a 200 μg dose in subjects with and without mucositis and does not cause local irritation on application to an area of grade 1 mucositis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International
Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy
Authors: Erica Barini, Odetta Antico, Yingjun Zhao, Francesco Asta, Valter Tucci, Tiziano Catelani, Roberto Marotta, Huaxi Xu, Laura Gasparini
Journal: Molecular Neurodegeneration (2016)

Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. Epidemiological and experimental evidence suggests a clear link between type 2 diabetes mellitus and AD. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance and diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy. However, their efficacy for tauopathy in vivo has not been tested. Here, we report that in the P301S mutant human tau (P301S) transgenic mouse model of tauopathy, chronic administration of metformin exerts paradoxical effects on tau pathology. Despite reducing tau phosphorylation in the cortex and hippocampus via AMPK/mTOR and PP2A, metformin increases insoluble tau species (including tau oligomers) and the number of inclusions with β-sheet aggregates in the brain of P301S mice. In addition, metformin exacerbates hindlimb atrophy, increases P301S hyperactive behavior, induces tau cleavage by caspase 3 and disrupts synaptic structures. These findings indicate that metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action, possibly leading to an overall increase of the risk of tauopathy in elderly diabetic patients.
ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets).
Authors: Cristiano Ferrario, Stephen Welch, Jorge M Chaves, Luke N. Walker, Ian E. Krop, Erika Paige Hamilton, Virginia F. Borges, Stacy L. Moulder
Journal: Journal of Clinical Oncology (2015)

612 Background: Up to half of pts with HER2+ metastatic breast cancer (MBC) will develop CNS mets. Surgery and/or radiation remain the mainstay of treatment for HER2+ CNS disease as systemic treatment options have limited efficacy and are often associated with significant GI and skin toxicity. ONT-380, a potent, selective small molecule inhibitor of HER2 with minimal EGFR-like side effects, has been associated with increased survival compared to lapatinib or neratinib in animal models of HER2+ CNS disease. Here we describe 9 pts with CNS mets treated with ONT-380 in combination with other systemic therapies. Methods: Pts with untreated asymptomatic (asx) or post-treatment progressive CNS mets were enrolled in CNS expansion cohorts of ongoing phase 1b studies of ONT-380 + ado-trastuzumab emtansine (T-DM1) or ONT-380 + trastuzumab (T) +/-capecitabine (C). All pts received treatment in 21 day cycles including ONT-380 300 mg PO BID and approved doses of either T-DM1 or T +/-C. Eligibility criteria included prior treatment with T and a taxane, and for pts receiving T+/-C, prior T-DM1. Prior lapatinib was allowed. Assessments included safety and CNS tumor response on MRI per modified RECIST 1.1 every 2 cycles. Results: 9 pts (4 with asx mets and 5 with progressive disease after local therapy) have received ONT-380 plus T-DM1 (n = 5), T (n = 4) or T+C (n = 1) for 1-8 cycles. 8 pts are evaluable for response (at least one follow-up MRI): 3 PR (T-DM1 n = 2; T+C n = 1) and 4 SD (T-DM1 n = 2; T n = 2). 1 pt with 15% increase in target lesion underwent resection; pathology, however, revealed only necrotic tissue. Pts with PR (1 with hx prior lapatinib) all had > 50% decrease in CNS target lesions. One non-evaluable pt (T-DM1) discontinued early due to treatment-related Gr 3 AST/ALT elevation. One other pt in T-DM1 cohort with Gr 3 ALT/AST increase remains on study following dose reduction. No other ≥ Gr 3 ONT-380 related events have been reported. Conclusions: ONT-380 has previously shown activity in the CNS in pre-clinical models. This case series demonstrates early clinical signs of promising activity of ONT-380 against HER2+ CNS mets in combination with other systemic agents. Further study of the CNS activity of ONT-380 is ongoing. Updated results will be reported. Clinical trial information: NCT01983501, NCT02025192.
Prognostic significance of metabolic adaptation for hypoxic environment in oral squamous cell carcinoma
Authors: S. Hong, S. Roh, Y. Koh, H. Won, B. Shim, J. Byun, M. Lee, I. Woo, J. Kang, Y. Hong
Journal: Journal of Clinical Oncology (2009)

6082 Background: During tumor growth, tumor adapts the hypoxic environment and increases glycolysis. This metabolic switch is related to the aggressive malignant behavior. We investigated the connection between the biomarkers related to the glycolytic metabolism (HIF-1α, PDK-1, LDH-5) and clinicopathologic characteristics in oral cavity and oropharynx squamous cell carcinoma (SCC). Methods: Eligibility criteria was the patients diagnosed oral SCC, received curative radical resection and had available tissue samples. Immunohistochemical stain of the HIF-1α, PDK-1, and LDH-5 was done. Statistical analysis was performed to compare biomarkers between patients and time point. Results: Overall 74 patients were enrolled and stage grouping of the patients was as follows: stage I, 25 (33.8%) patients; stage II 17 (23.0%); stage III 8 (10.8%); stage IV 24 (32.4%). 25 patients were relapsed and 5-year disease-free survival (DFS) rate was 61.4%. High expression of HIF-1α was related to the advanced T stage (p = 0.029), more invasive tumor (p = 0.003) and tumor recurrence (p = 0.037). High expression of PDK-1 was related to the advanced N stage (p = 0.026) and high expression of LDH-5 was related to the lymphatics invasion (p = 0.028), advanced N stage (p = 0.020) and more invasive tumor (p = 0.015). The high expression of HIF-1α, PDK-1, and LDH-5 showed a significant correlation to each other. 16 (21.6%) patients were highly expressed all three markers. High expression of all three markers correlated with more invasive tumor (p = 0.004) and tumor recurrence (p = 0.017). In survival analysis, high expression of HIF-1α and LDH-5 associated with shorter DFS in log rank test (p = 0.002 and p = 0.016, respectively). High expression of all three markers was also associated with shorter DFS (p = 0.002). In multivariate Cox regression analysis, high expression of all three markers was strong independent prognostic factor for DFS (p = 0.021). Conclusions: The oral SCC which glycolytic metabolism was changed showed a more invasive and aggressive phenotype. Taken together, biomarkers related tumor metabolism may be independent prognostic markers for the DFS in the patients with oral SCC. No significant financial relationships to disclose.
High density tumor tissue arrays generated by cutting edge matrix assembly
Authors: H. Rui, T. H. Tran, N. Yang, F. E. Utama, A. Witkiewicz, J. P. Palazzo, K. L. Brill, K. Allen, A. L. Rosenberg
Journal: Journal of Clinical Oncology (2008)

22077 Background: Tumor tissue arrays allow cost-effective in situ analyses of protein biomarkers in large number of specimens without confounding interslide variation. Methods: We have developed a high density tissue arraying technology that is based on serial transverse cutting and edge-to-edge-bonding of thick tissue sections to assemble a high density matrix of rectangular tumor specimens, termed cutting edge matrix assembly (CEMA). In addition to space-saving, high-density packing of tumor tissues at densities not achievable by standard core-based tumor arrays, two key advantages of CEMA technology is that deep tissue arrays (>10 mm) of validated tumor content throughout the array block can be generated. In fact, more than 2,000 sections can be routinely cut from a single array block that even includes small tumors (< 10 mm), due to the flexible construction method. Standard core-based array blocks often become depleted after sampling of as few as 50–150 useable sections, since it is hard to anticipate tumor content throughout the depth of the core and the core depth is physically limited. Results: Combined with automated quantitative immunofluorescence-based biomarker analyses, CEMA arrays provide a powerful high throughput analytical approach to in situ cancer proteomics. We have used these technologies to analyze tumor biomarker expression in archival clinical cancer specimens, including normal and malignant breast, DCIS, tumor- stroma interactions, and metastatic progression. Importantly, we have also generated and analyzed biomarkers of responsiveness in arrays of freshly excised surgical breast cancer specimens that have been exposed to hormones and pharmacological agents in short-terms ex vivo tissue explant cultures. Conclusions: The CEMA arraying technology will be useful for analyses aimed at identifying drug responsiveness in cancer tissues, with the goal of improving personalized medicine this heterogeneous set of diseases. No significant financial relationships to disclose.
Abstract MP054: Coronary Calcification, C-reactive Protein and Prediction of Cardiovascular and All-Cause Mortality in Diabetes: Diabetes Heart Study
Authors: Subhashish Agarwal, Amanda J Cox, David M Herrington, Neal Jorgensen, Jianzhao Xu, John J Carr, Barry I Freedman, Donald W Bowden
Journal: Circulation (2012)

Objective: Does coronary artery calcium (CAC) and C-reactive protein (CRP) improve discrimination and risk stratification of cardiovascular (CVD) and all-cause mortality in diabetes. Background: Inflammation is associated in the pathogenesis and progression of atherosclerosis. Since diabetes is characterized by both atherosclerosis and high CRP levels, we hypothesized that CAC and CRP will predict CVD and all-cause mortality in diabetes beyond Framingham risk factors (FRS). Method: A total of 961 participants, ages 39-86, with complete data on diabetes, vascular imaging, and inflammation in the Diabetes Heart Study were followed for an average of 7.4 years. CAC was assessed by CT at baseline. CRP was measured using enzyme-linked immunosorbent assay. Risk estimates for CVD and all-cause mortality were obtained using logistic regression models. Model 1 included FRS; age, gender, smoking, systolic blood pressure, antihypertensive medication use, total and HDL cholesterol, and ethnicity. Model 2 included FRS plus CRP or CAC. Model 3 included FRS plus CRP and CAC. Models for CVD and all-cause mortality were compared using c-statistics. Results: During follow-up there were 183 (19%) deaths of which 80 (8%) were CVD deaths. In FRS adjusted models both CRP and CAC were independently associated with all-cause mortality, however only CAC was associated with CVD mortality. The addition of CAC to a model with FRS and CRP improves discrimination for CVD and all-cause mortality (both p=0.001). However, the addition of CRP to a model with FRS and CAC only improves discrimination in all-cause mortality (p=0.001) ( Table 1 ). Conclusion: In participants with T2DM, measures of CAC and CRP are significantly associated with CVD (CAC only) and all-cause (CAC and CRP) mortality independent of the FRS; however, the improvement in CVD and all-cause mortality prediction was predominantly driven by CAC. Table 1 C-Statistics for the Combined Assessment of Framingham Risk Factors, CAC and CRP in Predicting Cardiovascular and All-Cause Mortality CVD Mortality All-Cause Mortality C-Statistic p-value C-Statistic p-value Model 1 FRS Only 0.715 -- 0.701 -- Model 2 vs. Model 1 Adding CRP to FRS Adding CAC to FRS 0.715 0.768 P=0.737 P=0.001 0.709 0.760 p=0.002 P=0.001 Model 3 vs. Model 2 Adding CAC to FRS + CRP Adding CRP to FRS + CAC 0.769 0.769 P=0.001 P=0.981 0.765 0.765 P=0.001 P=0.001
NT-ProBNP prediction of major chemotherapy-related toxicity and death in lymphoma patients
Authors: A. Salar, B. Sanchez-Gonzalez, A. Alvarez-Larran, J. Comin, J. R. Gonzalez, E. Gimeno, M. Gomez, F. Garcia, J. Bruguera, C. Besses
Journal: Journal of Clinical Oncology (2009)

9569 Background: NT-Pro BNP provides diagnostic and prognostic information in many heart syndromes, but its role in oncologic patients is not established. Methods: We studied the association between NT-ProBNP levels and the risk of major toxicity associated with chemotherapy and death from all causes in 116 consecutive patients with lymphoma treated with curative intent. High resolution ultrasound echocardiography and serum NT-ProBNP levels were prospectively done previous the start of chemotherapy. Charlson Comorbidity Index was retrospectively calculated. A major toxicity event was defined as: when chemotherapy had to be discontinued, when chemotherapy had to be changed to a less intensive regimen, and treatment-related death. Results: High blood levels of NT-proBNP were associated with previous cardiologic history but not with left ventricular ejection fraction. With a median follow-up of 16 moths (0–49 months), 25 patients had a major toxic event with first line chemotherapy and 16 had died at last follow-up. The threshold of NT-ProBNP with better predictive accuracy for major toxicity-free and overall survival was 900 pg/mL. Patients with levels of NT-proBNP greater of 900 pg/mL had an adjusted hazard ratio (HR) for major toxicity after first-line chemotherapy for lymphoma of 6.4 (95%CI, 2.7–15.1). Two additional independent factors predicting higher major toxicity associated with chemotherapy were albumin &lt; 3.5 g/mL (HR 3.5, P=0.008) and number of extranodal sites ≥ 2 (HR 3.1, P&lt;0.007). For prediction of death from all causes, patients with a NT-ProBNP greater of 900 pg/mL had an HR of death of 15.3 (95%CI, 4.8–48.8; P&lt;0.001). ECOG ≥ 2 was also significant for predicting death (HR 3.6; 95%CI, 1.1–11.6; P=0.03). The NT-Pro BNP added prognostic information beyond that provided by conventional risk factors, including IPI, left ventricular ejection fraction and Charlson comorbidity index. Conclusions: NT-ProBNP is the stronger marker for predicting major toxicity after first-line chemotherapy and death from all causes in patients with lymphoma and provides prognostic information beyond that provided by conventional lymphoma risk factors and comorbidity indexes. No significant financial relationships to disclose.