Concurrent Chemoradiation for Vaginal Cancer

Background: It is not known whether the addition of chemotherapy to radiation therapy improves outcomes in primary vaginal cancer. Here, we review clinical outcomes in patients with primary vaginal cancer treated with radiation therapy (RT) or concurrent chemoradiation therapy (CRT). Methods: Seventy-one patients with primary vaginal cancer treated with definitive RT with or without concurrent chemotherapy at a single institution were identified and their records reviewed. A total of 51 patients were treated with RT alone; 20 patients were treated with CRT. Recurrences were analyzed. Overall survival (OS) and disease-free survival (DFS) rates were estimated using the Kaplan-Meier method. Cox regression analysis was performed. Results: The median age at diagnosis was 61 years (range, 18–92 years) and the median follow-up time among survivors was 3.0 years. Kaplan-Meier estimates for OS and DFS differed significantly between the RT and CRT groups (3-yr OS = 56% vs. 79%, log-rank p = 0.037; 3-yr DFS = 43% vs. 73%, log-rank p = 0.011). Twenty-three patients (45%) in the RT group had a relapse at any site compared to 3 (15%) in the CRT group (p = 0.027). With regard to the sites of first relapse, 10 patients (14%) had local only, 4 (6%) had local and regional, 9 (13%) had regional only, 1 (1%) had regional and distant, and 2 (3%) had distant only relapse. On univariate analysis, the use of concurrent chemotherapy, FIGO stage, tumor size, and date of diagnosis were significant predictors of DFS. On multivariate analysis, the use of concurrent chemotherapy remained a significant predictor of DFS (hazard ratio 0.31 (95% CI, 0.10–0.97; p = 0.04)). Conclusions: Vaginal cancer results in poor outcomes. Adequate radiation dose is essential to ensure curative management. Concurrent chemotherapy should be considered for vaginal cancer patients

Neurocognitive Risk in Children With Cochlear Implants

IMPORTANCE Children who receive a cochlear implant (CI) for early severe to profound sensorineural hearing loss may achieve age-appropriate spoken language skills not possible before implantation. Despite these advances, reduced access to auditory experience may have downstream effects on fundamental neurocognitive processes for some children with CIs. OBJECTIVE To determine the relative risk (RR) of clinically significant executive functioning deficits in children with CIs compared with children with normal hearing (NH). DESIGN, SETTING, AND PARTICIPANTS In this prospective, cross-sectional study, 73 children at a hospital-based clinic who received their CIs before 7 years of age and 78 children with NH, with average to above average mean nonverbal IQ scores, were recruited in 2 age groups: preschool age (age range, 3–5 years) and school age (age range, 7–17 years). No children presented with other developmental, cognitive, or neurologic diagnoses. INTERVENTIONS Parent-reported checklist measures of executive functioning were completed during psychological testing sessions. MAIN OUTCOMES AND MEASURES Estimates of the RR of clinically significant deficits in executive functioning (≥ 1 SDs above the mean) for children with CIs compared with children with NH were obtained based on 2 parent-reported child behavior checklists of everyday problems with executive functioning. RESULTS In most domains of executive functioning, children with CIs were at 2 to 5 times greater risk of clinically significant deficits compared with children with NH. The RRs for preschoolers and school-aged children, respectively, were greatest in the areas of comprehension and conceptual learning (RR [95% CI], 3.56 [1.71–7.43] and 6.25 [2.64–14.77]), factual memory ( 4.88 [1.58–15.07] and 5.47 [2.03–14.77]), attention (3.38 [1.03–11.04] and 3.13 [1.56–6.26]), sequential processing (11.25 [1.55–81.54] and 2.44 [1.24–4.76]), working memory (4.13 [1.30–13.06] and 3.64 [1.61–8.25] for one checklist and 1.77 [0.82–3.83] and 2.78 [1.18–6.51] for another checklist), and novel problem-solving (3.93 [1.50–10.34] and 3.13 [1.46–6.67]). No difference between the CI and NH samples was found for visual-spatial organization (2.63 [0.76–9.03] and 1.04 [0.45–2.40] on one checklist and 2.86 [0.98–8.39] for school-aged children on the other checklist). CONCLUSIONS AND RELEVANCE A large proportion of children with CIs are at risk for clinically significant deficits across multiple domains of executive functioning, a rate averaging 2 to 5 times that of children with NH for most domains. Screening for risk of executive functioning deficits should be a routine part of the clinical evaluation of all children with deafness and CIs

Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma

<p>Abstract</p> <p>Background</p> <p>The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL). However, NF-κB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-κB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear.</p> <p>Results</p> <p>Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-κB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA). Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231) and a breast carcinoma cell line (MDA-MB-468), the bortezomib-resistant NF-κB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10) displayed bortezomib-resistant constitutive NF-κB activity.</p> <p>Conclusion</p> <p>Our findings show that bortezomib-resistant NF-κB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.</p

A Generalization of Martin's Axiom

We define the $\aleph_{1.5}$ chain condition. The corresponding forcing axiom is a generalization of Martin's Axiom and implies certain uniform failures of club--guessing on $\omega_1$ that don't seem to have been considered in the literature before.Comment: 36 page

The kinesin Eg5 drives poleward microtubule flux in Xenopus laevis egg extract spindles

Although mitotic and meiotic spindles maintain a steady-state length during metaphase, their antiparallel microtubules slide toward spindle poles at a constant rate. This “poleward flux” of microtubules occurs in many organisms and may provide part of the force for chromosome segregation. We use quantitative image analysis to examine the role of the kinesin Eg5 in poleward flux in metaphase Xenopus laevis egg extract spindles. Pharmacological inhibition of Eg5 results in a dose–responsive slowing of flux, and biochemical depletion of Eg5 significantly decreases the flux rate. Our results suggest that ensembles of nonprocessive Eg5 motors drive flux in metaphase Xenopus extract spindles

Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer

ADN tumoral circulant; Medicina de precisió; Càncer de pròstataADN tumoral circulante; Medicina de precisión; Cáncer de próstataCirculating tumor DNA; Precision medicine; Prostate cancerContext Genomic stratification can impact prostate cancer (PC) care through diagnostic, prognostic, and predictive biomarkers that aid in clinical decision-making. The temporal and spatial genomic heterogeneity of PC together with the challenges of acquiring metastatic tissue biopsies hinder implementation of tissue-based molecular profiling in routine clinical practice. Blood-based liquid biopsies are an attractive, minimally invasive alternative. Objective To review the clinical value of blood-based liquid biopsy assays in PC and identify potential applications to accelerate the development of precision medicine. Evidence acquisition A systematic review of PubMed/MEDLINE was performed to identify relevant literature on blood-based circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles (EVs) in PC. Evidence synthesis Liquid biopsy has emerged as a practical tool to profile tumor dynamics over time, elucidating features that evolve (genome, epigenome, transcriptome, and proteome) with tumor progression. Liquid biopsy tests encompass analysis of DNA, RNA, and proteins that can be detected in CTCs, ctDNA, or EVs. Blood-based liquid biopsies have demonstrated promise in the context of localized tumors (diagnostic signatures, risk stratification, and disease monitoring) and advanced disease (response/resistance biomarkers and prognostic markers). Conclusions Liquid biopsies have value as a source of prognostic, predictive, and response biomarkers in PC. Most clinical applications have been developed in the advanced metastatic setting, where CTC and ctDNA yields are significantly higher. However, standardization of assays and analytical/clinical validation is necessary prior to clinical implementation

Control of T lymphocyte morphology by the GTPase Rho

BACKGROUND: Rho family GTPase regulation of the actin cytoskeleton governs a variety of cell responses. In this report, we have analyzed the role of the GTPase Rho in maintenance of the T lymphocyte actin cytoskeleton. RESULTS: Inactivation of the GTPase Rho in the human T lymphocytic cell line HPB-ALL does not inhibit constitutively high adhesion to the integrin β1 substrate fibronectin. It did however result in the aberrant extension of finger-like dendritic processes on the substrates VCAM-1, Fn, and mAb specific to β1 integrins. Time-lapse video microscopy demonstrated that C3 induced extensions were primarily the result of an altered pseudopod elongation rather than retraction. Once the stellate pseudopodia extended, none retracted, and cells became completely immobile. Filipodial structures were absent and the dendritic-like processes in C3 treated cells were rich in filamentous actin. Immunolocalization of RhoA in untreated HPB-ALL cells spreading on fibronectin demonstrated a diffuse staining pattern within the pseudopodia. In C3 treated cells, clusters of RhoA were pronounced and localized within the altered extensions. CONCLUSIONS: GTPase Rho is actively involved in the regulation of T lymphocyte morphology and motility

Deformability of Tumor Cells versus Blood Cells

The potential for circulating tumor cells (CTCs) to elucidate the process of cancer metastasis and inform clinical decision-making has made their isolation of great importance. However, CTCs are rare in the blood, and universal properties with which to identify them remain elusive. As technological advancements have made single-cell deformability measurements increasingly routine, the assessment of physical distinctions between tumor cells and blood cells may provide insight into the feasibility of deformability-based methods for identifying CTCs in patient blood. To this end, we present an initial study assessing deformability differences between tumor cells and blood cells, indicated by the length of time required for them to pass through a microfluidic constriction. Here, we demonstrate that deformability changes in tumor cells that have undergone phenotypic shifts are small compared to differences between tumor cell lines and blood cells. Additionally, in a syngeneic mouse tumor model, cells that are able to exit a tumor and enter circulation are not required to be more deformable than the cells that were first injected into the mouse. However, a limited study of metastatic prostate cancer patients provides evidence that some CTCs may be more mechanically similar to blood cells than to typical tumor cell lines.Janssen Pharmaceutical Ltd.National Cancer Institute (U.S.). Physical Sciences Oncology Center (U54CA143874)MIT-Harvard Center of Cancer Nanotechnology Excellence (Grant 26697290-47281-A)Stand Up To CancerNational Institutes of Health (U.S.). P41 Biotechnology Resource CenterNational Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051

The Expression of TALEN before Fertilization Provides a Rapid Knock-Out Phenotype in Xenopus laevis Founder Embryos.

Recent advances in genome editing using programmable nucleases have revolutionized gene targeting in various organisms. Successful gene knock-out has been shown in Xenopus, a widely used model organism, although a system enabling less mosaic knock-out in founder embryos (F0) needs to be explored in order to judge phenotypes in the F0 generation. Here, we injected modified highly active transcription activator-like effector nuclease (TALEN) mRNA to oocytes at the germinal vesicle (GV) stage, followed by in vitro maturation and intracytoplasmic sperm injection, to achieve a full knock-out in F0 embryos. Unlike conventional injection methods to fertilized embryos, the injection of TALEN mRNA into GV oocytes allows expression of nucleases before fertilization, enabling them to work from an earlier stage. Using this procedure, most of developed embryos showed full knock-out phenotypes of the pigmentation gene tyrosinase and/or embryonic lethal gene pax6 in the founder generation. In addition, our method permitted a large 1 kb deletion. Thus, we describe nearly complete gene knock-out phenotypes in Xenopus laevis F0 embryos. The presented method will help to accelerate the production of knock-out frogs since we can bypass an extra generation of about 1 year in Xenopus laevis. Meantime, our method provides a unique opportunity to rapidly test the developmental effects of disrupting those genes that do not permit growth to an adult able to reproduce. In addition, the protocol shown here is considerably less invasive than the previously used host transfer since our protocol does not require surgery. The experimental scheme presented is potentially applicable to other organisms such as mammals and fish to resolve common issues of mosaicism in founders.K.M. was a Research Fellow at Wolfson College and was supported by the Herchel Smith Postdoctoral Fellowship.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.014294