tbuckley/cabot-search huggingface dataset:
The TORC1/2 inhibitor TAK228 sensitizes atypical teratoid rhabdoid tumors to cisplatin-induced cytotoxicity
Authors: Jeffrey A Rubens, Sabrina Z Wang, Antoinette Price, Melanie F Weingart, Sariah J Allen, Brent A Orr, Charles G Eberhart, Eric H Raabe
Journal: Neuro-Oncology (2017)

Atypical teratoid/rhabdoid tumors (AT/RTs) are deadly pediatric brain tumors driven by LIN28. Mammalian target of rapamycin (mTOR) is activated in many deadly, drug-resistant cancers and governs important cellular functions such as metabolism and survival. LIN28 regulates mTOR in normal cells. We therefore hypothesized that mTOR is activated downstream of LIN28 in AT/RT, and the brain-penetrating mTOR complex 1 and 2 (mTORC1/2) kinase inhibitor TAK228 would reduce AT/RT tumorigenicity.Activation of mTOR in AT/RT was determined by measuring pS6 and pAKT (Ser473) by immunohistochemistry on tissue microarray of 18 primary AT/RT tumors. In vitro growth assays (BrdU and MTS), death assays (CC3, c-PARP by western blot), and survival curves of AT/RT orthotopic xenograft models were used to measure the efficacy of TAK228 alone and in combination with cisplatin.Lentiviral short hairpin RNA-mediated knockdown of LIN28A led to decreased mTOR activation. Primary human AT/RT had high levels of pS6 and pAKT (Ser473) in 21% and 87% of tumors by immunohistochemistry. TAK228 slowed cell growth, induced apoptosis in vitro, and nearly doubled median survival of orthotopic xenograft models of AT/RT. TAK228 combined with cisplatin synergistically slowed cell growth and enhanced cisplatin-induced apoptosis. Suppression of AKT sensitized cells to cisplatin-induced apoptosis and forced activation of AKT protected cells. Combined treatment with TAK228 and cisplatin significantly extended survival of orthotopic xenograft models of AT/RT compared with each drug alone.TAK228 has efficacy in AT/RT as a single agent and synergizes with conventional chemotherapies by sensitizing tumors to cisplatin-induced apoptosis. These results suggest TAK228 may be an effective new treatment for AT/RT.
In Singletons Born at Term, Lower Gestational Age is Associated with Lower Cardiorespiratory Fitness Levels Through Adolescence to Young Adulthood: The Northern Ireland Young Hearts Project (NIYHP)
Authors: Isabel Ferreira, Pei T. Gbatu, Colin Boreham
Journal: Circulation (2017)

Decreases in the mean gestational age of term deliveries have been reported over the past decade in several developed countries, linked to increases in the rates of planned births by labour inducti...
Golgi phosphoprotein 3 promotes glioma progression via inhibiting Rab5-mediated endocytosis and degradation of epidermal growth factor receptor
Authors: Xiuping Zhou, Shao Xie, Shishuang Wu, Yanhua Qi, Zhaohao Wang, Hao Zhang, Dong Lu, Xu Wang, Yu Dong, Guanzheng Liu, Dongxu Yang, Qiong Shi, Wenbin Bian, Rutong Yu
Journal: Neuro-Oncology (2017)

Golgi phosphoprotein 3 (GOLPH3) is associated with worse prognosis of gliomas, but its role and mechanism in glioma progression remain largely unknown. This study aimed to explore the role and mechanism of GOLPH3 in glioma progression. The expression of GOLPH3 in glioma tissues was detected by quantitative PCR, immunoblotting, and immunohistochemistry. GOLPH3's effect on glioma progression was examined using cell growth assays and an intracranial glioma model. The effect of GOLPH3 on epidermal growth factor receptor (EGFR) stability, endocytosis, and degradation was examined by immunoblotting and immunofluorescence. The activity of Rab5 was checked by glutathione S-transferase pulldown assay. GOLPH3 was upregulated in gliomas, and its downregulation inhibited glioma cell proliferation both in vitro and in vivo. Furthermore, GOLPH3 depletion dampened EGFR signaling by enhancing EGFR endocytosis, driving EGFR into late endosome and promoting lysosome-mediated degradation. Interestingly, GOLPH3 bound to Rab5 and GOLPH3 downregulation promoted the activation of Rab5. In addition, Rab5 depletion abolished the effect of GOLPH3 on EGFR endocytosis and degradation. Our results imply that GOLPH3 promotes glioma cell proliferation via inhibiting Rab5-mediated endocytosis and degradation of EGFR, thereby activating the phosphatidylinositol-3 kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) signaling pathway. We find a new mechanism by which GOLPH3 promotes tumor progression through regulating cell surface receptor trafficking. Extensive and intensive understanding of the role of GOLPH3 in glioma progression may provide an opportunity to develop a novel molecular therapeutic target for gliomas.
Strategies for Preventing HIV Infection Among HIV-Uninfected Women Attempting Conception with HIV-Infected Men — United States
Authors: Jennifer F. Kawwass, Dawn K. Smith, Dmitry M. Kissin, Lisa B. Haddad, Sheree L. Boulet, Saswati Sunderam, Denise J. Jamieson
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

By the end of 2014, a total of 955,081 persons in the United States (299.5 per 100,000 population) had received a diagnosis of human immunodeficiency virus type 1 (HIV-1) infection (1). The annual estimated number of HIV infections and incidence rate in the United States decreased from 2010 to 2014, and the survival rate has increased over time (1). Effective highly active antiretroviral therapy (HAART) is helping persons with HIV to live longer, healthier lives. Many of these persons, including an unknown percentage in discordant relationships (i.e., one partner is HIV-infected, and the other is HIV-uninfected), might wish to have their own biologic children. When the female partner is HIV-infected and the male partner is not, a discordant couple can undergo autologous sperm intrauterine inseminations to achieve conception without placing the man at risk for infection. However, for HIV-discordant couples in which the man is HIV-infected and the woman is not, strategies to minimize the risk for sexual transmission are needed. In 1988, CDC recommended against insemination with semen from HIV-infected men (2). Since 1988, new information has emerged regarding prevention of HIV transmission in HIV-discordant couples. This report reviews laboratory and epidemiologic information regarding the prevention of HIV transmission for HIV-discordant couples, in which the male is HIV-infected and the female is HIV-uninfected, who would like to attempt conception.
Familial clustering of lung cancer (LC) cases in a south European population (sEp).
Authors: Iosune Baraibar, Eduardo Castanon Alvarez, José María López-Picazo, Alfonso Gurpide, Jose Luis Perez-Gracia, Juan Pablo Fusco, Patricia Martin, Leire Zubiri, Lucia Ceniceros, Jairo Legaspi, Marta Santisteban, Javier Rodriguez, Isabel Gil-Aldea, Javier Zulueta, Ignacio Gil-Bazo
Journal: Journal of Clinical Oncology (2015)

e12621 Background: The National Lung Cancer Screening Trial found, after 6.5 years, a 20% reduction in LC mortality in high-risk patients (pts) screened with low-dose computed tomography compared to chest x-ray. However, LC screening programs (SP) result controversial due to potential cost-effectiveness issues. Familial LC aggregation (fLCa) has been described previously. The estimated relative risk of LC is ∼1.8 for offspring of parents with LC. Linkage analysis has mapped a dominant locus to chromosome 6 in LC pedigrees. Therefore, in this high-risk subpopulation, SP may have clear advantages. This is the first study to investigate the incidence of fLCa conducted in a sEp. Methods: Overall, 509 cancer pts of Spanish (n = 473) or Portuguese (n = 36) origin were included in the analysis. A cohort of 236 consecutive pts (cases) diagnosed with LC was studied for family history (FH) of any type of cancer including LC. Another cohort of 273 pts (controls) with similar demographic characteristics diagnosed with cancer types other than LC was also studied for FH of cancer. We investigated whether LC pts show a higher incidence of fLCa than subjects with other solid tumors. Results: Among LC pts with a positive FH for LC, 36.7% showed one of their parents as the only LC relative, 26.5% showed one or more siblings, 18.4% one or more either uncle or aunt, 6.1% their grandfather/grandmother and 12.2% other combinations. Regarding the number of relatives affected, in our LC cohort one relative was the most frequent finding with 42/49 pts (85.7%), 2 in 3 cases (6.2%) and > 3 relatives in 4 subjects (8.1%). We studied the overall incidence of any type of family cancer among cases and controls. No differences were found between groups (72.9% vs 67.4%; p = 0.18). However, in our cohort of LC cases, 49/236 pts (20.8%) had a FH of LC in first or second degree whereas among cancer controls only 29/273 pts (10.6%) showed a LC FH (p = 0.002). Conclusions: This is the first estimation of LC FH in a non-selected sEp with LC. 20.8% of LC cases showed a positive FH for LC, being significantly higher (twofold) compared to other cancer pts. Therefore, the usefulness of directed SP for subjects with positive FH of LC should be prospectively evaluated and potential genomic drivers studied.
Prioritise children and over 65s for flu vaccination, say researchers
Authors: Anne Gulland
Journal: BMJ (2017)

People over 65 and young people aged 0-19 should be prioritised for influenza vaccination after high risk groups during times of limited vaccine supply, a study published in PLoS Computational Biology has recommended.1

Using computer modelling, researchers created a “synthetic population” in the US city of Chicago. They developed a population that works, moves, and mixes with others like a real community to build a more accurate …
Metagenomic Analysis Identified Human Rhinovirus B91 Infection in an Adult Suffering from Severe Pneumonia
Authors: Fugui Yan, Yan Xiao, Mingkun Li, Hao Zhang, Rong Zhang, Hongwei Zhou, Huahao Shen, Jianwei Wang, Wen Li, Lili Ren
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Resident memory CD8 <sup>+</sup> T cells in the upper respiratory tract prevent pulmonary influenza virus infection
Authors: Angela Pizzolla, Thi H. O. Nguyen, Jeffrey M. Smith, Andrew G. Brooks, Katherine Kedzierska, William R. Heath, Patrick C. Reading, Linda M. Wakim
Journal: Science Immunology (2017)

Nasal epithelial tissue of the upper respiratory tract is the first site of contact by inhaled pathogens such as influenza virus. We show that this region is key to limiting viral spread to the lower respiratory tract and associated disease pathology. Immunization of the upper respiratory tract leads to the formation of local tissue-resident memory CD8+ T cells (Trm cells). Unlike Trm cells in the lung, these cells develop independently of local cognate antigen recognition and transforming growth factor-β signaling and persist with minimal decay, representing a long-term protective population. Repertoire characterization revealed unexpected differences between lung and nasal tissue Trm cells, the composition of which was shaped by the developmental need for lung, but not nasal, Trm cells to recognize antigen within their local tissue. We show that influenza-specific Trm cells in the nasal epithelia can block the transmission of influenza virus from the upper respiratory tract to the lung and, in doing so, prevent the development of severe pulmonary disease. Our findings reveal the protective capacity and longevity of upper respiratory tract Trm cells and highlight the potential of targeting these cells to augment protective responses induced to respiratory viral vaccines.
Effect of intraperitoneal chemotherapy on survival for ovarian cancer in clinical practice and frequency of use.
Authors: Alexi A. Wright, Angel Cronin, Dana Milne, Michael A. Bookman, Robert Allen Burger, Mihaela C. Cristea, Jennifer J Griggs, Charles Levenback, Joyce C. Niland, Jane C. Weeks, David O'Malley
Journal: Journal of Clinical Oncology (2014)

5576 Background: In 2006 the National Cancer Institute (NCI) issued a rare clinical alert recommending intraperitoneal chemotherapy (IP) to treat ovarian cancer after GOG-172, a randomized clinical trial comparing IP and intravenous chemotherapy (IV), demonstrated a 16-month survival advantage with IP. The aims of this study were to determine: (1) changes in IP utilization over time, (2) factors associated with adoption of IP therapy, and (3) the impact of IP on survival. Methods: Prospective cohort study of women with stage III, optimally-cytoreduced ovarian cancer treated at National Comprehensive Cancer Network (NCCN) institutions. Trends were evaluated in 823 patients between 2003-2012. In 603 patients, diagnosed after 2006, multivariable logistic regression and propensity-score analyses were used to examine factors associated with receipt of IP therapy and associations between treatment modality, adverse events, and overall survival. Results: IP utilization rose from 0% to 33% between 2003-2006, increased to 50% in 2007-2008, and decreased to 43% during 2009-2012. At treatment initiation 43% of patients received modified IP regimens, 29% received the GOG 172 regimen, and 28% received IP on a clinical trial. In adjusted analyses, younger age, fewer comorbid conditions, and clinical trial enrollment were associated with IP therapy (all P≤0.01). NCCN center was independently associated with receipt of IP; the adjusted proportion of patients receiving IP varied by site between 16% and 71% (P<0.001). After propensity-score weighted adjustment, patients receiving IP were more likely to switch to IV due to toxicity (AOR=2.01, 95% CI=1.30-3.12) compared with IV. Adjusted 5-year overall survival rates were 57% for IP vs. 44% for IV (hazard ratio=0.69, 95% CI=0.50-0.94). Conclusions: The use of IP therapy increased significantly over the past decade at NCCN centers. However, recently only a minority of eligible patients have received it. Despite frequent modifications, IP chemotherapy is associated with significantly improved survival in clinical practice. Future studies should examine whether site-specific variations in IP utilization reflect patients’ informed treatment preferences.
CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission
Authors: L H Xie, M Biondo, S J Busfield, A Arruda, X Yang, G Vairo, M D Minden
Journal: Blood Cancer Journal (2017)

Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML. In vitro studies demonstrated that CSL362 potently induced antibody-dependent cell cytotoxicity (ADCC) of AML blasts including CD34+CD38-CD123+ LSCs by natural killer cells (NKs). Importantly, compared with healthy donor (HD) NKs, NKs drawn from AML patients in remission had a comparable ADCC activity against leukemic cells; of note, during remission, immature NKs were five times higher in AML patients than that in HDs. Significantly, we report a case where leukemic cells were resistant to autologous ADCC; however, the blasts were effectively lysed by CSL362 together with donor-derived NKs after allogeneic hematopoietic stem cell transplantation. These studies highlight CSL362 as a promising therapeutic option following chemotherapy and transplant so as to improve the outcome of AML patients.
Clinical and pathological characteristics of elderly colorectal cancer patients over 70 years old and comparison with patients under 50 years old.
Authors: Betul Erismis, Nadire Kucukoztas, Samed Rahatli, Selim Yalcin, Omer Dizdar, Ozden Altundag, Ozgur Ozyilkan
Journal: Journal of Clinical Oncology (2012)

e14174 Background: Incidence of colon cancer increases with age and generally is diagnosed at the age of between 60-75. Because of comorbidities in elderly patients who are older 70 years of age, lower doses of adjuvant or metastatic therapy is given them or the other option can be the chemotherapeutics which had less side effects. Methods: We aim to identify clinical and pathological characteristics of elderly colorectal cancer patients over 70 years of age who were followed at Baskent University Hospital and compare with CRC patients under the 50 years of age. Results: 182 CRC patients were assigned to the study who were followed between 1998-2011. We classified the patients into two categories according to the age. 91 participants were over 70 years of age and 91 participants were under 50 years of age. There were no significant differences between two groups for gender and percentage of patients having surgery (p=0.65/0.732). History of having systemic disease was significantly higher in the elderly group (p&lt;0.001). Adjvuvant chemotherapy was given to the 38 (53.5%) patients aged over 70 and 66 (91.7%) patients aged under 50 (p&lt;0.001). We compared the both groups for progression free and overall survival time for all stages. However, there were no statistically significant differences between two groups. Conclusions: Our study confirms that elderly CRC patients get benefit from the adjuvant chemotherapy treatment as the same as patients under 50 years of age. Therefore, physcians should consider about performance status and systemic disease in elderly patients and give an individual treatment to them.
Abstract P3-04-13: Protein tyrosine kinase 6 (PTK6) promotes survival of endocrine therapy-resistant ER+ breast cancer cells
Authors: HY Irie, SH Park, I Katsyv, W Zhang, A Nayak
Journal: Cancer Research (2017)

Abstract Background/Rationale: The non-receptor tyrosine kinase PTK6/Brk is highly expressed in the ER+/Luminal breast cancer subtypes. PTK6 expression has prognostic significance for patients with ER+ disease; higher transcript levels are associated with poorer survival. The functions of PTK6 in the context of ER+ breast cancer and sensitivity to endocrine therapy have not been explored. We sought to determine the functional roles of PTK6 in ER+ breast cancer cells, including those that are relatively resistant to current endocrine therapies. Methods/Results. We modulated the expression of PTK6 using both gain- and loss-of-function approaches. Enhanced expression of PTK6 in Tamoxifen-sensitive ER+ breast cancer cells was sufficient to confer relative Tamoxifen resistance. Furthermore, downregulation of PTK6 in ER+ breast cancer cells, including those that have acquired resistance to Tamoxifen, induced apoptosis, as evidenced by an increase in AnnexinV+ cells and increased levels of cleaved PARP. PTK6 downregulation impaired growth of Tamoxifen-resistant variants of ER+ MCF7 and T47D cells (MCF7TamR and T47DTamR) in 3D Matrigel culture, and virtually abrogated primary tumor growth of MCF7TamR xenografts. Mechanistically, p38MAPK activation is critical for PTK6 downregulation-induced apoptosis of ER+ breast cancer cells, as p38 inhibition partially rescues cells from PTK6 shRNA-associated apoptosis. Conclusions: Our studies highlight the critical role that PTK6 plays in the survival of ER+ breast cancer cells, including those that are resistant to endocrine therapy. Enhanced PTK6 expression in ER+ breast cancer cells is sufficient to promote endocrine therapy resistance, which could contribute to the poorer prognosis associated with higher PTK6 expression in ER+ patient tumors. As small molecule PTK6 inhibitors are becoming available, our studies support further evaluation of PTK6 as a candidate therapeutic target for endocrine therapy resistant ER+ breast cancers. Citation Format: Irie HY, Park SH, Katsyv I, Zhang W, Nayak A. Protein tyrosine kinase 6 (PTK6) promotes survival of endocrine therapy-resistant ER+ breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-13.
Morphological and molecular characterization of actinic lentigos reveals alterations of the dermal extracellular matrix
Authors: E. Warrick, C. Duval, S. Nouveau, P. Bastien, V. Piffaut, B. Chalmond, J-P. Ortonne, O. de Lacharrière, F. Bernerd
Journal: British Journal of Dermatology (2017)

Actinic lentigos (AL) are benign hyperpigmented skin lesions associated with photoageing. Despite their high prevalence, biological mechanisms driving their formation remain unclear.To provide new insights about the physiopathology of AL through a comprehensive description of their histological and molecular features.Quantitative analysis of dermoscopic images was used to select AL containing elongated patterns, predicted to display a highly deformed dermal-epidermal junction (DEJ), on the back of the hands of 15 Caucasian women. Biopsies from lesional and adjacent nonlesional (NL) areas were processed for histological analysis or gene expression profiling.Histological staining confirmed a drastic deformation of the DEJ in AL, with deep epidermal invaginations into the dermis. Although the melanin content was significantly higher in AL compared with NL epidermis, the distribution of melanocytes along the DEJ was unchanged. Transcriptomic analysis revealed a signature of 529 genes differently expressed in AL vs. NL skin. Alteration of epidermal homeostasis was confirmed by the dysregulation of keratinocyte proliferation and differentiation markers. Surprisingly, canonical genes involved in melanogenesis were not significantly modulated in AL. A striking finding was the overexpression of a large group of genes involved in dermal extracellular matrix organization and remodelling. Dermal alterations were confirmed by immunolabellings on AL and NL sections.Drastic disorganization of the cutaneous structure in AL is accompanied by a specific molecular signature revealing alterations in both epidermal and dermal compartments. In particular, our results suggest that local modifications of the dermal extracellular matrix might contribute to hyperpigmentation in AL.