tbuckley/cabot-search huggingface dataset:
Zoledronate acid modifies the lipid transporters profile in human prostate cancer cell lines
Authors: M. Toledo Lobo, M. Arenas Jiménez, L. Huertas Martínez, S. Sacristán lópez, A. Moyano Jato, E. Fernández Fernández, M. Martín Hidalgo, R. Martín del Río, A. Gómez Pinillos
Journal: Journal of Clinical Oncology (2007)

21135 Background: The mechanism through wich zoledronic acid exerts its activity is poorly understood. Low density lipoprotein receptor (LDLR) and scavenger receptor class B type 1 (SRBI) overproduction is an important mechanism in cancer cells for obtaining more essential fatty acids and cell growth. The effects of in vitro zoledronate treatment on the lipid metabolism of prostate cancer cell lines were studied. Methods: Three prostatic cancer cell lines, androgen insensitive PC3, androgen dependent low-passage (LP) LNCaP and androgen independent high-passage (HP) LNCaP cells were studied. Cells were plated either in RPMI with 5% foetal calf serum and lipoprotein depleted serum (LPDS) and were treated with zoledronate at different concentrations. The lipid transporters profile was analyzed by western blotting for LDLR and SRB1. Results: The same LDLR bands profile was observed in all cell lines, 160 and 105 kDa. The basal levels of LDLR were higher in the PC3 cells. Zoledronate therapy induced LDLR expression in all cell lines but PC3 were less sensitive to this effect. Cells cultured with LPDS showed an enhanced expression of LDLR and PC3 cells were less sensitive to this effect. HP LNCaP cells were the most affected by lipoprotein deprivation however this effect diminished 72 hours after treatment. The bands profile for SRBI consisted of a 65 kDa predominant band and a 40 kDa band in both LP/HP LNCaP cells. In PC3 cells main band was located in 65 kDa and accessory band in 30kDa. The basal levels of the 65kDa band were higher in HP than in LP LNCaP or PC3 cells and zoledronate therapy caused a dose- dependent induction in HP LNCaP and dose-dependent reduction in PC3 cells, LP LNCaP cells were resistant to the treatment. LPDS induced SRBI levels in all cell lines inverting the effect caused by zoledronate in HP LNCaP cells in complete culture medium and at high doses (100μM) a complete inhibition of SRBI protein was found. Low molecular weight bands changed in the same way as the 65 kDa band. Conclusions: LDL-R and SRBI have been isolated in prostate cancer cell lines. Based on previous cell growth studies, the lipid transporters profile might be significantly involved in the resistance to zoledronate therapy. Lipoprotein regulation pathways should be considered in the therapy of metastatic prostate cancer. No significant financial relationships to disclose.
Correction: Evaluation of ERK as a therapeutic target in acute myelogenous leukemia
Authors: Ellen Weisberg, Chengcheng Meng, Abigail Case, Martin Sattler, Hong L. Tiv, Prafulla C. Gokhale, Sara Buhrlage, Jinhua Wang, Nathanael Gray, Richard Stone, Suiyang Liu, Shripad V. Bhagwat, Ramon V. Tiu, Sophia Adamia, James D. Griffin
Journal: Leukemia (2020)
TBK1 Activation by VHL Loss in Renal Cell Carcinoma: A Novel HIF-Independent Vulnerability
Authors: Ziad Bakouny, David A. Barbie
Journal: Cancer Discovery (2020)

Abstract Summary: The Von Hippel-Lindau gene product is a tumor suppressor whose ubiquitin ligase function is key to oxygen-sensing in cells, whereas Tank-binding kinase (TBK1) is a kinase mostly implicated in innate immune response. The study by Hu and colleagues in this issue reveals that VHL suppresses TBK1 activity under normoxic conditions, and that loss of VHL in kidney cancer cells renders them sensitive to TBK1 inhibition, providing a new potential target for the treatment of clear cell renal cell carcinoma. See related article by Hu et al., p. 460.
Covid-19: emergency departments lack proper isolation facilities, senior medic warns
Authors: Gareth Iacobucci
Journal: BMJ (2020)

<h3>Introduction</h3> We hypothesized that an Integrated Lumbar Interbody Fusion Device (PILLAR SA, Orthofix, Lewisville, TX) will function biomechanically similar to a traditional anterior interbody spacer (PILLAR AL, Orthofix, Lewisville, TX) plus posterior instrumentation (FIREBIRD, Orthofix, Lewisville, TX). Purpose of this study was to determine if an Integrated Interbody Fusion Device (PILLAR SA) can stabilize single motion segments as well as an anterior interbody spacer (PILLAR AL) + pedicle screw construct (FIREBIRD). <h3>Methods</h3> Eight cadaveric lumbar spines (age: 43.9±4.3 years) were used. Each specimen9s range of motion was tested in flexion-extension (FE), lateral bending (LB), and axial rotation (AR) under intact condition, after L4-L5 PILLAR SA with intervertebral screws and after L4-L5 360° fusion (PILLAR AL + Pedicle Screws and rods (FIREBIRD). Each specimen was tested in flexion (8Nm) and extension (6Nm) without preload (0 N) and under 400N of preload, in lateral bending (±6 Nm) and axial rotation (±5 Nm) without preload. <h3>Results</h3> Integrated fusion using the PILLAR SA device demonstrated statistically significant reductions in range of motion of the L4-L5 motion segment as compared to the intact condition for each test direction. PILLAR SA reduced ROM from 8.9±1.9 to 2.9±1.1° in FE with 400N follower preload (67.4%), 8.0±1.7 to 2.5±1.1° in LB, and 2.2±1.2 to 0.7±0.3° in AR. A comparison between the PILLAR SA integrated fusion device versus 360° fusion construct with spacer and bilateral pedicle screws was statistically significant in FE and LB. The 360° fusion yielded motion of 1.0±0.5° in FE, 1.0±0.8° in LB (p0.05). <h3>Conclusions</h3> The PILLAR SA resulted in motions of less than 3° in all modes of motion and was not as motion restricting as the traditional 360° using bilateral pedicle screws. The residual segmental motions compare very favorably with published biomechanical studies of other interbody integrated fusion devices.
m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC
Authors: Dan Jin, Jiwei Guo, Yan Wu, Lijuan Yang, Xiaohong Wang, Jing Du, Juanjuan Dai, Weiwei Chen, Kaikai Gong, Shuang Miao, Xuelin Li, Hongliang Sun
Journal: Molecular Cancer (2020)

The importance of mRNA methylation erased by ALKBH5 in mRNA biogenesis, decay, and translation control is an emerging research focus. Ectopically activated YAP is associated with the development of many human cancers. However, the mechanism whereby ALKBH5 regulates YAP expression and activity to inhibit NSCLC tumor growth and metastasis is not clear.Protein and transcript interactions were analyzed in normal lung cell and NSCLC cells. Gene expression was evaluated by qPCR and reporter assays. Protein levels were determined by immunochemical approaches. Nucleic acid interactions and status were analyzed by immunoprecipitation. Cell behavior was analyzed by standard biochemical tests. The m6A modification was analyzed by MeRIP.Our results show that YAP expression is negatively correlated with ALKBH5 expression and plays an opposite role in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. ALKBH5 reduced m6A modification of YAP. YTHDF3 combined YAP pre-mRNA depending on m6A modification. YTHDF1 and YTHDF2 competitively interacted with YTHDF3 in an m6A-independent manner to regulate YAP expression. YTHDF2 facilitated YAP mRNA decay via the AGO2 system, whereas YTHDF1 promoted YAP mRNA translation by interacting with eIF3a; both these activities are regulated by m6A modification. Furthermore, ALKBH5 decreased YAP activity by regulating miR-107/LATS2 axis in an HuR-dependent manner. Further, ALKBH5 inhibited tumor growth and metastasis in vivo by reducing the expression and activity of YAP.The presented findings suggest m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC. Moreover, effective inhibition of m6A modification of ALKBH5 might constitute a potential treatment strategy for lung cancer.
Overcoming microenvironment-mediated protection from ATRA using CYP26-resistant retinoids
Authors: Daniela Hernandez, Laura Palau, Kelly Norsworthy, Nicole M. Anders, Salvador Alonso, Meng Su, Martin Petkovich, Rosh Chandraratna, Michelle A. Rudek, B. Douglas Smith, Richard J. Jones, Gabriel Ghiaur
Journal: Leukemia (2020)
Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling
Authors: Jian Chen, Abhisek Mitra, Shulin Li, Shumei Song, Bao-Ngoc Nguyen, Jiun-Sheng Chen, Ji-Hyun Shin, Nancy R. Gough, Paul Lin, Vincent Obias, Aiwu Ruth He, Zhixing Yao, Tathiane M. Malta, Houtan Noushmehr, Patricia S. Latham, Xiaoping Su, Asif Rashid, Bibhuti Mishra, Ray-Chang Wu, Lopa Mishra
Journal: Cancer Research (2020)

Abstract RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients. Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.
Re-imagining cystic fibrosis care: next generation thinking
Authors: Catherine Rang, Dominic Keating, John Wilson, Tom Kotsimbos
Journal: European Respiratory Journal (2020)

Cystic fibrosis (CF) is a common multi-system genetically inherited condition, predominately found in individuals of Caucasian decent. Since the identification of the cystic fibrosis (CF) transmembrane conductance regulator ( CFTR ) gene in 1989, and the subsequent improvement in understanding of CF pathophysiology, significant increases in life-expectancy have followed. Initially this was related to improvements in the management and systems of care for treating the various affected organ systems. These cornerstone treatments are still essential for CF patients born today. However, over the last decade, the major advance has been in therapies that target the resultant genetic defect: the dysfunctional CFTR protein. Small molecule agents that target this dysfunctional protein via a variety of mechanisms have led to lung function improvements, reductions in pulmonary exacerbation rates and increases in weight and quality-of-life indices. As more patients receive these agents earlier and earlier in life, it is likely that general CF care will increasingly pivot around these specific therapies, although it is also likely that effects other than those identified in the initial trials will be discovered and need to be managed. Despite great excitement for modulator therapies, they are unlikely to be suitable or available for all; whether this is due to a lack of availability for specific CFTR mutations, drug-reactions or the health economic set-up in certain countries. Nevertheless, the CF community must be applauded for its ongoing focus on research and development for this life-limiting disease. With time, personalised individualised therapy would ideally be the mainstay of CF care.
Partha Kar: Is being a doctor a vocation?
Authors: Partha Kar
Journal: BMJ (2020)

Is there some sort of higher calling to join the medical profession, or is it simply a highly skilled job? This age old debate generates more heat than light, and it’s not clear why the two need to be mutually exclusive.

Did some form of vision appear to me and drive me to be a doctor? No—I grew up in a family of doctors, in the heart of Kolkata, before the economic boom. My choice was pretty much made for me by my parents: I can’t think of a time when I didn’t want to be a doctor or thought of a different career. In the hubbub of Kolkata the job came …
Abstract P407: Association of Obesity at Baseline and Change Over Time With 6 Minute Walk Distance: The Multi-ethnic Study of Atherosclerosis
Authors: Morgana Mongraw-Chaffin, Haiying Chen, Denise K Houston, Sanjiv J Shah, Alain G Bertoni
Journal: Circulation (2020)

Introduction: The 6 minute walk distance (6MWD) may be an indicator of frailty and is strongly associated with risk of mortality. Obesity is increasingly shown to be associated with decreased physical function, frailty, and disability, and is also associated with multiple major cardiometabolic comorbidities that cause early mortality. Studies of 6MWD have generally been limited in scope by the use of a single measurement of BMI for obesity, highly selected samples, and by lack of racial/ethnic diversity. Methods: 6MWD was measured in participants at Visit 6 (2016-2018) of the Multi-Ethnic Study of Atherosclerosis (MESA) who were able to ambulate without assistance. MESA participants were diverse with 62% non-white and 50% female, aged 45-84 and free of CVD at Visit 1 (2000-2002). We used multivariable linear regression with robust standard errors that account for within person correlation to investigate the association of baseline BMI categories and BMI change over time (from Visit 1 to Visit 6) with 6MWD. We used normal weight (BMI 18.5 - &lt;25.0kg/m 2 ) and no BMI change (-1 to +1 kg/m 2 ) as reference categories. Results: Among 2525 participants with 6MWD at Visit 6, mean Visit 1 BMI was 28.2 kg/m 2 , mean Visit 6 BMI was 28.4 kg/m 2 , mean BMI change was 0.22kg/m 2 , and mean 6MWD was 410 m. Average time between BMI measurements was 15.8 years. Baseline overweight and obesity were strongly and significantly associated with lower 6MWD, as was increase in BMI over time ( Figure ). Adjustment for potential confounders and mediators did not explain these associations, although significant interaction by age was found for BMI decrease ≥ -4kg/m 2 (p = 0.003) with those over 70 having lower 6MWD (-31.2 (-50.6, -11.8)) and younger participants having non-significantly higher 6MWD (17.2 (-8.2, 42.5)). There was no significant heterogeneity by sex or race/ethnicity. Conclusion: Even modest increase in BMI (1≤ change &lt;4 kg/m 2 ) with aging is associated with lower 6MWD in MESA. Consensus about the impact of weight loss in older adults remains a major challenge.
Abstract P356: Modeling the Impact of Flexibility in Fat Levels of Dairy Foods Consumed to Meet Recommendations From the 2015 Dietary Guidelines for Americans Healthy U.S.-style Eating Pattern
Authors: Julie M Hess, Christopher J Cifelli, Jill Nicholls, Victor Fulgoni
Journal: Circulation (2020)

Introduction: The 2015 Dietary Guidelines for Americans (DGA) recommends consuming low-fat or fat-free dairy foods due to concerns about excess intake of energy, which can lead to overweight or obesity, and saturated fat, a type of fat that can increase blood levels of low-density lipoprotein cholesterol, a blood biomarker used to predict cardiovascular disease risk. The 2015 DGA recommends limiting intake of saturated fats to less than 10% of calories per day and balancing energy intake. Hypothesis: The objective of this study was to assess the impact of replacing one serving of fat-free dairy foods provided in current models of the 2000-calorie Healthy U.S.-Style Eating Pattern (HUSEP) with one serving of whole- or reduced-fat dairy foods. We hypothesized that this replacement would still result in an eating pattern within calorie, saturated fat, and sodium limits. Methods: Utilizing the same food pattern modeling procedures used for the 2015 DGA, we assessed the energy and nutrient composition of six alternative models of the 2000-calorie HUSEP. In each pattern, we replaced 1 of the 3 servings of the USDA’s fat-free dairy food composite with whole- or reduced-fat dairy products or whole-/reduced-fat dairy composites. The 6 replacement models included replacements with: 1) a whole-fat dairy food composite, 2) a reduced-fat dairy food composite, 3) whole milk, 4) reduced-fat milk, 5) whole-fat cheese, and 6) reduced-fat cheese. Results: In all 6 models, the amount of saturated fat did not exceed 10% of total calories. In models 2, 3, and 4, saturated fat was 9% of total calories. The amount of energy increased slightly in all models. The original HUSEP provided 2003 calories, and the 6 models in this study provided an additional 45 (Model 4) to 94 (Model 5) additional calories. The amount of sodium also increased. The original HUSEP provides 1787 mg of sodium, and these models provided between 2082 and 2683 mg of sodium. While still lower than the current average sodium intake (3,440 mg/d), the amount of sodium in Models 1, 2, 5, and 6 exceeds 2,300 mg/d, the Chronic Disease Risk Reduction Intake level for sodium. Conclusions: Results of this study indicate that some reduced- and whole-fat dairy foods, especially milk, can fit into calorie-balanced healthy eating patterns that also align with saturated fat and sodium recommendations. Allowing some flexibility in fat level of dairy food servings aligns with the 2010 DGA recommendation that calories from solid fats and added sugars are best used to increase the palatability of nutrient-dense foods, which includes milk, cheese, and yogurt.
Treatment of Highly Drug-Resistant Pulmonary Tuberculosis
Authors: Francesca Conradie, Andreas H. Diacon, Nosipho Ngubane, Pauline Howell, Daniel Everitt, Angela M. Crook, Carl M. Mendel, Erica Egizi, Joanna Moreira, Juliano Timm, Timothy D. McHugh, Genevieve H. Wills, Anna Bateson, Robert Hunt, Christo Van Niekerk, Mengchun Li, Morounfolu Olugbosi, Melvin Spigelman
Journal: New England Journal of Medicine (2020)

Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.
Use of Disposable Perioperative Jackets and Surgical Site Infections
Authors: Lisa Spruce
Journal: JAMA Surgery (2020)

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Validation of nomogram-revised risk index and comparison with other models for extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: indication for prognostication and clinical decision-making
Authors: Si-Ye Chen, Yong Yang, Shu-Nan Qi, Ying Wang, Chen Hu, Xia He, Li-Ling Zhang, Gang Wu, Bao-Lin Qu, Li-Ting Qian, Xiao-Rong Hou, Fu-Quan Zhang, Xue-Ying Qiao, Hua Wang, Gao-Feng Li, Yu-Jing Zhang, Yuan Zhu, Jian-Zhong Cao, Sheng-Min Lan, Jun-Xin Wu, Tao Wu, Su-Yu Zhu, Mei Shi, Li-Ming Xu, Zhi-Yong Yuan, Joachim Yahalom, Richard Tsang, Yu-Qin Song, Jun Zhu, Hang Su, Ye-Xiong Li
Journal: Leukemia (2020)

Abstract Derived from our original nomogram study by using the risk variables from multivariable analyses in the derivation cohort of 1383 patients with extranodal NK/T-cell lymphoma, nasal-type (ENKTCL) who were mostly treated with anthracycline-based chemotherapy, we propose an easily used nomogram-revised risk index (NRI), validated it and compared with Ann Arbor staging, the International Prognostic Index (IPI), Korean Prognostic Index (KPI), and prognostic index of natural killer lymphoma (PINK) for overall survival (OS) prediction by examining calibration, discrimination, and decision curve analysis in a validation cohort of 1582 patients primarily treated with non-anthracycline-based chemotherapy. The calibration of the NRI showed satisfactory for predicting 3- and 5-year OS in the validation cohort. The Harrell’s C-index and integrated Brier score (IBS) of the NRI for OS prediction demonstrated a better performance than that of the Ann Arbor staging system, IPI, KPI, and PINK. Decision curve analysis of the NRI also showed a superior outcome. The NRI is a promising tool for stratifying patients with ENKTCL into risk groups for designing clinical trials and for selecting appropriate individualized treatment.
TMEM173 Drives Lethal Coagulation in Sepsis
Authors: Hui Zhang, Ling Zeng, Min Xie, Jiao Liu, Borong Zhou, Runliu Wu, Lizhi Cao, Guido Kroemer, Haichao Wang, Timothy R. Billiar, Herbert J. Zeh, Rui Kang, Jianxin Jiang, Yan Yu, Daolin Tang
Journal: Cell Host & Microbe (2020)

The discovery of TMEM173/STING-dependent innate immunity has recently provided guidance for the prevention and management of inflammatory disorders. Here, we show that myeloid TMEM173 occupies an essential role in regulating coagulation in bacterial infections through a mechanism independent of type I interferon response. Mechanistically, TMEM173 binding to ITPR1 controls calcium release from the endoplasmic reticulum in macrophages and monocytes. The TMEM173-dependent increase in cytosolic calcium drives Gasdermin D (GSDMD) cleavage and activation, which triggers the release of F3, the key initiator of blood coagulation. Genetic or pharmacological inhibition of the TMEM173-GSDMD-F3 pathway blocks systemic coagulation and improves animal survival in three models of sepsis (cecal ligation and puncture or bacteremia with Escherichia coli or Streptococcus pneumoniae infection). The upregulation of the TMEM173 pathway correlates with the severity of disseminated intravascular coagulation and mortality in patients with sepsis. Thus, TMEM173 is a key regulator of blood clotting during lethal bacterial infections.