tbuckley/cabot-search huggingface dataset:
Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites
Authors: Xiaoxiao Wan, James W. Thomas, Emil R. Unanue
Journal: The Journal of Experimental Medicine (2016)

Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node-islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis.
Targeting the therapy: Octreotide in thymoma relapse
Authors: M. S. Rosati, F. Longo, C. G. M. Messina, D. Vitolo, F. Venuta, M. Anile, F. Scopinaro, G. P. Di Santo, G. F. Coloni
Journal: Journal of Clinical Oncology (2005)

2064 Background: Thymomas are rare slowly growing neoplasms, associated with myasthenia gravis, hypogammaglobulinemia and pure red-cell aplasia. Its malignant behavior is indicated by micro- or macroscopic invasion of tumor capsule or sorrounding organs. About 40% of thymomas are invasive and some well encapsulated tumor recur years after surgical resection. The 5 years survival rate in patients with noninvasive thymomas is 70 - 85% and decreases at 50 - 67% for invasive thymomas with the worst trend for stage IV (23%). Recurrence rate is usually low (2%) for stage I encapsulated thymomas while for stage II and III is approximately 28% and it seems to decrease at 5% when thymectomy is followed by RT. Thymomas have a high content of somatostatin receptors so they could show an elevated Indium-labeled octreotide (111In-DTPA-D - Phe - octreotide) uptake when OCTREOSCAN is performed. Methods: We tested 29 patients (pts) (tab.1) whose CT showed thymoma's relapse and 27.5% (n=8) resulted scintigraphically positive. Of these, 2 pts showed a partial response to chemotherapy after surgery and 6 relapsed. On the basis of positive octreotide uptake, after the patients' informed consent had been obtained, we decided to treat them with octreotide (SANDOSTATINA LAR 20mg) every 2 weeks. We also monitored CgA and NSE tumor markers. One of them refused the treatment. Results: Seven positive scintigraphy were treated with octreotide and showed stable disease at CT scan examination. Three pts of these had a significative CgA and NSE markers level reduction. Treatment was well tolerated and no side-effects were recorded. Conclusions: Treating thymoma recurrences or residual disease with octreotide seems to be feasible and safe; all the pts treated showed good compliance. Positive scintigraphy gives the oncologist the possibility to address a new target, the somatostatin's receptor, through the octreotide. No significant financial relationships to disclose.
Interpretability of the Modified Melasma Area and Severity Index (mMASI)
Authors: Michelle Rodrigues, Ana Sofía Ayala-Cortés, Adriana Rodríguez-Arámbula, Linda S. Hynan, Amit G. Pandya
Journal: JAMA Dermatology (2016)

means for MASI were highest for those with severe MSS and the lowest for those with mild MSS (means: mild, 6.9 [95% CI, 4.9-8.8];moderate, 12.4 [95 CI, 11.1-13.7];severe, 20.2 [95% CI, 18.6-21.9]).Discussion | This study provides a framework that facilitates meaningful clinical interpretation of the numerical mMASI score.The ranges for mMASI provided herein correspond to global levels of severity using the MSS.Such categorization in MSS levels can assist clinicians in interpreting clinical trial data, severity of disease, and response to treatment.The mMASI is a simple, reliable validated tool that is a modification of the most commonly used outcome measure for melasma.This user-friendly tool can now be correlated with the newly proposed clinical ranges of severity presented in the Figure, which can be used to assist researchers in determining entry criteria for clinical trains for melasma and improvement of melasma with treatment.
A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice
Authors: Doori Park, Chan-Won Park, YoungJin Choi, Jingjing Lin, Dong-Hyun Seo, Han-Sung Kim, Soo Young Lee, In-Cheol Kang
Journal: Biomaterials (2016)
Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits
Authors: Li Jiang, Srikanya Kundu, James D. Lederman, Gretchen Y. López-Hernández, Elizabeth C. Ballinger, Shaohua Wang, David A. Talmage, Lorna W. Role
Journal: Neuron (2016)
A Lesson from Wheat Evolution: Wild and Landraces Genetic Diversity the Key to Improving the Nutritional Value of Our Spaghetti Dish
Authors: Joseph Caspermeyer
Journal: Molecular Biology and Evolution (2016)

heart disease, colon cancer, and many other inflammationrelated conditions. Treating individuals according to whether they carry 0, 1, or 2 copies of the insertion, and their influence on fatty acid metabolites, can be an important consideration for precision medicine and nutrition. The insertion mutation may be favored in populations subsisting primarily on vegetarian diets and possibly populations having limited access to diets rich in polyunsaturated fats, especially fatty fish. Very interestingly, the deletion of the same sequence might have been adaptive in populations which are based on marine diet, such as the Greenlandic Inuit. The authors will follow up the study with additional worldwide populations to better understand the mutations and these genes as a genetic marker for disease risk. “With little animal food in the diet, the long chain polyunsaturated fatty acids must be made metabolically from plant PUFA precursors. The physiological demand for arachidonic acid, as well as omega-3 EPA and DHA, in vegetarians is likely to have favored genetics that support efficient synthesis of these key metabolites,” said Brenna and Kothapalli in a joint comment. “Changes in the dietary omega-6 to omega3 balance may contribute to the increase in chronic disease seen in some developing countries.”
A multi-institutional double-blind phase II study evaluating response and surrogate biomarkers to carboplatin and nab-paclitaxel (CP) with or without vorinostat as preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer (TBCRC008).
Authors: R. M. Connolly, S. Jeter, J. Zorzi, Z. Zhang, D. K. Armstrong, J. H. Fetting, A. C. Wolff, M. P. Goetz, A. M. Storniolo, V. Stearns
Journal: Journal of Clinical Oncology (2010)

TPS111 Background: Traditionally, systemic treatment recommendations for women with breast cancer have been based on clinicopathologic factors following definitive surgery. PST allows for improved surgical outcomes and assessment of response without compromising long- term outcomes. Chemotherapy is currently the most effective treatment for women with triple-negative (ER-, PR-, HER2-) or luminal type B breast cancers. Many women suffer recurrence and death despite optimal chemotherapy, emphasizing the need for new strategies. Epigenetic modifiers may sensitize tumors to chemotherapy and enhance outcomes. We hypothesized that preoperative CP combined with the histone deacetylase inhibitor vorinostat is a better option than CP alone in women with triple-negative or luminal type B breast cancer who are candidates for PST. Methods: This study includes both a run-in phase to investigate the safety of 12 weekly doses of C (AUC 2) and P (100 mg/m2) with vorinostat 400mg po daily (first 3 out of every 7 days) in women with unresected stage II-III HER2-negative breast cancer and a randomized phase II portion. Eligible women are stratified by hormone receptor status and randomly assigned in a 1:1 ratio to CP plus placebo or vorinostat. The primary endpoint is rate of pathologic complete response (pCR) with secondary endpoints including correlation of baseline and change in standardized uptake values on positron emission tomography with pCR and clinical CR, evaluation of safety and long-term outcomes. Exploratory endpoints include comparison of pCR and clinical CR in women with triple- negative/basal-like features versus those without and evaluation of baseline and change in candidate gene methylation, gene expression and histone acetylation in tumor tissue. A sample size of 31 patients per arm will enable detection of a 25% pCR rate from a null response rate of 10% using a Simon two-stage design with 80% power and a 10% type I error rate. To date, 6 women have completed the run-in phase without dose-limiting toxicities and one woman has completed the phase II portion. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth AstraZeneca Abraxis BioScience, Merck, Novartis, Pfizer
Transforming Growth Factor-β Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands
Authors: Victor S. Cortez, Luisa Cervantes-Barragan, Michelle L. Robinette, Jennifer K. Bando, Yaming Wang, Theresa L. Geiger, Susan Gilfillan, Anja Fuchs, Eric Vivier, Joe C. Sun, Marina Cella, Marco Colonna
Journal: Immunity (2016)
Caffeine Induces Ventricular Tachyarrhythmias Possibly Due to Triggered Activity in Rabbits in Vivo
Authors: Shuji Ishida, Morio Ito, Naohiko Takahashi, Takao Fujino, Tadafumi Akimitsu, Tetsunori Saikawa
Journal: Circulation (1996)

Caffeine induces delayed afterdepolarizations (DADs) and triggered activity in isolated cardiac tissue. We investigated the ability of caffeine to induce triggered ventricular arrhythmias in rabbits in vivo. During continuous infusion of caffeine at doses of 0.3 or 1.0 mg/kg per min, ventricular pacing was performed with 50 stimuli with a cycle length of 220 msec (basic pacing train) every 5 min until ventricular tachycardia (VT) was induced. The effects of programmed stimulation and pharmacologic agents on the induction of ventricular ectopic beats (VEBs) were examined. Pacing protocols were carried out in the presence of vagal-induced slowing of sinus rhythm. VT was induced by a basic pacing train during the infusion of caffeine at 1.0 mg/kg per min, but not at 0.3 mg/kg per min. An increase in the pacing rate or the number of stimuli resulted in 1) a decrease in the first postpacing interval, and 2) an increase in the number of postpacing VEBs. Induction of VT was suppressed by intravenous bolus injections of verapamil, propranolol and adenosine. At the time of the initial induction of VT, the plasma concentration of caffeine was 87 +/- 2 micrograms/ml and the plasma level of norepinephrine increased from 666 +/- 166 pg/ml at baseline to 1121 +/- 245 pg/ml. These results suggest that catecholamine-associated triggered activity may be responsible for caffeine-induced VT.
Influence of Estrogen Administration on Tumor Characteristics and Survival in Women With Cutaneous Melanoma&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J S Lederman, R A Lew, H K Koh, A J Sober
Journal: JNCI Journal of the National Cancer Institute (1985)

A prospective study on 289 women with clinical stage I cutaneous melanoma was done to determine the relationship between estrogen administration, tumor characteristics, and survival. Eighty-two women took oral contraceptives (OC) and 44 took menopausal estrogens (MPE) prior to the diagnosis of melanoma. Users of OC presented with thinner primary tumors than nonusers of OC (P less than .01). A similar trend was observed in users of MPE. Women who used OC in the year prior to the diagnosis of melanoma had statistically thinner tumors than those who had discontinued use of OC more than 1 year prior to diagnosis (P less than .025). A statistically significant preponderance of truncal lesions was observed among users of OC (P less than .01). Other tumor characteristics were unaltered by estrogen administration. Duration of use and time in relation to diagnosis of melanoma did not affect survival. Women who took hormones had slightly better 5- and 9-year survival rates than nonusers. These results suggest that prior estrogen use and, particularly, use of OC in women developing melanoma have no deleterious effect.
Significant clinical and biologic activity of RAF/VEGF-R kinase inhibitor BAY 43–9006 in patients with metastatic papillary thyroid carcinoma (PTC): Updated results of a phase II study
Authors: R. Kloos, M. Ringel, M. Knopp, J. Heverhagen, J. Rittenberry, L. Weldy, D. Arbogast, M. Collamore, M. King, D. Young, M. Shah
Journal: Journal of Clinical Oncology (2006)

5534 Purpose: Oncogenic defects in the genes involving RAS-RAF-MAPK signaling pathway (RAS, BRAF, or RET/PTC) occur in ∼60% of PTC. VEGF also plays a critical role in thyroid cancer progression. Due to lack of effective treatment, systemic therapy for iodine-refractory PTC is desperately needed. Methods: The primary endpoint of this phase II trial was to assess the objective response rates of BAY 43–9006 in pts with metastatic PTC. Secondary endpoints included clinical response correlation with 1) serum thyroglobulin (Tg) levels; 2) functional imaging including FDG-PET, and DCE-MRI; and 3) tumor genotype and degree of signaling inhibition in tumor biopsies. Using a minimax 2-stage design, 16 or 25 chemo-naïve pts with iodine-refractory PTC were to be enrolled in Arm A (accessible tumor for biopsy). An exploratory Arm B was designed with a plan to halt accrual as soon as Arm A was fully accrued. Eligible pts for Arm B had other subtypes of thyroid cancer or prior chemo, and did not require tumor biopsies. Pts received BAY 43–9006 at the dose of 400 mg PO BID. Response was assessed every 8 wks using RECIST. Results: A total of 58 pts (Arm A = 20, Arm B = 38) were enrolled from October 2004 to August 2005. Median duration of follow-up is 36 weeks (range, 16–60). Of 56 pts assessable for toxicity, serious adverse events (AEs) included aspergillus infection (gr 5, n = 1), secondary AML (gr 5, n = 1) and diverticular rupture (gr 3, n = 1). Common Gr 3 AEs were hand-foot syndrome (n = 9) and musculoskeletal pain (n = 10). Two confirmed partial responses (PRs) and 6 minor responses (23–29% decrease in sum of the longest diameter) were observed in 16 evaluable pts on Arm A. In 10 Tg-response evaluable pts on Arm A, median decrease in Tg was 70% (range, 45–90). Significant decreases in tumor perfusion and SUVs were noted in such pts. In addition, one PR and one minor response (27% decrease in sum of longest diameter; 85% reduction in Tg) have been observed among 20 pts with PTC on Arm B. Data for functional imaging and tissue correlative studies will be presented. Conclusions: BAY 43–9006 is a well-tolerated targeted therapy that has significant clinical and biologic anti-tumor activity in pts with iodine-refractory metastatic PTC. No significant financial relationships to disclose.
Is the presence of acellular mucin in rectal cancer patients with a pathologic complete response to preoperative chemoradiation of prognostic significance?
Authors: K. D. Smith, P. Das, G. J. Chang, B. W. Feig, J. M. Skibber, C. Eng, S. Krishnan, C. H. Crane, M. A. Rodriguez- Bigas
Journal: Journal of Clinical Oncology (2008)

4119 Background: Rectal cancer patients who achieve a pathologic complete response (pCR) to preoperative chemoradiation have decreased local recurrence and improved survival rates. The presence of acellular mucin pools in the resected specimen is frequently reported; however, the prognostic significance of this finding is unknown. The objective of this study was to determine the prevalence and prognostic significance of acellular mucin within resected specimens of rectal cancer patients with a pCR to preoperative chemoradiation. Methods: Data from a retrospective rectal cancer database was used to analyze clinical courses of 562 patients with nonmetastatic rectal adenocarcinoma treated with preoperative chemoradiation and mesorectal excision between 1989 and 2004. Pathologic CR was defined as the absence of tumor cells in the operative pathologic specimen, at the primary site, or in lymph node regions. The presence or absence of acellular mucin within the specimen was determined by review of operative pathology reports. Results: Among the 562 patients, 108 patients (19%) had pCR. Patients (N=3) who had a post-operative death or second malignancy were excluded from this study. Of the remaining 105 patients with pCR, acellular mucin was present in 29 (28%) patients. The median follow-up interval was 86 months (range 1–198 months). Local and distant failures occurred in 0 and 2 patients with acellular mucin, and in 1 and 7 patients without acellular mucin, respectively. Among the 105 patients with pCR, there were 17 deaths. The actuarial 7-year overall survival rates were 85% for patients with acellular mucin and 92% for patients without acellular mucin (p=0.64). The actuarial 7-year disease-free survival rates were 82% and 86% (p=0.74) and the 7-year freedom from relapse rates were 93% and 90% (p=0.72) in patients with and without acellular mucin, respectively. Conclusions: The presence of acellular mucin within resected specimens in rectal cancer patients with a pCR after preoperative chemoradiation has no prognostic significance. No significant financial relationships to disclose.
Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury
Authors: Jennifer Laskowski, Brandon Renner, Moglie Le Quintrec, Sarah Panzer, Jonathan P. Hannan, Danica Ljubanovic, Marieta M. Ruseva, Dorin-Bogdan Borza, Alexandra H. Antonioli, Matthew C. Pickering, V. Michael Holers, Joshua M. Thurman
Journal: Kidney International (2016)
Conditional Spike Transmission Mediated by Electrical Coupling Ensures Millisecond Precision-Correlated Activity among Interneurons In Vivo
Authors: Ingrid van Welie, Arnd Roth, Sara S.N. Ho, Shoji Komai, Michael Häusser
Journal: Neuron (2016)

Many GABAergic interneurons are electrically coupled and in vitro can display correlated activity with millisecond precision. However, the mechanisms underlying correlated activity between interneurons in vivo are unknown. Using dual patch-clamp recordings in vivo, we reveal that in the presence of spontaneous background synaptic activity, electrically coupled cerebellar Golgi cells exhibit robust millisecond precision-correlated activity which is enhanced by sensory stimulation. This precisely correlated activity results from the cooperative action of two mechanisms. First, electrical coupling ensures slow subthreshold membrane potential correlations by equalizing membrane potential fluctuations, such that coupled neurons tend to approach action potential threshold together. Second, fast spike-triggered spikelets transmitted through gap junctions conditionally trigger postjunctional spikes, depending on both neurons being close to threshold. Electrical coupling therefore controls the temporal precision and degree of both spontaneous and sensory-evoked correlated activity between interneurons, by the cooperative effects of shared synaptic depolarization and spikelet transmission.
Microbiota and caspase-1/caspase-8 regulate IL-1β-mediated bone disease
Authors: Farrah C. Phillips, Prajwal Gurung, Thirumala-Devi Kanneganti
Journal: Gut Microbes (2016)

A leucine-to-proline missense mutation at residue 98 in the proline-serine-threonine phosphatase interacting protein 2 (Pstpip2) gene leads to autoinflammatory disease that is characterized by splenomegaly, necrosis, and spontaneous development of osteomyelitis in mice (Pstpip2cmo). Disease progression in these mice resembles that of chronic recurrent multifocal osteomyelitis in humans. Our group and others have shown that disease progression in Pstpip2cmo mice is mediated by the cytokine IL-1β, independently of inflammasomes or IL-1α. Our recent publication highlighted herein establishes that diet-induced changes in intestinal microbiota provide protection against the development of osteomyelitis in Pstpip2cmo mice. Moreover, the proteases caspase-1 and caspase-8 have redundant roles in cleaving IL-1β and promoting disease. This addendum reviews the current literature on the Pstpip2cmo murine disease model and the clinical significance of the role of PSTPIP2 in regulating autoinflammatory osteomyelitis, which is mediated by innate components of immune cells.
Alternatively activated macrophages determine repair of the infarcted adult murine heart
Authors: Manabu Shiraishi, Yasunori Shintani, Yusuke Shintani, Hidekazu Ishida, Rie Saba, Atsushi Yamaguchi, Hideo Adachi, Kenta Yashiro, Ken Suzuki
Journal: Journal of Clinical Investigation (2016)

Alternatively activated (also known as M2) macrophages are involved in the repair of various types of organs. However, the contribution of M2 macrophages to cardiac repair after myocardial infarction (MI) remains to be fully characterized. Here, we identified CD206+F4/80+CD11b+ M2-like macrophages in the murine heart and demonstrated that this cell population predominantly increases in the infarct area and exhibits strengthened reparative abilities after MI. We evaluated mice lacking the kinase TRIB1 (Trib1-/-), which exhibit a selective depletion of M2 macrophages after MI. Compared with control animals, Trib1-/- mice had a catastrophic prognosis, with frequent cardiac rupture, as the result of markedly reduced collagen fibril formation in the infarct area due to impaired fibroblast activation. The decreased tissue repair observed in Trib1-/- mice was entirely rescued by an external supply of M2-like macrophages. Furthermore, IL-1α and osteopontin were suggested to be mediators of M2-like macrophage-induced fibroblast activation. In addition, IL-4 administration achieved a targeted increase in the number of M2-like macrophages and enhanced the post-MI prognosis of WT mice, corresponding with amplified fibroblast activation and formation of more supportive fibrous tissues in the infarcts. Together, these data demonstrate that M2-like macrophages critically determine the repair of infarcted adult murine heart by regulating fibroblast activation and suggest that IL-4 is a potential biological drug for treating MI.
Reinfection in Histoplasmosis
Authors: J SCHWARZ, G L BAUM
Journal: JAMA (1963)

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