5-Aza-2'-deoxycytidine (AzaD), also known as Decitabine, is a deoxycytidine analog that is typically used to activate methylated and silenced genes by promoter demethylation. However, a survey of the ...scientific literature indicates that promoter demethylation may not be the only (or, indeed, the major) mechanism by which AzaD affects gene expression. Regulation of gene expression by AzaD can occur in several ways, including some that are independent of DNA demethylation. Results from several studies indicate that the effect of AzaD on gene expression is highly context-dependent and can differ for the same gene under different environmental settings. This may, in part, be due to the nature of the silencing mechanism(s) involved - DNA methylation, repressive histone modifications, or a combination of both. The varied effects of AzaD on such context-dependent regulation of gene expression may underlie some of the diverse responses exhibited by patients undergoing AzaD therapy. In this review, we describe the salient properties of AzaD with particular emphasis on its diverse effects on gene expression, aspects that have barely been discussed in most reviews of this interesting drug.
Background
Complete pathologic response (CPR) after neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer seems associated with improved survival compared to partial or ...no response (NPR). However, previous reports have been limited by small sample size and single-institution design.
Methods
A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR and NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Study end points included rates of CPR, local recurrence (LR), distant recurrence (DR), 5-year overall survival (OS), and disease-free survival (DFS).
Results
Twelve studies (1,913 patients) with rectal cancer treated with CMT were included. CPR was observed in 300 patients (15.6%). CPR and NPR patient groups were similar with respect to age, sex, tumor size, distance of tumor from the anus, and stage of disease before treatment. Median follow-up ranged from 23 to 46 months. CPR patients had lower rates of LR 0.7% vs. 2.6%; odds ratio (OR) 0.45, 95% confidence interval (CI) 0.22–0.90,
P
= 0.03, DR (5.3% vs. 24.1%; OR 0.15, 95% CI 0.07–0.31,
P
= 0.0001), and simultaneous LR + DR (0.7% vs. 4.8%; OR 0.32, 95% CI 0.13–0.79,
P
= 0.01). OS was 92.9% for CPR versus 73.4% for NPR (OR 3.6, 95% CI 1.84–7.22,
P
= 0.002), and DFS was 86.9% versus 63.9% (OR 3.53, 95% CI 1.62–7.72,
P
= 0.002).
Conclusions
CPR after CMT for rectal cancer is associated with improved local and distal control as well as better OS and DFS.
Clefts of the lip and palate are thought to be caused by genetic and environmental insults but the role of epigenetic mechanisms underlying this common birth defect are unknown. We analyzed the ...expression of over 600 microRNAs in the murine medial nasal and maxillary processes isolated on GD10.0–GD11.5 to identify those expressed during development of the upper lip and analyzed spatial expression of a subset. A total of 142 microRNAs were differentially expressed across gestation days 10.0–11.5 in the medial nasal processes, and 66 in the maxillary processes of the first branchial arch with 45 common to both. Of the microRNAs exhibiting the largest percent increase in both facial processes were five members of the Let‐7 family. Among those with the greatest decrease in expression from GD10.0 to GD11.5 were members of the microRNA‐302/367 family that have been implicated in cellular reprogramming. The distribution of expression of microRNA‐199a‐3p and Let‐7i was determined by in situ hybridization and revealed widespread expression in both medial nasal and maxillary facial process, while that for microRNA‐203 was much more limited. MicroRNAs are dynamically expressed in the tissues that form the upper lip and several were identified that target mRNAs known to be important for its development, including those that regulate the two main isoforms of p63 (microRNA‐203 and microRNA‐302/367 family). Integration of these data with corresponding proteomic datasets will lead to a greater appreciation of epigenetic regulation of lip development and provide a better understanding of potential causes of cleft lip.
Acute calculus cholecystitis (ACC) has a high incidence in the general population. The presence of several areas of uncertainty, along with the availability of new evidence, prompted the current ...update of the 2016 WSES (World Society of Emergency Surgery) Guidelines on ACC.
The WSES president appointed four members as a scientific secretariat, four members as an organization committee and four members as a scientific committee, choosing them from the expert affiliates of WSES. Relevant key questions were constructed, and the task force produced drafts of each section based on the best scientific evidence from PubMed and EMBASE Library; recommendations were developed in order to answer these key questions. The quality of evidence and strength of recommendations were reviewed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (see https://www.gradeworkinggroup.org/ ). All the statements were presented, discussed and voted upon during the Consensus Conference at the 6th World Congress of the World Society of Emergency Surgery held in Nijmegen (NL) in May 2019. A revised version of the statements was voted upon via an online questionnaire until consensus was reached.
The pivotal role of surgery is confirmed, including in high-risk patients. When compared with the WSES 2016 guidelines, the role of gallbladder drainage is reduced, despite the considerable technical improvements available. Early laparoscopic cholecystectomy (ELC) should be the standard of care whenever possible, even in subgroups of patients who are considered fragile, such as the elderly; those with cardiac disease, renal disease and cirrhosis; or those who are generally at high risk for surgery. Subtotal cholecystectomy is safe and represents a valuable option in cases of difficult gallbladder removal.
ELC has a central role in the management of patients with ACC. The value of surgical treatment for high-risk patients should lead to a distinction between high-risk patients and patients who are not suitable for surgery. Further evidence on the role of clinical judgement and the use of clinical scores as adjunctive tools to guide treatment of high-risk patients and patients who are not suitable for surgery is required. The development of local policies for safe laparoscopic cholecystectomy is recommended.
Objective
Normal development of the embryonic orofacial region requires precise spatiotemporal coordination between numerous genes. MicroRNAs represent small, single-stranded, non-coding molecules ...that regulate gene expression. This study examines the role of microRNA-22 (miR-22) in murine orofacial ontogeny.
Methods
Spatiotemporal and differential expression of miR-22 (mmu-miR-22-3p) within the developing secondary palate was determined by in situ hybridization and quantitative real-time PCR, respectively. Bioinformatic approaches were used to predict potential mRNA targets of miR-22 and analyze their association with cellular functions indispensable for normal orofacial ontogeny. An in vitro palate organ culture system was used to assess the role of miR-22 in secondary palate development.
Results
There was a progressive increase in miR-22 expression from GD12.5 to GD14.5 in palatal processes. On GD12.5 and GD13.5, miR-22 was expressed in the future oral, nasal, and medial edge epithelia. On GD14.5, miR-22 expression was observed in the residual midline epithelial seam (MES), the nasal epithelium and the mesenchyme, but not in the oral epithelium. Inhibition of miR-22 activity in palate organ cultures resulted in failure of MES removal. Bioinformatic analyses revealed potential mRNA targets of miR-22 that may play significant roles in regulating apoptosis, migration, and/or convergence/extrusion, developmental processes that modulate MES removal during palatogenesis.
Conclusions
Results from the current study suggest a key role for miR-22 in the removal of the MES during palatogenesis and that miR-22 may represent a potential contributor to the etiology of cleft palate.
•We demonstrated that cigarette smoke extract (CSE) reduces global DNA methylation in primary cultures of first branchial arch-derived cells (1-BA cells), which contribute to the formation of the lip ...and palate.•Documented significant CSE-induced alteration of genes encoding two DNMTs and two Methyl CpG-binding proteins (Mbds) in 1-BA cells.•CSE induced degradation of the DNMTs and the MBD proteins in 1-BA cells by the proteasomal pathway.•Proteasomal degradation could be completely rescued by pre-treatment of 1-BA cells with the proteasomal inhibitor, MG-132.•We reported a potential epigenetic molecular mechanism underlying maternal cigarette smoke exposure-induced orofacial clefting.
Orofacial clefts, the most prevalent of developmental anomalies, occur with a frequency of 1 in 700 live births. Maternal cigarette smoking during pregnancy represents a risk factor for having a child with a cleft lip and/or cleft palate. Using primary cultures of first branchial arch-derived cells (1-BA cells), which contribute to the formation of the lip and palate, the present study addressed the hypothesis that components of cigarette smoke alter global DNA methylation, and/or expression of DNA methyltransferases (Dnmts) and various methyl CpG-binding proteins. Primary cultures of 1-BA cells, exposed to 80μg/mL cigarette smoke extract (CSE) for 24h, exhibited a >13% decline in global DNA methylation and triggered proteasomal-mediated degradation of Dnmts (DNMT-1 and -3a), methyl CpG binding protein 2 (MeCP2) and methyl-CpG binding domain protein 3 (MBD-3). Pretreatment of 1-BA cells with the proteasomal inhibitor MG-132 completely reversed such degradation. Collectively, these data allow the suggestion of a potential epigenetic mechanism underlying maternal cigarette smoke exposure-induced orofacial clefting.
Background Laparoscopic adrenalectomies are being performed increasingly, either with transperitoneal or retroperitoneal approaches. Studies comparing the 2 approaches have not shown the superiority ...of either technique, but these studies are limited by small sample sizes and single-institution designs. To overcome these limitations, we performed a meta-analysis of studies comparing lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy. Methods A systematic review of studies comparing lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy was conducted. Study endpoints included perioperative outcomes and measures of postoperative recovery. Meta-analysis was performed using a random effects model, pooling variables evaluated by more than 3 studies. Results Twenty-one studies comparing a total of 1,205 lateral transperitoneal adrenalectomies and 688 retroperitoneal adrenalectomies were suitable for meta-analysis. Patients in the 2 groups were similar in term of age, sex, body mass index, lesion size and location, and rates of malignancy. There were no statistically significant differences between lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy in terms of operative time, blood loss, hospital stay, time to oral intake, overall and major morbidity, and mortality. Conclusion Both lateral transperitoneal adrenalectomy and retroperitoneal adrenalectomy are associated with very low rates of perioperative complications. According to our meta-analysis, clinical outcomes after either technique are similar. For most adrenal lesions requiring operation, minimally invasive adrenalectomy can be performed safely and effectively with either transperitoneal or the retroperitoneal approach. Additional studies may be needed to analyze if any difference in long-term results exist.
Background
The current literature suggests that minimally invasive distal pancreatectomy (MIDP) is associated with faster recovery and less morbidity than open surgery. However, most studies have ...been limited by a small sample size and a single-institution design. To overcome this problem, the first metaanalysis of studies comparing MIDP and open distal pancreatectomy (ODP) has been performed.
Methods
A systematic literature review was conducted to identify studies comparing MIDP and ODP. Perioperative outcomes (e.g., morbidity and mortality, pancreatic fistula rates, blood loss) constituted the study end points. Metaanalyses were performed using a random-effects model.
Results
For the metaanalysis, 10 studies including 349 patients undergoing MIDP and 380 patients undergoing ODP were considered suitable. The patients in the two groups were similar with respect to age, body mass index (BMI), American Society of Anesthesiology (ASA) classification, and indication for surgery. The rate of conversion from full laparoscopy to hand-assisted procedure was 37%, and that from minimally invasive to open procedure was 11%. Patients undergoing MIDP had less blood loss, a shorter time to oral intake, and a shorter postoperative hospital stay. The mortality and reoperative rates did not differ between MIDP and ODP. The MIDP approach had fewer overall complications odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27–0.89, major complications (OR, 0.57; 95% CI, 0.34–0.96), surgical-site infections (OR, 0.32; 95% CI, 0.19–0.53), and pancreatic fistulas (OR, 0.68; 95% CI, 0.47–0.98).
Conclusions
The MIDP procedure is feasible, safe, and associated with less blood loss and overall complications, shorter time to oral intake, and shorter postoperative hospital stay. Furthermore, the minimally invasive approach reduces the rate of pancreatic leaks and surgical-site infections after ODP.
Robotics represents the most technologically advanced approach in minimally invasive surgery (MIS). Its application in general surgery has increased progressively, with some early experience reported ...in emergency settings. The present position paper, supported by the World Society of Emergency Surgery (WSES), aims to provide a systematic review of the literature to develop consensus statements about the potential use of robotics in emergency general surgery.
This position paper was conducted according to the WSES methodology. A steering committee was constituted to draft the position paper according to the literature review. An international expert panel then critically revised the manuscript. Each statement was voted through a web survey to reach a consensus.
Ten studies (3 case reports, 3 case series, and 4 retrospective comparative cohort studies) have been published regarding the applications of robotics for emergency general surgery procedures. Due to the paucity and overall low quality of evidence, 6 statements are proposed as expert opinions. In general, the experts claim for a strict patient selection while approaching emergent general surgery procedures with robotics, eventually considering it for hemodynamically stable patients only. An emergency setting should not be seen as an absolute contraindication for robotic surgery if an adequate training of the operating surgical team is available. In such conditions, robotic surgery can be considered safe, feasible, and associated with surgical outcomes related to an MIS approach. However, there are some concerns regarding the adoption of robotic surgery for emergency surgeries associated with the following: (i) the availability and accessibility of the robotic platform for emergency units and during night shifts, (ii) expected longer operative times, and (iii) increased costs. Further research is necessary to investigate the role of robotic surgery in emergency settings and to explore the possibility of performing telementoring and telesurgery, which are particularly valuable in emergency situations.
Many hospitals are currently equipped with a robotic surgical platform which needs to be implemented efficiently. The role of robotic surgery for emergency procedures remains under investigation. However, its use is expanding with a careful assessment of costs and timeliness of operations. The proposed statements should be seen as a preliminary guide for the surgical community stressing the need for reevaluation and update processes as evidence expands in the relevant literature.
MicroRNAs as Biomarkers for Birth Defects Seelan, Ratnam S; Pisano, M Michele; Greene, Robert M
MicroRNA (Shariqah, United Arab Emirates),
01/2022, Volume:
11, Issue:
1
Journal Article
Peer reviewed
It is estimated that 2-4% of live births will have a birth defect (BD). The availability of biomarkers for the prenatal detection of BDs will facilitate early risk assessment, prompt medical ...intervention and ameliorating disease severity. miRNA expression levels are often found to be altered in many diseases. There is, thus, a growing interest in determining whether miRNAs, particularly extracellular miRNAs, can predict, diagnose, or monitor BDs. These miRNAs, typically encapsulated in exosomes, are released by cells (including those of the fetus and placenta) into the extracellular milieu, such as blood, urine, saliva and cerebrospinal fluid, thereby enabling interaction with target cells. Exosomal miRNAs are stable, protected from degradation, and retain functionality. The observation that placental and fetal miRNAs can be detected in maternal serum, provides a strong rationale for adopting miRNAs as noninvasive prenatal biomarkers for BDs. In this mini-review, we examine the current state of research involving the use of miRNAs as prognostic and diagnostic biomarkers for BD.
PDF
