tbuckley/cabot-search huggingface dataset:
Chile’s 2014 sugar-sweetened beverage tax and changes in prices and purchases of sugar-sweetened beverages: An observational study in an urban environment
Authors: Juan Carlos Caro, Camila Corvalán, Marcela Reyes, Andres Silva, Barry Popkin, Lindsey Smith Taillie
Journal: PLoS Medicine (2018)

Background On October 1, 2014, the Chilean government modified its previous sugar-sweetened beverage (SSB) tax, increasing the tax rate from 13% to 18% on industrialized beverages with high levels of sugar (H-SSBs) (greater than 6.25 grams [g] sugar/100 milliliters [mL]) and decreasing the tax rate from 13% to 10% on industrialized beverages with low or no sugar (L-SSBs) (less than 6.25 g sugar/100 mL). This study examines changes in beverage prices and household beverage purchases following the implementation of the tax reform. Methods and findings We used longitudinal data collected between January 1, 2013, and December 31, 2015, from 2,000 households. We defined the pretax period as January 1, 2013, to September 30, 2014, and the posttax period as October 1, 2014, to December 31, 2015. We conducted a pre–post analysis for changes in prices and purchases, with the latter examined by volume and calories. We compared posttax changes in prices and purchases to a counterfactual, defined as what would have been expected in the posttax period based on pretax trends. All results are stated as comparisons to this counterfactual. We linked beverages at the bar code level to nutrition facts panel data collected by a team of Chilean nutritionists who categorized them by taxation level and beverage subcategory, which included carbonated and noncarbonated H-SSBs and concentrated, ready-to-drink L-SSBs and untaxed beverages. We reconstituted concentrated beverages and analyzed all beverages using as-consumed volumes and calories. Posttax monthly prices of H-SSBs increased, but these changes were small. Prices of carbonated H-SSBs increased by 2.0% (95% confidence interval [CI] 1.0%–3.0%), while those of noncarbonated H-SSBs increased by 3.9% (95% CI 1.6%–6.2%). Prices of L-SSB concentrates decreased after the tax by 6.7% (95% CI −8.2%–−4.6%), and prices of ready-to-drink L-SSBs increased by 1.5% (95% CI 0.3%–2.7%). Households decreased monthly per capita purchases of H-SSBs by 3.4% by volume (95% CI −5.9%–−0.9%) and 4.0% by calories (95% CI −6.3%–−1.9%), and this change was greater among high socioeconomic status (SES) households. The volume of household purchases of L-SSBs increased 10.7% (95% CI 7.5%–13.9%), while that of untaxed beverage purchases decreased by 3.1% (95% CI −5.1%–−1.1%). The main limitation of this study was that there was no control group, so we were unable to assess the causal impact of the tax. Conclusions The modifications of Chile's SSB tax were small, and observed changes in prices and purchases of beverages after the tax were also small. Our results are consistent with previous evidence indicating that small increases in SSB taxes are unlikely to promote large enough changes in SSB purchases to reduce obesity and noncommunicable diseases (NCDs).
Boost funding for social care to achieve integration with health, says watchdog
Authors: Jacqui Wise
Journal: BMJ (2018)

Without adequate and sustainable funding for social care, efforts to integrate health and social care will be hampered, the public spending watchdog has warned.

The National Audit Office (NAO) has said that the financial pressure that the NHS and local governments are under makes closer working between them difficult and can divert them from focusing on efforts to transform services.1

It acknowledged the recent announcement of a 3.4% boost for healthcare over the next five years23 but said that this may not be enough in the face of the growing needs of an ageing population. In the past, short term funding boosts have been used to cope with financial pressures rather …
Abstract 4021: The evaluation of carcinogenicity evidence of dibenzanthracenes
Authors: Feng Tsai, Jennifer C. Hsieh, Gwendolyn Osborne, Martha Sandy
Journal: Cancer Research (2018)

Abstract Dibenzanthracenes (DBAs) are identified as carcinogens and are on the California Proposition 65 list. DBAs are five-ring polycyclic aromatic hydrocarbons (PAHs). This chemical group consists of three isomers: DB[a,c]A, DB[a,h]A, and DB[a,j]A. DBAs are products of the incomplete combustion or pyrolysis of organic matter and can be formed during high temperature cooking. They are air pollutants present in engine exhaust, tobacco and marijuana smoke, and may also contaminate soil and water. DB[a,h]A is a well-studied International Agency for Research on Cancer (IARC) Group 2A carcinogen, whereas fewer studies relevant to carcinogenicity have been conducted with DB[a,c]A and DB[a,j]A. Carcinogenicity evidence from multiple data streams was integrated in the hazard identification of this chemical group. These data streams include animal cancer bioassays, mechanistic studies and other relevant data, including high-throughput studies (e.g., ToxCast), toxicogenomic studies, and information from quantitative structure-activity relationship (QSAR) models. Structure activity comparisons across the three DBAs and related carcinogenic PAHs served to bridge the data gaps for the two less studied isomers. The results of our analyses showed that each of the DBAs share similar biological activities in animals: all induce tumors in mice, are mouse skin tumor initiators, form DNA adducts, are genotoxic, and form metabolites that are also genotoxic and initiators of mouse skin tumors. All three DBAs activate the aryl hydrocarbon receptor (AhR) in reporter gene assays, and DB[a,h]A and DB[a,c]A have been shown to bind to the AhR. In addition to strong evidence of genotoxicity, other carcinogenic mechanisms are likely also operative, including receptor activation (e.g., AhR), immune suppression, altered cell proliferation, apoptosis, and cell cycle regulation. There are strong structure-activity similarities among the DBAs and several carcinogenic 4-, 5- and 6-ring PAHs, including benzo[a]pyrene and dibenzo[a,h]pyrene. In addition, DB[a,c]A and DB[a,j]A were predicted to be mutagenic and carcinogenic in several QSAR models, including VEGA, Lazar and OECD QSAR Toolbox. Integration of the evidence from these multiple data streams resulted in the identification of the DBAs as a chemical group as carcinogens. Citation Format: Feng Tsai, Jennifer C. Hsieh, Gwendolyn Osborne, Martha Sandy. The evaluation of carcinogenicity evidence of dibenzanthracenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4021.
A gel system for single instillation of non-muscle-invasive bladder Cancer: A “divide-and-rule” strategy
Authors: Pengyu Guo, Wenting Shang, Li Peng, Lu Wang, Hongzhi Wang, Ziyu Han, Hongmei Jiang, Jie Tian, Kun Wang, Wanhai Xu
Journal: Journal of Controlled Release (2018)
Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion
Authors: Haaglim Cho, Youngha Seo, Kin Man Loke, Seon-Wook Kim, Seong-Min Oh, Jun-Hyeong Kim, Jihee Soh, Hyoen Sik Kim, Hyunju Lee, Jin Kim, Jung-Joon Min, Da-Woon Jung, Darren Reece Williams
Journal: Clinical Cancer Research (2018)

Abstract Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network. Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database. Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell–activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data. Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the “henchmen” for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407–21. ©2018 AACR.
Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer
Authors: Shuai Li, Shengwu Liu, Jiehui Deng, Esra A. Akbay, Josephine Hai, Chiara Ambrogio, Long Zhang, Fangyu Zhou, Russell W. Jenkins, Dennis O. Adeegbe, Peng Gao, Xiaoen Wang, Cloud P. Paweletz, Grit S. Herter-Sprie, Ting Chen, Laura Gutiérrez-Quiceno, Yanxi Zhang, Ashley A. Merlino, Max M. Quinn, Yu Zeng, Xiaoting Yu, Yuting Liu, Lichao Fan, Andrew J. Aguirre, David A. Barbie, Xianghua Yi, Kwok-Kin Wong
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among patients with lung cancer, it is valuable to test potential therapeutics in KRAS mutation–driven mouse models. Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRASG12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRASG12C tumors compared with KRASG12D tumors. Moreover, we generated KRASG12C/p53R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition. Results: We determined higher pERK1/2 in KRASG12C lung tumors compared with KRASG12D. Using mouse models, we further identified that KRASG12C tumors are significantly more sensitive to selumetinib compared with KrasG12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice. Interestingly, p53 co-mutation rendered KRASG12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy. Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRASG12C and wild-type p53 status. Clin Cancer Res; 24(19); 4854–64. ©2018 AACR.
Abstract 3630: Deep and durable response with dual anti-CTLA-4 and PD-1 blockade in mismatch repair (MMR) proficient endometrial cancer
Authors: Michael S. Oh, Young Chae
Journal: Cancer Research (2018)

Abstract Immune checkpoint inhibitors have shown promising efficacy in multiple cancer types, but have yet to be extensively validated in endometrial cancer. However, the recent FDA approval of PD-1 inhibitors for mismatch repair (MMR) deficient tumors has extended use of these treatments to all cancer types. PD-L1 positivity in tumor tissue has also been shown to predict susceptibility to immunotherapy and has been used to guide use of these treatments. Despite these advances, the response to immunotherapy in endometrial cancer remains poorly understood. Here, we describe the case of a patient with MMR proficient, PD-L1-negative stage IV endometrial cancer with positive response to combination PD-1 and CTLA-4 inhibition. The patient initially presented with ascites and elevated tumor markers, and cytology from peritoneal fluid showed endometrial adenocarcinoma with squamous and mucinous differentiation and clear cell features. She underwent surgical debulking with both neoadjuvant and adjuvant cycles of docetaxel and carboplatin, but unfortunately had progressive metastatic disease within 4 months. The patient declined further chemotherapeutic agents, and thus was instead trialed on combination nivolumab and ipilimumab despite her cancer exhibiting MMR proficiency and negative PD-L1. She demonstrated deep and durable on-going partial response to this treatment that has persisted still after 10 months. Her course has notably been complicated by hypophysitis that manifested after 5 months of treatment as worsening fatigue, but she has been able to continue with her treatment regimen. This case indicates the potential existence of an endometrial cancer subtype that is sensitive to immune checkpoint blockade, but based on mechanisms other than those driven by MMR deficiency or PD-L1 positivity. Improved understanding of immunotherapy in advanced endometrial cancer is clearly needed and offers the potential to significantly enhance patient outcomes. Citation Format: Michael S. Oh, Young Chae. Deep and durable response with dual anti-CTLA-4 and PD-1 blockade in mismatch repair (MMR) proficient endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3630.
An explanation for the mysterious distribution of melanin in human skin: a rare example of asymmetric (melanin) organelle distribution during mitosis of basal layer progenitor keratinocytes
Authors: N. Joly-Tonetti, J.I.D. Wibawa, M. Bell, D.J. Tobin
Journal: British Journal of Dermatology (2018)

Melanin is synthesized by melanocytes in the basal layer of the epidermis. When transferred to surrounding keratinocytes melanin is the key ultraviolet radiation‐protective biopolymer responsible for skin pigmentation. Most melanin is observable in the proliferative basal layer of the epidermis and only sparsely distributed in the stratifying/differentiating epidermis. The latter has been explained as 'melanin degradation' in suprabasal layers. To re‐evaluate the currently accepted basis for melanin distribution in human epidermis and to discover whether this pattern is altered after a regenerative stimulus. Normal epidermis of adult human skin, at rest and after tape‐stripping, was analysed by a range of (immuno)histochemical and high‐resolution microscopy techniques. In vitro models of melanin granule uptake by human keratinocytes were attempted. We propose a different fate for melanin in the human epidermis. Our evidence indicates that the bulk of melanin is inherited only by the nondifferentiating daughter cell postmitosis in progenitor keratinocytes via asymmetric organelle inheritance. Moreover, this preferred pattern of melanin distribution can switch to a symmetric or equal daughter cell inheritance mode under conditions of stress, including regeneration. In this preliminary report, we provide a plausible and histologically supported explanation for how human skin pigmentation is efficiently organized in the epidermis. Steady‐state epidermis pigmentation may involve much less redox‐sensitive melanogenesis than previously thought, and at least some premade melanin may be available for reuse. The epidermal melanin unit may be an excellent example with which to study organelle distribution via asymmetric or symmetric inheritance in response to microenvironment and tissue demands.
Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes
Authors: Ahmed Karam Farag, Eun Joo Roh
Journal: Medicinal Research Reviews (2018)

Abstract Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death‐associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin‐dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs’ modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small‐molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.
Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells
Authors: Fiona Simpkins, Kibeom Jang, Hyunho Yoon, Karina E. Hew, Minsoon Kim, Diana J. Azzam, Jun Sun, Dekuang Zhao, Tan A. Ince, Wenbin Liu, Wei Guo, Zhi Wei, Gao Zhang, Gordon B. Mills, Joyce M. Slingerland
Journal: Clinical Cancer Research (2018)

Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition.
사례보고 : 알코올간경변증 환자에서 간세포암종으로 오인된 과혈관성 과형성 결절 1예
Authors: 박재은 ( Jae Eun Park ), 김병석 ( Byung Seok Kim ), 이창형 ( Chang Hyeong Lee ), 최준혁 ( Joon Hyuck Choi ), 박영찬 ( Young Chan Park ), 박관규 ( Kwan Kyu Park )
Journal: Clinical and Molecular Hepatology (2009)
Plasma Cortisol and Progression of Dementia in Subjects With Alzheimer-Type Dementia
Authors: John Csernansky
Journal: American Journal of Psychiatry (2006)

Objective: Studies of subjects with dementia of the Alzheimer type have reported correlations between increases in activity of the hypothalamic-pituitary-adrenal (HPA) axis and hippocampal degeneration. In this study, the authors sought to determine whether increases in plasma cortisol, a marker of HPA activity, were associated with clinical and cognitive measures of the rate of disease progression in subjects with Alzheimer-type dementia. Method: Thirty-three subjects with very mild and mild Alzheimer-type dementia and 21 subjects without dementia were assessed annually for up to 4 years with the Clinical Dementia Rating scale and a battery of neuropsychological tests. Plasma was obtained at 8 a.m. on a single day and assayed for cortisol. Rates of change over time in the clinical and cognitive measures were derived from growth curve models. Results: In the subjects with dementia, but not in those without dementia, higher plasma cortisol levels were associated with more rapidly increasing symptoms of dementia and more rapidly decreasing performance on neuropsychological tests associated with temporal lobe function. No associations were observed between plasma cortisol levels and clinical and cognitive assessments obtained at the single assessment closest in time to the plasma collection. Conclusions: Higher HPA activity, as reflected by increased plasma cortisol levels, is associated with more rapid disease progression in subjects with Alzheimer-type dementia.
Abstract 3636: The immune checkpoint, HVEM, is associated with PDL1 expression in lung cancer cell lines
Authors: Shengxiang Ren, Nadav Amar, Hui YU, Christopher Rivard, Kim Ellison, Leslie Rozeboom, Fred R. Hirsch
Journal: Cancer Research (2018)

Abstract Background: Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (BTLA) or activation of immune activity (LIGHT). This study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in cell lines and patient tumor tissue.Methods: A TMA of 53 characterized NSCLC, 48 SCLC cell lines and 35 malignant tumors were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was Dako Link48 autostainer using a polyclonal antibody from R&amp;D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.Results: IHC HVEM staining was optimized and demonstrated membranous staining with little or no cytoplasmic or nuclear staining. HVEM expression in the NSCLC and SCLC cell lines and malignant tumor TMA revealed a positive H-score more than 1 was 45.3%, 58.3% and 82.9% respectively. In comparison, PDL1 TPS expression of more than 1% was in 59.2%, 16.67% and 45.71% in NSCLC, SCLC cell lines and malignant tumor respectively. A significant correlation of HVEM with PDL1 expression was found in the NSCLC cell lines (r=0.518, p&amp;lt;0.001), while there was no significant association of HVEM with PDL1 expression in the small cell line cohort (r=0.059, p=0.688). Conclusion: HVEM expression was found to be higher in SCLC cell lines as compared to NSCLC cell lines and substantially greater in the general malignant tumor tissues. HVEM expression is associated with PD-L1 expression in NSCLC cell lines but not in SCLC cell lines. This data suggests a potential benefit of combined PD-L1 and HVEM blockade in patients with NSCLC to improve the efficacy of immune-therapy. Table 1. HVEM Expression in the studyH score01-100101-200201-300NSCLC Cell lines(n=53)29 (54.72%)23 (43.4%)1 (1.8%)0SCLC Cell lines(n=48)20 (41.67%)26 (54.17%)2 (4.17%)0Malignant TMA n=356 (17.14%)16 (45.71%)9 (25.71%)4 (11.43%) Citation Format: Shengxiang Ren, Nadav Amar, Hui YU, Christopher Rivard, Kim Ellison, Leslie Rozeboom, Fred R. Hirsch. The immune checkpoint, HVEM, is associated with PDL1 expression in lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3636.