Planned oocyte cryopreservation (Planned OC): systematic review and meta-analysis of cost-efficiency and patients' perspective.

BACKGROUND: Advances in vitrification techniques have enabled planned oocyte cryopreservation ('Planned OC'). OBJECTIVES: To explore the cost-efficiency and utilisation of planned OC, as well as patients' perspectives on the process. SEARCH STRATEGY: A systematic search in PubMed/MEDLINE, Embase, Cochrane Database and PsychINFO, for all relevant studies published between January 2007 and December 2019. SELECTION CRITERIA: The protocol followed PRISMA guidelines in PECO format, and was registered with PROSPERO. DATA COLLECTION AND ANALYSIS: Two independent reviewers evaluated all manuscripts for inclusion eligibility. Authors were contacted for missing data. Included studies were assessed for risk of bias and for heterogeneity. Weighted effects were measured and plotted. MAIN RESULTS: The search yielded 12 545 records, of which 43 were included. Planned OC is cost-efficient at 35, assuming 60% utilisation; and at 37 assuming utilising donor sperm when necessary. At 38 it is cost-efficient to defer planned OC in favour of undergoing 2 IVF cycles. Currently, utilisation of banked-oocytes within 22-58 months, is up to 15%. Nine percent of warmed banked oocytes result in life births. Online resources and treating physicians are equally important sources of information regarding planned OC. Most patients think planned OC is ideal before age 35 and are not fully aware of what the process entails and tend to overestimate the success rates. The main barrier to wider endorsement of planned OC is being wary of potential health implications or of limited success. CONCLUSION: Planned OC is an adequate method for preserving fertility. However, knowledge gaps result in under-utilisation leading to reduced cost-efficiency. TWEETABLE ABSTRACT: Identifying facilitators and barriers for wider adoption of banking oocytes can enhance the cost-efficiency of this modality.

Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine lymphoid tissue.

The ATM protein kinase, functionally missing in patients with the human genetic disorder ataxia-telangiectasia, is a master regulator of the cellular network induced by DNA double-strand breaks. The ATM gene is also frequently mutated in sporadic cancers of lymphoid origin. Here, we applied a functional genomics approach that combined gene expression profiling and computational promoter analysis to obtain global dissection of the transcriptional response to ionizing radiation in murine lymphoid tissue. Cluster analysis revealed a prominent pattern characterizing dozens of genes whose response to irradiation was Atm-dependent. Computational analysis identified significant enrichment of the binding site signatures of NF-kappaB and p53 among promoters of these genes, pointing to the major role of these two transcription factors in mediating the Atm-dependent transcriptional response in the irradiated lymphoid tissue. Examination of the response showed that pro- and antiapoptotic signals were simultaneously induced, with the proapoptotic pathway mediated by p53 targets, and the prosurvival pathway by NF-kappaB targets. These findings further elucidate the molecular network induced by IR, point to novel putative NF-kappaB targets, and suggest a mechanistic model for cellular balancing between pro- and antiapoptotic signals induced by IR in lymphoid tissues, which has implications for cancer management. The emerging model suggests that restoring the p53-mediated apoptotic arm while blocking the NF-kappaB-mediated prosurvival arm could effectively increase the radiosensitivity of lymphoid tumors.

Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase.

Resistance to pharmacologic agents used in chemotherapy is common in most human carcinomas, including pancreatic ductal adenocarcinoma (PDA), which is resistant to almost all drugs, including gemcitabine, a nucleoside analog used as a first-line treatment. Poor survival rates of PDA patients have, therefore, not changed much over 4 decades. Recent data indicated that tumor-associated macrophages (TAMs), which are abundant in the microenvironment of several tumors, including PDA, secrete pro-tumorigenic factors that contribute to cancer progression and dissemination. In this study, we show for the first time that TAMs can also induce chemoresistance of PDA by reducing gemcitabine-induced apoptosis. Macrophages co-cultured with cancer cells or TAM-conditioned medium significantly reduced apoptosis and activation of the caspase-3 pathway during gemcitabine treatment. In vivo PDA models of mice, which have reduced macrophage recruitment and activation, demonstrated improved response to gemcitabine compared with controls. Similarly, inhibition of monocytes/macrophages trafficking by a CSF1-receptor antagonist GW2580 augmented the effect of gemcitabine in a transgenic mouse PDA model that was resistant to gemcitabine alone. Analysis of multiple proteins involved in gemcitabine delivery and metabolism revealed that TAMs induced upregulation of cytidine deaminase (CDA), the enzyme that metabolizes the drug following its transport into the cell. Decreasing CDA expression by PDA cells blocked the protective effect of TAMs against gemcitabine. These results provide the first evidence of a paracrine effect of TAMs, which mediates acquired resistance of cancer cells to chemotherapy. Modulation of macrophage trafficking or inhibition of CDA may offer a new strategy for augmenting the response of PDA to chemotherapy.

Antiparkinsonian medication is not a risk factor for the development of hallucinations in Parkinson's disease.

BACKGROUND: It was commonly assumed that psychotic phenomena in Parkinson's disease (PD) are mainly drug related. Accumulating evidence suggests the existence of other risk factors for psychosis in PD. Aims. To evaluate the contribution of the drug profile of patients with PD to emergence of hallucinations. METHODS: We compared patients with and without hallucinations, using Cox proportional hazards model, concerning drug profile at the time of hallucinations emergence. RESULTS: Of 422 consecutive patients, 113 had dementia, while 90 patients experienced hallucinations (46 had both dementia and hallucinations). The mean levodopa dose for the group of patients with hallucinations was 650 +/- 279 mg/day at the time of hallucinations onset, which was not significantly different from the levodopa dose at last visit for the group without hallucinations (621 +/- 326 mg/day). Supplementary treatment with amantadine, selegiline, dopamine agonists, entacapone and anticholinergics did not increase the risk for the development of hallucinations. CONCLUSIONS: We did not confirm drug treatment as a risk factor for hallucinations in PD. Our study suggests the existence of "endogenic" factors as substantial contributors in the genesis of PD hallucinations. The clinical implications may be earlier administration of antipsychotic treatment and not as traditionally accepted, dose reduction of antiparkinsonian drugs.

Astrocyte activation by Sindbis virus: expression of GFAP, cytokines, and adhesion molecules.

Sindbis virus (SV) is a member of the alphaviruses which has served as a model system for studying viral encephalitis. Although astrocytes are reported to be involved in the pathogenesis of various virus-related diseases, the effects of SV on astrocyte function have not been reported. In this study we compared the effects of two strains of SV, SVA, and SVNI, which differ in their neurovirulent properties, on astrocytes with the use of cultured mouse astrocytes and the rat C6 glial cell line. We found that although both strains can similarly infect and replicate in astrocytes, they induced different changes in the function of these cells. The neurovirulent strain, SVNI, induced a decrease in cell number and a marked increase in the expression of GFAP, whereas SVA did not alter these parameters. In addition, SVNI induced the secretion of the cytokines TNF-alpha and IL-6, the expression of adhesion molecules, and the production of the neurotrophic factor NGF. In contrast, SVA induced smaller increases in the secretion of IL-6 and NGF but did not alter the secretion of TNF-alpha and the expression of the adhesion molecules. Neither virus induced the secretion of IL-2, IL-4, IL-10 and IFN-gamma or the expression of iNOS in the cells. These results indicate that astrocytes, similar to neurons, can serve as target cells to SV infection in the CNS. Moreover, the infection of astrocytes by SVNI leads to changes characteristic of reactive astrogliosis which may contribute to the pathogenesis of SV-induced encephalitis by enhancing the local immune response in the CNS.