tbuckley/cabot-search huggingface dataset:
Cotransporting Ion is a Trigger for Cellular Endocytosis of Transporter‐Targeting Nanoparticles: A Case Study of High‐Efficiency SLC22A5 (OCTN2)‐Mediated Carnitine‐Conjugated Nanoparticles for Oral Delivery of Therapeutic Drugs
Authors: Longfa Kou, Qing Yao, Mengchi Sun, Chunnuan Wu, Jia Wang, Qiuhua Luo, Gang Wang, Yuqian Du, Qiang Fu, Jian Wang, Zhonggui He, Vadivel Ganapathy, Jin Sun
Journal: Advanced Healthcare Materials (2017)

OCTN2 (SLC22A5) is a Na+ -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na+ . Computational OCTN2 docking analysis shows that the presence of Na+ is important for the formation of the energetically stable intermediate complex of transporter-Na+ -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles.
Impact of 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on HER2 fluorescent in situ hybridization (FISH) testing in breast cancers: Experience from a national reference laboratory.
Authors: Eric Johnson, Evin H Gulbahce
Journal: Journal of Clinical Oncology (2017)

e23188 Background: Accurate HER2 testing is expected to identify patients who will benefit from HER2 directed therapy (HDT) minimizing false positive and negatives. Like many biologic processes, HER2 protein expression and gene copy numbers are a continuum, however these tests are expected to be reported dichotomously. In 2013, ASCO/CAP revised the guidelines in an attempt to decrease false negative results and reverted to FDA approved ratio of ≥ 2.0 for HER2 positivity. We reviewed HER2 FISH testing results after the implementation of 2013 ASCO/CAP guidelines to determine the effects on HER2 reporting from our national reference laboratory. Methods: HER2 FISH testing performed between 5/2015-4/2016 at ARUP Labs following current 2013 ASCO/CAP guidelines was included. HER2 to control probe ratios, mean HER2 and control probe copy numbers were used to reassign HER2 status using 2007 ASCO/CAP, and FDA guidelines for each case. Results: HER2 FISH results were available in 2,017 cases. 342 (17.0%) cases were amplified, 301 (14.9%) were equivocal, and 1374 (68.1%) were non-amplified. After additional testing with alternate probe, 93 (31.2%) of the equivocal cases were reclassified as amplified increasing amplified cases to 21.6%. All of the equivocal cases which were reinterpreted as amplified with alternate probe showed low level amplification (range: 2.0-3.6; mean: 2.3). HER2 positivity rates following 2013 ASCO/CAP guidelines, both at initial testing and after additional testing to resolve equivocal results were significantly higher compared to 2007 ASCO/CAP guidelines and FDA criteria. Conclusions: 2013 ASCO/CAP guidelines lead to higher number of HER2 FISH positive and equivocal cases. In a reference laboratory setting where alternative control probe was used to resolves equivocal FISH cases, 31.2% of patients with initial equivocal results become HER2 positive. However, it is not known if these patients benefit from targeted therapies as they would not be included in the original adjuvant or metastatic trials.
False Positive Uptake in Bilateral Gynecomastia on 68Ga-PSMA PET/CT Scan
Authors: Arun Sasikumar, Ajith Joy, Bindu P. Nair, M.R. A. Pillai, Jayaprakash Madhavan
Journal: Clinical Nuclear Medicine (2017)

A 66-year-old man on hormonal therapy with prostate cancer was referred for 68Ga-PSMA PET/CT scan for biochemical recurrence. 68Ga-PSMA PET/CT scan detected moderate heterogeneous tracer concentration in bilateral breast parenchyma, in addition to the abnormal tracer concentration in enlarged prostate gland, right external iliac lymph node, and sclerotic lesion in L4 vertebra. On clinical examination, he was found to have bilateral gynecomastia. Abnormal concentration of 68Ga-PSMA in breast cancer is now well known, and in this context, it is important to know that tracer localization can occur in gynecomastia as well, as evidenced in this case.
A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective
Authors: Baoqi Yu, Stefan Kiechl, Dan Qi, Xiaocong Wang, Yanting Song, Siegfried Weger, Agnes Mayr, Alexandra Le Bras, Eirini Karamariti, Zhongyi Zhang, Ivan del Barco Barrantes, Christof Niehrs, Georg Schett, Yanhua Hu, Wen Wang, Johann Willeit, Aijuan Qu, Qingbo Xu
Journal: Circulation (2017)

Dickkopf-related protein 3 (DKK3) is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis.We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed with apolipoprotein E-/- mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models.In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and 5-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced reendothelialization, and neointima formation in both DKK3-/-/apolipoprotein E-/- and DKK3+/+/apolipoprotein E-/- mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed reendothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration activated ROR2 and DVL1, activated Rac1 GTPases, and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of the ROR2 receptor using specific siRNA or transfection of a dominant-negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation.This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis.
MDV3100-08: A phase I open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of MDV3100 in women with incurable breast cancer.
Authors: Anthony D. Elias, Jennifer K. Richer, Patricia LoRusso, Amy C. Peterson, Joyce Leta Steinberg, Joyce Mordenti, Christian Lopez, Clifford Hudis, Tiffany A. Traina
Journal: Journal of Clinical Oncology (2012)

TPS668 Background: MDV3100 is a novel, orally administered small molecule that directly binds the androgen receptor (AR) to potently inhibit AR-mediated signaling via three mechanisms: inhibition of androgen binding to AR; inhibition of AR nuclear translocation; and inhibition of nuclear AR association with DNA. MDV3100 is not known to agonize AR signaling, can be taken without prednisone, and demonstrated an overall survival benefit in post-docetaxel prostate cancer at 160 mg/day. AR expression is observed in ~70% of all breast cancer (BCa) regardless of histologic subtypes (estrogen receptor [ER] positive, HER2+, and triple negative [TN] disease). MDV3100 has demonstrated preclinical activity in AR+/TN and AR+/ ER+ BCa and could be a potential therapeutic strategy in patients with AR+ BCa. Methods: This Phase 1 study has 2 stages: a standard 3+3 dose-escalation stage (S1), evaluating safety, tolerability, and pharmacokinetics (PK) of MDV3100, starting at 80 mg MDV3100; and a dose-expansion stage (S2), evaluating the recommended Phase 2 dose in ~15 women with AR+ BCa. All patients must have received ≥2 chemotherapy-containing regimens for their incurable BCa, or ≥3 anti-HER2 containing regimens for their incurable HER2+ BCa to be eligible; ER+ patients must be post-menopausal. In S1, patients will receive their assigned dose of MDV3100 on Day 1, and PK samples will be collected through Day 8. Daily dosing will begin on Day 8 and will continue until predefined discontinuation criterion is met. Dose-limiting toxicities will be recorded through Day 35 and used to determine the Phase 2 dose. Extensive PK sampling is performed on Days 1 and 50 with predose PK samples collected throughout. In S2, patients with AR+ BCa (defined as 10% or more tumor cells with nuclear AR expression) will take daily MDV3100 at the recommended Phase 2 dose; there is no single dose PK period. Tumor tissue submission is mandatory in S2. Safety and tolerability will be documented by frequent assessments of adverse events, vital signs, and laboratory assessments. Tumor assessments occur at 2 months then approximately every 3 months thereafter. Enrollment of 27 subjects is anticipated.
Abstract 18195: Prognostic Significance of Diastolic Dysfunction in Patients With Normal Ejection Fraction who are Undergoing Kidney Transplantation
Authors: Michael Lawrenz F Co, Martin Hertl, Burhan Mohamedali
Journal: Circulation (2016)

Introduction:  Diastolic dysfunction is frequently impaired in patients with ESRD. Our study aimed to determine whether diastolic dysfunction and echo parameters could predict mortality among kidney transplant (KT) patients who had normal pre-transplantation EF.   Methods:  We retrospectively enrolled 703 patients with normal EF who underwent a KT at our institution from 2005-2015. Diastolic parameters including diastolic grade, left ventricular end diastolic and systolic volumes (LVEDD, LVESD), septal and posterior wall thickness, mitral E-wave, A-wave and E/A ratio were available in 381 patients with preoperative echocardiograms. Demographic and survival data were obtained from medical records. Mann-Whitney, chi-square, ROC and Kaplan-Meier (KM) analyses were performed.   Results:  Patients were followed up for a median duration of 3 years (IQR 1-5.4) during which period 45 deaths were recorded. The mean EF of the cohort was 62%. Except for higher LVEDD (5.3 cm vs 4.9 cm, p=0.02) and LVESD (3.7 cm vs 3.3 cm, p=0.029) in expired patients, there was no statistical difference in the aforementioned parameters between survivors and non-survivors. ROC analysis showed cut-off points for LVEDD of 5.1 cm (sen 83%, sp 57%, AUC 0.7) and LVESD of 3.4 cm (sen 83%, sp 56%, AUC 0.7). Stratification based on these points revealed a higher mortality in patients with LVEDD greater than 5.1 cm (9.9% vs 1.6%, p=0.006) and LVESD greater than 3.4 cm(9.9% vs 1.7%, p=0.007). KM analyses confirmed these findings (Figure 1A/B).   Conclusions:  Although diastolic grade and other parameters were not predictive of survival post KT, LVEDD and LVESD were statistically significant predictors of post-transplant survival. Our findings suggest that a dilated left ventricle portends a poor prognosis in KT. These easy-to-measure echocardiographic parameters can be used to risk-stratify patients with preserved EF who are undergoing KT.
First report: A retrospective trial for evaluating the safety and efficacy of TAS-102 for patients with metastatic colorectal cancer: HGCSG1503
Authors: Masayoshi Dazai, Satoshi Yuki, Hiroshi Nakatsumi, Yasushi Tsuji, Yoshimitsu Kobayashi, Kazuteru Hatanaka, Hiroyuki Okuda, Ayumu Hosokawa, Koichi Furukawa, Kohei Ogawa, Shinya Minami, Atsushi Ishiguro, Takuya Honda, Tomoyuki Ohta, Kazunori Eto, Takashi Kato, Junta Nakajima, Takahide Sasaki, Michio Nakamura, Yoshiaki Shindo, Yuh Sakata, Yoshito Komatsu
Journal: Annals of Oncology (2017)
Chronic fatigue syndrome
Authors: James I. Hudson, Harrison G. Pope, Don L. Goldenberg
Journal: JAMA (1991)

<h3>To the Editor. —</h3> Gold et al<sup>1</sup>reported that patients with chronic fatigue displayed no evidence of ongoing EBV infection but showed a strikingly high prevalence of depressive illness. We offer further evidence to support the latter finding. Chronic fatigue syndrome has been shown to overlap significantly with fibromyalgia,<sup>2,3</sup>an idiopathic rheumatic condition characterized by chronic generalized pain, multiple tender points, and, frequently, persistent fatigue. We recently interviewed 33 consecutive patients with fibromyalgia using the<i>Structured Clinical Interview</i>for<i>Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition</i>(SCID),<sup>4</sup>a structured interview designed to assess the prevalence of current or past major psychiatric disorders. We also administered a supplemental interview in SCID format assessing chronic fatigue syndrome, irritable bowel syndrome, migraine, and narcolepsy. Of the 33 patients with fibromyalgia, 14 (42%) met the full interview criteria for chronic fatigue syndrome, and nine others (27%) fell only
EpCAM-mediated hypomethylation of BMP and cell adhesion genes is associated with advanced endometrial cancer
Authors: Ya Ting Hsu, Fei Gu, Yi Wen Huang, Joseph Liu, Jianhua Ruan, Rui-Lan Huang, Chiou Miin Wang, Chun Liang Chen, Rohit R. Jadhav, Yao Ming Wang, Victor X. Jin, Hung-Cheng Lai, David G. Mutch, Paul J. Goodfellow, Ian M. Thompson, Nameer B. Kirma, Tim Hui Ming Huang
Journal: Cancer Research (2014)
Clinical and laboratory evidence of Haff disease – case series from an outbreak in Salvador, Brazil, December 2016 to April 2017
Authors: Antonio C Bandeira, Gubio S Campos, Guilherme S Ribeiro, Cristiane W Cardoso, Claudilson JC Bastos, Tiago L Pessoa, Karine A Araujo, Maria Fernanda R Grassi, Alessandra P Castro, Rejane H Carvalho, Ana Paula P B Prates, Luana L Gois, Veronica FD Rocha, Silvia I Sardi
Journal: Eurosurveillance (2017)

We describe a series of 15 Haff disease cases from an outbreak in Salvador, Brazil, starting early December 2016. Eleven cases were grouped in four family clusters of two to four individuals, four were isolated cases. All but one patient consumed cooked fish; 11 within 24h before symptoms onset. Cases consumed ‘Olho de Boi’ ( Seriola spp.) and ’Badejo’ (Mycteroperca spp.). A total of 67 cases were detected, the last case was reported on 5 April 2017.
Mechanism and Activity of ILC2 Cells Post Allo-BMT
Authors: Danny W Bruce, Heather E Stefanski, Benjamin G. Vincent, Trisha Dant, Shannon Reisdorf, Hemamalini Bommiasamy, David Serody, Justin E Wilson, Karen McKinnon, Warren D Shlomchik, Paul M. Armistead, Jenny PY Ting, John T Woosley, Dietmar MW Zaiss, Bruce R. Blazar, Andrew NJ McKenzie, James Coghill, Jonathan S. Serody
Journal: Blood (2016)
Juniors will have role in new GMC procedures NHS cuts are threatening medical education Trust chief executives' salaries rise by 6.2% Hippocratic Oath updated
Authors: Linda Beecham
Journal: BMJ (1997)

# Juniors will have role in new GMC procedures {#article-title-2}

The BMA Junior Doctors Committee will maintain and update a list of doctors willing to act as assessors in the General Medical Council's performance procedures which will be introduced in September. Junior doctors who are interested should contact the JDC secretariat at BMA House.

Earlier this year the chairman of the BMA council wrote to the GMC because it seemed that doctors were to be excluded from acting as assessors because of the requirement to have completed five years' specialist experience and to be on the Specialist Register. When the president of the GMC, Sir Donald Irvine, attended the last JDC meeting he explained that the council did not expect that it would be necessary for junior doctors to be covered by the procedures because the normal training and supervision arrangements should deal with instances where a junior doctor's performance was inadequate. But if the council decides that a performance assessment is appropriate the assessment panel will always include a junior doctor, probably from the specialist register. The GMC will ask the JDC and the royal colleges for names of doctors who will receive appropriate …
Putting social care on the map
Authors: Tony G Egan, Chrys Jaye, Jessica Young, Martyn Williamson
Journal: BMJ (2017)

McCartney’s call for reflection on the status of social care and its integration with the health system will resonate with many.1 Our recent, modest innovation might facilitate mutual awareness of the various people who support and care for patients.

We have been investigating the concept of a “community of clinical practice”2 (adapted from Wegner’s community of practice …
Dasatinib blocks the growth, migration, and invasion of breast cancer cells through inhibition of Src family kinases
Authors: Christina Pichot, Ling Xia, Francis Lee, Seth Corey
Journal: Cancer Research (2007)

5415  Src family tyrosine kinases (SFK) control essential properties of cancerous cells, such as cell cycle progression, survival, and metastasis. Specific, small molecule inhibitors of SFK are currently in pre-clinical and clinical trials. The FDA has recently approved dasatinib (BMS-354825), an orally available, dual Src/Abl inhibitor, for imatinib-resistant, BCR-ABL+ leukemia. Because dasatinib also has activity against receptor tyrosine kinases such as Platelet-Derived Growth Factor Receptor (PDGFR), c-kit, and the Ephrin receptors, its multi-kinase effects suggest a therapeutic role for solid tumors. We determined the efficacy and mechanism of dasatinib in inhibiting the proliferation and migration/invasion of a panel of breast cancer cell lines chosen for their contrasting migratory and invasive capabilities as well as expression of endogenous Src family members. We studied three breast cancer cell lines: MDA-MB-231 (strongly invasive), and MCF-7 and T-47D (both weakly invasive). Dasatinib inhibits the growth of MDA-MB-231, MCF-7, and T-47D cells with calculated GI50 values of 0.7 uM, 1.6 uM, and 0.9 uM, respectively. Dasatinib caused cell cycle arrest in the G1 phase, but it does not induce apoptosis or cell death, as determined by viability assays and flow cytometry with annexin V and propidium iodide staining. Most strikingly, dasatinib treatment blocked cytoskeletal rearrangement. MDA-MB-231 cells, the most invasive line in our panel, undergo a dramatic contraction of the actin and tubulin cytoskeleton upon treatment with 0.1 uM dasatinib. Treated cells showed a dose-responsive loss of the well-organized dendritic processes that are normally present in untreated cells. These cells became much more round, suggesting a loss of adhesion points, but did not fully detach from the culture surface. With 0.1uM of dasatinib treatment, there was a 90% inhibition of MDA-MB-231 invasiveness through a Matrigel matrix when compared to a DMSO control (p=0.007). Migration of MDA-MB-231 cells in wound healing assays was also greatly reduced (74% below DMSO control). In support of our in vitro data, our studies of mouse xenograft models of MCF-7 cell growth demonstrate that dasatinib treatment reduces the establishment and growth of solid tumors. Since most patients die from metastatic disease, our data provide rationale for therapeutic targeting of Src by dasatinib in women with advanced breast cancer.
Endogenous Interleukin-8 (IL-8) Surge in Granulocyte Colony-Stimulating Factor–Induced Peripheral Blood Stem Cell Mobilization
Authors: T. Watanabe, Y. Kawano, S. Kanamaru, T. Onishi, S. Kaneko, Y. Wakata, R. Nakagawa, A. Makimoto, Y. Kuroda, Y. Takaue, J.E. Talmadge
Journal: Blood (1999)
Abstract B12: Polymorphisms in the Arntl2 promoter affect metastatic susceptibility in breast cancer
Authors: Ngoc-Han Ha, Kent W. Hunter
Journal: Cancer Research (2016)

Abstract Metastasis accounts for the majority of cancer-related deaths. Although exact mechanisms are unknown, studies in our laboratory have demonstrated that germline polymorphisms could alter tumorigenesis and metastasis. Our lab developed a mouse genetics approach to investigate the effect of inherited single nucleotide polymorphisms (SNPs) on metastasis by crossing inbred mice of various backgrounds and subsequent mapping of quantitative trait loci (QTL) responsible for the phenotype. Using this approach, we crossed a highly metastatic (FVB) and low metastatic (MOLF) mouse strain and identified Arntl2, a circadian rhythm transcription factor, as a gene with differential expression that predicted distant metastasis-free survival in breast cancer patients. shRNA-mediated reduction in Arntl2 expression suppressed lung metastases, establishing Arntl2 as a metastasis modifier. Initial analysis revealed no polymorphisms in coding regions that could account for the differential expression in FVB and MOLF. Therefore, we performed whole genome sequencing of MOLF to identify SNP differences between MOLF and FVB. Overlapping this analysis with DNAse hypersensitivity sites in mouse mammary tumor cell lines revealed 13 polymorphisms in the predicted promoter region of Arntl2. FVB and MOLF promoters exhibited differential promoter activity in vitro, suggesting that these SNPs could explain the difference in Arntl2 expression between these two strains. In order to validate the causative role of the SNPs in vivo, metastatic cell lines were engineered using CRISPR technology to specifically replace the FVB with the MOLF promoter. Substitution of this promoter reduced Arntl2 transcript levels and subsequently decreased pulmonary metastases, as expected. Since Arntl2 is a transcription factor, current studies are focused on identifying Arntl2-regulated genes to investigate the pathways that are involved in modulating metastasis. This study will have important implications regarding the function of circadian rhythm in cancer progression and provide a potential molecular mechanism to explain the increased risk of breast cancers in nightshift workers. Furthermore, to the best of our knowledge this would be the first example of genome editing to validate polymorphisms in transcriptional control elements associated with inherited susceptibility for metastasis. Citation Format: Ngoc-Han Ha, Kent W. Hunter. Polymorphisms in the Arntl2 promoter affect metastatic susceptibility in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B12.
Mitochondrial dysfunction and potential anticancer therapy
Authors: Matilde E. Lleonart, Robert Grodzicki, Dmitri M. Graifer, Alex Lyakhovich
Journal: Medicinal Research Reviews (2017)

Abstract Mitochondrial dysfunction (MDF) has been identified as an important factor in various diseases ranging from neurological disorders, to diseases of the cardiovascular system and metabolic syndromes. MDF was also found in cancer as well as in cancer predisposition syndromes with defective DNA damage response (DDR) machinery. Moreover, a recent highlight arises from the detection of MDF in eukaryotic cells upon treatment with antibiotics. In this review, we focus on recent studies of MDF in pathological conditions with a particular emphasis on the effects of various classes of antibiotics on mitochondria. Special attention is given to the role of autophagy/mitophagy in MDF and repurposing antibiotics as anticancer drugs.