tbuckley/cabot-search huggingface dataset:
Abstract 204: Loss Of Akt Caused Aging-induced Cardiac Systolic Dysfunction But Is Independent From Comorbid Diastolic Dysfunction In Aging.
Authors: Morihiko Aoyama, Yasuko K Bando, Akio Monji, Toko Mitusi, Haruya Kawase, Toyoaki Murohara
Journal: Circulation Research (2013)

PURPOSE: Aging is one of the primary factors causing cardiac dysfunction. Diastolic dysfunction (DD) is primary characteristics for aging-induced heart failure. Clinical evidences demonstrate a sustained exercise (EX) ameliorates DD; however, it remains unclear whether EX may ameliorate the aging-related DD and the underlying molecular mechanism. We thus evaluated whether EX may ameliorate cardiac dysfunction in aging and the role of Akt in the EX-induced effects on aging heart. Methods: Male senescence-accelerated (SAM) mice (P10) and its aging-resistant control (R1) were allocated to exercise [EX; 60-min running on treadmill every single day for 6 months (P10-EX and R1-EX)] and exercise-free control groups (P10-ctl and R1-ctl). Age-matched C57BL6 mice were subjected to the same EX protocol (C57-EX and C57-ctl) to compare any influence of genetic background. To elucidate the role of Akt in aging-induced changes in heart, analysis of aged Akt knockout mice (AktKO) were conducted. Results: At baseline, cardiac geometry of R1 strain revealed normal, whereas P10 strain exhibited reduced LV wall thickness and DD. The s-LVF of both strains was preserved. After EX, the body and heart weight of R1 mice were increased (BW; +6.7% and HW; +3.5% versus R1-ctl); however, EX had no influence on BW and HW of P10. EX promoted LV hypertrophy in R1, which was absent in P10-EX. The d-LVF of R1-EX was impaired but their s-LVF was unchanged. In contrast, s-LVF of P10-EX turned impaired [EF(%) 68.9±1.5 vs 74.3±1.2 for P10-ctl], whereas the underlying DD of P10 was unaffected by EX. In C57-EX, cardiac function exhibited the similar trends observed in R1-EX. Cardiac Akt activity of R1-EX and C57-EX were enhanced compared to controls, which was diminished in P10-EX. Aged AktKO exhibited impaired s-LVF [EF(%)61.3±1.0], nonetheless their DD remained unchanged [E/A=2.5±0.3, Dct (msec)= 35.0±2.4]. Conclusions: Our study demonstrates that #1 Akt is essential for adaptive response of LV hypertrophy to EX, #2 aging impairs Akt signaling in heart, leading to systolic dysfunction, and #3 Akt is independent from modulation of cardiac DD induced by aging. Clinical implications are drawn that the benefit of EX on DD may be irrelevant to the aged population.
"Multiplex" targeting of metastatic cells: The IRS-2 paradigm.
Authors: Anja Huq, Desmond Mascarenhas
Journal: Clinical Cancer Research (2007)

B19  Disseminated metastatic disease is the primary cause of cancer deaths. What differentiates a metastatic variant from the original tumor community is not well understood, but may involve an improved phenotypic ability to adapt to new environments and cope with stress. Biochemical correlates of such phenotypes may include deregulated IRS-2/Akt signalling, NF-kappa-B and p38 MAPK stress kinase, all secondary to an underlying genetic propensity for change. We show that MDA-MB-231 cells that successfully metastasize to liver have higher IRS2:IRS1 ratios than the parental cell population. Bone marrow has been suggested as an important point of intervention in metastatic process for breast cancer and leukemia. We have used the metal-binding domain (MBD) of IGFBP-3 to target small and large protein molecules directly and efficiently into cells of bone marrow in vivo. Effective reduction of disseminated disease was achieved in mouse models of breast cancer and leukemia when multiple inhibitor sequences targeting NF-kappa-B, MDM-2, P38MAPK, and PKC were combined on an MBD peptide scaffold or on an MBD-scFV antibody scaffold. In vitro, these same multiplex drug candidates show exquisite selectivity to cancer (when compared to matched non-cancer cells from the same patient).
Single-Nephron Glomerular Filtration Rate in Healthy Adults
Authors: Aleksandar Denic, Jerry Mathew, Lilach O. Lerman, John C. Lieske, Joseph J. Larson, Mariam P. Alexander, Emilio Poggio, Richard J. Glassock, Andrew D. Rule
Journal: New England Journal of Medicine (2017)

The glomerular filtration rate (GFR) assesses the function of all nephrons, and the single-nephron GFR assesses the function of individual nephrons. How the single-nephron GFR relates to demographic and clinical characteristics and kidney-biopsy findings in humans is unknown.We identified 1388 living kidney donors at the Mayo Clinic and the Cleveland Clinic who underwent a computed tomographic (CT) scan of the kidney with the use of contrast material and an iothalamate-based measurement of the GFR during donor evaluation and who underwent a kidney biopsy at donation. The mean single-nephron GFR was calculated as the GFR divided by the number of nephrons (calculated as the cortical volume of both kidneys as assessed on CT times the biopsy-determined glomerular density). Demographic and clinical characteristics and biopsy findings were correlated with the single-nephron GFR.A total of 58% of the donors were women, and the mean (±SD) age of the donors was 44±12 years. The mean GFR was 115±24 ml per minute, the mean number of nephrons was 860,000±370,000 per kidney, and the mean single-nephron GFR was 80±40 nl per minute. The single-nephron GFR did not vary significantly according to age (among donors <70 years of age), sex, or height (among donors ≤190 cm tall). A higher single-nephron GFR was independently associated with larger nephrons on biopsy and more glomerulosclerosis and arteriosclerosis than would be expected for age. A higher single-nephron GFR was associated with a height of more than 190 cm, obesity, and a family history of end-stage renal disease.Among healthy adult kidney donors, the single-nephron GFR was fairly constant with regard to age, sex, and height (if ≤190 cm). A higher single-nephron GFR was associated with certain risk factors for chronic kidney disease and certain kidney-biopsy findings. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
Salvage guideline for local-regional failure after stereotactic ablative radiotherapy for early-stage non-small cell lung cancer.
Authors: Eric Brooks, Bing Sun, Lina Zhao, Ritsuko Komaki, Zhongxing X. Liao, Melenda Jeter, Michael O'Reilly, James William Welsh, Daniel Richard Gomez, Quynh Nguyen, Mara Antonoff, Stephen M. Hahn, John Heymach, David C. Rice, Joe Y. Chang
Journal: Journal of Clinical Oncology (2017)

8501 Background: Up to 1 in 7 patients receiving stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) will develop local-regional recurrence. While SABR is the pillar of treatment for medically inoperable patients, little is known about outcomes and management for this potentially curable, local-regionally recurrent patient group. Methods: We present the first long-term results for the largest group of salvaged patients with local-regional recurrence after SABR. 772 patients with clinically early-stage I-II NSCLC were treated with SABR (50 Gy in 4 or 70 Gy in 10 fractions) between 2004-2014 at our center. Patients with isolated local recurrence (LR, n = 34) or regional recurrence (RR, n = 41) were analyzed and compared to patients with no recurrence (NR, n = 569). Results: Median time to LR or RR after SABR was 14 months. Salvage was performed in 79.4% of LR and 92.7% of RR patients. Salvage consisted of surgery (20% LR, 2% RR), re-irradiation (24% LR, 17% RR), radiofrequency ablation (15% LR), chemotherapy (15% LR, 26% RR), and chemoradiation (6% LR, 44% RR) based on a standard multi-disciplinary decision approach (Figure 1). 5-year OS was 37.1% for LR and 39.1% for RR patients. Of LR and RR patients, those receiving salvage had significantly better 5-year OS compared to those not receiving salvage (45.2% LR, 42.9% RR, 0% no salvage; p = 0.009). 5-year OS for salvaged patients was not statistically different from patients with NR (53.5% NR, p = 0.466). 5-year lung-cancer specific survival was 51% for LR and 55.1% for RR patients. Subsequent DM occurred in 20.5% of LR and 29.3% of RR patients at a median of 8.4-10.3 months. No salvaged patient experienced grade 5 toxicity. Conclusions: Patients with local or regional recurrence after SABR have excellent outcomes with salvage therapy, with no statistical difference in 5- year OS between LR and RR patients salvaged after SABR, and patients with no recurrence. Because a standard multidisciplinary approach was applied to any LR or RR patient after SABR, a novel treatment algorithm is generated. We offer a much needed management guide for thoracic oncologists treating patients who local-regionally recur after SABR.
Influence of preparative regimen and methotrexate for GVHD prophylaxis on engraftment after related cord blood transplant for patients with hemoglobinopathies. An eurocord group analysis
Authors: F. Locatelli, V. Rocha, M. Ertem, S. Graphacos, F. Bernaudin, X. Li, B. Brichard, Arnon Nagler, R. Miniero, I. Roberts, I. Yaniv, P. Lutz, A. Will, T. Raja, F. Garnier, E. Gluckman
Journal: Blood (2000)
Differences in the symptomatic phase preceding ACPA-positive and ACPA-negative RA: a longitudinal study in arthralgia during progression to clinical arthritis
Authors: Leonie E Burgers, Hanna W van Steenbergen, Robin M ten Brinck, Tom WJ Huizinga, Annette HM van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2017)

Although anticitrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) have different aetiopathology, the clinical presentation at the time of diagnosis is similar. This study evaluated whether there are phenotypic differences in the symptomatic pre-RA phase.Patients with arthralgia included in the Leiden clinically suspect arthralgia cohort who developed arthritis during follow-up were studied (n=67). Symptoms at symptom onset, symptoms and signs at presentation with arthralgia and time to arthritis development were compared between ACPA-positive and ACPA-negative patients.In ACPA-negative patients (n=37), the location of initial symptoms less often included the lower extremities (22% vs 50%, p=0.014). At presentation with arthralgia, ACPA-positive patients had a longer symptom duration (median 22 vs 14 weeks, p=0.005), less tender joints (mean 5 vs 9, p=0.007) and less difficulty making a fist (11% vs 43%, p=0.004). However, after presentation with arthralgia, ACPA-positive patients developed arthritis more quickly (median 6 vs 18 weeks, p=0.015). A partial least squares regression analysis showed clustering of ACPA-positive and ACPA-negative patients based on the above-mentioned clinical variables.This study is the first showing that ACPA-positive and ACPA-negative patients have clinical differences in the symptomatic phase preceding clinical arthritis. This contributes to the notion that ACPA-positive and ACPA-negative RA develop differently.
Liposome-encapsulated doxorubicin plus cyclophosphamide followed by trastuzumab plus docetaxel as neoadjuvant therapy for HER2-positive breast cancer (BC): A multicenter single-arm phase II study.
Authors: Silvana Saracchini, Luisa Foltran, Sandro Sulfaro, Fausto Tuccia, Alessandro Del Conte, Manuela Bertola, Anna Bassini, Elvia Micheli, Stefania Manente, Giuseppina Gusso, Tania Baresic, Salvatore Tumolo
Journal: Journal of Clinical Oncology (2013)

641 Background: Trastuzumab combined to sequential chemotherapy with taxanes and anthracyclines as primary treatment achieved high rates of pathologic complete response (pCR) in HER2 positive BC. Liposome-encapsulated doxorubicin (DLNP) shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab associated with chemotherapy for early or locally advanced HER2 positive BC. Methods: Primary objective of the study was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Preoperative treatment included DLNP (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Patients (pts) were scheduled to receive adjuvant trastuzumab (8 mg/mq loading dose, then 6 mg/mq iv) every 3 weeks for 12 cycles and radiation and hormonal therapy according to guidelines. Results: From December 2005 to September 2011, 43 pts were treated at 3 centers in Italy. 39 out of 43 pts were evaluable for the purpose of the study. Median age was 53 years (range: 31-78). The majority of pts had cT2 (63%), grade 3 (93%), N+ (77%) ER positive (56%) and MIB-1 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. The histological regression score (Von Minckwitz G, J Clin Oncol 2012) is shown in the Table. A significant correlation between MIB-1 ≥20% at baseline and pCR was observed (p=0.018). Pts with pCR had a time to response (29.4 weeks, 95% CI 28-31) lower than pts without pCR (32.9 weeks, 95% CI 27-39). No cardiac toxicity or discontinuation of trastuzumab was reported. After a median follow-up of 30 months only 2 pts relapsed, both with pCR. Conclusions: This study confirms the high activity of trastuzumab combined with chemotherapy based on anthracyclines and taxanes as primary treatment for HER2 positive BC. DLNP is an active and safe option to minimize cardiotoxicity. [Table: see text]
Functional analysis of thymosin beta-4 using over-expressing transgenic mice
Authors: Hee Jae Cha, Deborah Philp, Hye-Sung Moon, Takashi Nakamura, Hynda K. Kleinman
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1057 

Thymosin beta-4, an actin-binding 43 amino acid peptide, has multi-functional roles in cell physiology. It was first identified as a thymic maturation factor and recently has been shown to accelerate wound healing, hair growth, and angiogenesis. Furthermore, we found that thymosin beta-4 stimulates tumor growth and metastasis by induction of cell migration and vascular endothelial growth factor (VEGF)- mediated angiogenesis. Using a construct on the keratin 5 promoter, we have now developed thymosin beta-4 over-expressing transgenic mice to further study its functional roles. We are examining if the mouse will develop more spontaneous cancers or be more susceptible to tumor-promoting agents. The over-expression of thymosin beta-4 in the skin of transgenic mice was confirmed by both western blot and immunohistochemical analyses. The phenotype of thymosin beta-4 over-expressing mice was examined. Spontaneous tumors or developmental differences were not observed in any of the organs except the mice had unusually shaped teeth. The teeth have dull incisors and white color similar to the enamel complex deficient mice. Both wound healing and hair growth were accelerated in the thymosin beta-4 over-expressing mice. The susceptibility of these mice to cancer promoting agents was also evaluated, but thymosin beta-4 expression had no effect on tumor progression/formation. We conclude that thymosin beta-4 does affect certain developmental processes and can promote tumor metastasis, but that it is not oncogenic.
Reply to Syn et al.
Authors: C. Wai, K. Ho
Journal: Endoscopy (2004)

We thank Syn et al. for their interest in our article [1]. With their report and ours and another one in a recent issue of Endoscopy [2], six cases of dislodgment of ligator caps have now been described. All the cases occurred when upper gastrointestinal endoscopes were being upgraded to slimmer models, and the endoscopists were unaware of a mismatch between the outer diameters of the upgraded endoscopes and the fitting sizes of the band ligator caps. Table [1] shows the different sizes of some of the currently available endoscopes and variceal band ligator caps.
Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study
Authors: S K Kumar, M A Dimopoulos, E Kastritis, E Terpos, H Nahi, H Goldschmidt, J Hillengass, X Leleu, M Beksac, M Alsina, A Oriol, M Cavo, E M Ocio, M V Mateos, E K O'Donnell, R Vij, H M Lokhorst, N W C J van de Donk, C Min, T Mark, I Turesson, M Hansson, H Ludwig, S Jagannath, M Delforge, C Kyriakou, P Hari, U Mellqvist, S Z Usmani, D Dytfeld, A Z Badros, P Moreau, K Kim, P R Otero, J H Lee, C Shustik, D Waller, W J Chng, S Ozaki, J-J Lee, J de la Rubia, H S Eom, L Rosinol, J J Lahuerta, A Sureda, J S Kim, B G M Durie
Journal: Leukemia (2017)
Abstract 259: Role of Connexin 43 in Human Bone Marrow Derived Mesenchymal Stem Cell Cardiac Integration and Cardiac Stem cell Niche Formation.
Authors: Cristina Sanina, Claudia Rodrigues, Michael Bellio, Ivonne Schulman, Wayne Balkan, Konstantinos Hatzistergos, Irene Margitich, Joshua Hare
Journal: Circulation Research (2013)

Introduction: Bone marrow-derived mesenchymal stem cells (MSCs) and cardiac progenitor cells (CPCs) have been used successfully as a cell-based approach for cardiac regeneration after myocardial infarction. While MSCs and CPCs are effective, in part due to differentiation, paracrine effect, and integration into the heart, the mechanism underlying these effects remains controversial. Objective: We hypothesized that functional connexin 43 (Cx43) gap junctions are crucial for MSC and CPCs interaction and integration into cardiac tissue and cardiac stem cell niche formation. Methods and Results: Human MSCs were co-cultured with neonatal rat ventricular cardiomyocytes (NRVMs). The ability of MSCs to form gap junctions was modulated using lentiviral constructs to either knockdown (Cx43KD) or overexpress (Cx43OE) Cx43. Co-culture of Cx43OE or control MSCs with NRVMs led to the formation of beating, three-dimensional tubes whereas Cx43KD MSCs failed to form tubes (n=5, p&lt;0.05). Furthermore, we replicated the cardiac stem cell niche by combining human CPCs and MSCs in an in vitro model (the same lentiviral constructs were used). As a result, Cx43 expressing MSCs and CPCs formed organotypic three-dimensional structures similar to human MSCs and NRVMs, whereas the lack of Cx43 significantly affected the structure formation (n=6, p&lt;0.05). Cx43KD significantly increased proliferation (n=5, p&lt;0.05) and changed culture phenotype (n=4, p&lt;0.05) of MSCs or CPCs cultured separately. The angiogenic tube length, assessed by a Matrigel assay in vitro, was significantly reduced in MSCs and HUVEC Cx43 KD groups compared to control (n=5, p&lt;0.05). The change/onset of endothelial (KDR, PECAM-1, VE-cadherin), and cardiomyocyte (Nkx2.5, Gata4, Troponin I, Na+ channel, K+ channel, Ca2+ channel, Na+-Ca2+ exchanger) gene expression was investigated in co-culture of MSCs and CPCs. Only voltage ion channel gene expression was upregulated in control and Cx43OE groups by co-culture (n=5, p&lt;0.05), but not affected in Cx43KD group. Conclusion: These findings reveal that cell−cell contact mediated by Cx43 gap junctions enables MSCs to interact with CPCs, integrate and reconstitute cardiac stem cell niches.
Electronic Cigarettes as an Introductory Tobacco Product Among Eighth and 11th Grade Tobacco Users — Oregon, 2015
Authors: Jonas Z. Hines, Steven C. Fiala, Katrina Hedberg
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

During 2011-2015, increased electronic cigarette (e-cigarette) and hookah use offset declines in cigarette and other tobacco product use among youths (persons aged <18 years) (1). Limited information exists about which tobacco product introduced youths to tobacco product use. Patterns of first use of e-cigarettes among Oregon youths who were tobacco users were assessed in the Oregon Healthy Teens 2015 survey, a cross-sectional survey of eighth and 11th grade students in Oregon. Respondents were asked, "The very first time you used any tobacco or vaping product, which type of product did you use?" Among students who had ever used any tobacco product (ever users), e-cigarettes were the most common introductory tobacco product reported by both eighth (43.5%) and 11th (34.4%) grade students. Among students who used a tobacco product for ≥1 day during the past 30 days (current users), e-cigarettes were the most common introductory tobacco product reported by eighth grade students (44.4%) and the second most common introductory tobacco product reported by 11th grade students (31.0%). Introductory use of e-cigarettes was commonly reported among youths in Oregon who were ever or current tobacco users, underscoring the importance of proven interventions to prevent all forms of tobacco use among youths (2,3).
Cost-effectiveness of Xpert MTB/RIF for tuberculosis diagnosis in South Africa: a real-world cost analysis and economic evaluation
Authors: Anna Vassall, Mariana Siapka, Nicola Foster, Lucy Cunnama, Lebogang Ramma, Katherine Fielding, Kerrigan McCarthy, Gavin Churchyard, Alison Grant, Edina Sinanovic
Journal: The Lancet Global Health (2017)

In 2010 a new diagnostic test for tuberculosis, Xpert MTB/RIF, received a conditional programmatic recommendation from WHO. Several model-based economic evaluations predicted that Xpert would be cost-effective across sub-Saharan Africa. We investigated the cost-effectiveness of Xpert in the real world during national roll-out in South Africa.For this real-world cost analysis and economic evaluation, we applied extensive primary cost and patient event data from the XTEND study, a pragmatic trial examining Xpert introduction for people investigated for tuberculosis in 40 primary health facilities (20 clusters) in South Africa enrolled between June 8, and Nov 16, 2012, to estimate the costs and cost per disability-adjusted life-year averted of introducing Xpert as the initial diagnostic test for tuberculosis, compared with sputum smear microscopy (the standard of care).The mean total cost per study participant for tuberculosis investigation and treatment was US$312·58 (95% CI 252·46-372·70) in the Xpert group and $298·58 (246·35-350·82) in the microscopy group. The mean health service (provider) cost per study participant was $168·79 (149·16-188·42) for the Xpert group and $160·46 (143·24-177·68) for the microscopy group of the study. Considering uncertainty in both cost and effect using a wide range of willingness to pay thresholds, we found less than 3% probability that Xpert introduction improved the cost-effectiveness of tuberculosis diagnostics.After analysing extensive primary data collection during roll-out, we found that Xpert introduction in South Africa was cost-neutral, but found no evidence that Xpert improved the cost-effectiveness of tuberculosis diagnosis. Our study highlights the importance of considering implementation constraints, when predicting and evaluating the cost-effectiveness of new tuberculosis diagnostics in South Africa.Bill & Melinda Gates Foundation.
Phase 2 Randomized Trial Comparing Standard RCHOP Versus Brcap (bortezomib, rituximab, cyclophosphamide, adriamycin and prednisone) As First Line Treatment in Young Patients with High-Risk Diffuse Large B-Cell Lymphoma (DLBCL). a Study from Spanish Group Geltamo
Authors: Eva González-Barca, Estrella Carrillo-Cruz, Carlos Grande, Alejandro Martín, Mónica Coronado, Santiago Montes-Moreno, Santiago Mercadal, Josep Maria Roncero, Jaime Pérez de Oteyza, Concepción Nicolás, María José Rodríguez-Salazar, Juan-Manuel Sancho, Luis Palomera, Javier López-Jiménez, Carmen Albo, Francisco-Javier Peñalver, José Ángel Hernández, Armando López-Guillermo, María José Ramírez, Isidro Jarque, Joan Bargay, Miguel Canales, Eulogio Conde, Dolores Caballero
Journal: Blood (2016)