tbuckley/cabot-search huggingface dataset:
Receptor-mediated cellular entry of nuclear localizing anti-DNA antibodies via myosin 1.
Authors: K Yanase, R M Smith, A Puccetti, L Jarett, M P Madaio
Journal: Journal of Clinical Investigation (1997)

A unique subset of anti-DNA antibodies enters living cells, interacts with DNase 1, and inhibits endonuclease activity, before their nuclear localization and subsequent attenuation of apoptosis. We now report that endocytosis of these immunoglobulins is mediated by cell surface binding to brush border myosin (myosin 1). Cellular entry and internalization via this unique receptor provides initial contact for entry and sorting these immunoglobulins to translocate to the nuclear pore and enter the nucleus, interact with DNase 1 within the cytoplasm, or recycle back to the cell surface. This internalization pathway provides clues to the translocation of large proteins across cell membranes and the functional effects of intracellular antibodies on cytopathology. This is the first demonstration that brush border myosin functions as a specific cell surface receptor for internalization of large proteins.
Enhancing the Quality of Life of Dementia Caregivers from Different Ethnic or Racial Groups
Authors: Steven H. Belle
Journal: Annals of Internal Medicine (2006)

Background: Caring for a family member with dementia is extremely stressful, contributes to psychiatric and physical illness among caregivers, and increases the risk for caregiver death. Finding better ways to support family caregivers is a major public health challenge. Objective: To test the effects of a structured multicomponent intervention on quality of life and clinical depression in caregivers and on rates of institutional placement of care recipients in 3 diverse racial or ethnic groups. Design: Randomized, controlled trial. Setting: In-home caregivers in 5 U.S. cities. Participants: 212 Hispanic or Latino, 219 white or Caucasian, and 211 black or African-American caregivers and their care recipients with Alzheimer disease or related disorders. Intervention: Caregivers within each racial or ethnic group were randomly assigned to an intervention or to a control group. The intervention addressed caregiver depression, burden, self-care, and social support and care recipient problem behaviors through 12 in-home and telephone sessions over 6 months. Caregivers in the control group received 2 brief "check-in" telephone calls during the 6-month intervention. Measurements: The primary outcome was a quality-of-life indicator comprising measures of 6-month caregiver depression, burden, self-care, and social support and care recipient problem behaviors. Secondary outcomes were caregiver clinical depression and institutional placement of the care recipient at 6 months. Results: Hispanic or Latino and white or Caucasian caregivers in the intervention group experienced significantly greater improvement in quality of life than those in the control group (P < 0.001 and P = 0.037, respectively). Black or African-American spouse caregivers also improved significantly more (P = 0.003). Prevalence of clinical depression was lower among caregivers in the intervention group (12.6% vs. 22.7%; P = 0.001). There were no statistically significant differences in institutionalization at 6 months. Limitations: The study used only a single 6-month follow-up assessment, combined heterogeneous cultures and ethnicities into a single group, and excluded some ethnic groups. Conclusions: A structured multicomponent intervention adapted to individual risk profiles can increase the quality of life of ethnically diverse dementia caregivers. ClinicalTrials.gov identifier: NCT00177489.
Randomized Open-Label Phase II Study of Decitabine in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes
Authors: Guillermo Garcia-Manero, Elias Jabbour, Gautam Borthakur, Stefan Faderl, Zeev Estrov, Hui Yang, Sirisha Maddipoti, Lucy A. Godley, Nashat Gabrail, Jesus G. Berdeja, Ahmed Nadeem, Laurent Kassalow, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2013)

This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1-risk myelodysplastic syndrome (MDS).Patients received decitabine 20 mg/m(2) SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m(2) SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death.Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B; OIR was 23% for schedule A (seven CRs, three HIs) and 23% for schedule B (one mCR, one PR, three HIs). No differences were observed in secondary end points. Median OS was not reached; approximately 70% of patients were alive at 500 days. Patients in schedule A (67%) and schedule B (59%) were RBC/platelet independent on study. The most frequent drug-related adverse events overall were neutropenia (28% v 36%), anemia (23% v 18%), and thrombocytopenia (16% v 32%).In this phase II study, low-dose decitabine showed promising results in patients with low- or intermediate-1-risk MDS.
Functional assessment of knee joint position sense following anterior cruciate ligament reconstruction
Authors: S M Mir, M-R Hadian, S Talebian, N Nasseri
Journal: British Journal of Sports Medicine (2008)

The anterior cruciate ligament (ACL) has both mechanical and proprioceptive (sensory) functions. Knee-joint proprioception has been assessed using either reproduction of position or threshold to detect passive motion in non-weight-bearing positions. It has been suggested that a more functional and dynamic/active assessment of proprioception might clarify the effects of injury and reconstruction on the proprioceptive function of ACL at the knee joint.To assess knee joint position sense (JPS) following ACL reconstruction in functional positions.Twelve male patients who had undergone ACL reconstruction and 12 male healthy control subjects participated in the study.JPS was evaluated by reproduction of the angles in weight-bearing position with limb movement into flexion and extension. The dominant knee of healthy subjects and both (reconstructed and uninjured) knees of the patients were tested. Absolute angular error was used as a dependent variable.There was no significant difference between the operated and uninjured knees of patients or between patients and healthy controls (p>or=0.05). These results were measured during two tasks of limb movement into flexion and extension.We found no evidence of impaired JPS in weight-bearing positions in subjects with ACL reconstruction at a mean follow-up of 11 months after surgery compared with subjects with healthy knees.
Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis
Authors: Graig C. Suvannavejh, Mauro C. Dal Canto, Louis A. Matis, Stephen D. Miller
Journal: Journal of Clinical Investigation (2000)

PLP139-51–induced experimental autoimmune encephalomyelitis (R-EAE) displays a relapsing-remitting paralytic course in female SJL mice. We investigated the role of apoptosis/activation-induced cell death (AICD) in the spontaneous recovery from acute disease. Clinical EAE was significantly enhanced in Fas (CD95/APO-1)–deficient SJL lpr/lpr mice, which displayed significantly increased mean peak clinical scores, reduced remission rates, and increased mortality when compared with their SJL +/lpr littermates. PLP139-151–specific proliferative responses were fairly equivalent in the 2 groups, but draining lymph node T cells from SJL lpr/lpr mice produced dramatically increased levels of IFN-γ. Central nervous system (CNS) Fas and FasL mRNA levels in wild-type SJL (H-2s) mice peaked just before spontaneous disease remission and gradually declined as disease remitted. We applied the terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) assay to detect apoptosis in situ in spinal cords of mice at various clinical stages of EAE. Most TUNEL+ cells were found during active periods of inflammation: the acute, peak, and relapse time points. Significantly fewer apoptotic cells were observed at preclinical and remission time points. Collectively, these findings indicate that Fas-mediated apoptosis/AICD plays a major role in the spontaneous remission after the initial acute inflammatory episode and represents an important intrinsic mechanism in regulation of autoimmune responses.
Refractory aggressive keratoacanthoma centrifugum marginatum of the scalp controlled with the epidermal growth factor receptor inhibitor erlotinib
Authors: T.K. Bulj, A.L. Krunic, A.S. Cetner, J.L. Villano
Journal: British Journal of Dermatology (2010)

Keratoacanthomas are squamous cell neoplasms known to be abundant in epidermal growth factor receptors (EGFRs). Erlotinib (Tarceva®; Roche) is a low molecular weight oral quinazoline compound that binds to the intracellular EGFR tyrosine kinase domain and inhibits receptor phosphorylation and downstream signalling. We report a case of refractory, locally aggressive keratoacathoma centrifugum marginatum of the scalp having strong EGFR expression and demonstrating excellent response to erlotinib.
Anchored p90 Ribosomal S6 Kinase 3 Is Required for Cardiac Myocyte Hypertrophy
Authors: Jinliang Li, Michael D. Kritzer, Jennifer J. Carlisle Michel, Andrew Le, Hrishikesh Thakur, Marjorie Gayanilo, Catherine L. Passariello, Alejandra Negro, Joshua B. Danial, Behzad Oskouei, Michael Sanders, Joshua M. Hare, Andre Hanauer, Kimberly Dodge-Kafka, Michael S. Kapiloff
Journal: Circulation Research (2012)

Rationale: Cardiac myocyte hypertrophy is the main compensatory response to chronic stress on the heart. p90 ribosomal S6 kinase (RSK) family members are effectors for extracellular signal-regulated kinases that induce myocyte growth. Although increased RSK activity has been observed in stressed myocytes, the functions of individual RSK family members have remained poorly defined, despite being potential therapeutic targets for cardiac disease. Objective: To demonstrate that type 3 RSK (RSK3) is required for cardiac myocyte hypertrophy. Methods and Results: RSK3 contains a unique N-terminal domain that is not conserved in other RSK family members. We show that this domain mediates the regulated binding of RSK3 to the muscle A-kinase anchoring protein scaffold, defining a novel kinase anchoring event. Disruption of both RSK3 expression using RNA interference and RSK3 anchoring using a competing muscle A-kinase anchoring protein peptide inhibited the hypertrophy of cultured myocytes. In vivo, RSK3 gene deletion in the mouse attenuated the concentric myocyte hypertrophy induced by pressure overload and catecholamine infusion. Conclusions: Taken together, these data demonstrate that anchored RSK3 transduces signals that modulate pathologic myocyte growth. Targeting of signaling complexes that contain select kinase isoforms should provide an approach for the specific inhibition of cardiac myocyte hypertrophy and for the development of novel strategies for the prevention and treatment of heart failure.
Association between the −514 c→t polymorphism of the hepatic lipase gene promoter and unstable carotid plaque in patients with severe carotid artery stenosis
Authors: Elisabetta Faggin, Alberto Zambon, Massimo Puato, Samir S Deeb, Sandra Bertocco, Saverio Sartore, Gaetano Crepaldi, Achille C Pessina, Paolo Pauletto
Journal: Journal of the American College of Cardiology (2002)
Premeal Insulin Treatment During Basal-Bolus Regimen in Young Children With Type 1 Diabetes
Authors: Valentino Cherubini, Antonio Iannilli, Dario Iafusco, Francesca Cardella, Maria Sole Giamprini, Carmine Fanelli, Giovanni Valentino Coppa
Journal: Diabetes Care (2006)

The introduction of insulin analogs in clinical practice suggests updating therapeutic schemes in subjects with type 1 diabetes. We read with interest the recent article by Alemzadeh et al. (1), which was designed to determine the feasibility of a flexible multiple daily insulin regimen in preschool children. Rapid-acting insulin analogs offer unquestionable advantages due to their pharmacokinetics and pharmacodynamic properties. However, when used in a basal-bolus regimen, they also need great accuracy in determining the carbohydrate content of the meal. A small mistake could generate a significant problem, including hyperglycemia or hypoglycemia. The meal carbohydrate count system seems to be effective and safe in controlling postmeal hyperglycemia in children treated with continuous subcutaneous insulin infusion (2), but when rapid-acting analogs are associated with glargine at bedtime, they could leave a “window” of low plasma insulin levels during the first portion of the night. Indeed, glargine-insulin plasma levels could not yet be consistently stable (3).

Moreover, when using rapid-acting insulin analogs, children need an additional insulin shot to control the carbohydrate intake of their afternoon snack, which is a common practice among children living in the Mediterranean area. The object of the present study was to evaluate fasting and postmeal metabolic effects in prepuberal children treated with glargine and regular or rapid-acting insulin using the carbohydrate counting system.

We recruited 30 prepuberal children aged 8.1 ± 1.8 years (means ± SD) with type 1 diabetes, having basal C-peptide <0.1 nmol/l, diabetes duration 5.2 ± …
MYC Activity Mitigates Response to Rapamycin in Prostate Cancer through Eukaryotic Initiation Factor 4E–Binding Protein 1–Mediated Inhibition of Autophagy
Authors: Bala S. Balakumaran, Alessandro Porrello, David S. Hsu, Wayne Glover, Adam Foye, Janet Y. Leung, Beth A. Sullivan, William C. Hahn, Massimo Loda, Phillip G. Febbo
Journal: Cancer Research (2009)

Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.
Association of Mutant<i>TP53</i>with Alternative Lengthening of Telomeres and Favorable Prognosis in Glioma
Authors: Yu-Jen Chen, Vicky Hakin-Smith, Mario Teo, George E. Xinarianos, David A. Jellinek, Thomas Carroll, David McDowell, Martin R. MacFarlane, Ronald Boet, Bruce C. Baguley, Antony W. Braithwaite, Roger R. Reddel, Janice A. Royds
Journal: Cancer Research (2006)

Abstract The molecular basis for alternative lengthening of telomeres (ALT), a prognostic marker for glioma patients, remains unknown. We examined TP53 status in relation to telomere maintenance mechanism (TMM) in 108 patients with glioblastoma multiforme and two patients with anaplastic astrocytoma from New Zealand and United Kingdom. Tumor samples were analyzed with respect to telomerase activity, telomere length, and ALT-associated promyelocytic leukemia nuclear bodies to determine their TMM. TP53 mutation was analyzed by direct sequencing of coding exons 2 to 11. We found an association between TP53 mutation and ALT mechanism and between wild-type TP53 and telomerase and absence of a known TMM (P &amp;lt; 0.0001). We suggest that TP53 deficiency plays a permissive role in the activation of ALT. (Cancer Res 2006; 66(13): 6473-6)
Murine T cells express a cell surface receptor for multiple extracellular matrix proteins. Identification and characterization with monoclonal antibodies.
Authors: S R Maxfield, K Moulder, F Koning, A Elbe, G Stingl, J E Coligan, E M Shevach, W M Yokoyama
Journal: The Journal of Experimental Medicine (1989)

Cell-cell and cell-extracellular (ECM) protein interactions are mediated through heterodimers termed integrins. We have demonstrated that dendritic epidermal T cell (DETC) lines adhere to the ECM proteins, fibronectin, fibrinogen, and vitronectin but not to collagen, laminin, or control proteins. This adhesion was blocked by the tetrapeptide RGDS, but not the control peptide, RGES. We have derived a hamster mAb H9.2B8, and a rat mAb, 8.18E12, from immunizations with DETC lines. The mAbs in combination, but not individually, specifically inhibited the adhesion of DETC lines to fibronectin, fibrinogen, and vitronectin. Immunoprecipitation analysis revealed that both mAbs reacted with a heterodimer composed of noncovalently linked 140- and 95-kD subunits. The 140-kD subunit can be reduced to 120- and 23-kD fragments. Although the two mAbs did not cross-compete for binding to DETC, sequential immunoprecipitation studies indicated that they react with the same 120-kD fragment. While all DETC cell lines and several T cell clones were reactive with the mAbs, the mAbs were not reactive with normal spleen, lymph node, thymus, or skin. Stimulation of splenic T cells with Con A or allogeneic cells induced mAb reactivity after 1 wk in vitro. These data demonstrate that a single lymphocyte receptor, with biochemical features characteristic of integrins, mediates RGD-dependent binding to the ECM proteins, fibronectin, fibrinogen, and vitronectin. Furthermore, since this integrin is expressed by long-term activated T cells, this receptor may play a physiological role in T cell function.
Reply to M.G. McNamara et al and M.S. Copur et al
Authors: Susan M. Domchek, Bella Kaufman, Michael Friedlander
Journal: Journal of Clinical Oncology (2015)

We thank the authors for their supportive comments and questions regarding our study, "Olaparib Monotherapy in Patients With Advanced Cancer and Germline BRCA1/2 Mutations." 1 McNamara et al 2 question the study design, end points, and dose modifications.This was a signal-seeking phase II study of olaparib with the inherent limitations of all phase II trials.The impact of olaparib on overall survival as well as on patient-reported outcomes such as symptom benefit is best addressed in randomized phase III trials.The primary aim of this trial was to look for an efficacy signal in heavily pretreated patients with germline BRCA mutations and a wide range of cancers that included ovarian, breast, pancreatic, and prostate, as well as others.These patients typically have limited treatment options and the results of phase II trials can drive progress.Indeed, the results of this study were included in the consideration by the US Food and Drug Administration for the approval of olaparib for women with BRCA-associated recurrent ovarian cancer after more than three lines of therapy (an unmet clinical need).McNamara et al 2 also question the dose modifications for toxicity and whether patients received adequate dose intensity.Future studies are needed to determine minimally effective dose.This is particularly relevant in patients who have been heavily pretreated who may be at risk of increased toxicities and require dose reductions.We agree that knowledge of poststudy treatment after olaparib would be helpful.Approximately 50% of individuals overall (40% with pancreatic cancer) received subsequent therapy but detailed information is not available.McNamara et al 2 ask whether an undiscovered PALB2 mutation could have contributed to hematologic adverse events.We think that this is unlikely given the rarity of coexistent homologous recombination (HR) gene mutations in BRCA mutation carriers and it is more likely that prior chemotherapy contributed to the toxicity seen. 3opur et al 4 asked about the impact on response rates of women with platinum-sensitive ovarian cancer who could not receive further platinum.Unfortunately, these data were not collected prospectively but are being retrospectively ascertained.A preliminary analysis suggests that approximately 70% had platinum-resistant/-refractory ovarian cancer.Once all data are available, we will report the response rates in ovarian patient by platinum status as well as address the percentage of patients with high-grade serous cancer.It is however likely that the majority had high-grade serous ovarian cancer in keeping with the literature.Although not reported in the original article, an equal number of patients with breast cancer had estrogen receptor (ER) -positive and ER-negative disease (each group with 31, 50%).Four patients in each group had a confirmed RECIST partial response.This is consistent with data from Tutt et al, 5 who did not observe difference in response rates to olaparib based on ER status.
Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival
Authors: J. Silva, V. García, Á. Zaballos, M. Provencio, L. Lombardía, L. Almonacid, J.M. García, G. Domínguez, C. Peña, R. Diaz, M. Herrera, A. Varela, F. Bonilla
Journal: European Respiratory Journal (2010)

The identification of tumour biomarkers that detect the presence of disease using noninvasive diagnostic procedures is a key part of cancer research. We determined in plasma the vesicle-related microRNA (miRNA) expression profile of nonsmall cell lung cancer (NSCLC) and evaluate whether plasma miRNAs can be both discriminating (between patients and healthy controls) and prognostic markers. 365 human miRNAs were analysed by Taqman® low-density arrays (Applied Biosystems, Foster City, CA, USA) in the plasma from 28 NSCLC patients and 20 controls. Five selected miRNAs (let-7f, miR-20b, miR-30e-3p, miR-223 and miR-301) were validated independently by real-time PCR in plasma from 78 NSCLC and 48 controls and correlated with pathologic parameters and survival. Levels of let-7f, miR-20b and miR-30e-3p were decreased in plasma vesicles of NSCLC patients. Moreover, levels of let-7f and miR-30e-3p distinguished between two groups of patients for stage of disease and therefore possibility of surgery. Plasma levels of miR-30e-3p and let-7f were associated with short disease-free survival and overall survival, respectively. NSCLC patients and healthy controls differ in vesicle-related miRNAs in plasma. Levels of let-7f and miR-30e-3p in NSCLC patients are associated with poor outcome. Thus, plasma vesicle-related miRNAs obtained by noninvasive methods could serve as circulating tumour biomarkers of discriminating and prognostic value.