bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of FOLFIRI + ramucirumab with recurrent colorectal cancer refractory to adjuvant chemotherapy with oxaliplatin / fluoropyrimidine (RAINCLOUD).
Authors: Sugimoto Naotoshi , Matsuda Chu , Hata Taishi , Satoh Taroh , Ikenaga Masakazu , Mizushima Tsunekazu , Murata Kohei , Ohue Masayuki , Doki Yuichiro , Mori Masaki 
Published: January 2019

TPS882 Background: The RAISE study demonstrated the superiority of FOLFIRI + ramucirumab (Ram) to FOLFIRI in second-line metastatic colorectal cancer patients progressed after oxaliplatin, fluoropyrimidine with bevacizumab. But no prospective data is existed that the efficacy and toxicity of FOLFIRI + Ram pretreated oxaliplatin, fluoropyrimidine without an anti-angiogenesis therapy. Methods: RAINCLOUD study is a multicenter single-arm phase II trial. Key eligibility criteria is as follows: histologically or cytologically confirmed colorectal cancer, confirmed recurrent colorectal cancer, refractory to fluoropyrimidine, refractory or intolerant of oxaliplatin without pretreated anti-angiogenesis therapy, has measureable or non-measurable lesion, PS = 0 or 1, has adequate coagulation function, 20 years or older. Primary endpoint of this study is progression-free survival. Secondary endpoints are overall survival, time to treatment failure, response rate, disease control rate and safety. Patients receive FOLFIRI (irinotecan: 180 mg/m2, l-levofolinate: 200 mg/m2, bolus fluorouracil: 400mg/m2, and continuous fluorouracil: 2400 mg/m2) plus Ram (8 mg/kg) every two weeks until progression or the development of unacceptable toxicity. We hypothesized that threshold of PFS in FOLFIRI + Ram is 3.9 months and expected PFS is 6.9 months and designed to have an 80% power to detect clinically meaningful improvement in PFS at the one-sided significance level of 0.05, minimal patient registration number is 44 in order that power 1-β outperforms 0.8. Taking a few ineligibility patients and dropout patients into consideration, number of target patients is set to be 48. Study recruitment started on September 2017. The association of exploratory biomarker study will be planned. Clinical trial information: UMIN000028677.
The nationwide screening project on plasma angiogenesis-related mediators for treatment selection of optimal antiangiogenic inhibitors in metastatic colorectal cancer: GI-SCREEN CRC-Ukit.
Authors: Yuki Satoshi , Yamazaki Kentaro , Taniguchi Hiroya , Sunakawa Yu , Kawazoe Akihito , Kagawa Yoshinori , Kato Ken , Hara Hiroki , Denda Tadamichi , Oki Eiji , Moriwaki Toshikazu , Shiozawa Manabu , Satoh Taroh , Kawakami HIsato , Esaki Taito , Furuse Junji , Abe Yukiko , Nomura Shogo , Ohtsu Atsushi , Yoshino Takayuki 
Published: January 2019

TPS885 Background: Antiangiogenic treatments are a proven useful tool to improve clinical outcomes in patients (pts) with metastatic colorectal cancer (mCRC). Recently, higher levels of vascular endothelial growth factor-D (VEGF-D) are a potential predictive biomarker for ramucirumab efficacy on overall and progression-free survival in mCRC (Tabernero J, et al. ESMO 2017). However, there are limited data on mCRC associating the efficacy of antiangiogenic therapy with angiogenesis-related mediators, such as VEGF family members and their receptors, and with dynamic transition among these mediators during clinical courses. In addition, immune-related factors such as interferon gamma (IFNγ) and transforming growth factor β1 (TGFβ1) may be associated with the regulation of angiogenesis. Methods: This prospective longitudinal study aims to investigate the association between plasma angiogenesis-related mediators and clinical outcomes in mCRC. The key eligibility criteria include pts with mCRC who will receive one of the following regimens: first-line chemotherapy plus bevacizumab, first-line chemotherapy plus anti-EGFR antibody (either cetuximab or panitumumab), second-line FOLFIRI plus ramucirumab, second-line FOLFIRI plus aflibercept, or second-line chemotherapy plus bevacizumab. Plasma is collected twice in pairs from all pts pre- and post-treatment. Comprehensive measurements of plasma angiogenesis-related mediators, such as placental growth factor (PlGF), hepatocyte growth factor (HGF), IL-6, IL-8, angiopoietin-2, neuropillin-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), thrombospondin-2 (TSP-2), osteopontin (OPN), sVEGFR-1, sVEGFR-2, sVEGFR-3, VEGF-A, VEGF-D, as well as key targets associated with immunotherapy such as IFNγ and TGFβ1 are analyzed in parallel by the multiplex assay with Luminex® technology. The target sample size is 1,000. This study was initiated in September 2017. Clinical trial information: UMIN000028616.
Glucose starvation triggers filamentous septin assemblies in an S. pombe septin-2 deletion mutant
Authors: Liu Minghua , Heimlicher Maria B. , Bächler Mirjam , Ibeneche-Nnewihe Chieze C. , Florin Ernst-Ludwig , Brunner Damian , Hoenger Andreas 
Published: January 2019

ABSTRACT
Using correlative light and electron microscopy (CLEM), we studied the intracellular organization by of glucose-starved fission yeast cells (Schizosaccharomyces pombe) with regards to the localization of septin proteins throughout the cytoplasm. Thereby, we found that for cells carrying a deletion of the gene encoding septin-2 (spn2Δ), starvation causes a GFP-tagged version of septin-3 (spn3-GFP) and family members, to assemble into a single, prominent filamentous structure. It was previously shown that during exponential growth, spn2Δ cells form septin-3 polymers. However, the polymers we observed during exponential growth are different from the spn3p-GFP structure we observed in starved cells. Using CLEM, in combination with anti-GFP immunolabeling on plastic-sections, we could assign spn3p-GFP to the filaments we have found in EM pictures. Besides septin-3, these filamentous assemblies most likely also contain septin-1 as an RFP-tagged version of this protein forms a very similar structure in starved spn2Δ cells. Our data correlate phase-contrast and fluorescence microscopy with electron micrographs of plastic-embedded cells, and further on with detailed views of tomographic 3D reconstructions. Cryo-electron microscopy of spn2Δ cells in vitrified sections revealed a very distinct overall morphology of the spn3p-GFP assembly. The fine-structured, regular density pattern suggests the presence of assembled septin-3 filaments that are clearly different from F-actin bundles. Furthermore, we found that starvation causes substantial mitochondria fission, together with massive decoration of their outer membrane by ribosomes.
Development and validation of RdRp Screen, a crystallization screen for viral RNA-dependent RNA polymerases
Authors: Riccio Federica , Talapatra Sandeep K. , Oxenford Sally , Angell Richard , Mazzon Michela , Kozielski Frank 
Published: January 2019

ABSTRACT
Members of the Flaviviridae family constitute a severe risk to human health. Whilst effective drugs have been developed against the hepacivirus HCV, no antiviral therapy is currently available for any other viruses, including the flaviviruses dengue (DENV), West Nile and Zika viruses. The RNA-dependent RNA polymerase (RdRp) is responsible for viral replication and represents an excellent therapeutic target with no homologue found in mammals. The identification of compounds targeting the RdRp of other flaviviruses is an active area of research. One of the main factors hampering further developments in the field is the difficulty in obtaining high-quality crystal information that could aid a structure-based drug discovery approach. To address this, we have developed a convenient and economical 96-well screening platform. We validated the screen by successfully obtaining crystals of both native DENV serotype 2 and 3 RdRps under several conditions included in the screen. In addition, we have obtained crystal structures of RdRp3 in complex with a previously identified fragment using both soaking and co-crystallization techniques. This work will streamline and accelerate the generation of crystal structures of viral RdRps and provide the community with a valuable tool to aid the development of structure-based antiviral design.
Transgenic and physiological mouse models give insights into different aspects of amyotrophic lateral sclerosis
Authors: De Giorgio Francesca , Maduro Cheryl , Fisher Elizabeth M. C. , Acevedo-Arozena Abraham 
Published: January 2019

ABSTRACT
A wide range of genetic mouse models is available to help researchers dissect human disease mechanisms. Each type of model has its own distinctive characteristics arising from the nature of the introduced mutation, as well as from the specific changes to the gene of interest. Here, we review the current range of mouse models with mutations in genes causative for the human neurodegenerative disease amyotrophic lateral sclerosis. We focus on the two main types of available mutants: transgenic mice and those that express mutant genes at physiological levels from gene targeting or from chemical mutagenesis. We compare the phenotypes for genes in which the two classes of model exist, to illustrate what they can teach us about different aspects of the disease, noting that informative models may not necessarily mimic the full trajectory of the human condition. Transgenic models can greatly overexpress mutant or wild-type proteins, giving us insight into protein deposition mechanisms, whereas models expressing mutant genes at physiological levels may develop slowly progressing phenotypes but illustrate early-stage disease processes. Although no mouse models fully recapitulate the human condition, almost all help researchers to understand normal and abnormal biological processes, providing that the individual characteristics of each model type, and how these may affect the interpretation of the data generated from each model, are considered and appreciated.
The cell biology behind the oncogenic PIP3 lipids
Authors: Carrera Ana C. , Anderson Richard 
Published: January 2019

ABSTRACT
The different mechanisms of phosphoinositide 3-kinase (PI3K) activation in cancer as well as the events that result in PI3K pathway reactivation after patient treatment with PI3K inhibitors was discussed on October 15–17th, 2018, in the medieval town of Baeza (Universidad Internacional de Andalucía, Spain) at the workshop entitled ‘The cell biology behind the oncogenic PIP3 lipids’. These topics and the data presented regarding cellular functions altered by PI3K deregulation, the cooperation of PI3K/PTEN mutations with other tumor drivers, and the lessons learned for PI3K-targeted therapy, are discussed below.
Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis
Authors: Ashwin Helen , Seifert Karin , Forrester Sarah , Brown Najmeeyah , MacDonald Sandy , James Sally , Lagos Dimitris , Timmis Jon , Mottram Jeremy C , Croft Simon L. , Kaye Paul M. 
Published: January 2019

Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease. Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.
An assessment of early functional rehabilitation and hospital discharge in conventional versus robotic-arm assisted unicompartmental knee arthroplasty
Authors: Kayani B. , Konan S. , Tahmassebi J. , Rowan F. E. , Haddad F. S. 
Published: January 2019

AimsThe objectives of this study were to compare postoperative pain, analgesia requirements, inpatient functional rehabilitation, time to hospital discharge, and complications in patients undergoing conventional jig-based unicompartmental knee arthroplasty (UKA) versus robotic-arm assisted UKA.Patients and MethodsThis prospective cohort study included 146 patients with symptomatic medial compartment knee osteoarthritis undergoing primary UKA performed by a single surgeon. This included 73 consecutive patients undergoing conventional jig-based mobile bearing UKA, followed by 73 consecutive patients receiving robotic-arm assisted fixed bearing UKA. All surgical procedures were performed using the standard medial parapatellar approach for UKA, and all patients underwent the same postoperative rehabilitation programme. Postoperative pain scores on the numerical rating scale and opiate analgesia consumption were recorded until discharge. Time to attainment of predefined functional rehabilitation outcomes, hospital discharge, and postoperative complications were recorded by independent observers.ResultsRobotic-arm assisted UKA was associated with reduced postoperative pain (p < 0.001), decreased opiate analgesia requirements (p < 0.001), shorter time to straight leg raise (p < 0.001), decreased number of physiotherapy sessions (p < 0.001), and increased maximum knee flexion at discharge (p < 0.001) compared with conventional jig-based UKA. Mean time to hospital discharge was reduced in robotic UKA compared with conventional UKA (42.5 hours (sd 5.9) vs 71.1 hours (sd 14.6), respectively; p < 0.001). There was no difference in postoperative complications between the two groups within 90 days’ follow-up.ConclusionRobotic-arm assisted UKA was associated with decreased postoperative pain, reduced opiate analgesia requirements, improved early functional rehabilitation, and shorter time to hospital discharge compared with conventional jig-based UKA.
Higher 30-day mortality associated with the use of intramedullary nails compared with sliding hip screws for the treatment of trochanteric hip fractures
Authors: Whitehouse M. R. , Berstock J. R. , Kelly M. B. , Gregson C. L. , Judge A. , Sayers A. , Chesser T. J. 
Published: January 2019

Aims The aim of this study was to investigate the association between the type of operation used to treat a trochanteric fracture of the hip and 30-day mortality. Patients and Methods Data on 82 990 patients from the National Hip Fracture Database were analyzed using generalized linear models with incremental case-mix adjustment for patient, non-surgical and surgical characteristics, and socioeconomic factors. Results The use of short and long intramedullary nails was associated with an increase in 30-day mortality (adjusted odds ratio (OR) 1.125, 95% confidence interval (CI) 1.040 to 1.218; p = 0.004) compared with the use of sliding hip screws (12.5% increase). If this were causative, it would represent 98 excess deaths over the four-year period of the study and one excess death would be caused by treating 112 patients with an intramedullary nail rather than a sliding hip screw. Conclusion There is a 12.5% increase in the risk of 30-day mortality associated with the use of an intramedullary nail compared with a sliding hip screw in the treatment of a trochanteric fractures of the hip.
Survivorship and long-term outcome of a consecutive series of 200 Scandinavian Total Ankle Replacement (STAR) implants
Authors: Clough T. , Bodo K. , Majeed H. , Davenport J. , Karski M. 
Published: January 2019

Aims We report the long-term clinical and radiological outcomes of a consecutive series of 200 total ankle arthroplasties (TAAs, 184 patients) at a single centre using the Scandinavian Total Ankle Replacement (STAR) implants. Patients and Methods Between November 1993 and February 2000, 200 consecutive STAR prostheses were implanted in 184 patients by a single surgeon. Demographic and clinical data were collected prospectively and the last available status was recorded for further survival analysis. All surviving patients underwent regular clinical and radiological review. Pain and function were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scoring system. The principal endpoint of the study was failure of the implant requiring revision of one or all of the components. Kaplan–Meier survival curves were generated with 95% confidence intervals and the rate of failure calculated for each year. Results A total of 84 patients (87 ankles) were alive by the end of this study. Of the surviving 84 patients (87 ankles; rheumatoid arthritis (RA), n = 40; OA, n = 47), 45 were women and 39 were men, with a mean age of 54 years (18 to 72 years) at the time of surgery. A total of 32 implants failed (16%), requiring revision surgery. The mean time to revision was 80 months (2 to 257). The implant survival at 15.8 years, using revision as an endpoint, was 76.16% (95% confidence interval (CI) 64.41 to 87.91). We found a steady but low decrease in survival over the study period. The mean AOFAS score improved from 28 (10 to 52) preoperatively to 61 (20 to 90) at long-term follow-up. Conclusion STAR prostheses in the United Kingdom have now been largely superseded by newer design TAAs, potentially with improved characteristics and surgical techniques. The long-term survivorship for the STAR prosthesis can provide a benchmark for these later designs of ankle arthroplasty.
Does having a rotator cuff repair prior to reverse total shoulder arthroplasty influence the outcome?
Authors: Erickson B. J. , Ling D. , Wong A. , Eno J. J. , Dines J. S. , Dines D. M. , Gulotta L. V. 
Published: January 2019

Aims The number of rotator cuff repairs that are undertaken is increasing. Reverse shoulder arthroplasty (RSA) is the procedure of choice for patients with rotator cuff arthropathy. We sought to determine whether patients who underwent rotator cuff repair and subsequent RSA had different outcomes compared with a matched control group who underwent RSA without a previous rotator cuff repair. Patients and Methods All patients with a history of rotator cuff repair who underwent RSA between 2000 and 2015 with a minimum follow-up of two years were eligible for inclusion as the study group. Outcomes, including the American Shoulder and Elbow Surgeons (ASES) scores, were compared with a matched control group of patients who underwent RSA without having previously undergone rotator cuff repair. Results The study group included 45 patients. Their mean age was 69 years (sd 8.6) and 27 patients (60%) were women. The mean ASES score improved from 43.1 to 76.6 two years postoperatively, and to 66.9 five years postoperatively. There was no significant difference between the outcomes at two years in the two groups (all p ≥ 0.05), although there was significantly more improvement in ASES scores in the control group (44.5 vs 33.4; p = 0.01). However, there was no significant difference between ASES scores at two and five years when baseline ASES scores were matched in the two groups (p = 0.42 at two years; p = 0.35 at five years). Conclusion Significant improvements in ASES scores were seen following RSA in patients who had previously undergone rotator cuff repair. They had higher baseline ASES scores than those who had not previously undergone this surgery. However, there was no significant difference in outcomes between the two groups, two years postoperatively. Previous rotator cuff repair does not appear to affect the early outcome after RSA adversely.
The critical size of a defect in the glenoid causing anterior instability of the shoulder after a Bankart repair, under physiological joint loading
Authors: Klemt C. , Toderita D. , Nolte D. , Di Federico E. , Reilly P. , Bull A. M. J. 
Published: January 2019

AimsPatients with recurrent anterior dislocation of the shoulder commonly have an anterior osseous defect of the glenoid. Once the defect reaches a critical size, stability may be restored by bone grafting. The critical size of this defect under non-physiological loading conditions has previously been identified as 20% of the length of the glenoid. As the stability of the shoulder is load-dependent, with higher joint forces leading to a loss of stability, the aim of this study was to determine the critical size of an osseous defect that leads to further anterior instability of the shoulder under physiological loading despite a Bankart repair.Patients and MethodsTwo finite element (FE) models were used to determine the risk of dislocation of the shoulder during 30 activities of daily living (ADLs) for the intact glenoid and after creating anterior osseous defects of increasing magnitudes. A Bankart repair was simulated for each size of defect, and the shoulder was tested under loading conditions that replicate in vivo forces during these ADLs. The critical size of a defect was defined as the smallest osseous defect that leads to dislocation.ResultsThe FE models showed a high risk of dislocation during ADLs after a Bankart repair for anterior defects corresponding to 16% of the length of the glenoid.ConclusionThis computational study suggests that bone grafting should be undertaken for an anterior osseous defect in the glenoid of more than 16% of its length rather than a solely soft-tissue procedure, in order to optimize stability by restoring the concavity of the glenoid.