bluuebunny/crossref_metadata_2025_split huggingface dataset:
The measurement of tissue interface pressures and changes in jugular venous parameters associated with cervical immobilisation devices: a systematic review
Authors: Sparke Alison , Voss Sarah , Benger Jonathan 
Published: December 2013

Abstract
Cervical immobilisation is commonly applied following trauma, particularly blunt head injury, but current methods of immobilisation are associated with significant complications. Semi-rigid disposable cervical collars are known to cause pressure ulcers, and impede effective airway management. These collars may also exacerbate a head injury by increasing intracranial pressure as a result of external compression of the jugular veins. There is a clear imperative to find ways of effectively immobilising the cervical spine whilst minimising complications, and any assessment of existing or new devices should include a standardized approach to the measurement of tissue interface pressures and their effect on jugular venous drainage from the brain. This systematic review summarises the research methods and technologies that have been used to measure tissue interface pressure and assess the jugular vein in the context of cervical immobilisation devices. 27 papers were included and assessed for quality. Laboratory investigations and biomechanical studies have gradually given way to methods that more accurately reflect clinical care. There are numerous accounts of skin ulceration associated with cervical collars, but no standardised approach to measuring tissue interface pressure. It is therefore difficult to compare studies and devices, but a pressure of less than 30 mmHg appears desirable. Cervical collars have been shown to have a compressive effect on the jugular veins, but it is not yet certain that this is the cause of the increased intracranial pressure observed in association with cervical collar use. This is the first review of its type. It will help guide further research in this area of trauma care, and the development and testing of new cervical immobilisation devices.
Soluble antigen traffics rapidly and selectively from the corneal surface to the eye draining lymph node and activates T cells when codelivered with CpG oligonucleotides
Authors: Dang Zexu , Kuffová Lucia , Liu Lei , Forrester John V 
Published: December 2013

ABSTRACTThe transport of antigen to the secondary lymphoid tissue is a central component in the initiation of the adaptive immune response. The mechanism of antigen delivery to the DLN from the avascular cornea has not been fully explored. Previous studies in the mouse have shown that cell-associated corneal antigen is delivered within 6 h to the eye draining SM DLN via DCs and macrophages. In this study, we used a system in which antigen and the processed p-MHCII complexes derived from the antigen could be tracked in vivo. We report that soluble antigen applied to an abraded cornea in the mouse is transported rapidly (within 30 min) to the SM DLN, where a proportion is taken up by resident DCs and presented as p-MHCII complexes, while the larger part is cleared by 8 h. At a later time, a second wave of antigen transport in migratory DCs enters the DLN and participates in further continued antigen presentation. With the use of an antigen-specific TCR transgenic mouse system, we demonstrate that T cell activation does not occur during the early stages of soluble antigen delivery to LN, even though p-MHCII complexes are generated. Antigen-specific T cell activation occurs in the later, presumed cell-associated phase but requires codelivery of a “danger” signal, such as the TLR ligand CpG. We suggest that the early delivery of soluble antigen is more likely to induce T cell nonresponsiveness (anergy) unless presented in the context of an innate-immune cell activation (danger) signal.
Incidence of New Primary Melanomas After Diagnosis of Stage III and IV Melanoma
Authors: Zimmer Lisa , Haydu Lauren E. , Menzies Alexander M. , Scolyer Richard A. , Kefford Richard F. , Thompson John F. , Schadendorf Dirk , Long Georgina V. 
Published: December 2013

Purpose New primary melanomas (NPMs) have developed in some patients with metastatic melanoma treated with BRAF inhibitors. We sought to determine the background incidence of spontaneous NPMs after a diagnosis of American Joint Committee on Cancer/International Union Against Cancer stage III or IV melanoma in patients not treated with a BRAF inhibitor. Patients and Methods Patients diagnosed with stage III or IV melanoma at Melanoma Institute Australia between 1983 and 2008 were analyzed, and those who received a BRAF inhibitor were excluded. Results Two hundred twenty-nine (5%) of 4,215 patients with stage III melanoma and 43 (1%) of 3,563 patients with stage IV melanoma had at least one NPM after diagnosis of stage III or IV disease. The 6-month, 1-year, and 10-year cumulative incidence rates of developing an NPM after stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively. The 3-month, 6-month, and 1-year cumulative incidence rates of NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively. In both patients with stage III and stage IV melanoma, male patients and patients with a prior history of multiple primaries had a higher incidence of NPM. Conclusion Patients with stage III and stage IV melanoma remain at risk for development of further primary melanomas, particularly if they have a history of multiple primary melanomas before stage III or IV disease. The incidence rates are lower than those reported in patients receiving BRAF inhibitors. However, the results must be compared with caution because dermatologic assessment is more frequent in BRAF inhibitor trials.
TMPRSS2:ERG Gene Fusion Predicts Subsequent Detection of Prostate Cancer in Patients With High-Grade Prostatic Intraepithelial Neoplasia
Authors: Park Kyung , Dalton James T. , Narayanan Ramesh , Barbieri Christopher E. , Hancock Michael L. , Bostwick David G. , Steiner Mitchell S. , Rubin Mark A. 
Published: December 2013

Purpose High-grade prostatic intraepithelial neoplasia (HGPIN) is considered a precursor lesion of prostate cancer (PCa). The predictive value of ERG gene fusion in HGPIN for PCa was interrogated as a post hoc analysis in the context of a randomized clinical trial. Patients and Methods The GTx Protocol G300104 randomly assigned 1,590 men with biopsy-diagnosed HGPIN to receive toremifene or placebo for 3 years or until a diagnosis of PCa was made on prostate biopsy. As part of this phase III clinical trial, a central pathologist evaluated biopsies of patients with isolated HGPIN at baseline and 12, 24, and 36 months of follow-up. ERG immunohistochemistry was performed on biopsies from 461 patients and evaluated for protein overexpression. Results ERG expression was detected in 11.1% of patients (51 of 461 patients) with isolated HGPIN. In the first year and during the 3-year clinical trial, 14.7% and 36.9% of 461 patients were diagnosed with PCa, respectively. Patients with ERG expression were more likely to develop PCa, with 27 (53%) of 51 ERG-positive and 143 (35%) of 410 ERG-negative patients experiencing progression to PCa (P = .014, Fisher's exact test). ERG expression was not associated with age, baseline PSA, Gleason score, or tumor volume. Conclusion This study underscores the necessity of more stringent follow-up for men with HGPIN that is also positive for ERG overexpression. Clinicians should consider molecular characterization of HGPIN as a means to improve risk stratification.
Fractionated 90Y-Ibritumomab Tiuxetan Radioimmunotherapy As an Initial Therapy of Follicular Lymphoma: An International Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria
Authors: Illidge Tim M. , Mayes Sam , Pettengell Ruth , Bates Andrew T. , Bayne Mike , Radford John A. , Ryder W. David J. , Le Gouill Steven , Jardin Fabrice , Tipping Jill , Zivanovic Maureen , Kraeber-Bodere Françoise , Bardies Manuel , Bodet-Milin Caroline , Malek Emmanuel , Huglo Damien , Morschhauser Franck 
Published: December 2013

Purpose We report an international, multicenter phase II trial to evaluate the efficacy and toxicity of fractionated 90Y-ibritumomab tiuxetan (90Y-IT) as initial therapy of follicular lymphoma (FL). Patients and Methods A total of 74 patients, with a median age of 61 years (range, 28 to 80 years), were recruited requiring initial therapy by Groupe d'Etude des Lymphomes Folliculaires (GELF)/British National Lymphoma Investigation (BNLI) criteria. Among them, 78% had stage III-IV disease, 32% intermediate, and 44% high-risk (according to FL International Prognostic Index). Treatment consisted of two doses of 90Y-IT (11.1 MBq/kg) administered 8 to 12 weeks apart. Patients with more than 20% lymphoma infiltration of bone marrow (BM) received one infusion per week for 4 consecutive weeks of rituximab (375 mg/m2) and proceeded to fractionated radioimmunotherapy (RIT) only if a repeat BM biopsy demonstrated clearing of lymphoma to less than 20% involvement. The primary end point was end of treatment response of the intention-to-treat population. Secondary objectives were safety and progression-free survival (PFS). Results Initial overall response rate (ORR) was 94.4% (68 of 72 patients) with combined complete response (CR/CRu) of 58.3% (42 of 72 patients). Nine patients subsequently improved response making an ORR of 95.8% (69 of 72 patients) and CR/CRu of 69.4% (50 of 72 patients). At a median follow-up of 3.1 years (range, 0.2 to 5.2 years) estimated 3-year PFS is 58%, treatment-free survival 66%, and overall survival 95%. Median PFS is 40.2 months. Thirty patients have experienced disease progression and 24 have required further treatment. The treatment was well tolerated with few (2.8%) grade 3 or 4 infectious episodes or adverse events and manageable hematologic toxicity. Conclusion Fractionated RIT using 90Y-IT is an effective initial treatment for advanced-stage FL in patients with higher tumor burden requiring treatment.
Randomized Phase III Trial of Temsirolimus Versus Sorafenib As Second-Line Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma
Authors: Hutson Thomas E. , Escudier Bernard , Esteban Emilio , Bjarnason Georg A. , Lim Ho Yeong , Pittman Kenneth B. , Senico Peggy , Niethammer Andreas , Lu Dongrui Ray , Hariharan Subramanian , Motzer Robert J. 
Published: December 2013

Purpose This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. Patients and Methods In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non–clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. Results Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. Conclusion In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.
Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: INTORACT Trial
Authors: Rini Brian I. , Bellmunt Joaquim , Clancy Jill , Wang Kongming , Niethammer Andreas G. , Hariharan Subramanian , Escudier Bernard 
Published: December 2013

Purpose To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC). Patients and Methods In a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear-cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25 mg intravenously, weekly) or IFN (9 MIU subcutaneously thrice weekly) with bevacizumab (10 mg/kg intravenously, every 2 weeks). The primary end point was independently assessed progression-free survival (PFS). Results Median PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR], 1.1; 95% CI, 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 ν 25.5 months; HR, 1.0; P = .6) or objective response rate (27.0% ν 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI) –15 and FKSI-Disease Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade ≥ 3 adverse events more common (P < .001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2. Conclusion Temsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC.
Minireview: Role Of Orphan Nuclear Receptors in Cancer and Potential as Drug Targets
Authors: Safe Stephen , Jin Un-Ho , Hedrick Erik , Reeder Alexandra , Lee Syng-Ook 
Published: December 2013

AbstractThe nuclear orphan receptors for which endogenous ligands have not been identified include nuclear receptor (NR)0B1 (adrenal hypoplasia congenita critical region on chromosome X gene), NR0B2 (small heterodimer partner), NR1D1/2 (Rev-Erbα/β), NR2C1 (testicular receptor 2), NR2C2 (testicular receptor 4), NR2E1 (tailless), NR2E3 (photoreceptor-specific NR [PNR]), NR2F1 chicken ovalbumin upstream promoter transcription factor 1 (COUP-TFI), NR2F2 (COUP-TFII), NR2F6 (v-erbA-related protein), NR4A1 (Nur77), NR4A2 (Nurr1), NR4A3 (Nor1), and NR6A1 (GCNF). These receptors play essential roles in development, cellular homeostasis, and disease including cancer where over- or underexpression of some receptors has prognostic significance for patient survival. Results of receptor knockdown or overexpression in vivo and in cancer cell lines demonstrate that orphan receptors exhibit tumor-specific pro-oncogenic or tumor suppressor-like activity. For example, COUP-TFII expression is both a positive (ovarian) and negative (prostate and breast) prognostic factor for cancer patients; in contrast, the prognostic activity of adrenal hypoplasia congenita critical region on chromosome X gene for the same tumors is the inverse of COUP-TFII. Functional studies show that Nur77 is tumor suppressor like in acute leukemia, whereas silencing Nur77 in pancreatic, colon, lung, lymphoma, melanoma, cervical, ovarian, gastric, and some breast cancer cell lines induces one or more of several responses including growth inhibition and decreased survival, migration, and invasion. Although endogenous ligands for the orphan receptors have not been identified, there is increasing evidence that different structural classes of compounds activate, inactivate, and directly bind several orphan receptors. Thus, the screening and development of selective orphan receptor modulators will have important clinical applications as novel mechanism-based agents for treating cancer patients overexpressing one or more orphan receptors and also for combined drug therapies.
The Omics of Triple-Negative Breast Cancers
Authors: Xu Hong , Eirew Peter , Mullaly Sarah C , Aparicio Samuel 
Published: December 2013

Abstract

BACKGROUND
Triple-negative breast cancers (TNBC) do not represent a single disease subgroup and are often aggressive breast cancers with poor prognoses. Unlike estrogen/progesterone receptor and HER2 (human epidermal growth factor receptor 2) breast cancers, which are responsive to targeted treatments, there is no effective targeted therapy for TNBC, although approximately 50% of patients respond to conventional chemotherapies, including taxanes, anthracyclines, cyclophosphamide, and platinum salts.

CONTENT
Genomic studies have helped clarify some of the possible disease groupings that make up TNBC. We discuss the findings, including copy number–transcriptome analysis, whole genome sequencing, and exome sequencing, in terms of the biological properties and phenotypes that make up the constellation of TNBC. The relationships between subgroups defined by transcriptome and genome analysis are discussed.

SUMMARY
TNBC is not a uniform molecular or disease entity but a constellation of variably well-defined biological properties whose relationship to each other is not understood. There is good support for the existence of a basal expression subtype, p53 mutated, high–genomic instability subtype of TNBC. This should be considered a distinct TNBC subtype. Other subtypes with variable degrees of supporting evidence exist within the nonbasal/p53wt (wild-type p53) TNBC, including a group of TNBC with PI3K (phosphoinositide 3-kinase) pathway activation that have better overall prognosis than the basal TNBC. Consistent molecular phenotyping of TNBC by whole genome sequencing, transcriptomics, and functional studies with patient-derived tumor xenograft models will be essential components in clinical and biological studies as means of resolving this heterogeneity.
Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial
Authors: van Genugten Renate E , van Raalte Daniël H , Muskiet Marcel H , Heymans Martijn W , Pouwels Petra J W , Ouwens D Margriet , Mari Andrea , Diamant Michaela 
Published: December 2013

ObjectiveAnti-inflammatory glucocorticoid (GC) therapy often induces hyperglycemia due to insulin resistance and islet-cell dysfunction. Incretin-based therapies may preserve glucose tolerance and pancreatic islet-cell function. In this study, we hypothesized that concomitant administration of the dipeptidyl peptidase-4 inhibitor sitagliptin and prednisolone in men at high risk to develop type 2 diabetes could protect against the GC-induced diabetogenic effects.Design and methodsMen with the metabolic syndrome but without diabetes received prednisolone 30 mg once daily plus sitagliptin 100 mg once daily (n=14), prednisolone (n=12) or sitagliptin alone (n=14) or placebo (n=12) for 14 days in a double-blind 2×2 randomized-controlled study. Glucose, insulin, C-peptide, and glucagon were measured in the fasted state and following a standardized mixed-meal test. β-cell function parameters were assessed both from a hyperglycemic–arginine clamp procedure and from the meal test. Insulin sensitivity (M-value) was measured by euglycemic clamp.ResultsPrednisolone increased postprandial area under the curve (AUC)-glucose by 17% (P<0.001 vs placebo) and postprandial AUC-glucagon by 50% (P<0.001). Prednisolone reduced 1st and 2nd phase glucose-stimulated- and combined hyperglycemia–arginine-stimulated C-peptide secretion (all P≤0.001). When sitagliptin was added, both clamp-measured β-cell function (P=NS for 1st and 2nd phase vs placebo) and postprandial hyperglucagonemia (P=NS vs placebo) remained unaffected. However, administration of sitagliptin could not prevent prednisolone-induced increment in postprandial glucose concentrations (P<0.001 vs placebo). M-value was not altered by any treatment.ConclusionFourteen-day treatment with high-dose prednisolone impaired postprandial glucose metabolism in subjects with the metabolic syndrome. Concomitant treatment with sitagliptin improved various aspects of pancreatic islet-cell function, but did not prevent deterioration of glucose tolerance by GC treatment.
SMG-ly Knocking Out Gene Expression in Specific Cells: An Educational Primer for Use with “A Novel Strategy for Cell-Autonomous Gene Knockdown in Caenorhabditis elegans Defines a Cell-Specific Function for the G-Protein Subunit GOA-1”
Authors: Meneely Philip M , Bloom Jordana C 
Published: December 2013

SUMMARY
A recent article by Maher et al. in GENETICS introduces an alternative approach to cell-type-specific gene knockdown in Caenorhabditis elegans, using nonsense-mediated decay. This strategy has the potential to be applicable to other organisms (this strategy requires that animals can survive without nonsense-mediated decay—not all can). This Primer article provides a guide and resource for educators and students by describing different gene knockdown methodologies, by assisting with the technically difficult portions of the Maher et al. article, and by providing conceptual questions relating to the article.
Related article in GENETICS: Maher, K. N., A. Swaminathan, P. Patel, and D. L. Chase, 2013 A novel strategy for cell-autonomous gene knockdown in Caenorhabditis elegans defines a cell-specific function for the G-protein subunit GOA-1. Genetics 194: 363–373.