tbuckley/cabot-search huggingface dataset:
Cognitive Function Deficits Associated With Long-Duration Type 1 Diabetes and Vascular Complications
Authors: Gail Musen, Liane J. Tinsley, Katrina A. Marcinkowski, David Pober, Jennifer K. Sun, Maya Khatri, Richie Huynh, Annie Lu, George L. King, Hillary A. Keenan
Journal: Diabetes Care (2018)

OBJECTIVE Patients with type 1 diabetes now live long enough to experience cognitive decline. During middle age, they show mild cognitive deficits, but it is unknown whether severity increases with aging or whether cognitive profiles are similar to those of age-matched peers with and without diabetes. RESEARCH DESIGN AND METHODS We tested and compared cognition in 82 individuals with 50 or more years of type 1 diabetes (Medalists), 31 age-matched individuals with type 2 diabetes, and 30 age-matched control subjects without diabetes. Medical histories and biospecimens were collected. We also evaluated the association of complications with cognition in Medalists only. RESULTS Compared with control subjects, both individuals with type 1 diabetes and individuals with type 2 diabetes performed worse on immediate and delayed recall (P ≤ 0.002) and psychomotor speed in both hands (P ≤ 0.01) and showed a trend toward worse executive function (P = 0.05). In Medalists, cardiovascular disease was associated with decreased executive function and proliferative diabetic retinopathy with slower psychomotor speed. CONCLUSIONS Both patients with type 1 and patients with type 2 diabetes showed overall worse cognition than control subjects. Further, in Medalists, a relationship between complications and cognition was seen. Although both groups with diabetes showed similar deficit patterns, the underlying mechanisms may be different. Now that patients with type 1 diabetes are living longer, efforts should be made to evaluate cognition and to identify modifying behaviors to slow decline.
A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer.
Authors: Cristina Saura, Fiona Thistlethwaite, Udai Banerji, Simon Lord, Victor Moreno, Iain MacPherson, Valentina Boni, Christian Diego Rolfo, Elisabeth G.E. de Vries, Carla M.L.- Van Herpen, Sylvie Rottey, Jill J.J. Geenen, Ferry Eskens, Marta Gil Martin, Ellen Mommers, Norbert Peter Koper, Roel Mulder, Philippe Georges Aftimos
Journal: Journal of Clinical Oncology (2018)

1014 Background: SYD985, (vic-)trastuzumab duocarmazine, is a HER2-targeting antibody-drug conjugate with a cleavable linker-duocarmycin payload that causes irreversible alkylation of the DNA in tumor cells. The dose-escalation part of a Phase I study was completed previously; we herein present preliminary efficacy data of the breast cancer expansion cohorts and safety data of all expansion cohorts (breast, gastric, urothelial and endometrial cancer). Methods: HER2 tumor expression was determined by a central lab and had to be immunohistochemistry (IHC) 1+ or higher; HER2-positive was defined as IHC 2+/3+/ISH+ and HER2-low as IHC 1+/2+/ISH-. Patients were treated with 1.2 mg/kg SYD985 IV every 3 weeks until disease progression or unacceptable toxicity. Tumor evaluation scans were done every 6 weeks. Results: Ninety-nine (99) breast cancer patients were enrolled. Of the 50 patients with HER2-positive breast cancer, the majority received 3 or more prior HER2-targeting regimens in the locally advanced or metastatic setting, including (ado-)trastuzumab emtansine in 80% of the patients. Preliminary results showed that SYD985 demonstrated an overall response rate (ORR) of 33% and a median PFS of 9.4 months. At the time of data cut-off, 8 patients (16%) received SYD985 for over one year and 5 patients (10%) continued to receive treatment. Efficacy has also been demonstrated in heavily pretreated patients with HER2-low metastatic breast cancer, including hormone-receptor positive (N = 32) and triple-negative breast cancer (N = 17). The ORRs were 27% and 40%, respectively, with several patients ongoing on SYD985. The safety profile was manageable and mainly characterized by grade 1 and 2 events. The most common adverse drug reactions were fatigue, dry eyes, conjunctivitis and increased lacrimation. Grade 3/4 adverse drug reactions most commonly reported included neutropenia (6%) and conjunctivitis (4%). Conclusions: SYD985 shows promising efficacy in heavily pretreated patients with breast cancer, in both HER2-positive and HER2-low tumors with or without hormone receptor expression. A Phase III study (TULIP) is currently ongoing in HER2-positive breast cancer patients. Clinical trial information: NCT02277717.
Bioactive hydrogels for bone regeneration
Authors: Xin Bai, Mingzhu Gao, Sahla Syed, Jerry Zhuang, Xiaoyang Xu, Xue-Qing Zhang
Journal: Bioactive Materials (2018)

Bone self-healing is limited and generally requires external intervention to augment bone repair and regeneration. While traditional methods for repairing bone defects such as autografts, allografts, and xenografts have been widely used, they all have corresponding disadvantages, thus limiting their clinical use. Despite the development of a variety of biomaterials, including metal implants, calcium phosphate cements (CPC), hydroxyapatite, etc., the desired therapeutic effect is not fully achieved. Currently, polymeric scaffolds, particularly hydrogels, are of interest and their unique configurations and tunable physicochemical properties have been extensively studied. This review will focus on the applications of various cutting-edge bioactive hydrogels systems in bone regeneration, as well as their advantages and limitations. We will examine the composition and defects of the bone, discuss the current biomaterials for bone regeneration, and classify recently developed polymeric materials for hydrogel synthesis. We will also elaborate on the properties of desirable hydrogels as well as the fabrication techniques and different delivery strategies. Finally, the existing challenges, considerations, and the future prospective of hydrogels in bone regeneration will be outlined.
Persistence of an outbreak of gonorrhoea with high-level resistance to azithromycin in England, November 2014‒May 2018
Authors: Christa Smolarchuk, Adrian Wensley, Simon Padfield, Helen Fifer, Andrew Lee, Gwenda Hughes
Journal: Eurosurveillance (2018)

Between November 2014 and May 2018, 118 laboratory-confirmed cases of high-level azithromycin resistant Neisseria gonorrhoeae were identified in England. Cases emerged among heterosexuals in Leeds but spread across England and into sexual networks of men who have sex with men as the outbreak progressed. The few epidemiological links identified indicate substantial under-diagnosis of cases and this, along with the upturn in cases in 2017, highlights the difficulties in controlling the outbreak.
Ultrasound-guided fine needle aspiration of retropharyngeal lymph nodes after radiotherapy for nasopharyngeal carcinoma: a novel technique for accurate diagnosis
Authors: Long‐Jun He, Chuanbo Xie, Yin Li, Lin‐Na Luo, Ke Pan, Xiao‐Yan Gao, Li‐Zhi Liu, Jian‐Ming Gao, Guang‐Yu Luo, Hong‐Bo Shan, Ming‐Yuan Chen, Chong Zhao, Wei‐Jun Fan, Ping Yang, Guo‐Liang Xu, Jian‐Jun Li
Journal: Cancer Communications (2018)

Enlarged retropharyngeal lymph nodes (RLNs) are very common in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. The most suitable treatment option for enlarged RLNs depends on the pathological results. However, RLN sampling is difficult and imminent in the clinic setting. We recently developed a novel minimally invasive technique termed endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for sampling RLN tissues sufficient for pathological or cytological diagnosis.We enrolled 30 post-radiotherapy patients with NPC with suspected RLN metastasis detected via magnetic resonance imaging (MRI). The EUS probe was introduced into the nasopharynx via the nostrils, and EUS was then used to scan the retropharyngeal space and locate the RLN in the anterior carotid sheath. EUS-FNA was subsequently performed. The safety and efficacy of using EUS-FNA to sample the RLN tissues were assessed.Strips of tissue were successfully sampled from all patients using EUS-FNA. Of the 30 patients, 23 were confirmed to have cancer cells in the biopsied tissues via pathology or cytology examinations with 1 EUS-FNA biopsy session. The seven cases without confirmed cancer cells were subsequently reanalyzed by using another EUS-FNA biopsy session, and two more cases were confirmed possessing cancer cells. The other five patients without confirmed cancer cells were closely followed with MRI every month for 3 months. After follow-up for 3 months, three patients were still considered cancer-free due to the presence of RLNs with stable or shrinking diameters. The rest two patients who showed progressive disease underwent a third EUS-FNA biopsy procedure and were further confirmed to be cancer cell-positive. In the whole cohort reported here, the EUS-FNA procedure was not associated with any severe complications.EUS-FNA is a safe and effective diagnostic approach for sampling tissues from the RLNs in patients with suspected recurrent NPC.
Overall survival in female Medicare beneficiaries with early stage breast cancer receiving bisphosphonates or denosumab.
Authors: Raul A Herrera Pena, Xiudong Lei, Mariana Chavez-MacGregor, Hui Zhao, Sharon Hermes Giordano, Maria E. Suarez-Almazor
Journal: Journal of Clinical Oncology (2018)

530 Background: Adjuvant bisphosphonates in early breast cancer (BC) have resulted in reduction in bone metastasis and improved overall survival (OS), particularly in post-menopausal women. We aim to evaluate the effect of bone-modifying agents (BMA) on survival in a population based cohort of older BC patients. Methods: Patients aged ≥ 66 yo diagnosed with stage I-III BC between 2007 and 2013 were identified in SEER-Medicare and TCR-Medicare database. Patients were required to have Medicare Parts A, B and D coverage. Patients receiving at least 6 months of an oral bisphosphonate, two doses of ibandronate or one dose of zoledronate or denosumab at doses equivalent or higher to those approved for osteoporosis, during the first two years of BC diagnosis were identified as having received a BMA. Five year-OS was estimated with Kaplan-Meier with groups compared with the log rank test. Cox proportional hazards models were fitted to determine the association of BMA and OS after propensity score adjustment. Subgroup analysis were stratified by stage. Results: The final cohort included 37,604 patients. Median age was 75 years. 32,045 (85.2%) of the patients had hormone receptor-positive tumors. Overall, 8,591 (22.8%) of the patients were treated with BMA. Of these, 7,349 (85.5%) received bisphosphonates only. The unadjusted 5 year OS was 81% and 77 % for those who did and did not receive BMA, respectively (P < 0.0001). After multivariate analysis including propensity scores adjustment, treatment with BMA was associated with a statistically significant increased survival (Hazard ratio [HR] 0.91, 95% CI = 0.85-0.96). When stratified by stage, BMA vs no BMA showed an improvement in unadjusted 5 year OS in patients with Stage II (5y OS 79% vs 72%, P < 0.0001) and Stage III (64% vs 57%, P = 0.002) but not for Stage I (86% vs 85%, P = 0.88). After multivariate adjustment, survival remained significant for Stage II (HR 0.81, 95% CI = 0.73-0.90) but not for Stage III (HR 0.91, 95% CI = 0.78-1.07). Conclusions: Use of BMA in post-menopausal woman with early stage BC patients was associated with improved 5 year OS. Stage stratified subgroup analysis showed that the difference in survival was significant only for patients with stage II.
Perceived facilitators and barriers to physical exercise adherence in esophageal cancer patients after surgery.
Authors: Jonna van Vulpen, Lenja Witlox, Alida Methorst - de Haan, Petra H.M. Peeters, Richard van Hillegersberg, Grard A. P. Nieuwenhuijzen, Ewout Kouwenhoven, Peter Siersema, Anne Maria May
Journal: Journal of Clinical Oncology (2018)

94 Background: To achieve optimal effects of exercise interventions in esophageal cancer patients, high adherence is needed. Knowledge on facilitators and barriers can help improving exercise adherence. Hence, the aim of this study is to evaluate perceived facilitators and barriers to physical exercise adherence in esophageal cancer patients in the first year after surgery. Methods: Semi-structured interviews were conducted with patients (n = 16) who were randomised to the exercise group of the Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) Study. Patients participated in a 12-week supervised combined aerobic and resistance exercise program twice weekly, and were advised to be physically active at least 30 minutes each day. Physiotherapists registered attendance at the supervised sessions and compliance (i.e., performing the exercises according to protocol). Transcribed interviews were analysed using a thematic content approach. Results: Median attendance was 97.9%, interquartile range (IQR): 91.7 – 100%. Median compliance to both components of the exercise program was high: 89.6% (IQR 75.5 – 95.8%) for aerobic exercise and 88.0% (IQR 73.8 – 93.6%) for resistance exercise. The most important perceived facilitators were patients’ own attitudes towards exercise (i.e. motivation, commitment and personal goals) and supervision by a physiotherapist. There were only few perceived barriers, of which the most frequently mentioned were logistic factors (i.e. holidays, conflicting activities and weather circumstances) and impaired physical condition due to regular endoscopic esophageal dilation therapy or general physical complaints, such as fatigue. Conclusions: Esophageal cancer patients after surgery are well capable to perform physical exercise with moderate-to-high intensity. The most important perceived facilitators for the high adherence rates are patients’ own attitudes towards exercise and supervision by a physiotherapist. Completion of the exercise program was only minimally affected by perceived barriers as logistic factors and physical complaints. This information can help in designing future exercise programs for clinical practice.
ATR inhibition controls aggressive prostate tumors deficient in Y-linked histone demethylase KDM5D
Authors: Kazumasa Komura, Yuki Yoshikawa, Teppei Shimamura, Goutam Chakraborty, Travis A. Gerke, Kunihiko Hinohara, Kalyani Chadalavada, Seong Ho Jeong, Joshua Armenia, Shin-Yi Du, Ying Z. Mazzu, Kohei Taniguchi, Naokazu Ibuki, Clifford A. Meyer, Gouri J. Nanjangud, Teruo Inamoto, Gwo-Shu Mary Lee, Lorelei A. Mucci, Haruhito Azuma, Christopher J. Sweeney, Philip W. Kantoff
Journal: Journal of Clinical Investigation (2018)

Epigenetic modifications control cancer development and clonal evolution in various cancer types. Here, we show that loss of the male-specific histone demethylase lysine-specific demethylase 5D (KDM5D) encoded on the Y chromosome epigenetically modifies histone methylation marks and alters gene expression, resulting in aggressive prostate cancer. Fluorescent in situ hybridization demonstrated that segmental or total deletion of the Y chromosome in prostate cancer cells is one of the causes of decreased KDM5D mRNA expression. The result of ChIP-sequencing analysis revealed that KDM5D preferably binds to promoter regions with coenrichment of the motifs of crucial transcription factors that regulate the cell cycle. Loss of KDM5D expression with dysregulated H3K4me3 transcriptional marks was associated with acceleration of the cell cycle and mitotic entry, leading to increased DNA-replication stress. Analysis of multiple clinical data sets reproducibly showed that loss of expression of KDM5D confers a poorer prognosis. Notably, we also found stress-induced DNA damage on the serine/threonine protein kinase ATR with loss of KDM5D. In KDM5D-deficient cells, blocking ATR activity with an ATR inhibitor enhanced DNA damage, which led to subsequent apoptosis. These data start to elucidate the biological characteristics resulting from loss of KDM5D and also provide clues for a potential novel therapeutic approach for this subset of aggressive prostate cancer.
Comparison of breast conservative therapy to mastectomy in male breast cancer: A NCDB analysis.
Authors: Sarah Bateni, Anders J. Davidson, Mili Arora, Richard J. Bold, Robert J. Canter, Candice A. Sauder
Journal: Journal of Clinical Oncology (2018)

565 Background: Current treatment guidelines for male breast cancer (MBC) are largely based on clinical trials limited to female participants. With limited MBC research, it remains unclear if breast conservative therapy (BCT) is equivalent to mastectomy in MBC. Therefore, the purpose of this study was to compare survival among MBC patients for BCT vs. mastectomy using a large national database. Methods: We performed a retrospective analysis of 11,406 MBC patients with stage I-III disease from the National Cancer Database (NCDB) years 2004-2015, excluding Paget’s, T4/inflammatory, and multicentric disease. Patients were grouped according to surgical and radiation therapy (i.e. BCT, lumpectomy alone, mastectomy alone, and mastectomy with radiation). After performing standard parametric and nonparametric univariate analyses, cox proportional hazards multivariate regression analysis was performed to compare overall survival by treatment group controlling for demographic and clinicopathologic group differences. Results: The majority of MBC patients underwent mastectomy alone (n = 6,326, 55%), with the remaining 19% (n = 2,162) undergoing mastectomy with radiation, 18% (n = 2,085) undergoing BCT, and 7% (n = 833) undergoing lumpectomy alone. Compared with mastectomy alone and mastectomy with radiotherapy, BCT was associated with younger age (62 vs. 66 vs. 63 years old, p < 0.01), smaller tumors (median 1.5 cm IQR 0.9-2.0 vs. 2.0 cm IQR 1.4-2.6 vs. 2.5 cm IQR 1.8-3.5, p < 0.001), and lower nodal disease rates (21% vs. 31% vs. 81%, p < 0.001). In the multivariate model, BCT was associated with greater survival compared to mastectomy alone (HR 1.69, 95%CI 1.44-1.98, p < 0.001), mastectomy with radiation (HR 1.52, 95%CI 1.27-1.83, p < 0.001), and lumpectomy alone (HR 1.91, 1.56-2.33, p < 0.001). Increased age, T stage, N stage, histological grade, and triple negative hormone receptor/HER2 status were associated with poorer survival (p < 0.05). Conclusions: Although mastectomy is more common among MBC, BCT is associated with greater survival. These findings support the use of BCT as a viable treatment approach in MBC and consideration of greater adoption among surgeons and oncologists.
Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis
Authors: Elahu G. Sustarsic, Tao Ma, Matthew D. Lynes, Michael Larsen, Iuliia Karavaeva, Jesper F. Havelund, Carsten H. Nielsen, Mark P. Jedrychowski, Marta Moreno-Torres, Morten Lundh, Kaja Plucinska, Naja Z. Jespersen, Trisha J. Grevengoed, Barbara Kramar, Julia Peics, Jakob B. Hansen, Farnaz Shamsi, Isabel Forss, Ditte Neess, Susanne Keipert, Jianing Wang, Katharina Stohlmann, Ivan Brandslund, Cramer Christensen, Marit E. Jørgensen, Allan Linneberg, Oluf Pedersen, Michael A. Kiebish, Klaus Qvortrup, Xianlin Han, Bente Klarlund Pedersen, Martin Jastroch, Susanne Mandrup, Andreas Kjær, Steven P. Gygi, Torben Hansen, Matthew P. Gillum, Niels Grarup, Brice Emanuelli, Søren Nielsen, Camilla Scheele, Yu-Hua Tseng, Nils J. Færgeman, Zachary Gerhart-Hines
Journal: Cell Metabolism (2018)

Activation of energy expenditure in thermogenic fat is a promising strategy to improve metabolic health, yet the dynamic processes that evoke this response are poorly understood. Here we show that synthesis of the mitochondrial phospholipid cardiolipin is indispensable for stimulating and sustaining thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response through overexpression of cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency in thermogenic adipocytes diminishes inducible mitochondrial uncoupling and elicits a nuclear transcriptional response through endoplasmic reticulum stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake, which renders animals insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin has a powerful impact on organismal energy homeostasis through thermogenic fat bioenergetics.
Cardiovascular disease risk after treatment-induced primary ovarian insufficiency in female survivors of Hodgkin lymphoma.
Authors: Flora Van Leeuwen, Inge Krul, Annemieke Opstal-Van Winden, Cecile P.M. Janus, Laurien Daniels, Angela Maas, Rianne Van Nimwegen, Simone de Vries, Michael Hauptmann, Katarzyna Józwiak, Berthe M.P. Aleman
Journal: Journal of Clinical Oncology (2018)

114 Background: Female survivors of Hodgkin lymphoma (HL) treated with alkylating chemotherapy (CT) and/or pelvic radiotherapy (RT) have an increased risk of primary ovarian insufficiency (POI). Among women with a natural menopause, POI has been associated with increased risk of cardiovascular disease (CVD). We examined whether treatment-induced POI increases long-term CVD risk in HL survivors. Methods: From a large Dutch cohort of 5-year HL survivors, we selected 918 women who were treated before 41 years of age between 1965 and 2000. Data on HL treatment, menopausal status and cardiovascular events (ischemic heart disease (IHD), heart failure (HF) and valvular heart disease (VHD)) were obtained from medical records, general practitioners and patient questionnaires. CVD risks were estimated with Cox regression models using time-dependent covariates and attained age as the time scale. Results: After a median follow-up of 24 years, 299 out of 918 women (33%) had developed POI (median menopausal age, 34 years). We identified 463 cardiovascular events in 300 women, of whom 85 developed CVD after POI. POI was not associated with subsequent CVD risk (HR:0.85, 95% CI 0.62-1.16) compared with a menopausal age of ≥40 years. Compared with women who reached menopause at ages ≥50 years, the HRs for menopausal ages of &lt; 30 years, 30-39 and 40-49 years were 0.90 (95% CI 0.52-1.56), 0.87 (95% CI 0.57-1.33) and 0.96 (95% CI 0.64-1.44), respectively. Furthermore, a short duration of intact ovarian function after HL treatment ( &lt; 5 years) did not increase CVD risk compared to a long duration (≥25 years) (HR:0.72, 95% CI 0.44-1.20). 177 women had used HRT, of whom 115 (65%) with POI (median duration of HRT use, 8.3 years). Women who used HRT for ≥5 years did not have a higher CVD risk than non-HRT users (HR 1.02, 95% CI 0.64-1.62). Similar results were found in analyses with IHD, HF and VHD as separate outcomes. Conclusions: POI and duration of post-treatment intact ovarian function did not affect CVD risk in HL survivors, suggesting that an early artificial menopause does not increase CVD risk.