Target of Rapamycin Inhibitors (TOR-I; Sirolimus and Everolimus) for Primary Immunosuppression in Kidney Transplant Recipients

Background: Target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus) are immunosuppressive agents with a novel mode of action but an uncertain clinical role. Objectives: To investigate the benefits and harms of immunosuppressive regimens containing TOR-I when compared to other regimens as initial therapy for kidney transplant recipients. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), the specialised register of the Cochrane Renal Group (June 2005)., and contacted authors and pharmaceutical companies to identify relevant studies. Selection criteria: All randomised controlled trials (RCTs) and quasi-RCTs where drug regimens containing TOR-I were compared to alternative drug regimens in the immediate post-transplant period were included, without age restriction, dosage or language of report. Data collection and analysis: Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) or weight mean difference (MD) with 95% confidence intervals (CI). Main results: Thirty three trials (142 reports) were included (sirolimus (27), everolimus (5), head-to-head (1)). When TOR-I replaced CNI there was no difference in acute rejection, but serum creatinine was lower (MD -18.31 micromol/L, -30.96 to -5.67), and bone marrow more suppressed (leucopenia: RR 2.02 1.12 to 3.66; thrombocytopenia: RR 6.97 2.97 to 16.36; anaemia: RR 1.67, 1.27 to 2.20). When TOR-I replaced antimetabolites, acute rejection (RR 0.84, 0.71 to 0.99) and cytomegalovirus infection (CMV) (RR 0.49; 0.37 to 0.65) were reduced, but hypercholesterolaemia was increased (RR 1.65, 1.32 to 2.06). For low versus high-dose TOR-I, with equal CNI dose, rejection was increased (RR 1.23, 1.06 to 1.43) but calculated GFR higher (MD 4.27 mL/min, 1.12 to 7.41), and for low-dose TOR-I/standard-dose CNI versus higher-dose TOR-I/reduced CNI, acute rejection (RR 0.67, 0.52 to 0.88) and calculated GFR (MD -9.46 mL/min, -12.16 to -6.76) were reduced. There was no significant difference in mortality, graft loss or malignancy risk for TOR-I in any comparison. Authors' conclusions: TOR-I have been evaluated in four different primary immunosuppressive algorithms; as replacement for CNI and for antimetabolites, in combination with CNI at low and high dose and with variable dose of CNI. Generally, surrogate endpoints for graft survival favour TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust RCTs are still needed

eHealth interventions for people with chronic kidney disease

Background Chronic kidney disease (CKD) is associated with high morbidity and death, which increases as CKD progresses to end‐stage kidney disease (ESKD). There has been increasing interest in developing innovative, effective and cost‐efficient methods to engage with patient populations and improve health behaviours and outcomes. Worldwide there has been a tremendous increase in the use of technologies, with increasing interest in using eHealth interventions to improve patient access to relevant health information, enhance the quality of healthcare and encourage the adoption of healthy behaviours. Objectives This review aims to evaluate the benefits and harms of using eHealth interventions to change health behaviours in people with CKD. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 14 January 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria Randomised controlled trials (RCTs) and quasi‐RCTs using an eHealth intervention to promote behaviour change in people with CKD were included. There were no restrictions on outcomes, language or publication type. Data collection and analysis Two authors independently assessed trial eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was assessed using GRADE. Main results We included 43 studies with 6617 participants that evaluated the impact of an eHealth intervention in people with CKD. Included studies were heterogeneous in terms of eHealth modalities employed, type of intervention, CKD population studied and outcomes assessed. The majority of studies (39 studies) were conducted in an adult population, with 16 studies (37%) conducted in those on dialysis, 11 studies (26%) in the pre‐dialysis population, 15 studies (35%) in transplant recipients and 1 studies (2%) in transplant candidates We identified six different eHealth modalities including: Telehealth; mobile or tablet application; text or email messages; electronic monitors; internet/websites; and video or DVD. Three studies used a combination of eHealth interventions. Interventions were categorised into six types: educational; reminder systems; self‐monitoring; behavioural counselling; clinical decision‐aid; and mixed intervention types. We identified 98 outcomes, which were categorised into nine domains: blood pressure (9 studies); biochemical parameters (6 studies); clinical end‐points (16 studies); dietary intake (3 studies); quality of life (9 studies); medication adherence (10 studies); behaviour (7 studies); physical activity (1 study); and cost‐effectiveness (7 studies). Only three outcomes could be meta‐analysed as there was substantial heterogeneity with respect to study population and eHealth modalities utilised. There was found to be a reduction in interdialytic weight gain of 0.13kg (4 studies, 335 participants: MD ‐0.13, 95% CI ‐0.28 to 0.01; I2 = 0%) and a reduction in dietary sodium intake of 197 mg/day (2 studies, 181 participants: MD ‐197, 95% CI ‐540.7 to 146.8; I2 = 0%). Both dietary sodium and fluid management outcomes were graded as being of low evidence due to high or unclear risk of bias and indirectness (interdialytic weight gain) and high or unclear risk of bias and imprecision (dietary sodium intake). Three studies reported death (2799 participants, 146 events), with 45 deaths/1000 cases compared to standard care of 61 deaths/1000 cases (RR 0.74, CI 0.53 to 1.03; P = 0.08). We are uncertain whether using eHealth interventions, in addition to usual care, impact on the number of deaths as the certainty of this evidence was graded as low due to high or unclear risk of bias, indirectness and imprecision. Authors' conclusions eHealth interventions may improve the management of dietary sodium intake and fluid management. However, overall these data suggest that current evidence for the use of eHealth interventions in the CKD population is of low quality, with uncertain effects due to methodological limitations and heterogeneity of eHealth modalities and intervention types. Our review has highlighted the need for robust, high quality research that reports a core (minimum) data set to enable meaningful evaluation of the literature

Target of rapamycin inhibitors (TOR‐I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Background Kidney transplantation is the therapy of choice for many patients with end‐stage kidney disease (ESKD) with an improvement in survival rates and satisfactory short term graft survival. However, there has been little improvement in long‐term survival. The place of target of rapamycin inhibitors (TOR‐I) (sirolimus, everolimus), which have different modes of action from other commonly used immunosuppressive agents, in kidney transplantation remains uncertain. This is an update of a review first published in 2006. Objectives To evaluate the short and long‐term benefits and harms of TOR‐I (sirolimus and everolimus) when used in primary immunosuppressive regimens for kidney transplant recipients. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 20 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria All randomised controlled trials (RCTs) and quasi‐RCTs in which drug regimens, containing TOR‐I commenced within seven days of transplant, were compared to alternative drug regimens, were included without age restriction, dosage or language of report. Data collection and analysis Three authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random‐effects model. The certainty of the evidence was assessed using GRADE Main results Seventy studies (17,462 randomised participants) were included; eight studies included two comparisons to provide 78 comparisons. Outcomes were reported at six months to three years post transplant. Risk of bias was judged to be low for sequence generation in 25 studies, for allocation concealment in 23 studies, performance bias in four studies, detection bias in 65 studies, attrition bias in 45 studies, selective reporting bias in 48 studies, and for other potential bias in three studies. Risk of bias was judged to be at high risk of bias for sequence generation in two studies, allocation concealment in two studies, performance bias in 61 studies, detection bias in one study, attrition bias in four studies, for selective reporting bias in 11 studies and for other potential risk of bias in 46 studies. Compared with CNI and antimetabolite, TOR‐I with antimetabolite probably makes little or no difference to death (RR 1.31, 95% CI 0.87 to 1.98; 19 studies) or malignancies (RR 0.86, 95% CI 0.50 to 1.48; 10 studies); probably increases graft loss censored for death (RR 1.32, 95% CI 0.96 to 1.81; 15 studies), biopsy‐proven acute rejection (RR 1.60, 95% CI 1.25 to 2.04; 15 studies), need to change treatment (RR 2.42, 95% CI 1.88 to 3.11; 14 studies) and wound complications (RR 2.56, 95% CI 1.94 to 3.36; 12 studies) (moderate certainty evidence); but reduces CMV infection (RR 0.43, 95% CI 0.29 to 0.63; 13 studies) (high certainty evidence). Compared with antimetabolites and CNI, TOR‐I with CNI probably makes little or no difference to death (RR 1.06, 95% CI 0.84 to 1.33; 31 studies), graft loss censored for death (RR 1.09, 95% CI 0.82 to 1.45; 26 studies), biopsy‐proven acute rejection (RR 0.95, 95% CI 0.81 to 1.12; 24 studies); and malignancies (RR 0.83, 95% CI 0.64 to 1.07; 17 studies); probably increases the need to change treatment (RR 1.56, 95% CI 1.28 to 1.90; 25 studies), and wound complications (RR 1.56, 95% CI 1.28 to 1.91; 17 studies); but probably reduces CMV infection (RR 0.44, 95% CI 0.34 to 0.58; 25 studies) (moderate certainty evidence). Lower dose TOR‐I and standard dose CNI compared with higher dose TOR‐I and reduced dose CNI probably makes little or no difference to death (RR 1.07, 95% CI 0.64 to 1.78; 9 studies), graft loss censored for death (RR 1.09, 95% CI 0.54 to 2.20; 8 studies), biopsy‐proven acute rejection (RR 0.87, 95% CI 0.67 to 1.13; 8 studies), and CMV infection (RR 1.42, 95% CI 0.78 to 2.60; 5 studies) (moderate certainty evidence); and may make little or no difference to wound complications (RR 0.95, 95% CI 0.53 to 1.71; 3 studies), malignancies (RR 1.04, 95% CI 0.36 to 3.04; 7 studies), and the need to change treatments (RR 1.18, 95% CI 0.58 to 2.42; 5 studies) (low certainty evidence). Lower dose of TOR‐I compared with higher doses probably makes little or no difference to death (RR 0.84, 95% CI 0.67 to 1.06; 13 studies), graft loss censored for death (RR 0.92, 95% CI 0.71 to 1.19; 12 studies), biopsy‐proven acute rejection (RR 1.26, 95% CI 1.10 to 1.43; 11 studies), CMV infection (RR 0.87, 95% CI 0.63 to 1.21; 9 studies), wound complications (RR 0.92, 95% CI 0.66 to 1.29; 7 studies), and malignancy (RR 0.84, 95% CI 0.54 to 1.32; 10 studies) (moderate certainty evidence); and may make little or no difference to the need to change treatments (RR 0.91, 95% CI 0.78 to 1.05; 10 studies) (low certainty evidence). It is uncertain whether sirolimus and everolimus differ in their effects on kidney function and lipid levels because the certainty of the evidence is very low based on a single small study with only three months of follow‐up. Authors' conclusions In studies with follow‐up to three years, TOR‐I with an antimetabolite increases the risk of graft loss and acute rejection compared with CNI and an antimetabolite. TOR‐I with CNI potentially offers an alternative to an antimetabolite with CNI as rates of graft loss and acute rejection are similar between interventions and TOR‐I regimens are associated with a reduced risk of CMV infections. Wound complications and the need to change immunosuppressive medications are higher with TOR‐I regimens. While further new studies are not required, longer‐term follow‐up data from participants in existing methodologically robust RCTs are needed to determine how useful immunosuppressive regimens, which include TOR‐I, are in maintaining kidney transplant function and survival beyond three years

Teacher led school-based surveillance can allow accurate tracking of emerging infectious diseases - evidence from serial cross-sectional surveys of febrile respiratory illness during the H1N1 2009 influenza pandemic in Singapore

10.1186/1471-2334-12-336BMC Infectious Diseases12-BIDM

Fuzzy Tandem Repeats Containing p53 Response Elements May Define Species-Specific p53 Target Genes

Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2) gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species

Stabilization of Dicentric Translocations through Secondary Rearrangements Mediated by Multiple Mechanisms in S. cerevisiae

The gross chromosomal rearrangements (GCRs) observed in S. cerevisiae mutants with increased rates of accumulating GCRs include predicted dicentric GCRs such as translocations, chromosome fusions and isoduplications. These GCRs resemble the genome rearrangements found as mutations underlying inherited diseases as well as in the karyotypes of many cancers exhibiting ongoing genome instabilityThe structures of predicted dicentric GCRs were analyzed using multiple strategies including array-comparative genomic hybridization, pulse field gel electrophoresis, PCR amplification of predicted breakpoints and sequencing. The dicentric GCRs were found to be unstable and to have undergone secondary rearrangements to produce stable monocentric GCRs. The types of secondary rearrangements observed included: non-homologous end joining (NHEJ)-dependent intramolecular deletion of centromeres; chromosome breakage followed by NHEJ-mediated circularization or broken-end fusion to another chromosome telomere; and homologous recombination (HR)-dependent non-reciprocal translocations apparently mediated by break-induced replication. A number of these GCRs appeared to have undergone multiple bridge-fusion-breakage cycles. We also observed examples of chromosomes with extensive ongoing end decay in mec1 tlc1 mutants, suggesting that Mec1 protects chromosome ends from degradation and contributes to telomere maintenance by HR.HR between repeated sequences resulting in secondary rearrangements was the most prevalent pathway for resolution of dicentric GCRs regardless of the structure of the initial dicentric GCR, although at least three other resolution mechanisms were observed. The resolution of dicentric GCRs to stable rearranged chromosomes could in part account for the complex karyotypes seen in some cancers

Dedifferentiation of Foetal CNS Stem Cells to Mesendoderm-Like Cells through an EMT Process

Tissue-specific stem cells are considered to have a limited differentiation potential. Recently, this notion was challenged by reports that showed a broader differentiation potential of neural stem cells, in vitro and in vivo, although the molecular mechanisms that regulate plasticity of neural stem cells are unknown. Here, we report that neural stem cells derived from mouse embryonic cortex respond to Lif and serum in vitro and undergo epithelial to mesenchymal transition (EMT)-mediated dedifferentiation process within 48 h, together with transient upregulation of pluripotency markers and, more notably, upregulation of mesendoderm genes, Brachyury (T) and Sox17. These induced putative mesendoderm cells were injected into early gastrulating chick embryos, which revealed that they integrated more efficiently into mesoderm and endoderm lineages compared to non-induced cells. We also found that TGFβ and Jak/Stat pathways are necessary but not sufficient for the induction of mesendodermal phenotype in neural stem cells. These results provide insights into the regulation of plasticity of neural stem cells through EMT. Dissecting the regulatory pathways involved in these processes may help to gain control over cell fate decisions

Rapid Selection and Proliferation of CD133(+) Cells from Cancer Cell Lines: Chemotherapeutic Implications

Cancer stem cells (CSCs) are considered a subset of the bulk tumor responsible for initiating and maintaining the disease. Several surface cellular markers have been recently used to identify CSCs. Among those is CD133, which is expressed by hematopoietic progenitor cells as well as embryonic stem cells and various cancers. We have recently isolated and cultured CD133 positive [CD133(+)] cells from various cancer cell lines using a NASA developed Hydrodynamic Focusing Bioreactor (HFB) (Celdyne, Houston, TX). For comparison, another bioreactor, the rotary cell culture system (RCCS) manufactured by Synthecon (Houston, TX) was used. Both the HFB and the RCCS bioreactors simulate aspects of hypogravity. In our study, the HFB increased CD133(+) cell growth from various cell lines compared to the RCCS vessel and to normal gravity control. We observed a (+)15-fold proliferation of the CD133(+) cellular fraction with cancer cells that were cultured for 7-days at optimized conditions. The RCCS vessel instead yielded a (−)4.8-fold decrease in the CD133(+)cellular fraction respect to the HFB after 7-days of culture. Interestingly, we also found that the hypogravity environment of the HFB greatly sensitized the CD133(+) cancer cells, which are normally resistant to chemo treatment, to become susceptible to various chemotherapeutic agents, paving the way to less toxic and more effective chemotherapeutic treatment in patients. To be able to test the efficacy of cytotoxic agents in vitro prior to their use in clinical setting on cancer cells as well as on cancer stem cells may pave the way to more effective chemotherapeutic strategies in patients. This could be an important advancement in the therapeutic options of oncologic patients, allowing for more targeted and personalized chemotherapy regimens as well as for higher response rates