Chronomodulated Administration of Chemotherapy in Advanced Colorectal Cancer : A Systematic Review and Meta-Analysis

We would like to thank Kirsty Morrison, Senior Information Specialist, Royal College of Surgeons of England Library and Archives Team, for conducting the literature searches. The datasets generated during and/or analysed during the current study are available in the [SoF copy2.xlsx] and [chronomodulation.rm5] at: https://1drv.ms/u/s!AlzdopwEri123kc7F0pt4YnN8drW?e=lylmBq. AN contributed to abstract screening, full-text review, data extraction, analysis, designing, and writing of the manuscript. AA contributed to abstract screening, full-text review, and data extraction. GR contributed to a substantive and major revision of the draft. MB contributed to conceptualisation, resolution of conflicts during abstract screening and full-text review, and major revision of the draft and is the corresponding author. All authors approved the final version prior to submission.Peer reviewedPublisher PD

Dynamics and controls of urban heat sink and island phenomena in a desert city:development of a local climate zone scheme using remotely-sensed inputs

This study aims to determine the dynamics and controls of Surface Urban Heat Sinks (SUHS) and Surface Urban Heat Islands (SUHI) in desert cities, using Dubai as a case study. A Local Climate Zone (LCZ) schema was developed to subdivide the city into different zones based on similarities in land cover and urban geometry. Proximity to the Gulf Coast was also determined for each LCZ. The LCZs were then used to sample seasonal and daily imagery from the MODIS thermal sensor to determine Land Surface Temperature (LST) variations relative to desert sand. Canonical correlation techniques were then applied to determine which factors explained the variability between urban and desert LST. Our results indicate that the daytime SUHS effect is greatest during the summer months (typically ∼3.0 °C) with the strongest cooling effects in open high-rise zones of the city. In contrast, the night-time SUHI effect is greatest during the winter months (typically ∼3.5 °C) with the strongest warming effects in compact mid-rise zones of the city. Proximity to the Arabian Gulf had the largest influence on both SUHS and SUHI phenomena, promoting daytime cooling in the summer months and night-time warming in the winter months. However, other parameters associated with the urban environment such as building height had an influence on daytime cooling, with larger buildings promoting shade and variations in airflow. Likewise, other parameters such as sky view factor contributed to night-time warming, with higher temperatures associated with limited views of the sky

Primary Submucosal Squamous Cell Carcinoma of the Rectum Diagnosed by Endoscopic Ultrasound: Case Report and Literature Review

Primary colorectal squamous cell carcinoma (SCC) is one of the very rare malignancies of the gastrointestinal tract. The diagnosis cannot be made before ruling out other common primary sites. Using the endoscopic ultrasound (EUS) technique to get a tissue biopsy for submucosal tumors has not been demonstrated as the best diagnostic approach in the literature. Surgery is the gold standard treatment with arising evidence of good efficacy following conventional chemoradiation therapy. A 49-year-old male presented with rectal discomfort. Sigmoidoscopy revealed multiple submucosal masses in the rectosigmoid colon. Mucosal biopsies showed nonspecific inflammation. Subsequently, an EUS with fine needle biopsy was done and established the diagnosis of rectal SCC. There were no other primary sites noticed in the extensive evaluation. The patient chose to be treated only with chemoradiation without surgery. At the time of writing this report he had no evidence of recurrence achieving 2.5 years of survival. EUS is an emerging excellent approach to diagnose submucosal colorectal SCC. This case will add supportive evidence of having a complete response following combining treatment with squamous cell directed chemotherapy and external beam radiotherapy without preceded surgery

Vasoactive agents in acute mesenteric ischaemia in critical care. A systematic review

Acknowledgements With thanks to Helen Fulbright, PhD, MA, PGDip LIS, BA (Hons), MCLIP, Information Specialist, Royal College of Surgeons of England Library and Archives Team, for conducting the literature searchesPeer reviewedPublisher PD

Genotypes and serotype distribution of macrolide resistant invasive and non- invasive Streptococcus pneumoniae isolates from Lebanon

<p>Abstract</p> <p>Background</p> <p>This study determined macrolide resistance genotypes in clinical isolates of <it>Streptococcus pneumoniae </it>from multiple medical centers in Lebanon and assessed the serotype distribution in relation to these mechanism(s) of resistance and the source of isolate recovery.</p> <p>Methods</p> <p>Forty four macrolide resistant and 21 macrolide susceptible <it>S. pneumoniae </it>clinical isolates were tested for antimicrobial susceptibility according to CLSI guidelines (2008) and underwent molecular characterization. Serotyping of these isolates was performed by Multiplex PCR-based serotype deduction using CDC protocols. PCR amplification of macrolide resistant <it>erm </it>(encoding methylase) and <it>mef </it>(encoding macrolide efflux pump protein) genes was carried out.</p> <p>Results</p> <p>Among 44 isolates resistant to erythromycin, 35 were resistant to penicillin and 18 to ceftriaxone. Examination of 44 macrolide resistant isolates by PCR showed that 16 isolates harbored the <it>erm</it>(B) gene, 8 isolates harbored the <it>mef </it>gene, and 14 isolates harbored both the <it>erm</it>(B) and <it>mef </it>genes. There was no amplification by PCR of the <it>erm</it>(B) or <it>mef </it>genes in 6 isolates. Seven different capsular serotypes 2, 9V/9A,12F, 14,19A, 19F, and 23, were detected by multiplex PCR serotype deduction in 35 of 44 macrolide resistant isolates, with 19F being the most prevalent serotype. With the exception of serotype 2, all serotypes were invasive. Isolates belonging to the invasive serotypes 14 and 19F harbored both <it>erm</it>(B) and <it>mef </it>genes. Nine of the 44 macrolide resistant isolates were non-serotypable by our protocols.</p> <p>Conclusion</p> <p>Macrolide resistance in <it>S. pneumoniae </it>in Lebanon is mainly through target site modification but is also mediated through efflux pumps, with serotype 19F having dual resistance and being the most prevalent and invasive.</p

Long-term Safety of Epoetin Alfa-epbx for the Treatment of Anemia in ESKD: Pooled Analyses of Randomized and Open-label Studies

Rationale & Objective Epoetin alfa-epbx is a biosimilar to the reference product, epoetin alfa. We compare the safety of epoetin alfa-epbx versus epoetin alfa based on a pooled analysis of findings from 2 randomized, double-blind, comparative clinical studies, and report new data for the long-term safety of epoetin alfa-epbx. Study Design Pooled analyses of previously conducted studies. Setting & Participants Hemodialysis patients with anemia. Interventions Data from patients who received 1 or more subcutaneous or intravenous doses of study drug were integrated across route of administration in combined randomized groups (epoetin alfa-epbx, n = 423; epoetin alfa, n = 426). Data from patients who received 1 or more doses of epoetin alfa-epbx in either open-label extension trial were integrated across route of administration in a combined long-term safety studies group (n = 576). Outcomes Adverse events (AEs), immunogenicity, and other outcomes were assessed. Results Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were similar between combined randomized epoetin alfa-epbx and epoetin alfa, which had mean treatment durations of 18.1 and 17.7 weeks, respectively. Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were 86.5%, 39.4%, and 6.6%, respectively, for the combined long-term safety studies group, which had a mean treatment duration of 40.0 weeks. In total, 12 patients across the combined randomized groups (epoetin alfa-epbx, n = 5; epoetin alfa, n = 7) and 9 patients in the combined long-term safety studies group tested anti-recombinant human erythropoietin antibody positive in 1 or more visits during study conduct. No patient in any group developed neutralizing antibodies or pure red blood cell aplasia. Limitations Epoetin alfa comparator not included in the long-term safety studies, greater cumulative exposure to study drug for epoetin alfa-epbx, shorter follow-up in the randomized studies, and potential for selection bias among patients in the open-label long-term safety studies. Conclusions This analysis reinforces previous conclusions of similar safety profiles between epoetin alfa-epbx and epoetin alfa. Furthermore, epoetin alfa-epbx had no unexpected safety signals during long-term treatment

Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli.

Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9(-/-) mice. Deletion of NaV1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE2, and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9, and there was a rightward shift in stimulus-response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in NaV1.9(-/-) afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9(-/-) mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics

Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.</p> <p>Methods/design</p> <p>We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.</p> <p>Discussion</p> <p>Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.</p

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer