Restelli U, Ceresoli GL, Croce D et al. Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: a cost of illness study. Cancer Management and Research. ...2017;9:789-800.On page 796, above the Disclosure section, the Acknowledgment section is missing. The missing text is:AcknowledgmentThe authors thank Ray Hill, an independent medical writer, who provided English-language editing and journal styling prior to submission on behalf of Health Publishing & Services Srl. Editorial support was funded through an unconditional contribution by Bayer SpA.Read the original article.
Suppressive subtractive hybridization (SSH) was used to analyse the muscle transcriptome and identify genes affecting meat quality within an Italian pig population of Large White and Landrace ...purebred individuals. Seven phenotypes were recorded at slaughter: dorsal fat thickness, ham fat thickness, ham fat coverage, muscle compactness, marbling, meat colour and colour uniformity. Two subtractive libraries were created from longissimus dorsi tissue of selected pigs with extreme phenotypes for meat quality. Eighty-four differentially expressed ESTs were identified, which showed homology to expressed pig sequences and/or to genomic pig sequences produced within the pig genome project. Sixty-eight sequences were mapped on the pig genome, and most of these sequences co-localized with the same chromosomal positions as QTLs that have been previously identified for meat quality. Thirty sequences, including eight matching known genes previously related to muscle metabolic pathways, were selected to statistically validate their differential expression. Association analysis and t-test results indicated that 28 ESTs of the 30 analysed were associated with phenotypes investigated here and have significant differential expression levels (P ≤ 0.05) between the two tails of the phenotypic distribution.
Prostate cancer (PCa) accounts for 20% of all cancers in subjects over 50 years in Italy. The majority of patients with PCa present with localized disease at the time of diagnosis, but many patients ...develop recurrent metastatic disease after treatment with curative intent. Androgen deprivation therapy is the standard of care for metastatic PCa patients; unfortunately, most of them progress to castrate-resistant prostate cancer (CRPC) within 5 years. Metastatic CRPC (mCRPC) heavily affects patients in terms of quality of life, side effects, and survival, and greatly impacts economic costs. The approval of new effective agents in recent years, including cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, has dramatically changed patient management.
Here, we aimed to estimate the current costs of illness of mCRPC in Italy. All patients affected by mCRPC and treated with a single agent in an annual time horizon were considered. Therefore, the analysis was not focused on the management pathway of single patients through different lines of treatment. Direct medical costs referred to therapy, adverse event management, and skeletal-related event management were analyzed. A bottom-up approach was used to estimate the resource consumption: through national guidelines and expert opinions, the mean cost per patient was estimated and then multiplied by the total number of patients diagnosed with mCRPC.
Direct medical costs ranged from €196.5 million to €228.0 million, representing ~0.2% of the financing of the Italian National Health Service in 2016. The main cost driver was the cost of treatment, which represented more than 77% of the overall economic burden.
Our analysis, reflective of real clinical practice, shows for the first time the high economic cost of mCRPC in Italy.
STUDY QUESTION
What are the anatomic variants (and their frequencies) of double uterus, obstructed hemivagina and ipsilateral renal agenesis?
SUMMARY ANSWER
Most cases examined (72.4%) were of the ...classic anatomic variant of the Herlyn-Werner-Wunderlich syndrome (with didelphys uterus, obstructed hemivagina and ipsilateral renal agenesis) but the 27.6% of cases are of a rare variant of the syndrome (with uterus septum or cervical agenesis), showing relevant clinical and surgical implications.
WHAT IS KNOWN ALREADY
The extreme variability of anatomic structures involved in this syndrome (both uterus, cervico-vaginal and renal anomalies) is well known, even if a complete and uniform analysis of all its heterogeneous presentations in a large series is lacking.
STUDY DESIGN, SIZE, DURATION
This is a retrospective study with 87 patients referred to our third level referral center between 1981 and 2011.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We analyzed the laparoscopic and chart records of 87 women, who referred to our institute with double uterus, unilateral cervico-vaginal obstruction and ipsilateral renal anomalies.
MAIN RESULTS
Sixty-three of 87 patients had the more classic variant of didelphys uterus with obstructed hemivagina; 10/87 patients had septate bicollis uterus with obstructed hemivagina; 9/87 patients had bicornuate bicollis uterus with obstructed hemivagina; 4/87 patients had didelphys uterus with unilateral cervical atresia; 1/87 patients had bicornuate uterus with one septate cervix and unilateral obstructed hemivagina.
LIMITATIONS
This is a retrospective study with a long enrolling period (30 years).
WIDER IMPLICATIONS OF THE FINDINGS
New insights in the anatomic variants of this rare syndrome with their relevant surgical implications.
STUDY FUNDING/COMPETING INTEREST
No specific funding was obtained for this study. None of the authors have any competing interests to declare.
TRIAL REGISTRATION NUMBER
N/A.
A semi-implicit and semi-Lagrangian discontinuous Galerkin method for the shallow water equations is proposed, for applications to geophysical scale flows. A non conservative formulation of the ...advection equation is employed, in order to achieve a more treatable form of the linear system to be solved at each time step. The method is equipped with a simple p-adaptivity criterion, that allows to adjust dynamically the number of local degrees of freedom employed to the local structure of the solution. Numerical results show that the method captures well the main features of gravity and inertial gravity waves, as well as reproducing correct solutions in nonlinear test cases with analytic solutions. The accuracy and effectiveness of the method are also demonstrated by numerical results obtained at high Courant numbers and with automatic choice of the local approximation degree.
The molecular mechanisms that control the biosynthetic trafficking, surface delivery, and degradation of TrkA receptor are essential for proper nerve growth factor (NGF) function, and remain poorly ...understood. Here, we identify Tetraspanin1 (Tspan1) as a critical regulator of TrkA signaling and neuronal differentiation induced by NGF. Tspan1 is expressed by developing TrkA-positive dorsal root ganglion (DRG) neurons and its downregulation in sensory neurons inhibits NGF-mediated axonal growth. In addition, our data demonstrate that Tspan1 forms a molecular complex with the immature form of TrkA localized in the endoplasmic reticulum (ER). Finally, knockdown of
Tspan1
reduces the surface levels of TrkA by promoting its preferential sorting towards the autophagy/lysosomal degradation pathway. Together, these data establish a novel homeostatic role of Tspan1, coordinating the biosynthetic trafficking and degradation of TrkA, regardless the presence of NGF.
As part of a broader effort to develop next-generation models for numerical weather prediction and climate applications, a hydrostatic atmospheric dynamical core is developed as an intermediate step ...to evaluate a finite-difference discretization of the primitive equations on spherical icosahedral grids. Based on the need for mass-conserving discretizations for multi-resolution modelling as well as scalability and efficiency on massively parallel computing architectures, the dynamical core is built on triangular C-grids using relatively small discretization stencils. This paper presents the formulation and performance of the baseline version of the new dynamical core, focusing on properties of the numerical solutions in the setting of globally uniform resolution. Theoretical analysis reveals that the discrete divergence operator defined on a single triangular cell using the Gauss theorem is only first-order accurate, and introduces grid-scale noise to the discrete model. The noise can be suppressed by fourth-order hyper-diffusion of the horizontal wind field using a time-step and grid-size-dependent diffusion coefficient, at the expense of stronger damping than in the reference spectral model. A series of idealized tests of different complexity are performed. In the deterministic baroclinic wave test, solutions from the new dynamical core show the expected sensitivity to horizontal resolution, and converge to the reference solution at R2B6 (35 km grid spacing). In a dry climate test, the dynamical core correctly reproduces key features of the meridional heat and momentum transport by baroclinic eddies. In the aqua-planet simulations at 140 km resolution, the new model is able to reproduce the same equatorial wave propagation characteristics as in the reference spectral model, including the sensitivity of such characteristics to the meridional sea surface temperature profile. These results suggest that the triangular-C discretization provides a reasonable basis for further development. The main issues that need to be addressed are the grid-scale noise from the divergence operator which requires strong damping, and a phase error of the baroclinic wave at medium and low resolutions.
Abstract
STUDY QUESTION
Can traceability of gametes and embryos be ensured during IVF?
SUMMARY ANSWER
The use of a simple and comprehensive traceability system that includes the most susceptible ...phases during the IVF process minimizes the risk of mismatches.
WHAT IS KNOWN ALREADY
Mismatches in IVF are very rare but unfortunately possible with dramatic consequences for both patients and health care professionals. Traceability is thus a fundamental aspect of the treatment. A clear process of patient and cell identification involving witnessing protocols has to be in place in every unit. To identify potential failures in the traceability process and to develop strategies to mitigate the risk of mismatches, previously failure mode and effects analysis (FMEA) has been used effectively. The FMEA approach is however a subjective analysis, strictly related to specific protocols and thus the results are not always widely applicable. To reduce subjectivity and to obtain a widespread comprehensive protocol of traceability, a multicentre centrally coordinated FMEA was performed.
STUDY DESIGN, SIZE, DURATION
Seven representative Italian centres (three public and four private) were selected. The study had a duration of 21 months (from April 2015 to December 2016) and was centrally coordinated by a team of experts: a risk analysis specialist, an expert embryologist and a specialist in human factor. Principal investigators of each centre were first instructed about proactive risk assessment and FMEA methodology. A multidisciplinary team to perform the FMEA analysis was then formed in each centre. After mapping the traceability process, each team identified the possible causes of mistakes in their protocol. A risk priority number (RPN) for each identified potential failure mode was calculated. The results of the FMEA analyses were centrally investigated and consistent corrective measures suggested. The teams performed new FMEA analyses after the recommended implementations.
PARTICIPANTS/MATERIALS, SETTING, METHODS
In each centre, this study involved: the laboratory director, the Quality Control & Quality Assurance responsible, Embryologist(s), Gynaecologist(s), Nurse(s) and Administration. The FMEA analyses were performed according to the Joint Commission International.
MAIN RESULTS AND THE ROLE OF CHANCE
The FMEA teams identified seven main process phases: oocyte collection, sperm collection, gamete processing, insemination, embryo culture, embryo transfer and gamete/embryo cryopreservation. A mean of 19.3 (SD ± 5.8) associated process steps and 41.9 (SD ± 12.4) possible failure modes were recognized per centre. A RPN ≥15 was calculated in a mean of 6.4 steps (range 2–12, SD ± 3.60). A total of 293 failure modes were centrally analysed 45 of which were considered at medium/high risk. After consistent corrective measures implementation and re-evaluation, a significant reduction in the RPNs in all centres (RPN <15 for all steps) was observed. A simple and comprehensive traceability system was designed as the result of the seven FMEA analyses.
LIMITATIONS, REASONS FOR CAUTION
The validity of FMEA is in general questionable due to the subjectivity of the judgments. The design of this study has however minimized this risk by introducing external experts for the analysis of the FMEA results. Specific situations such as sperm/oocyte donation, import/export and pre-implantation genetic testing were not taken into consideration. Finally, this study is only limited to the analysis of failure modes that may lead to mismatches, other possible procedural mistakes are not accounted for.
WIDER IMPLICATIONS OF THE FINDINGS
Every single IVF centre should have a clear and reliable protocol for identification of patients and traceability of cells during manipulation. The results of this study can support IVF groups in better recognizing critical steps in their protocols, understanding identification and witnessing process, and in turn enhancing safety by introducing validated corrective measures.
STUDY FUNDING/COMPETING INTEREST(S)
This study was designed by the Italian Society of Embryology Reproduction and Research (SIERR) and funded by the Italian National Transplant Centre (CNT) of the Italian National Institute of Health (ISS). The authors have no conflicts of interest.
TRIAL REGISTRATION NUMBER
N/A.
Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. Approximately 40% of DLBCL patients have refractory disease or disease that will relapse after an ...initial response to the combinatorial chemo-immunotherapy. Thus, finding new therapeutic approaches is urgently needed for this lymphoma. Experimental evidence showed that high levels of Myc protein is very common in DLBCL and correlated with poor survival prognosis of DLBCL patients, suggesting that Myc is a crucial target for DLBCL therapy. The checkpoint kinases Chk1 and Wee1 are key cell cycle regulators, required during normal S phase to avoid deleterious DNA breakage, and to maintain cancer cell survival under replication stress. Chk1 inhibitors have been recently shown to be effective in Myc overexpressing cells and are strongly synergistic with Wee1 inhibitors in many experimental systems. We herein investigated the effects of Chk1 and Wee1 inhibition in DLBCL cell lines differently expressing Myc protein. Material and Methods: Eleven cell lines derived from germinal center B-cell like (GCB) and activated B cell like (ABC) DLBCL were treated with the Chk1 inhibitor PF-00477736 and the Wee1 inhibitor AZD-1775 alone and in combination. Drug combination was quantified by calculating the Combination Index (CI) (Chou Talalay method). Cell cycle analysis by FACS and detection of apoptosis by caspase-3 activity were performed after such treatments. Myc protein levels and DNA damage markers were evaluated by Western Blot Analysis. Results: Myc protein levels and the degree of endogenous constitutive DNA damage (yH2AX activation and pS317-Chk1) detected in the different DLBCL cell lines did not correlate with the extent of sensitivity to PF-00477736 and to AZD-1775 (IC50s ranging respectively from 68 to 1023 nM and from 114 to 968 nM). The combined treatment is strongly synergistic in all the DLBCL cell lines, with CI values, evaluated at the IC50 doses, ranging from 0.06 to 0.77. The drug combination induced an S phase delay and an accumulation of DNA damage measured by yH2AX activation. Enhanced caspase-3 activity observed after the combined treatment suggested that cell death by apoptosis is also occurring. Interestingly a strong decrease of Myc protein levels not associated with Myc mRNA down-regulation was observed after the dual inhibition of Chk1 and Wee1. Molecular investigation is undergoing to elucidate the mechanisms at the basis of this Myc protein expression modulation. Conclusions: Overall these data suggest that combining Chk1 and Wee1 inhibitors could be a new and effective therapeutic strategy to test in clinical setting in DLBCL.
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