tbuckley/cabot-search huggingface dataset:
<i>CYP2D6</i> Genotype–Guided Tamoxifen Dosing in Hormone Receptor–Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study
Authors: Kenji Tamura, Chiyo K. Imamura, Toshimi Takano, Shigehira Saji, Takeharu Yamanaka, Kan Yonemori, Masato Takahashi, Junji Tsurutani, Reiki Nishimura, Kazuhiko Sato, Akira Kitani, Naoto T. Ueno, Taisei Mushiroda, Michiaki Kubo, Yasuhiro Fujiwara, Yusuke Tanigawara
Journal: Journal of Clinical Oncology (2019)

In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether CYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome.Patients who needed first-line tamoxifen therapy were enrolled. Based on individual CYP2D6 genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes.Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% v 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM v 51.1 nM; P < .0001) and were also higher compared with wt/wt patients (72.0 nM; P = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months (P = .43).In patients with CYP2D6-variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen.
Overall and progression-free survival with everolimus, temsirolimus, or sorafenib as second targeted therapies for metastatic renal cell carcinoma: A retrospective U.S. chart review.
Authors: Hongbo Yang, Michael K.K. Wong, James E. Signorovitch, Xufang Wang, Zhimei Liu, Nathan S. Liu, Zhengyun Qi, Daniel J. George
Journal: Journal of Clinical Oncology (2012)

4612 Background: Tyrosine kinase inhibitors (TKIs) (sorafenib, sunitinib, pazopanib) and inhibitors of the mammalian target of rapamycin (mTORs) (everolimus, temsirolimus) are used for treating metastatic renal cell carcinoma (mRCC) following initial treatment with a TKI. This study’s objective was to establish the effectiveness of the most commonly used 2 nd line treatments based on real-use data. Methods: mRCC patients who received a TKI as their 1 st targeted therapy and everolimus, temsirolimus or sorafenib as their 2 nd therapy were identified by oncologists (85% in community practice) throughout the US as part of an online chart review study. Baseline characteristics were assessed prior to 2 nd targeted therapy, including type and duration of initial TKI, response, histological subtype, performance status, and sites of metastasis. Overall survival (OS) and progression free-survival (PFS) were assessed after initiating 2 nd targeted therapy. OS and PFS were compared between treatment groups using Cox proportional hazards models adjusted for baseline characteristics. Results: Charts were reviewed for 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib after an initial TKI, respectively. Median age was 64 years and 70.4% were male. Prior to initiating a 2 nd targeted therapy, 86.0% used sunitinib and 85.9% had disease progression. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS compared to temsirolimus (hazard ratio [HR] 0.56; CI 0.40-0.78; p&lt;0.001) and sorafenib (HR 0.65; CI 0.42-0.99; p=0.047). Everolimus was associated with significantly longer PFS compared to temsirolimus (HR 0.73; CI 0.55-0.96; p=0.025), and non-statistically significant longer PFS compared to sorafenib (HR 0.75; CI 0.53-1.07; p=0.110). Results were similar in the subgroup with sunitinib as 1 st targeted therapy and the subgroup with progression on 1 st TKI. Conclusions: Among mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.
Phase II/III randomized trial of CID-ATT with radiotherapy compared with CHOP with radiotherapy as first-line treatment for previously untreated early staging extranodal NK/T-cell lymphoma, nasal type (ENKL).
Authors: Tongyu Lin, He Huang, Chao Yong Liang, Chengcheng Guo, Ying Tian, Tingzhi Liu, Xue Ying Li, Mengping Zhang, Huang Ming Hong, Dr.Prem Raj Shrestha
Journal: Journal of Clinical Oncology (2013)

8508 Background: Extranodal NK/T cell lymphoma, nasal type (ENKL) is more prevalent in Asia and has worse prognosis than B-NHL. No therapeutic strategy is currently identified for ENKL. This phase II/III study was undertaken to compare CHOP-B/IMVD/DHAP-Alternating Triple Therapy (CID-ATT) and standard CHOP regimen as first-line treatment prospectively. Methods:109 patients (pts) initially diagnosed as ENKL (16-70 ys old) with Ann Abor Stage I to II were randomized to receive CID-ATT or CHOP regimen from Jan 2006 to Jan 2012. CID-ATT alternated among CHOP-B, IMVD, and DHAP, given in alternating sequence for a total of 6 courses (2 circle). Involved field radiation was administered after 6 courses(2 circle) of CID-ATT regimen or 6 cycles of CHOP regimen. All pts received prophylactic granulocyte colony-stimulating factor, interleukin-11and thrombopoietin for each DHAP cycle. Results: 109 pts were evaluable (54CID-ATT; 55 CHOP). With a median follow-up of 40.3months,OS and PFS was significantly prolonged with CID-ATT compared with CHOP (1yOS :80.2% vs 78.6%, 3yOS:68.0% vs 42.3%, 5yOS: 64.2% vs 34.5%,P=0.023; 1yPFS: 74.9% vs 59.6%, 3yPFS:60.5% vs 32.0%, 5yPFS: 60.5% vs 32.0% ; P=0.016). Compared to CHOP group, CID-ATT group has a much higher complete remission rate (CID-ATT:47/54,87.0 % vs CHOP:29/55,52.7%, P&lt;0.001). The survivals for pts who achieved CR after One circle (3 courses) were significantly better than those who were in non-CR group.(5yOS: CR group in ATT:75.3%, non-CR group in ATT:51.5%, CR group in CHOP:39.3%, non-CR group in CHOP:31.0%; P=0.003). No treatment related death was observed, although Grade III/IV neutropenia (30/54,55.6%) and thrombocytopenia (33/54,61.1%) were observed in CID-ATT regimen, especially in DHAP cycle. Conclusions: Our study has demonstrated that the CID-ATT regimen as an optimal first-line therapy achieved promising clinical activity with safe and tolerated toxicity under close monitoring and good supportive care of untreated early staging ENKL pts. CR of induce chemotherapy following radiotherapy is very important for ENKL survival. Clinical trial information: CSWOG0002.
Moesin, an Ezrin/Radixin/Moesin Family Member, Regulates Hepatic Fibrosis
Authors: Serhan Karvar, Ephraim A. Ansa‐Addo, Jo Suda, Shweta Singh, Lixin Zhu, Zihai Li, Don C. Rockey
Journal: Hepatology (2019)

Background and Aims Moesin, an ezrin/radixin/moesin family member, is involved in the regulation of cell adhesion, polarity, and migration by cross‐linking between the actin cytoskeleton and plasma membrane. The primary effector cell in hepatic fibrosis is the hepatic stellate cell (HSC), which undergoes activation during liver injury leading to increased extracellular matrix production. Approach and Results Here, we have hypothesized that moesin plays a critical role in linking the HSC cytoskeleton to the fibrogenic cascade during HSC activation. Moesin phosphorylation was up‐regulated during HSC activation and fibrogenesis. Using moesin wild‐type (WT) and mutant constructs (phosphomimicking T558D and nonphosphorylatable T558A), we found that cellular motility and contraction were increased in moesin WT‐infected and T558D‐infected cells, paralleled by an increase in smooth muscle α‐actin and collagen 1 expression. In contrast, overexpression of nonphosphorylatable moesin and moesin knockout (KO) decreased cellular motility and contraction. Most importantly, moesin KO led to abrogation of liver fibrosis. The mechanism of moesin's effect was a reduction in myocardin‐related transcription factor‐A and serum‐response factor (SRF)–mediated changes in the actin cytoskeleton, which in turn modulated the expression of matrix genes. Conclusions Taken together, our findings suggest that the linkage between cytoskeletal dynamics and the correlated MRTF/SRF signaling pathway has a pivotal role in HSC activation and fibrogenesis.
Ischemia and Bleeding in Cancer Patients Undergoing Percutaneous Coronary Intervention
Authors: Yasushi Ueki, Benjamin Vögeli, Alexios Karagiannis, Thomas Zanchin, Christian Zanchin, Daniel Rhyner, Tatsuhiko Otsuka, Fabien Praz, George C.M. Siontis, Christina Moro, Stefan Stortecky, Michael Billinger, Marco Valgimigli, Thomas Pilgrim, Stephan Windecker, Thomas Suter, Lorenz Räber
Journal: JACC CardioOncology (2019)

The purpose of this study was to evaluate ischemic and bleeding outcomes of unselected cancer patients undergoing percutaneous coronary intervention (PCI).
Response to: ‘European League against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus: the laboratory immunologist's point of view’ by Infantino <i>et al</i>
Authors: Martin Aringer, Karen H Costenbader, Thomas Dörner, Sindhu R Johnson
Journal: Annals of the Rheumatic Diseases (2019)

In their letter, Drs Infantino, Manfredi and Bizzaro express concerns regarding the low specificity of antinuclear antibodies (ANA) for systemic lupus erythematosus (SLE) classification.1 In particular, they propose that the entry criterion definition of positive ANA in the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria as ‘Antinuclear antibodies (ANA) at a titre of ≥1:80 on HEp-2 cells or an equivalent positive test at least once. Testing by immunofluorescence on HEp-2 cells or a solid phase ANA screening immunoassay with at least equivalent performance is highly recommended’2 3 could be associated with low specificity for SLE.

While specificity is important for classification criteria, …
ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline
Authors: Jean-Marc Dumonceau, Christine Kapral, Lars Aabakken, Ioannis S. Papanikolaou, Andrea Tringali, Geoffroy Vanbiervliet, Torsten Beyna, Mario Dinis-Ribeiro, Istvan Hritz, Alberto Mariani, Gregorios Paspatis, Franco Radaelli, Sundeep Lakhtakia, Andrew M. Veitch, Jeanin E. van Hooft
Journal: Endoscopy (2019)

Main Recommendations Prophylaxis 1 ESGE recommends routine rectal administration of 100 mg of diclofenac or indomethacin immediately before endoscopic retrograde cholangiopancreatography (ERCP) in all patients without contraindications to nonsteroidal anti-inflammatory drug administration. Strong recommendation, moderate quality evidence. 2 ESGE recommends prophylactic pancreatic stenting in selected patients at high risk for post-ERCP pancreatitis (inadvertent guidewire insertion/opacification of the pancreatic duct, double-guidewire cannulation). Strong recommendation, moderate quality evidence. 3 ESGE suggests against routine endoscopic biliary sphincterotomy before the insertion of a single plastic stent or an uncovered/partially covered self-expandable metal stent for relief of biliary obstruction. Weak recommendation, moderate quality evidence. 4 ESGE recommends against the routine use of antibiotic prophylaxis before ERCP. Strong recommendation, moderate quality evidence. 5 ESGE suggests antibiotic prophylaxis before ERCP in the case of anticipated incomplete biliary drainage, for severely immunocompromised patients, and when performing cholangioscopy. Weak recommendation, moderate quality evidence. 6 ESGE suggests tests of coagulation are not routinely required prior to ERCP for patients who are not on anticoagulants and not jaundiced. Weak recommendation, low quality evidence. Treatment 7 ESGE suggests against salvage pancreatic stenting in patients with post-ERCP pancreatitis. Weak recommendation, low quality evidence. 8 ESGE suggests temporary placement of a biliary fully covered self-expandable metal stent for post-sphincterotomy bleeding refractory to standard hemostatic modalities. Weak recommendation, low quality evidence. 9 ESGE suggests to evaluate patients with post-ERCP cholangitis by abdominal ultrasonography or computed tomography (CT) scan and, in the absence of improvement with conservative therapy, to consider repeat ERCP. A bile sample should be collected for microbiological examination during repeat ERCP. Weak recommendation, low quality evidence.
Erratum. Overall Quality of Care Predicts the Variability of Key Risk Factors for Complications in Type 2 Diabetes: An Observational, Longitudinal Retrospective Study. Diabetes Care 2019;42:514–519
Authors: Antonio Ceriello, Maria Chiara Rossi, Salvatore De Cosmo, Giuseppe Lucisano, Roberto Pontremoli, Paola Fioretto, Carlo Giorda, Antonio Pacilli, Francesca Viazzi, Giuseppina Russo, Antonio Nicolucci
Journal: Diabetes Care (2019)

The affiliations listed for author Antonio Ceriello have been amended to a single affiliation note, …
Functional TLR-9 expression, regulation and clinical significance in GBM patients
Authors: Gentao Liu, Zhaohui Zeng, Hiushan Ng, Iman Abdulkadir, Lizhi Lu, Keith Black, John Yu
Journal: Cancer Research (2007)

3557  Toll-like receptor-9 (TLR-9) is a pattern recognition receptor, which plays very important role in innate immunity. Placyticoid dendritic cells, B cells, langerhans and NK cells express TLR-9. Unmethylated CpG from bacterials can activate TLR-9. However, TLR-9 expression in tumor cells and its function is still unclear. We found that TLR-9 mRNA was expressed in 65% glioblastoma multiforme (GBM) cultured tumor cells by RT-PCR analysis. The protein expression of TLR-9 in tumor cells and tissue was confirmed by flow cytometry and immunofluorence analysis. Different type of commercial available CpG ODN was tested the function of TLR-9 in GBM. We found that class A CpG increased TRAIL expression and inhibited GBM cells proliferation while class B CpG stimulated IL-6 expression and increased GBM cells proliferation. Receptor tyrosine kinase inhibitor (RTK) geldanamycin and cyclooxygenase-2 (COX-2) inhibitor could significantly increased TLR-9 expression, however, TNF-α treatment significantly decreased TLR-9 expression. Finally, we found that TLR-9 positive GBM patients presented significantly longer survival than those of TLR-9 negative GBM patients. This study suggested that TLR-9 could be a useful prognosis biomarker in GBM patients and class A CpG ODN may be a promising reagent for cancer immunotherapy.
Diabetes is associated with genotypically drug-resistant tuberculosis
Authors: Carolien Ruesen, Lidya Chaidir, Cesar Ugarte-Gil, Jakko van Ingen, Julia A. Critchley, Philip C. Hill, Rovina Ruslami, Prayudi Santoso, Martijn A. Huynen, Hazel M. Dockrell, David A.J. Moore, Bachti Alisjahbana, Reinout van Crevel
Journal: European Respiratory Journal (2019)

<b>In a study in Peru and Indonesia, diabetes was associated with an increased risk of tuberculosis caused by <i>Mycobacterium tuberculosis</i> strains with resistance mutations, particularly against rifampicin, and this was not explained by previous TB treatment</b>http://bit.ly/2QCvUEM
Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial
Authors: Maria-Victoria Mateos, Michele Cavo, Joan Blade, Meletios A Dimopoulos, Kenshi Suzuki, Andrzej Jakubowiak, Stefan Knop, Chantal Doyen, Paulo Lucio, Zsolt Nagy, Ludek Pour, Mark Cook, Sebastian Grosicki, Andre Crepaldi, Anna Marina Liberati, Philip Campbell, Tatiana Shelekhova, Sung-Soo Yoon, Genadi Iosava, Tomoaki Fujisaki, Mamta Garg, Maria Krevvata, Ying Chen, Jianping Wang, Anupa Kudva, Jon Ukropec, Susan Wroblewski, Ming Qi, Rachel Kobos, Jesus San-Miguel
Journal: The Lancet (2019)
Identity-based motivation and the paradox of the future self: Getting going requires thinking about time (later) in time (now)
Authors: Daphna Oyserman, Andrew Dawson
Journal: Behavioral and Brain Sciences (2019)

Abstract People can imagine their future selves without taking future-focused action. Identity-based motivation theory explains why. Hoerl &amp; McCormack outline how. Present-focused action prevails because future “me” feels irrelevant to the choices facing current “me” unless future “me” is experienced as occurring now or as linked to current “me” via if-then simulations. This entails reasoning in time and about time.
A Discrete Presynaptic Vesicle Cycle for Neuromodulator Receptors
Authors: Damien Jullié, Miriam Stoeber, Jean-Baptiste Sibarita, Hanna L. Zieger, Thomas M. Bartol, Seksiri Arttamangkul, Terrence J. Sejnowski, Eric Hosy, Mark von Zastrow
Journal: Neuron (2019)
Reverse innovation, power imbalances, language, and avoiding cultural appropriation
Authors: Amali U Lokugamage, Christine Douglass, Faye Gishen, Molly V Fyfe
Journal: BMJ (2019)

We thank Skopec and colleagues1 for their essay on reverse innovation and note that it could herald an age of increased cultural humility for the global north and assist with dissipating prejudices towards innovations from the global south. Bringing in new ideas from “outside” requires disrupting entrenched power and value systems around knowledge. …
Abstract 391: Variation in Time to Notification After Enrollment in Trials Conducted Under Exception From Informed Consent for Emergency Research
Authors: Graham Nichol, Rui Zhuang, Tom P Aufderheide, Eileen Bulger, Clifton W Callaway, Jim Christenson, Mohamud R Daya, Ahamed H Idris, Peter Kudenchuk, Laurie J Morrison, Martin A Schreiber, George Sopko, Jeremy Sugarman, Christian Vaillancourt, Henry E Wang, Myron Weisfeldt, Susanne May
Journal: Circulation (2019)

Context: Research in an emergency setting is challenging because the window of opportunity to treat may be short, and preclude time to obtain informed consent from the patient or their representative. Such research can be conducted under exception from informed consent (EFIC) if specific criteria are met. In the United States, this includes notification of an enrolled subject or their representative as soon as feasible after enrollment so that they have autonomy to opt out from ongoing study participation. To date, there is limited empiric information about time to notification (TTN). Objective: To describe variation in TTN among sites participating in randomized trials conducted under exception from informed consent for emergency research. Methods: Notification strategies were determined at each site prior to initiation of subject enrollment, and approved by a local institutional review board or equivalent. TTN was summarized overall, as well as stratified by site and clinical outcome among patients enrolled in multiple trials conducted by the Resuscitation Outcomes Consortium (ROC). Results: Included were 34,868 patients enrolled in four trials. Of these, 33,805 had with out-of-hospital cardiac arrest; and 1,063 had life-threatening traumatic injury. TTN varied (Table). Conclusions: There is large variation in TTN in trials conducted under EFIC for emergency research. Early notification is difficult; delayed notification may reduce the autonomy of patients or their representative.
Working in New Zealand
Authors: Helen Jones
Journal: BMJ (2020)

New Zealand has a shortage of medical staff across many different fields. The Royal New Zealand College of General Practitioners published a survey this year that showed that almost half of GPs intend to retire in the next 10 years and that 70% are working in a practice with a GP vacancy.

It’s little surprise that the country relies heavily on doctors from overseas. According to the Medical Council of New Zealand (MCNZ), 40% of doctors practising in the country were trained abroad—and those from the UK and Ireland are highly sought after because of their similar training. New Zealand is also a favourite destination for doctors looking for adventure, proximity to the great outdoors, and a more relaxed way of life.

There is demand for junior doctors across all areas of …
Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease
Authors: Sebastian Werneburg, Jonathan Jung, Rejani B. Kunjamma, Seung-Kwon Ha, Nicholas J. Luciano, Cory M. Willis, Guangping Gao, Natalia P. Biscola, Leif.A. Havton, Stephen J. Crocker, Brian Popko, Daniel S. Reich, Dorothy P. Schafer
Journal: Immunity (2019)
Abstract #1256: The nuclear pore protein Nup153 has two distinct roles during cell division
Authors: Katharine Ullman, Suzanne Elgort, Douglas Mackay
Journal: Cancer Research (2009)

Accurate inheritance of genomic content during cell division is dependent on coordinated changes in cellular organization and chromosome dynamics. Once chromosomes undergo condensation, nuclear membranes and nuclear pore complexes are disassembled. Formation of daughter cells involves such hallmark events as segregation of chromosomal content, followed by rapid rebuilding of nuclei and, finally, abscission at the mid-body, a structure which connects the daughter cells until cytokinesis is complete. Understanding these events and how they are coordinated will allow us to better analyze how errors in cell proliferation lead to cancer and will also provide new therapeutic strategies to arrest uncontrolled cell growth. Our previous results in a cell-free system that recapitulates early embryonic conditions suggested that the nuclear pore protein Nup153 is a good candidate for playing a role in cell cycle coordination. To decipher whether this is the case in mammalian somatic cells, we reduced the levels of this nucleoporin in HeLa cells and monitored the consequences on cell growth. We found that reduction of Nup153 levels results in a delay during the late stages of mitosis, accompanied by an increase in unresolved cytokinetic mid-bodies. Live imaging analysis revealed a pronounced defect early in mitosis when Nup153 was depleted to an even lower threshold. Concomitantly, there was an accumulation of cells with multilobed nuclei, which could reflect a role for Nup153 in forming nuclear structure or a role in proper chromosome compaction and/or segregation, which has been found to result in similar nuclear morphology. Rescue of the defects in the resolution of mitosis required the Nup153 C-terminal domain. In contrast, rescue of the multilobed nuclei phenotype was independent of this domain. These phenotypes and rescue requirements indicate that Nup153 plays at least two distinct roles critical to the execution of mitosis. The C-terminal domain of Nup153 houses an FG-rich motif known to be important for trafficking through the nuclear pore. We found, however, that protein trafficking was not significantly altered under the depletion conditions used here, thus the FG-rich motif of Nup153 may play a novel role during cell division.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1256.