tbuckley/cabot-search huggingface dataset:
Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4
Authors: Daisuke Yasuda, Daiki Kobayashi, Noriyuki Akahoshi, Takayo Ohto-Nakanishi, Kazuaki Yoshioka, Yoh Takuwa, Seiya Mizuno, Satoru Takahashi, Satoshi Ishii
Journal: Journal of Clinical Investigation (2019)

Lysophosphatidic acid (LPA) is a potent lipid mediator with various biological functions mediated through six G protein-coupled receptors (GPCRs), LPA1-6. Previous studies have demonstrated that LPA-Gα12/Gα13 signaling plays an important role in embryonic vascular development. However, the responsible LPA receptors and underlying mechanisms are poorly understood. Here, we show a critical role of LPA4 and LPA6 in developmental angiogenesis. In mice, Lpa4;Lpa6 double knockout (DKO) embryos were lethal due to global vascular deficiencies, and endothelial cell (EC)-specific Lpa4;Lpa6 DKO retinas had impaired sprouting angiogenesis. Mechanistically, LPA activated the transcriptional regulators YAP and TAZ through LPA4/LPA6-mediated Gα12/Gα13-Rho-ROCK signaling in ECs. YAP/TAZ knockdown increased β-catenin- and Notch intracellular domain (NICD)-mediated endothelial expression of the Notch ligand delta-like 4 (DLL4). Fibrin gel sprouting assay revealed that LPA4/LPA6, Gα12/Gα13, or YAP/TAZ knockdown consistently blocked EC sprouting, which was rescued by a Notch inhibitor. Of note, the inhibition of Notch signaling also ameliorated impaired retinal angiogenesis in EC-specific Lpa4;Lpa6 DKO mice. Overall, these results suggest that the Gα12/Gα13-coupled receptors LPA4 and LPA6 synergistically regulate endothelial Dll4 expression through YAP/TAZ activation. This could in part account for the mechanism of YAP/TAZ-mediated developmental angiogenesis. Our findings provide a novel insight into the biology of GPCR-activated YAP/TAZ.
Revised-International Staging System (R-ISS) Is Independently Predictive and Prognostic for Early Relapse (<24 months) after Upfront Autologous Hematopoietic Cell Transplantation (AHCT) for Newly Diagnosed Multiple Myeloma (MM
Authors: Sathish Kumar, Anita D'Souza, Emma C. Scott, Raphael Fraser, Omar Davila, Cristina J. Gasparetto, Shaji K Kumar, Tomer M Mark, Yago Nieto, Parameswaran Hari
Journal: Blood (2017)
Medical Overuse and Appendicitis Treatment
Authors: Seth D. Goldstein, Mehul V. Raval
Journal: JAMA Pediatrics (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Endoscopic ultrasound-guided choledochoduodenostomy and duodenal stenting for combined malignant biliary and duodenal obstruction
Authors: Yu Jun Wong, Jonathan Guo Xiang Teh, Christopher Khor, Damien Meng Yew Tan
Journal: Endoscopy (2019)

A 64-year-old man with metastatic cecal adenocarcinoma on palliative chemotherapy presented with both cholangitis and persistent vomiting. Computed tomography demonstrated a dilated common bile duct and gastric outlet obstruction from a malignant stricture at the second part of the duodenum (D2) involving the papilla ([Fig. 1]). A diagnosis of type 2 combined malignant biliary and duodenal obstruction (CMBDO) was made.
What do autistic people want from autism research?
Authors: Chloe Silverman
Journal: Behavioral and Brain Sciences (2019)

Abstract Research that engages the experiences and insights of autistics and their caregivers can be more ethical, less stigmatizing, and innovative. To avoid reproducing established assumptions, researchers should learn how autistics and their caregivers understand behavioral and communicative differences, and how they prioritize interventions and accommodations. Fostering “autistic flourishing” requires that researchers focus on similarities between autistics and neurotypical people while allowing for autistic differences. Consulting autistics helps ensure that their personhood is acknowledged.
Abstract #1291: Efficient knockdown of MMR proteins in human CRCcells using chained microRNA constructs
Authors: Kristen Lacombe, Brenda Coomber
Journal: Cancer Research (2009)

In colorectal cancer, microsatellite instability (MSI) is a frequent occurrence which causes an increase in mutation rate leading to tumor progression. Previous studies in our laboratory established that MSH2 expression is mediated by ischemia, and that this leads to de novo point mutations in the transforming oncogene KRAS. Since the cells previously used had been genetically manipulated to loose an activating allele of KRAS, we wished to create an in vitro model that is able to sufficiently mimic the mutator phenotype seen in MSI colorectal cancer earlier in progression (i.e. prior to KRAS activation). We achieved this by knocking-down the expression of two key mismatch repair proteins, MSH2 and MLH1. This was done by stably transfecting Caco-2 colorectal cells (which are mismatch repair proficient and microsatellite stable) with a plasmid (BLOCK-iT; Invitrogen) containing chained microRNAs (miRNAs) designed to target both MSH2 and MLH1 mRNAs. Cells were then seeded at low density in selection media containing blasticidin and different clones were isolated. Protein knock-down in each clone was then examined through western blotting. Greater than 99% protein knockdown was achieved through miRNA targeting of MSH2 alone, and we found chained constructs were more effective than single miRNA sequences. Co-repression of MSH6 but not MLH1 was also observed in MSH2 knockdown cells. Further studies will be done to determine the MSI status of these cells as well as other molecular changes they have undergone. This study will further elucidate the effects of decreased MMR protein expression on cell behavior and aid in our understanding of its involvement in tumor progression.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1291.
19 G aspiration needle versus 19 G core biopsy needle for endoscopic ultrasound-guided liver biopsy: a prospective randomized trial
Authors: Rafael A. Ching-Companioni, David L. Diehl, Amitpal S. Johal, Bradley D. Confer, Harshit S. Khara
Journal: Endoscopy (2019)

Abstract Background Endoscopic ultrasound-guided liver biopsy (EUS-LB) is a safe and effective method for accomplishing parenchymal liver biopsy. The aim of this study was to compare a 19 G aspiration needle (FNA) with a 19 G Franseen-tip core biopsy needle (FNB) for EUS-LB. Methods This was a prospective, parallel group, randomized trial comparing the tissue yields and adequacy of a 19 G FNA needle vs. a 19 G FNB needle for EUS-LB. The primary outcome was length of the longest piece of liver core specimen. Secondary outcomes were aggregate specimen length, number of complete portal triads (CPTs), and adverse events. One transgastric pass and one transduodenal pass were performed with the same needle in each patient. Specimen lengths were measured before and after histological processing. Results 40 patients referred for EUS-LB were randomized to either the FNA group (n = 20) or the FNB group (n = 20). Both groups had similar patient characteristics. FNB biopsies yielded longer mean (standard deviation) specimen lengths (pre-processing mean 2.09 cm [0.41] vs. mean 1.47 cm [0.46], and post-processing mean 1.78 cm [0.66] vs. mean 1.05 cm [0.42]; both P &lt; 0.001), a longer aggregate specimen length (pre-processing mean 15.78 cm [5.19] vs. 10.89 cm [4.38]; P = 0.003), and more CPTs (mean 42.6 25 vs 18.1 [9.3]; P &lt; 0.001) compared with the FNA needle. There were no severe adverse events or difference in adverse event rate between the two needles. Post-biopsy pain was noted in 37.5 %. Conclusion EUS-LB using the FNB needle delivered longer liver biopsy specimens with more CPTs than the regular (non-core) needle.
The persistence of disseminated tumor cells after systemic therapy and their influence on prognosis in early breast cancer patients.
Authors: Andreas D. Hartkopf, Markus Wallwiener, Ines Gruber, Hans Neubauer, Markus Hahn, Diethelm Wallwiener, Florin-Andrei Taran, Tanja N. Fehm
Journal: Journal of Clinical Oncology (2013)

1030 Background: Detection of disseminated tumor cells (DTC) in the bone marrow (BM) of early breast cancer (EBC) patients before the administration of systemic therapy is associated with poor outcome. The aim of this study was to evaluate the impact of DTC on overall survival (OS) and disease free survival (DFS) in a large cohort of EBC patients after the administration of systemic therapy. Methods: EBC patients receiving systemic therapy (endocrine therapy and/or chemotherapy +/- HER2-directed treatment) either prior to surgery (neoadjuvant systemic therapy, NST) or after surgery (adjuvant systemic therapy, AST) at Tuebingen University Hospital, Germany between 01/2003 and 06/2012 were available for this analysis. BM aspirates were collected during surgery / one year after surgery in patients receiving NST / AST. DTC were identified by immunocytochemistry (pancytokeratin antibody A45/B3) and cytomorphology. Survival was analyzed using univariate (log-rank test) and multivariate analysis (cox regression). Results: DTC were detected in 201 of 608 (35%) patients. 175 of 419 (42%) patients treated with NST and 35 of 189 (19%) patients treated with AST were DTC-positive. Chemotherapy / endocrine therapy was administered prior to BM aspiration in 399 (96%) / 19 (5%) of the patients receiving NST and in 99 (52%) / 158 (84%) of the patients receiving AST. On univariate analysis, the detection of DTC was a significant predictor of poor DFS (HR: 2.27, 95% CI: 1.48 – 3.48, p&lt;0.001) and poor OS (HR: 1.89, 95% CI: 1.19 – 3.00, p=0.007). On multivariate analysis (considering all clinicopathological factors and the DTC-status), independent factors for DFS were DTC-status (negative vs. positive), grading (G2-3 vs. G3), nodal-status (negative vs. positive), and the ER-status (negative vs. positive). Independent factors for OS were grading, PR-status (negative vs. positive) and nodal-status. Conclusions: The persistence of DTC in the BM of EBC patients after systemic treatment is a strong and independent marker of poor prognosis. Determination of the DTC-status is thus promising to monitor the effect of systemic therapy and to identify patients that are in need of additional adjuvant therapy.
DAPSA versus cDAPSA: Do we need to use CRP?
Authors: Rafaela Silva Guimarães Gonçalves, Lays Miranda de Almeida Martins, Henrique de Ataide Mariz, Andrea Tavares Dantas, Angela Luzia Branco Pinto Duarte
Journal: Annals of the Rheumatic Diseases (2019)

In recent years, there has been a paradigm shift towards the development of disease activity indexes that correspond to the clinical measures and also the results reported by the patients, thus capturing the total burden of the disease.1

Disease Activity Index for Psoriatic Arthritis (DAPSA)2 is an index for measuring disease activity in psoriatic arthritis (PsA) that use C-reactive protein (CRP) as activity biomarker. Recently, van Mens et al 1 shown that the use of clinical DAPSA (cDAPSA) was similar to DAPSA using CRP. Our objective is evaluating whether CRP influences the achievement of different DAPSA disease states, and therefore we compared DAPSA with and without CRP.

Trained rheumatology collected clinical data from 124 eligible patients, including swollen and tender joint count (SJC 66 and TJC 68 joints).

DAPSA is calculated with the number of painful joints …
Effect of BSA dosing on 5-FU exposure among colorectal cancer patients depending on their gender and age.
Authors: Abebe Haregewoin, Stephanie A. Hamilton, Charles E. Grier, Rajesh R. Kaldate
Journal: Journal of Clinical Oncology (2012)

3627 Background: 5-fluorouracil (5-FU) remains the cornerstone of colorectal cancer (CRC) therapy and its dosing is based on body surface area (BSA). Although convenient, BSA dosing disregards factors that impact 5-FU PK such as genotype, age, gender, etc. Thus, patients receiving the same BSA based dose show a wide range of 5-FU plasma levels (measured as AUC in mg · h/L), resulting in ineffective or toxic doses affecting therapy outcome. An optimal therapeutic AUC target range of 20-30 mg · h/L has been proposed. Methods: Plasma samples from the initial treatment cycle of 927 CRC patients who received 2,400 mg/m 2 continuous infusion of 5-FU over 44-48 hours, with or without bevacizumab, were tested for 5-FU exposure using an immune-based assay (OnDose). AUC results were analyzed to evaluate gender and age effects. Results: There are 391 (42.2%) female and 536 (57.8%) male patients with age ranging from 17-93 years (mean/SD: 58.5/11.8). See table. These analyses indicate that in comparison to the proposed optimal AUC target range of 20-30 mg · h/L, females receive supra-optimal doses compared to males (p=0.0083). Age also affects the 5-FU AUC (p=0.0002), with younger patients more likely to receive suboptimal doses than older patients. Conclusions: BSA dosing is an unreliable indicator of exposure and may lead to under dosing in males and younger patients, and overdosing in females and older patients, potentially resulting in corresponding diminished efficacy or increased toxicity. Data suggest that therapy could be optimizedby 5-FU dose adjustment in subsequent cycles based on PK monitoring so that AUC values will converge towards the target range irrespective of gender or age. A large clinical trial is in progress to validate these findings. [Table: see text]
Can we predict injury in male football players based on the functional movement screen and other tests of injury risk? (PhD Academy Award)
Authors: Fraser Philp
Journal: British Journal of Sports Medicine (2019)

I investigated the validity of the functional movement screen (FMS)1 for measuring movements and predicting injury. I also validated models that predict injury occurrence in football players.

To reduce injury for individual players, and mitigate the impact of injury rates on team performance, clinicians regularly advise players whether they are safe to train/play during the preseason and in season. The FMS is the most commonly used movement screening test used in football to inform decision-making. Evidence that the test is valid is lacking.2 3 A second approach to assess readiness to play is to use statistical models, informed by guidelines of football governing bodies that include a variety of potential risk factors.4 5 Existing models lack precision or clinical usefulness in predicting events such as injury. The inability to prospectively …
Postacute Care — The Piggy Bank for Savings in Alternative Payment Models?
Authors: Michael L. Barnett, Ateev Mehrotra, David C. Grabowski
Journal: New England Journal of Medicine (2019)

The shift away from fee-for-service payment puts pressure on hospitals to reduce low-value care and to manage care delivered outside their walls. Thus far, hospitals have found savings by using an unusually consistent strategy: reducing institutional postacute care.
Air Pollution and Human Health
Authors: Mary O. Amdur
Journal: New England Journal of Medicine (1962)

In addition to the acute effects of transient increases in pollution levels on the most sensitive segment of the population there are possible long-term chronic effects of average levels of pollution on urban dwellers. An assessment of these effects is not simple since many things such as living standards, occupational history and smoking habits must be taken into account in epidemiologic studies if valid conclusions are to be reached.A wide variety of common air pollutants are known to be irritant to mucous membranes; thus, a state of chronic irritation of the respiratory tract is one condition that might result . . .
A multicenter phase I-II trial of weekly paclitaxel and carboplatin plus bevacizumab in women with triple-negative metastatic breast cancer.
Authors: Emmanouil S. Saloustros, Aristidis Polyzos, Charalampos Christophyllakis, Nikolaos K. Kentepozidis, Lampros Vamvakas, Kostas Kalbakis, Sofia Agelaki, Vassilis Georgoulias, Dimitrios Mavroudis
Journal: Journal of Clinical Oncology (2013)

1045 Background: Triple-negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents. The combination of carboplatin and paclitaxel administered weekly is active and well tolerated. Bevacizumab when added to paclitaxel prolonged progression-free survival in metastatic breast cancer (MBC). We investigated the activity and toxicity of paclitaxel plus carboplatin and bevacizumab in triple-negative MBC. Methods: The study’s primary objective was to estimate the objective response rate [complete (CR) + partial remission (PR)] and toxicity of the combination in women with triple negative MBC who had no prior chemotherapy for metastatic disease. The study followed the Simon's two-stage optimal design with 16 patients initially evaluated for response and toxicity and then expanding to a total of 46 patients. The null hypothesis that the objective response rate is ≤40% could be rejected if the number of CR/PR was ≥23. Paclitaxel 90mg/m 2 and Carboplatin AUC 2 were administered on days 1, 8, and 15 every 4 weeks, preceded by bevacizumab 10 mg/kg on days 1 and 15. Results: 45 women with triple negative MBC have been recruited thus far. Of them, 12 were premenopausal and 27 had prior (neo-)adjuvant chemotherapy. The median cycles administered were 5 (range 1-8). Of 38 evaluable patients we observed 7 CR, 22 PR’s for an objective response rate 76%. Seven patients achieved stable disease, while two had disease progression. Median duration of response was 8.1 months with median time to progression 9.2 months. Neutropenia grade 3 and 4 was experienced by 13 and 6 patients, respectively, with one toxic death due to febrile neutropenia. Other grade 3 toxicities included anemia/neurotoxicity (n=2), thrombocytopenia/diarrhea (n=1). Conclusions: Although still ongoingthe study has achieved the primary objective of demonstrating clinical activity for weekly carboplatin and paclitaxel in combination with bevacizumab in triple negative MBC. We believe that this triplet combination merits further evaluation in this patient population for whom there is no standard treatment. Clinical trial information: NCT00691379.
Identification of novel variant of EML4-ALK fusion gene in NSCLC: Potential benefits of the RT-PCR method.
Authors: Martin Karl Herbert Maus, Craig Stephens, Gary Zeger, Peter Philipp Grimminger, Eric Huang
Journal: Journal of Clinical Oncology (2012)

e12007 Background: The discovery of the transforming fusion gene of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein like 4 (EML4) as an oncogene in 2007 has led to its validation as a clinical target in NSCLC patients in a short period of time. The inhibition of the anaplastic lymphoma receptor tyrosine kinase has demonstrated to prolong progression-free survival compared to the standard of care chemotherapy in patients with advanced NSCLC that are ALK positive. However, the clinical implications of the 15 different variants of the EML4-ALK transforming gene described so far are currently not defined. Here we present a novel variant of the EML4-ALK fusion gene which we named variant 3c. Methods: RNA extracted from formalin fixed paraffin embedded (FFPE) specimens from patients with advanced and metastatic NSCLC was amplified, using primers and probes designed to detect specific EML4-ALK fusion gene fragments. Gel electrophoresis showed a different band for the new variant 3c compared to the known bands of positive cell lines for variant 3a and 3b. These findings were further investigated by dye-terminator Sequencing and FISH. Results: The novel variant, detected in two NSCLC specimens, is longer than v3a and shorter than v3b, representing an 18 base pair insertion of intron 19 of ALK between exon 6 of EML4 and exon 20 of ALK. All of the two samples showed exactly the same sequencing result. One of the samples was negative for FISH break apart testing and the other one showed a positive result, defined by ≥ 15% split nuclei as indicative of an ALK rearrangement. Conclusions: Compared to FISH technology, RT-PCR enables the detection of different isoforms of the EML4-ALK transforming gene, which can be validated by sequencing. Only one out of two samples that were positive for the new variant by RT-PCR could be confirmed by FISH. The clinical significance of the different variants, notably to resistance and response to ALK-Inhibitors and the concordance and sensitivity of FISH and RT-PCR should be subject to further investigations.
A randomized phase II study comparing gemcitabine plus nadroparine versus gemcitabine in patients with locally advanced or metastatic pancreatic carcinoma: The GEMFRAX trial
Authors: T. V. Voorthuizen, W. L. Vervenne, E. H. Van Daalen, S. S. Phoa, D. J. Gouma, M. J. Bruno, D. J. Richel
Journal: Journal of Clinical Oncology (2006)

4112 Background: Gemcitabine is considered to be the standard chemotherapy regimen for advanced pancreatic cancer. The advantage of gemcitabine over best supportive care however is limited. Preclinical and clinical data have shown that low molecular weight heparin (LMWH) has an inhibitory effect on tumor progression. Two years ago provoking and promising results were presented at ASCO in a pancreatic cancer population. In this study we wanted to confirm these promising results, in which 6-month survival was the primary endpoint. Methods: Patients (pts) with advanced pancreatic carcinoma were randomized to either gemcitabine 1000 mg/m 2 on day 1, 8 and 15 every 4 weeks (arm A) or gemcitabine plus nadroparine 5700 IU twice daily from day 1 to 21 every 4 weeks (arm B). Simon’s optimal two-stage design was applied to each arm to assess the treatment efficacy within each arm. This design required to enter 10 pts in the experimental arm in the first stage with the hypothesis that 70% instead of the expected 45% would be alive at 6 months. If 5 or less pts were alive at 6 months, the trial would be stopped and the regimen would be declared as ineffective. Results: 27 pts, all with metastatic disease, have been enrolled to date, 16 in arm A and 11 in arm B. Of the first 10 pts in the experimental arm only 4 were alive at 6 months (arm A: 6 of 10 pts alive).The median overall survival (OS) of these pts was 5.6 months and the median progression free survival (PFS) was 4.1 months (in arm A 8.7 and 5.1 months, respectively). The best response was stable disease (80%). No bleeding complications were seen. Conclusions: This small sized study was designed to detect a large, clinically relevant, difference in 6-month survival in pts with advanced pancreatic cancer treated with a combination of gemcitabine plus nadroparine compared to gemcitabine alone. Adding nadroparine to gemcitabine was feasible and gave no serious toxicity attributable to nadroparine. According to Simon’s two-step design a planned analysis after entering 10 pts in the experimental arm rejected the assumption that the combination induced an absolute increase in 6-month survival of 25% (5% type I error rate and 80% power). No significant financial relationships to disclose.