NUMERICAL MODELLING OF HEAT TRANSFER FROM AN ISOTHERMAL CYLINDER BURIED IN HETEROGENEOUS POROUS MEDIA

Heat transfer from an isothermal pipe buried in porous media and superimposed by a fluid layer has been investigated numerically using the commercial software FLUENT (6.3.26). Due to natural and induced heterogeneity, soils have variations in their hydraulic and volumetric properties; these must be considered for accurate design purposes. Two types of porous media have been investigated, sand and clay. For sand media, the study investigates the effects of different flow and geometric conditions on the heat transfer process. The flow parameters are represented by the Rayleigh number, the permeability ratio of the backfill to the seabed and the permeability anisotropy of the backfill, while the geometric parameters are represented by the trench size and shape and the position of the pipe in the trench. For clay media, two states of the backfill were investigated; these are slurried and lumpy clays. The study also shows the impact of the different trenching conditions on insulation of the pipe as opposed to expensive coating. Lowest heat losses were achieved for a sand backfill of a permeability 100 times the permeability of the seabed and permeability anisotropy of (Kth/Ktv=50). Clay slurry backfill gave the lowest heat transfer results as the main mode of heat transfer in this case was conduction. In contrast, the high permeability and intergranular porosity of clay lumps, allowed for pure convection heat transfer. It was also noticed that clay lumps of sizes 5 and 10 cm allowed for more heat losses than for a pipe with no backfill at all

Rad5, HLTF, and SHPRH: A fresh view of an old story

Not only have helicase-like transcription factor (HLTF) and SNF2 histone-linker PHD-finger RING-finger helicase (SHPRH) proved to be important players in post-replication repair like their yeast counterpart, Rad5, but they are also involved in multiple biological functions and are associated with several human disorders. We provide here an updated view of their functions, associated diseases, and potential therapeutic approaches

Recent advances in stem cells therapy: A focus on cancer, Parkinson’s and Alzheimer’s

Stem cells serve as potential therapeutics due to their high proliferative capacity, low immunogenic reactivity and their differentiating capabilities. Several pre-clinical and early-stage clinical studies are carried out to treat genetic diseases, cancers and neurodegenerative disorders with promising preliminary results. However, there are still many challenges that scientists are trying to overcome such as the unclear expression profile of stem cells in vivo, the homing of stem cells to the site of injury and their potential immune-reactivity. Prospective research lies in gene editing of autologous stem cells in vitro and safe injection of these modified cells back into patients. Here, we review the clinical trials executed using stem cell therapy in an attempt to cure challenging diseases like cancer, Parkinson’s and Alzheimer’s diseases

Short‐acting erythropoiesis‐stimulating agents for anaemia in predialysis patients

Background The benefits of erythropoiesis‐stimulating agents (ESA) for chronic kidney disease (CKD) patients have been previously demonstrated. However, the efficacy and safety of short‐acting epoetins administered at larger doses and reduced frequency as well as of new epoetins and biosimilars remains uncertain. Objectives This review aimed to evaluate the benefits and harms of different routes, frequencies and doses of epoetins (epoetin alpha, epoetin beta and other short‐acting epoetins) for anaemia in adults and children with CKD not receiving dialysis. Search methods We searched the Cochrane Kidney and Transplant Specialised Register to 12 September 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria We included randomised control trials (RCTs) comparing different frequencies, routes, doses and types of short‐acting ESAs in CKD patients. Data collection and analysis Two authors independently assessed study eligibility and four authors assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random‐effects model. Main results We identified 14 RCTs (2616 participants); nine studies were multi‐centre and two studies involved children. The risk of bias was high in most studies; only three studies demonstrated adequate random sequence generation and only two studies were at low risk of bias for allocation concealment. Blinding of participants and personnel was at low risk of bias in one study. Blinding of outcome assessment was judged at low risk in 13 studies as the outcome measures were reported as laboratory results and therefore unlikely to be influenced by blinding. Attrition bias was at low risk of bias in eight studies while selective reporting was at low risk in six included studies. Four interventions were compared: epoetin alpha or beta at different frequencies using the same total dose (six studies); epoetin alpha at the same frequency and different total doses (two studies); epoetin alpha administered intravenously versus subcutaneous administration (one study); epoetin alpha or beta versus other epoetins or biosimilars (five studies). One study compared both different frequencies of epoetin alpha at the same total dose and at the same frequency using different total doses. Data from only 7/14 studies could be included in our meta‐analyses. There were no significant differences in final haemoglobin (Hb) levels when dosing every two weeks was compared with weekly dosing (4 studies, 785 participants: MD ‐0.20 g/dL, 95% CI ‐0.33 to ‐0.07), when four weekly dosing was compared with two weekly dosing (three studies, 671 participants: MD ‐0.16 g/dL, 95% CI ‐0.43 to 0.10) or when different total doses were administered at the same frequency (four weekly administration: one study, 144 participants: MD 0.17 g/dL 95% CI ‐0.19 to 0.53). Five studies evaluated different interventions. One study compared epoetin theta with epoetin alpha and found no significant differences in Hb levels (288 participants: MD ‐0.02 g/dL, 95% CI ‐0.25 to 0.21). One study found significantly higher pain scores with subcutaneous epoetin alpha compared with epoetin beta. Two studies (165 participants) compared epoetin delta with epoetin alpha, with no results available since the pharmaceutical company withdrew epoetin delta for commercial reasons. The fifth study comparing the biosimilar HX575 with epoetin alpha was stopped after patients receiving HX575 subcutaneously developed anti‐epoetin antibodies and no results were available. Adverse events were poorly reported in all studies and did not differ significantly within comparisons. Mortality was only detailed adequately in four studies and only one study included quality of life data. Authors' conclusions Epoetin alpha given at higher doses for extended intervals (two or four weekly) is non‐inferior to more frequent dosing intervals in maintaining final Hb levels with no significant differences in adverse effects in non‐dialysed CKD patients. However the data are of low methodological quality so that differences in efficacy and safety cannot be excluded. Further large, well designed, RCTs with patient‐centred outcomes are required to assess the safety and efficacy of large doses of the shorter acting ESAs, including biosimilars of epoetin alpha, administered less frequently compared with more frequent administration of smaller doses in children and adults with CKD not on dialysis

A role for Rad5 in ribonucleoside monophosphate (rNMP) tolerance

YesRibonucleoside monophosphate (rNMP) incorporation in genomic DNA poses a significant threat to genomic integrity. In addition to repair, DNA damage tolerance mechanisms ensure replication progression upon encountering unrepaired lesions. One player in the tolerance mechanism is Rad5, which is an E3 ubiquitin ligase and helicase. Here, we report a new role for yeast Rad5 in tolerating rNMP incorporation, in the absence of the bona fide ribonucleotide excision repair pathway via RNase H2. This role of Rad5 is further highlighted after replication stress induced by hydroxyurea or by increasing rNMP genomic burden using a mutant DNA polymerase (Pol ε - Pol2-M644G). We further demonstrate the importance of the ATPase and ubiquitin ligase domains of Rad5 in rNMP tolerance. These findings suggest a similar role for the human Rad5 homologues helicase-like transcription factor (HLTF) and SNF2 Histone Linker PHD RING Helicase (SHPRH) in rNMP tolerance, which may impact the response of cancer cells to replication stress-inducing therapeutics

High glucose increases DNA damage and elevates the expression of multiple DDR genes

The DNA Damage Response (DDR) pathways sense DNA damage and coordinate robust DNA repair and bypass mechanisms. A series of repair proteins are recruited depending on the type of breaks and lesions to ensure overall survival. An increase in glucose levels was shown to induce genome instability, yet the links between DDR and glucose are still not well investigated. In this study, we aimed to identify dysregulation in the transcriptome of normal and cancerous breast cell lines upon changing glucose levels. We first performed bioinformatics analysis using a microarray dataset containing the triple-negative breast cancer (TNBC) MDA-MB-231 and the normal human mammary epithelium MCF10A cell lines grown in high glucose (HG) or in the presence of the glycolysis inhibitor 2-deoxyglucose (2DG). Interestingly, multiple DDR genes were significantly upregulated in both cell lines grown in HG. In the wet lab, we remarkably found that HG results in severe DNA damage to TNBC cells as observed using the comet assay. In addition, several DDR genes were confirmed to be upregulated using qPCR analysis in the same cell line. Our results propose a strong need for DDR pathways in the presence of HG to oppose the severe DNA damage induced in cells

A role for Rad5 in ribonucleoside monophosphate (rNMP) tolerance

Ribonucleoside monophosphate (rNMP) incorporation in genomic DNA poses a significant threat to genomic integrity. In addition to repair, DNA damage tolerance mechanisms ensure replication progression upon encountering unrepaired lesions. One player in the tolerance mechanism is Rad5, which is an E3 ubiquitin ligase and helicase. Here, we report a new role for yeast Rad5 in tolerating rNMP incorporation, in the absence of the bona fide ribonucleotide excision repair pathway via RNase H2. This role of Rad5 is further highlighted after replication stress induced by hydroxyurea or by increasing rNMP genomic burden using a mutant DNA polymerase (Pol ε - Pol2-M644G). We further demonstrate the importance of the ATPase and ubiquitin ligase domains of Rad5 in rNMP tolerance. These findings suggest a similar role for the human Rad5 homologues helicase-like transcription factor (HLTF) and SNF2 Histone Linker PHD RING Helicase (SHPRH) in rNMP tolerance, which may impact the response of cancer cells to replication stress-inducing therapeutics

High temperature drives topoisomerase mediated chromosomal break repair pathway choice

Cancer-causing mutations often arise from inappropriate DNA repair, yet acute exposure to DNA damage is widely used to treat cancer. The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in noncancerous cells. One approach is the acute exposure to hyperthermia, which suppresses DNA repair and synergizes with radiotherapy and chemotherapy. An exception, however, is the protective effect of hyperthermia on topoisomerase targeting therapeutics. The molecular explanation for this conundrum remains unclear. Here, we show that hyperthermia suppresses the level of topoisomerase mediated single- and double-strand breaks induced by exposure to topoisomerase poisons. We further uncover that, hyperthermia suppresses hallmarks of genomic instability induced by topoisomerase targeting therapeutics by inhibiting nuclease activities, thereby channeling repair to error-free pathways driven by tyrosyl-DNA phosphodiesterases. These findings provide an explanation for the protective effect of hyperthermia from topoisomerase-induced DNA damage and may help to explain the inverse relationship between cancer incidence and temperature. They also pave the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics

High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice.

YesCancer-causing mutations often arise from inappropriate DNA repair, yet acute exposure to DNA damage is widely used to treat cancer. The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in noncancerous cells. One approach is the acute exposure to hyperthermia, which suppresses DNA repair and synergizes with radiotherapy and chemotherapy. An exception, however, is the protective effect of hyperthermia on topoisomerase targeting therapeutics. The molecular explanation for this conundrum remains unclear. Here, we show that hyperthermia suppresses the level of topoisomerase mediated single- and double-strand breaks induced by exposure to topoisomerase poisons. We further uncover that, hyperthermia suppresses hallmarks of genomic instability induced by topoisomerase targeting therapeutics by inhibiting nuclease activities, thereby channeling repair to error-free pathways driven by tyrosyl-DNA phosphodiesterases. These findings provide an explanation for the protective effect of hyperthermia from topoisomerase-induced DNA damage and may help to explain the inverse relationship between cancer incidence and temperature. They also pave the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics

Malleable Penile Implant Is an Effective Therapeutic Option in Men With Peyronie's Disease and Erectile Dysfunction

BACKGROUND: The inflatable penile prosthesis (IPP) is typically the preferred implant for Peyronie's disease (PD) and malleable penile prostheses (MPPs) have been discouraged. Aims: To evaluate the effectiveness and patient satisfaction of the MPP vs IPP in patients with PD. METHODS: Men with PD and erectile dysfunction who elected for penile implant surgery constituted the study population. Preoperatively, demographic and comorbidity parameters were recorded. Curvature was measured with a goniometer at maximum rigidity after intracavernosal injection of a vasoactive agent. Postoperatively, overall satisfaction was measured at 3, 6, 12, and 24 months on 5-point Likert scale from 1 (dissatisfied) to 5 (very satisfied). RESULTS: 166 men with a mean age of 59 ± 10 years were analyzed. The mean preoperative curvature in the entire cohort was 65° (range = 30–130°). 94% of patients with MPP had total resolution of their curvature at the end of the operation, whereas 8 patients (6%) had residual curvature (25–40°). In the IPP group 25 of 30 (83.3%) had a straight penis at the end of surgery, whereas 5 of 30 (16.7%) had residual curvature, with the mean magnitude being 33° in the MPP group and 30° in the IPP group. 86% of all patients had diabetes. There were no differences between the 2 implant groups in age, hemoglobin A1c, body mass index, or smoking status. The mean patient satisfaction was 4.42 ± 0.70 (range = 2–5) and there was no difference between the 2 groups. The mean follow-up period was 23.4 months (range = 6–29 months). CONCLUSION: We found that the MPP is as effective as the IPP in curvature correction in patients with PD, with similar patient satisfaction for the 2 groups. Habous M, Farag M, Tealab A, et al. Malleable Penile Implant Is an Effective Therapeutic Option in Men With Peyronie's Disease and Erectile Dysfunction. Sex Med 2018;6:24–29