tbuckley/cabot-search huggingface dataset:
Abstract P4-06-14: CD146-suppresses breast tumor invasion via a novel transcription target TIMPv
Authors: S Shanmuganathan, Z AbdElmageed, A Fernando, R Gaur, A Ramkumar, S Bhat, I Gupta, S Muzumdar, L Hakkim, A Ouhtit
Journal: Cancer Research (2012)

Abstract The function of the cell adhesion receptor CD146, a recently discovered marker of endothelial cells and a tumor promoter of melanoma and other cancers, is controversial in breast cancer (BC). However several lines of evidence supports its role as a tumor suppressor in BC. Further, the molecular mechanisms underpinning this suppression are unknown, neither has the ligand for CD146 been identified. Using a novel validated Enhanced Green Fluorescent Protein (EGFP)-inducible systems of CD146 expression both in vitro and in vivo, we provide here molecular and functional evidence of CD146 and its novel transcriptional target TIMPv (a variant of tissue inhibitor of metallo-proteinases) in underpinning the suppression of BC invasion. Tetracycline (tet-on) CD146 system was developed in both MCF-7 and MDA-231 BC founder cell lines, and validated using time course RT-PCR and western blot analyses, and fluorescent microscopy. In functional experiments, induction of CD146 inhibited BC cell migration and invasion. TIMPv, the only endogenous protein inhibitor known for metallocarboxypeptidases, was identified by expression profiling as a novel transcriptional target of CD146-signaling, an association validated by quantitative PCR and immunoblotting experiments in a range of breast and melanoma cancer cells. However, siRNA inhibition of CD146 in the SKMel-28 melanoma cell line increased TIMPv expression, suggesting that while TIMPv is a positive transcriptional target of CD146 in BC cells, it is negatively regulated in melanoma cells. Furthermore, using invasion assay, the functional relevance of TIMPv to CD146-suppressed metastasis was demonstrated by selective suppression of TIMPv in CD146-expressing BC inducible cells using RNAi. More interestingly, induction of CD146 expression in vivo, using the tet-on CD146 expression system in BC Xenograft model resulted in suppression of breast tumor growth. Further, Clinical analysis of breast tissue samples by Immunohistochemistry showed that TIMPv expression patterns paralleled those of CD44s during breast tumor progression. Pharmacological and molecular approaches revealed that the activation of NFκB via Akt pathway couples CD146 to the transcription of TIMPv in BC cells. Our study is the first report to provide a functional molecular link of a novel transcriptional target of CD146, TIMPv, to cancer via a unique axis that underpin CD146-suppressed BC progression; TIMPv is a potential target for guiding the development of novel therapeutic strategies for BC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-14.
Abstract P2-01-16: CRISPR-Cas9 screen identifies TMEM106A as a suppressor of breast cancer metastasis
Authors: L Yang, S-J Yu, Z-M Shao
Journal: Cancer Research (2019)

Abstract Purpose: Breast cancer is one of the most common malignancies among women. The majority of cancer-associated deaths are caused by metastasis. Many biological alterations occur during this complex process, including the epithelial-mesenchymal transition (EMT), tumor immune escape, transendothelial migration (TEM). However, the biological mechanism of metastatic disease remains poorly understood and more need to be done to unify our understanding of underpinnings for metastasis in breast cancer. Methods: We performed functional screening with CRISPR-Cas9 Genome-Scale CRISPR Knock-Out (GeCKO) library to identify metastasis-associated genes in breast cancer. We confirmed the function of a set of genes by transwell assays to testify the efficacy of in vivo screening. Further, we conducted in vitro and in vivo assays to explore the mechanism of TMEM106A in suppressing metastasis of breast cancer. Results: The CRISPR-Cas9 library screening identified genes with potential of suppressing metastasis in breast cancer. Further validation of COPS2, SSBP2, TDG, DYRK4, GSG1, TMEM106A and PRR5L revealed that knock down of these genes promoted cell migration and invasion ability. In MDA-MB-231 and MDA-MB-468 cells, knock down of TMEM106A promoted in vitro migration, invasion, wound healing and in vivo pro-metastasis ability. In addition, E-cadherin was down-regulated and N-cadherin was up-regulated with suppression of TMEM106A. Accordingly, the potentiality of pro-metastasis was reversed when exogenous TMEM106A was expressed in MDA-MB-231 and MDA-MB-468 cells. We found the interaction between TMEM106A and WDR77 via Co-IP and MS analysis. Down-regulation of TMEM106A promoted expression of WDR77, which primarily occurred in the cytoplasm. To verify the association between TMEM106A and WDR77, we interfere WDR77 expression in MDA-MB-231 sg-TMEM106A, and the pro-metastasis effect of TMEM106A down-regulation was reversed. Discussion: CRISPR-Cas9 library screening is an effective strategy to identify genes associated with breast cancer metastasis. The positive selection provides us a set of genes with potentiality to repress migration and invasion. TMEM106A may suppress metastasis via influencing translocation of WDR77 in breast cancer. Citation Format: Yang L, Yu S-J, Shao Z-M. CRISPR-Cas9 screen identifies TMEM106A as a suppressor of breast cancer metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-16.
Гастроэнтерологические маски парциальной эпилепсии в клинической практике
Authors: V.V. Cherniavsky, N.O. Fedorchenko
Journal: GASTROENTEROLOGY (2019)

Целью статьи является привлечение внимания гастроэнтерологов к необходимости проведения более тщательной дифференциальной диагностики у пациентов с синдромом неисследованной диспепсии. В статье приведен иллюстративный клинический случай пациента с абдоминальным вариантом парциальной эпилепсии. Акцентировано внимание на анамнестических критериях, которые позволили заподозрить данное заболевание у пациента с диспепсией, назначить электроэнцефалографическое исследование и консультацию невролога для назначения правильного лечения. Парциальная эпилепсия должна быть внесена в список заболеваний, с которыми проводится дифференциальная диагностика при диспепсии. Гастроэнтерологи и врачи терапевтических специальностей должны быть ознакомлены с клиническими вариантами и симптомами течения парциальной эпилепсии, а также с особенностями ее медикаментозного лечения, что будет способствовать раннему выявлению и лучшим результатам лечения больных эпилепсией. Необходимо проводить детализированный опрос пациента с тщательным сбором жалоб и анамнеза заболевания. Необходимо направлять на консультацию к неврологу пациентов с функциональной диспепсией, в анамнезе которых присутствуют травмы головы, занятия боевыми, рукопашными видами спорта, футболом, недавно перенесенные тяжелые инфекционные заболевания с выраженным интоксикационным синдромом. Раннее выявление «соматических масок» парциальной эпилепсии, которые по своей природе фактически являются «аурой» возможного, непредвиденного вторично-генерализированного эпилептического приступа, позволит своевременно назначать лечение и предотвратить его развитие.
Abstract 5537: Surgical resection and survival in octagenarians and younger age cohorts of patients diagnosed with non-small cell lung cancer.
Authors: Robert O Dillman, Douglas R Zusman, Colin I Joyo
Journal: Cancer Research (2008)

Abstract Background and Purpose: As life expectancy has increased, and more former smokers are surviving into old age, an increasing proportion of newly diagnosed patients with non-small cell lung cancer (NSCLC) are over the age of 80 years. This has led to questions regarding the appropriateness of subjecting elderly patients with newly diagnosed NSCLC, to surgical resection, even if they have only localized disease. Patients and Methods: The Hoag Cancer Center data base was used to identify patients with non-small lung cancer diagnosed during 2000-2006, who underwent a surgical resection at Hoag Hospital. Actuarial survival curves were generated for each age cohort. Results: Of 1293 total patients, 17.2% were 80 years of age or older, 36.1% age 70-79, 29.2% age 60-69, 12.9% age 50-59, and 4.6% &amp;lt; 50 years of age. Surgical resections of primary lung cancer included 400 lobectomies, 59 wedge resections, and 23 pneumonectomies. There was a strong correlation (.954) between older age and a higher proportion of male patients. There was also a difference in the proportional distribution of histologies by age group (p=.0005) primarily because of a .973 inverse correlation between older age and adenocarcinoma histology, which was the predominant histology in all age groups. There also were differences in the stage distribution of cases by age (p&amp;lt;.0001), primarily because of a .961 correlation between older age and localized disease, and conversely, a .989 inverse correlation with distant metastatic disease. The proportion of the 482 patients undergoing surgery did not differ significantly among all cohorts (p=0.62), but a somewhat smaller proportion of patients age 80 or older underwent surgical resection of their primary lung cancer (31.7%) compared to patients less than 80 years of age (31.7% vs 38.5%, p=.046). Only 48/75 (64.0%) of patients age 80 or older with localized NSCLC underwent surgical resection compared to 254/306 (83.0%) for patients younger than age 80 (p=.0003). There was a similar trend for patients who had regionally advanced disease: 18/52 (34.6%) of patients age 80 or older underwent surgical resection versus 124/251 (49.4%) for patients less than age 80 (p=.052). Actuarial survival curves for patients revealed observed 5-year survival rates of 62%, 53%, 63%, 63%, and 79% from oldest to youngest cohort. Conclusion: A smaller proportion of patients 80 years of age or older underwent surgery compared to those less than 80 years of age, but survival for octogenarians with newly diagnosed NSCLC, who were selected to undergo surgical resection, was comparable to younger age groups. Older patients should not be denied potentially curative surgery simply because of age.
Finals revision courses
Authors: Laura Ingram Stirrat, Rachel L Phillips
Journal: BMJ (2010)

When the final year medical student is faced with a barrage of adverts for revision courses it is difficult to know which one to pick. In the United Kingdom, the number and variety of revision course providers seem to be growing every year. But do these courses prey on students’ insecurities and provide unnecessary repetition? Or do they provide an additional service that medical schools fail to supply? This is far from a comprehensive review, but we hope that this snapshot will shed some light for you amid the finals frenzy.

The Medical Defence Union and Medical Protection Society courses focus on consolidating knowledge. Given the lottery of medical school placements, the comprehensive overviews and detailed revision notes from these courses were useful to identify our knowledge gaps. Lectures from practising clinicians were interspersed with real life anecdotes, giving memorable and clinically relevant learning points. We benefited from attending the courses before specific rotations—understanding ileal conduits, for example—before seeing a single surgical patient.

Recommended for —Appreciation of breadth and depth of undergraduate syllabus.

Time —Early in revision, perhaps even before medical …
The Nobel prize in physiology or medicine
Authors: Anna Mead-Robson
Journal: BMJ (2010)

The Nobel prize originated in the will of Alfred Nobel, a Swedish chemist famous for inventing dynamite. Much to the dismay of his family, Nobel chose to contribute most of his estate towards the establishment of a prize for people who had conferred “the greatest benefit on mankind.” Originally the prize was awarded in five disciplines—physics, chemistry, physiology or medicine, literature, and contribution towards peace. …
Abstract P4-08-32: Derivation and validation of a novel prediction model in breast phyllodes tumors after surgery
Authors: E Song, X Chao, Y Nie, X Jin, C Tan, J Cui, H Hu, H Yao
Journal: Cancer Research (2019)

Abstract Aim This study aimed to develop a nomogram based on clinicopathological features to evaluate the recurrence probability of breast phyllodes tumors following surgery. The criteria for atypia, mitoses, overgrowth, and surgical margin (AMOS) were also validated. Method Data from 334 patients with breast phyllodes tumors, who underwent surgical treatment at Sun Yat-sen Memorial Hospital from January 2005 to December 2014, were used to develop a prediction model. Additionally, data of 36 patients from Peking University Shenzhen Hospital and data of 140 patients from Sun Yat-sen University Cancer Center during the same period were used to validate the model. The medical records and tumor slides were retrospectively reviewed. The log-rank and Cox regression tests were used to develop a clinical prediction model of breast phyllodes tumors as well as validating the AMOS criteriaAll statistical analyses were performed using R and STATA. Results Of all 334 patients included in the study, 224 had benign, 91 had borderline, and 19 had malignant tumors. The local and distant recurrence rate was 17.7%. The 1-,3-, and 5-year cumulative recurrence-free survival was 98.5%, 97.9%, and 96.8%, respectively. Surgical margin, mitoses, and tumor border were identified as independent risk factors for breast phyllodes tumors. A nomogram was developed based on these three variables. The C-index of internal and external validation was 0.71and 0.67, respectively. The area under the curve of AMOS criteria was 0.59. Conclusions The present study model presented a more concise and objective variables to evaluate the recurrence-free survival of patients after surgery compared with that using the AMOS criteria, which is more appropriate for clinical practice and also allows for a more accurate prediction. Citation Format: Song E, Chao X, Nie Y, Jin X, Tan C, Cui J, Hu H, Yao H. Derivation and validation of a novel prediction model in breast phyllodes tumors after surgery [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-32.
Overcoming the Blood–Brain Barrier with an Implantable Ultrasound Device
Authors: Adam M. Sonabend, Roger Stupp
Journal: Clinical Cancer Research (2019)

Ultrasound-based blood-brain barrier disruption enhances drug delivery. To bypass the human skull, an implantable ultrasound emitter was developed, and proven safe and feasible in a first-in-human trial. Next development steps aim for larger field of disruption, quantification of drug levels, use of various drugs, and ultimately a pivotal trial demonstrating improved outcome.See related article by Idbaih et al., p. 3793.
Lapses in professionalism cause medical students stress
Authors: Richard Thorley
Journal: BMJ (2013)

A survey has shown that medical students are experiencing “emotional stress” because they feel unable to challenge senior colleagues over lapses in professional behaviour.

More than 4000 students from England, Wales, Scotland, Northern Ireland, and Australia participated in the research carried out by Cardiff University and the University of Dundee, with more than 2000 incidences of lapses of professionalism reported.

Complaints from students included allegations of verbal abuse, being humiliated in front of patients, and having to perform menial tasks as punishment. Other common lapses included poor clinician hygiene, and breaches in confidentiality. One student anonymously reported witnessing “unprofessional embarrassing behaviour when treating a dementia patient, involving physical unnecessary restraint of the patient and a member of the clinical …
Transdiagnostic psychiatry: a systematic review
Authors: Paolo Fusar‐Poli, Marco Solmi, Natascia Brondino, Cathy Davies, Chungil Chae, Pierluigi Politi, Stefan Borgwardt, Stephen M. Lawrie, Josef Parnas, Philip McGuire
Journal: World Psychiatry (2019)

The usefulness of current psychiatric classification, which is based on ICD/DSM categorical diagnoses, remains questionable. A promising alternative has been put forward as the “transdiagnostic” approach. This is expected to cut across existing categorical diagnoses and go beyond them, to improve the way we classify and treat mental disorders. This systematic review explores whether self‐defining transdiagnostic research meets such high expectations. A multi‐step Web of Science literature search was performed according to an a priori protocol, to identify all studies that used the word “transdiagnostic” in their title, up to May 5, 2018. Empirical variables which indexed core characteristics were extracted, complemented by a bibliometric and conceptual analysis. A total of 111 studies were included. Most studies were investigating interventions, followed by cognition and psychological processes, and neuroscientific topics. Their samples ranged from 15 to 91,199 (median 148) participants, with a mean age from 10 to more than 60 (median 33) years. There were several methodological inconsistencies relating to the definition of the gold standard (DSM/ICD diagnoses), of the outcome measures and of the transdiagnostic approach. The quality of the studies was generally low and only a few findings were externally replicated. The majority of studies tested transdiagnostic features cutting across different diagnoses, and only a few tested new classification systems beyond the existing diagnoses. About one fifth of the studies were not transdiagnostic at all, because they investigated symptoms and not disorders, a single disorder, or because there was no diagnostic information. The bibliometric analysis revealed that transdiagnostic research largely restricted its focus to anxiety and depressive disorders. The conceptual analysis showed that transdiagnostic research is grounded more on rediscoveries than on true innovations, and that it is affected by some conceptual biases. To date, transdiagnostic approaches have not delivered a credible paradigm shift that can impact classification and clinical care. Practical “TRANSD”iagnostic recommendations are proposed here to guide future research in this field.
A randomized phase III study evaluating pegylated liposomal doxorubicin (PLD) versus capecitabine (CAP) as first-line therapy for metastatic breast cancer (MBC): Results of the PELICAN study.
Authors: E. Jäger, S. Al-Batran, S. Saupe, M. Schmidt, R. Kreienberg, L. Müller, B. J. Otremba, M. Warm, D. Waldenmaier, N. Harbeck
Journal: Journal of Clinical Oncology (2010)

1022 Background: PLD and CAP have significant antitumor activity in a wide range of solid tumors including MBC. The PELICAN trial was designed to compare efficacy and safety of first-line PLD vs. CAP in MBC. Methods: Patients (pts) with MBC were stratified by age and prior adjuvant anthracycline (A), and randomized to receive either PLD (50 mg/m2 every 28 days) or CAP (1,250 mg/m2 BID x 14 days every 21 days) as first-line therapy until disease progression or unacceptable toxicity. Primary objective was to compare the time to disease progression (TTP). Results: 210 pts (PLD: 105; CAP: 105) were randomized. Median age was 62 (22–85) years; most pts had an ECOG of 0 (51%) or 1 (43%). Prior adjuvant anthracycline was documented in 37% of pts. Pts received a median of 5 cycles of PLD and 5 cycles of CAP. Median TTP was comparable in both arms (6.7 mo with PLD vs. 7.1 mo with CAP, p > 0.3460), as was the overall survival (OS), with 1-year survival rates being 82% and 75% with PLD and CAP, respectively. The overall response rate was 24% with PLD and 26% with CAP. In the planned subgroup analyses, adjuvant A-pretreatment had a negative impact on TTP in the CAP group (4.8 mo with prior A vs. 9.0 mo without; p > 0.0098) but not in the PLD-group (5.9 mo with prior A vs. 6.9 mo without; p > 0.5584). Significantly more patients in the CAP group experienced grade 3/4 diarrhea (12% vs. 0%, p > 0.0002) and grade 3/4 thromboembolic events (10% vs. 2%, p > 0.0333) than in the PLD group. Hand-foot-syndrome was not significantly different between groups (PLD 36% vs. CAP 25%, respectively; p > 0.1352). Cardiac events were reported with 9% in the PLD group and 12% in the CAP group (p > 0.4999). Conclusions: First-line chemotherapy of MBC patients in the randomized phase III PELICAN trial using PLD or CAP showed to be similarly effective with respect to TTP. However, the PLD arm showed a better tolerability profile, which may also allow more treatment options for subsequent therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Essex Pharma Essex Pharma, Schering-Plough Schering-Plough
MicroRNA-145 Regulates the Differentiation of Adipose Stem Cells Toward Microvascular Endothelial Cells and Promotes Angiogenesis
Authors: Gemma Arderiu, Esther Peña, Rosa Aledo, Oriol Juan-Babot, Javier Crespo, Gemma Vilahur, Blanca Oñate, Fabrizio Moscatiello, Lina Badimon
Journal: Circulation Research (2019)

Adipose-derived stem cells (ASCs) are a potential adult mesenchymal stem cell source for restoring endothelial function in ischemic tissues. However, the mechanism that promotes ASCs differentiation toward endothelial cells (ECs) is not known.To investigate the mechanisms of ASCs differentiation into ECs.ASCs were isolated from clinical lipoaspirates and cultured with DMEM or endothelial cell-conditioned medium. Endothelial cell-conditioned medium induced downregulation of miR-145 in ASCs and promoted endothelial differentiation. We identified bFGF (basic fibroblast growth factor) released by ECs as inducer of ASCs differentiation through receptor-induced AKT (protein kinase B) signaling and phosphorylation of FOXO1 (forkhead box protein O1) suppressing its transcriptional activity and decreasing miR-145 expression. Blocking bFGF-receptor or PI3K/AKT signaling in ASCs increased miR-145 levels. Modulation of miR-145 in ASCs, using a miR-145 inhibitor, regulated their differentiation into ECs: increasing proliferation, migration, inducing expression of EC markers (VE-cadherin, VEGFR2 [vascular endothelial growth factor receptor 2], or VWF [von Willebrand Factor]), and tube-like formation. Furthermore, in vivo, downregulation of miR-145 in ASCs enhanced angiogenesis in subcutaneously implanted plugs in mice. In a murine hindlimb ischemia model injection of ASCs with downregulated miR-145 induced collateral flow and capillary formation evidenced by magnetic resonance angiography. Next, we identified ETS1 (v-ets avian erythroblastosis virus E26 oncogene homolog 1) as the target of miR-145. Upregulation of miR-145 in ASCs, by mimic miR-145, suppressed ETS1 expression and consequently abolished EC differentiation and the angiogenic properties of endothelial cell-conditioned medium-preconditioned ASCs; whereas, overexpression of ETS1 reversed the abrogated antiangiogenic capacity of miR-145. ETS1 overexpression induced similar results to those obtained with miR-145 knockdown.bFGF released by ECs induces ASCs differentiation toward ECs through miR-145-regulated expression of ETS1. Downregulation of miR-145 in ASCs induce vascular network formation in ischemic muscle.