tbuckley/cabot-search huggingface dataset:
Orally Deliverable Nanotherapeutics for the Synergistic Treatment of Colitis-Associated Colorectal Cancer
Authors: Weidong Han, Binbin Xie, Yiran Li, Linlin Shi, Jianqin Wan, Xiaona Chen, Hangxiang Wang
Journal: Theranostics (2019)

Purpose: Colitis-associated colorectal cancer (CAC) poses substantial challenges for effective treatment.Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the safe and effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract.Experimental Design: In this study, we developed orally deliverable nanotherapeutics for the synergistic treatment of inflammatory bowel diseases (IBDs) and CAC.Water-insoluble curcumin (CUR) and 7-ethyl-10-hydroxycamptothecin (SN38), which served as anti-inflammatory and cytotoxic agents, respectively, were chemically engineered into hydrophilic mucoadhesive chitosan for the generation of chitosan-drug amphiphiles.Results: The resulting amphiphilic constructs formed core-shell nanostructures in aqueous solutions and were orally administered for in vivo therapeutic studies.Using a preclinical CAC mouse model, we showed that the orally delivered nanotherapeutics locally accumulated in inflamed intestinal regions and tumor tissues.Furthermore, the therapeutic synergy of the combined nanotherapeutics in CAC mice was evaluated.Compared with their individual drug forms, combined CUR and SN38 nanoparticles yielded synergistic effects to alleviate intestinal inflammation and protect mice from ulcerative colitis.Notably, the combinatorial therapy demonstrated a remarkable tumor shrinkage with only ~6% of the total tumors exceeding 4 mm in diameter, whereas ~35% of tumors were observed to exceed a diameter of 4 mm in the saline-treated CAC mice.These data suggest a new and reliable approach for improving the treatment of IBD and CAC.Conclusions: Our results showed that bioadhesive chitosan materials can be used to produce colloidal-stable nanotherapeutics that are suitable for oral delivery.Both nanotherapeutics exhibited substantial accumulation in inflamed intestinal regions and tumor tissues and showed good synergy for treating CAC, warranting further clinical translation.
Putative function of goblet cells as epithelial sealing in ischaemia/reperfusion-induced intestinal barrier dysfunction
Authors: Yuk Lung Wong, Lars Hummitzsch, Ingmar Lautenschläger, Karina Zitta, Thilo Wedel, François Cossais, Clemens Schafmayer, Thomas Becker, Rouven Berndt, Matthias Gruenewald, Norbert Weiler, Markus Steinfath, Martin Albrecht
Journal: Gut (2019)

We read with great interest the article by Michael Camilleri who described in detail the important functions of goblet cells and the mucus component for intestinal barrier function.1 Apart from diseases resulting in intestinal inflammation and damage, intestinal ischaemia/reperfusion (I/R) injury also leads to epithelial cell damage, release of epithelial cells into the luminal space and as a consequence reduced barrier function.2–4 The latter enables bacterial translocation and in its severest form results in systemic inflammation and organ dysfunction.5 The fundamental importance of goblet cell secretory products in restricting bacterial translocation has also been reported previously in Gut by Grootjans et al who showed that colonic ischaemia leads to disruption of the mucus layer facilitating bacterial penetration into the underlying tissue and that this process is counteracted by increased secretory activity of goblet cells.6

We are currently performing a clinical trial in which the effects of remote ischaemic preconditioning …
P1.07 External Peer Review of the Western New South Wales Lung Cancer Service – A Unique Regional and Rural AUN Experience
Authors: S. Mallawathantri, R. Zielinski, M. Byrom, R. Punwani, K. Thuraisingam, K. Singh, L. Bradbury, T. Hollman, R. Rai, K. Turley, C. Prabhakar, F. Ferguson, M. Macleay, J. Begnell, R. Jones, N. Alam, Y. Mayorchak, P. Flynn, S. Kao, E.S. Choong, M. Duffy, R. Osborne, M. Phillips, K. Fong, D. Baldwin
Journal: Journal of Thoracic Oncology (2019)
Association of Race/Ethnicity With Hospital Discharge Disposition After Elective Total Knee Arthroplasty
Authors: Jasvinder A. Singh, Michael J. Kallan, Yong Chen, Michael L. Parks, Said A. Ibrahim
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Total knee arthroplasty (TKA) is one of the most common elective procedures performed in adults with end-stage arthritis. Racial disparities in TKA outcomes have been described in the literature. <h3>Objectives</h3> To assess the association of race/ethnicity with discharge disposition and hospital readmission after elective primary TKA and to assess the association of nonhome discharge disposition with hospital readmission risk. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used data from the Pennsylvania Health Care Cost Containment Council Database, a large regional database that included demographic data from all discharges of patients who underwent elective primary TKA in 170 nongovernmental acute care hospitals in Pennsylvania from April 1, 2012, to September 30, 2015. Data analyses were conducted from September 29, 2017, to November 29, 2017. <h3>Exposures</h3> Patient race/ethnicity and discharge disposition. <h3>Main Outcomes and Measures</h3> Discharge disposition and 90-day hospital readmission. <h3>Results</h3> Among 107 768 patients, 7287 (6.8%) were African American, 68 372 (63.4%) were women, 46 420 (43.1%) were younger than 65 years, and 60 636 (56.3%) were insured by Medicare. In multivariable logistic regression, among patients younger than 65 years, African American patients were more likely than white patients to be discharged to inpatient rehabilitation facility (IRF) (adjusted relative risk ratio [aRRR], 2.49 [95% CI, 1.42-4.36];<i>P</i> = .001) or a skilled nursing facility (SNF) (aRRR, 3.91 [95% CI, 2.17-7.06];<i>P</i> &lt; .001) and had higher odds of 90-day hospital readmission (adjusted odds ratio [aOR], 1.30 [95% CI, 1.02-1.67];<i>P</i> = .04). Compared with white patients 65 years or older, African American patients 65 years or older were more likely to be discharged to SNF (aRRR, 3.30 [95% CI, 1.81-6.02];<i>P</i> &lt; .001). In both age groups, discharge to an IRF (age &lt;65 years: aOR, 3.62 [95% CI, 2.33-5.64];<i>P</i> &lt; .001; age ≥65 years: aOR, 2.85 [95% CI, 2.25-3.61];<i>P</i> &lt; .001) or SNF (age &lt;65 years: aOR, 1.91 [95% CI, 1.37-2.65];<i>P</i> &lt; .001; age ≥65 years: aOR, 1.55 [95% CI, 1.27-1.89];<i>P</i> &lt; .001) was associated with higher odds of 90-day readmission. <h3>Conclusions and Relevance</h3> This cohort study found that race/ethnicity was associated with higher odds of discharge to an IRF or SNF for postoperative care after primary TKA. Among patients younger than 65 years, African American patients were more likely than white patients to be readmitted to the hospital within 90 days. Discharge to an IRF or SNF for postoperative care and rehabilitation was also associated with a higher risk of readmission to an acute care hospital.
Image Gallery: Zosteriform metastasis from melanoma
Authors: J. Aróstegui Aguilar, A. Larumbe Irurzun, J.I. Yanguas Bayona, M. Azcona Rodríguez, I. Martínez Espronceda Ezquerro, J. Sarriugarte Aldecoa‐Otalora
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, An 83‐year‐old man was examined in the dermatology department on account of a 9‐cm pigmented lesion in the right lumbar region. A skin biopsy of the lesion supported the diagnosis of superficial spreading melanoma (Clark level IV, Breslow thickness 8 mm, BRAF negative). Subsequently, 1 year later, the patient was brought to the emergency department with new lesions in the right pectoral region, which had been erroneously diagnosed as herpes zoster infection (a). The patient was examined some days later in the dermatology department and a skin biopsy was performed, which resulted in a diagnosis of metastasis from melanoma. Months later, new metastatic lesions in the lumbar and pectoral region appeared (b). ...
Inhibition of SMYD2 suppresses tumor progression by down-regulating microRNA-125b and attenuates multi-drug resistance in renal cell carcinoma
Authors: Libin Yan, Beichen Ding, Haoran Liu, Yangjun Zhang, Jin Zeng, Junhui Hu, Weimin Yao, Gan Yu, Ruihua An, Zhiqiang Chen, Zhangqun Ye, Jinchun Xing, Kefeng Xiao, Lily Wu, Hua Xu
Journal: Theranostics (2019)

SMYD2 is a histone methyltransferase that has been reported to be an important epigenetic regulator. This study aims to investigate SMYD2 as a prognostic indicator of clear cell renal cell carcinoma (ccRCC) and explore its role in tumorigenesis and multi-drug resistance. Methods: Tumor specimens, clinicopathologic information, and prognostic outcomes of 186 ccRCC patients from three hospitals in China were collected for SMYD2 immunohistochemistry staining, Kaplan-Meier analysis, and Cox proportional hazards-regression analysis. MicroRNA (miRNA)-microarray profiling identified differentially expressed miRNAs in renal cancer cells subjected to SMYD2 knockdown or treatment with the SMYD2 inhibitor AZ505. The effects of SMYD2 and candidate SMYD2-mediated miRNAs on renal cancer cell proliferation, migration, clonogenicity, and tumorigenicity were determined via cell-function assays and murine xenograft experiments. The half-inhibitory concentrations (IC50) of five antineoplastic drugs (cisplatin, doxorubicin, fluorouracil, docetaxel, and sunitinib) in AZ505-treated and control cells were calculated, and the effects of SMYD2 inhibition on P-glycoprotein (P-gP) expression and multiple-drug resistance were verified. Results: SMYD2 was overexpressed and acted as an oncogene in ccRCC. High SMYD2 expression correlated with a high TNM stage (P = 0.007) and early tumor relapse (P = 0.032). SMYD2 independently predicted a worse overall survival (P = 0.022) and disease-free survival (P = 0.048). AZ505 inhibited the binding of SMYD2 to the miR-125b promoter region (based on chromatin immunoprecipitation assays) and suppressed ccRCC cell migration and invasion by inhibiting the SMYD2/miR-125b/DKK3 pathway. SMYD2 and miR-125b inhibition acted synergistically with anticancer drugs via P-gP suppression in vitro and in vivo. Conclusions: These findings suggested that SMYD2 plays an important role in ccRCC development and could be a potential biomarker for the treatment and prognosis of RCC.
US advice to give anticoagulants after caesarean under scrutiny
Authors: Janice Hopkins Tanne
Journal: BMJ (2019)

Controversy has arisen in the US over possible industry influence on guidance advising anticoagulant use after caesarean sections, amid doubts about the validity of the recommendations.

In 2016, the National Partnership for Maternal Safety published seven articles in the journal Obstetrics and Gynaecology . One article recommended giving anticoagulants to almost all women who had delivered a baby by caesarean section.1

Alongside the recommendations was an editorial that called the benefits of anticoagulants “uncertain” and demanded better data to support their use.2

As hospitals began implementing the recommendations, Adam C Urato, a maternal-fetal medicine specialist in Framingham, Massachusetts, found that the National Partnership, through its Industry Forum, had ties with 16 corporations. Three—Bayer, Johnson and Johnson, and Pfizer—made or sold anticoagulants.3 The industry connections were …
Racial Disparities in Patient-Reported Measures of Physician Cultural Competency Among Cancer Survivors in the United States
Authors: Santino S. Butler, Karen M. Winkfield, Chul Ahn, Zirui Song, Edward C. Dee, Brandon A. Mahal, Nina N. Sanford
Journal: JAMA Oncology (2019)

Racial disparities in cancer incidence and outcomes have been well documented 1,2 and may be due in part to lack of physician cultural competency.A cancer diagnosis and discussions of prognosis and treatments can have widely different implications across different cultural contexts.Highlighting the importance of high-quality care for diverse cultures, the American Society of Clinical Oncology recently outlined goals for improving cultural competency within its policy statement on cancer disparities. 3,4However, nationally representative data on cultural competency among physicians is limited.We therefore examined patient-reported physician cultural competency among cancer survivors in the United States using data from a contemporary population-based survey.Methods | The National Health Interview Survey (NHIS) collects data on a range of health indicators for noninstitutionalized, civilian adults. 5In 2017, the NHIS included a supplemental set of questions regarding physician cultural competency (eg, "How often were you treated with respect by your providers?")(Figure).Harmonized data of participants reporting a cancer diagnosis were obtained through the Integrated Health Interview Series. 6 Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CIs for each patient-reported measure of cultural competency across respondent reported race/ethnicity (non-Hispanic white [referent] vs nonwhite minority [either Hispanic/Latino ethnicity or nonwhite race]), among other sociodemographic variables (Figure).Subpopulation sample weighting defined nationally representative estimates for all end points.Statistical testing was 2-sided (α = .05)and was performed with Stata/SE 15.1 (StataCorp).The University of Texas Southwestern Institutional Review Board deemed the study exempt from review and patient informed consent requirements because deidentified data were used.
Opportunities and Challenges for Antibodies against Intracellular Antigens
Authors: Xiaofeng Yang, Shenxia Xie, Xiaomei Yang, Juan C. Cueva, Xiaoqiong Hou, Zhuoran Tang, Hua Yao, Fengzhen Mo, Shihua Yin, Aiqun Liu, Xiaoling Lu
Journal: Theranostics (2019)

Therapeutic antibodies are one most significant advances in immunotherapy, the development of antibodies against disease-associated MHC-peptide complexes led to the introduction of TCR-like antibodies.TCR-like antibodies combine the recognition of intracellular proteins with the therapeutic potency and versatility of monoclonal antibodies (mAb), offering an unparalleled opportunity to expand the repertoire of therapeutic antibodies available to treat diseases like cancer.This review details the current state of TCR-like antibodies and describes their production, mechanisms as well as their applications.In addition, it presents an insight on the challenges that they must overcome in order to become commercially and clinically validated.
OA01.06 Safety, Efficacy, and Pharmacokinetics of AMG 510, a Novel KRASG12C Inhibitor, in Patients with Non-Small Cell Lung Cancer
Authors: R. Govindan, M. Fakih, T. Price, G. Falchook, J. Desai, J. Kuo, J. Strickler, J. Krauss, B. Li, C. Denlinger, G. Durm, J. Ngang, H. Henary, G. Ngarmchamnanrith, E. Rasmussen, P.K. Morrow, D. Hong
Journal: Journal of Thoracic Oncology (2019)
Sonoprinting liposomes on tumor spheroids by microbubbles and ultrasound
Authors: S. Roovers, J. Deprez, D. Priwitaningrum, G. Lajoinie, N. Rivron, H. Declercq, O. De Wever, E. Stride, S. Le Gac, M. Versluis, J. Prakash, S.C. De Smedt, I. Lentacker
Journal: Journal of Controlled Release (2019)
Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2
Authors: Hsiao-Yun Chen, Mong-Lien Wang, Benoit Laurent, Chih-Hung Hsu, Ming-Teh Chen, Liang-Ting Lin, Jia Shen, Wei-Chao Chang, Jennifer Hsu, Mien-Chie Hung, Yi-Wei Chen, Pin-I Huang, Yi-Ping Yang, Chung-Pin Li, Hsin-I Ma, Chung-Hsuan Chen, Wen-Chang Lin, Shih-Hwa Chiou
Journal: Theranostics (2019)

Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. However, the underlined molecular mechanism remains obscure. Methods: We found Musashi-1 (MSI1) transported into cytosol under stress condition by confocal microscopy and cell fractionation. Argonaute 2 (AGO2) was then identified as a cytosolic binding partner of MSI1 by Mass Spectrametry, immunoprecipitation, and recombinant protein pull-down assay. We used RNA-IP to determine the MSI1/AGO2 associated regions on downstream target mRNAs. Finally, we overexpressed C-terminus of MSI1 to disrupt endogenous MSI1/AGO2 interaction and confirm it effects on tmor progression. Results: Malignant tumors exhibit elevated level of cytosolic Musashi-1 (MSI1), which translocates into cytosol in response to stress and promote tumor progression. Cytosolic MSI1 forms a complex with AGO2 and stabilize or destabilize its target mRNAs by respectively binding to their 3´ untranslated region or coding domain sequence. Both MSI1 translocation and MSI1/AGO2 binding are essential for promoting tumor progression. Blocking MSI1 shuttling by either chemical inhibition or point mutation attenuates the growth of GBM-xenografts in mice. Importantly, overexpression of the C-terminus of MSI1 disrupts endogenous MSI1/AGO2 interaction and effectively reduces stress-induced tumor progression. Conclusion: Our findings highlight novel molecular functions of MSI1 during stress-induced carcinomatous recurrence, and suggest a new therapeutic strategy for refractory malignancies by targeting MSI1 translocation and its interaction with AGOs.
β1-Integrin– and KV1.3 channel–dependent signaling stimulates glutamate release from Th17 cells
Authors: Katharina Birkner, Beatrice Wasser, Tobias Ruck, Carine Thalman, Dirk Luchtman, Katrin Pape, Samantha Schmaul, Lynn Bitar, Eva-Maria Krämer-Albers, Albrecht Stroh, Sven G. Meuth, Frauke Zipp, Stefan Bittner
Journal: Journal of Clinical Investigation (2019)

Although the impact of Th17 cells on autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We discovered soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex proteins in Th17 cells that enable a vesicular glutamate release pathway that induces local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of β1-integrin to vascular cell adhesion molecule 1 (VCAM-1) on neurons in the inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or KV1.3 channels, which are known to be linked to integrin expression and highly expressed on stimulated T cells. Although KV1.3 is not expressed in CNS tissue, intrathecal administration of a KV1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from patients with multiple sclerosis secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that β1-integrin- and KV1.3 channel-dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.
Declared pharmaceutical industry involvement in a random sample of abstracts from the ASCO Annual Meetings
Authors: A. L. Masson, A. Mangabeira, E. D. Saad, F. E. Prisco
Journal: Journal of Clinical Oncology (2009)

e17525 Background: The pharmaceutical industry (PI) plays an important role in drug development. We examined the extent and correlates of declared PI involvement in abstracts presented at ASCO Meetings 2001–2003 and 2006–2008. Methods: After stratification of abstracts into three categories of presentation ([1] oral, including plenary and oral presentations, and integrated symposia; [2] poster, including poster discussion and general poster; and [3] publication only), we randomly selected 10% of the abstracts for each of the 3-year periods of interest. Involvement by the PI was defined as declared sponsorship or by co-authorship in abstracts. Multivariate analysis (MVA) was done using logistic regression. Results: In the 2,206 abstracts analyzed, there was declared sponsorship or co-authorship by the PI in 425 (19.3%) of cases. Declared sponsorship (N = 73) was less frequent than co-authorship (N = 364). Declared sponsorship or co-authorship was present in 160 of 332 (48.2%) multinational studies, 222 of 969 (22.9%) multicenter, uninational studies, and 43 of 905 (4.3%) of single-institution studies (p &lt; 0.001). For the 30.6% of abstracts stating the study phase in the title or text, PI involvement was present in 116 of 239 (48.5%) phase I studies, 95 of 364 (26.1%) phase II studies, and 26 of 72 (36.1%) phase III trials (p &lt; 0.001). PI involvement was present in 280 of 1,080 (25.9%) US studies and in 145 of 1,126 (12.9%) non-US studies (p &lt; 0.001). In MVA, significant predictors of PI involvement were multinationality (odds ratio [OR] = 6.61), phase I/II/III (versus other, OR = 3.65), and US nationality (OR = 2.98). Conclusions: Declared PI involvement is seen in nearly 20% of abstracts and is more frequent in multinational studies, clinical trials and studies with US nationality. Additional work is needed to assess the correlation between PI involvement, abstract quality and likelihood of future publication. No significant financial relationships to disclose.
Secreted protein acidic and rich in cysteine mediates active targeting of human serum albumin in U87MG xenograft mouse models
Authors: Cho Rong Park, Jung Hwan Jo, Myung Geun Song, Ji Yong Park, Young-Hwa Kim, Hyewon Youn, Sun Ha Paek, June-Key Chung, Jae Min Jeong, Yun-Sang Lee, Keon Wook Kang
Journal: Theranostics (2019)

Human serum albumin (HSA) is the most abundant plasma protein.The main reason for using HSA as a versatile tool for drug delivery is based on its ability to accumulate in tumors.However, the mechanism of albumin accumulation in tumors is not yet clear.Many researchers using HSA as a drug-carrier have focused on the passive tumor targeting by enhanced permeability and retention (EPR) effect, while other investigators proposed that albumin binding proteins mediate albumin accumulation in tumors.We investigated whether HSA accumulation in tumors is mediated by the EPR effect or by secreted protein acidic and rich in cysteine (SPARC), which is known to be an albumin-binding protein.Methods: To investigate the role of SPARC on HSA accumulation in tumors, we compared HSA uptake in U87MG glioblastoma cells with different SPARC expression.U87MG cells generally express high levels of SPARC and were, therefore, used as SPARC-rich cells.SPARC-less U87MG (U87MG-shSPARC) cells were established by viral-shSPARC transduction.We detected cellular uptake of fluorescence-labeled HSA by confocal microscopy in U87MG and U87MG-shSPARC cells.To demonstrate the mechanism of HSA accumulation in tumors, we injected FNR648-labeled HSA and FITC-labeled dextran in U87MG and U87MG-shSPARC tumor-bearing mice and observed their micro-distribution in tumor tissues.Results: HSA was internalized in cells by binding with SPARC in vitro.HSA accumulation in U87MG glioma was associated with SPARC expression in vivo.FITC-dextran was distributed in U87MG tumors in the vicinity of blood vessels.The distribution of HSA, on the other hand, was observed in the regions remote from blood vessels of U87MG tumor tissues but not in U87MG-shSPARC tumor tissues. Conclusion:Our results demonstrate that the tumor-distribution of HSA is affected not only by the EPR-effect but also by SPARC expression.SPARC enhances HSA accumulation in U87MG glioma and mediates active targeting of HSA in tumors.