The metal catalyzed reactions of diazo compounds have been broadly used in organic synthesis. The resulting metal-carbenoid intermediates are capable of undergoing a range of unconventional ...reactions, and due to their high energy, they are ideal for initiating cascade sequences leading to the rapid generation of structural complexity. This tutorial review will give an overview of the most versatile reactions of donor/acceptor carbenoids, an exciting class of intermediates capable of highly selective reactions. This will include cyclopropanation, 4 + 3 cycloaddition, and C-H functionalization methodologies. The application of this chemistry to the synthesis of a range of natural products will be described.
Background
Although several non-randomized studies comparing robotic pancreaticoduodenectomy (RPD) and open pancreaticoduodenectomy (OPD) recently demonstrated that the two operative techniques could ...be equivalent in terms of safety outcomes and short-term oncologic efficacy, no definitive answer has arrived yet to the question as to whether robotic assistance can contribute to reducing the high rate of postoperative morbidity.
Methods
Systematic literature search was performed using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE databases. Prospective and retrospective studies comparing RPD and OPD as surgical treatment for periampullary benign and malignant lesions were included in the systematic review and meta-analysis with no limits of language or year of publication.
Results
18 non-randomized studies were included for quantitative synthesis with 13,639 patients allocated to RPD (
n
= 1593) or OPD (
n
= 12,046). RPD and OPD showed equivalent results in terms of mortality (3.3% vs 2.8%;
P
= 0.84), morbidity (64.4% vs 68.1%;
P
= 0.12), pancreatic fistula (17.9% vs 15.9%;
P
= 0.81), delayed gastric emptying (16.8% vs 16.1%;
P
= 0.98), hemorrhage (11% vs 14.6%;
P
= 0.43), and bile leak (5.1% vs 3.5%;
P
= 0.35). Estimated intra-operative blood loss was significantly lower in the RPD group (352.1 ± 174.1 vs 588.4 ± 219.4;
P
= 0.0003), whereas operative time was significantly longer for RPD compared to OPD (461.1 ± 84 vs 384.2 ± 73.8;
P
= 0.0004). RPD and OPD showed equivalent results in terms of retrieved lymph nodes (19.1 ± 9.9 vs 17.3 ± 9.9;
P
= 0.22) and positive margin status (13.3% vs 16.1%;
P
= 0.32).
Conclusions
RPD is safe and feasible as surgical treatment for malignant or benign disease of the pancreatic head and the periampullary region. Equivalency in terms of surgical radicality including R0 curative resection and number of harvested lymph nodes between the two groups confirmed the reliability of RPD from an oncologic point of view.
IMPORTANCE: Intra-aortic balloon pump (IABP) therapy is a widely used intervention for acute myocardial infarction with cardiogenic shock. Guidelines, which previously strongly recommended it, have ...recently undergone substantial change. OBJECTIVE: To assess IABP efficacy in acute myocardial infarction. DATA SOURCES: Human studies found in Pubmed, Embase, and Cochrane libraries through December 2014 and in reference lists of selected articles. Search strings were “myocardial infarction” or “acute coronary syndrome” and “intra-aortic balloon pump” or “counterpulsation.” STUDY SELECTION: Randomized clinical trials (RCTs) and observational studies comparing use of IABP with no IABP in patients with acute myocardial infarction. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted the data, and risk of bias in RCTs was assessed using the Cochrane risk of bias tool. We conducted separate meta-analyses of the RCTs and observational studies. Data were quantitatively synthesized using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Thirty-day mortality. RESULTS: There were 12 eligible RCTs randomizing 2123 patients. In the RCTs, IABP use had no statistically significant effect on mortality (odds ratio OR, 0.96 95% CI, 0.74-1.24), with no significant heterogeneity among trials (I2 = 0%; P = .52). This result was consistent when studies were stratified by the presence (OR, 0.94 95% CI, 0.69-1.28; P = .69, I2 = 0%) or absence (OR, 0.98 95% CI, 0.57-1.69; P = .95, I2 = 17%) of cardiogenic shock. There were 15 eligible observational studies totaling 15 530 patients. Their results were mutually conflicting (heterogeneity I2 = 97%; P < .001), causing wide uncertainty in the summary estimate for the association with mortality (OR, 0.96 95% CI, 0.54-1.70). A simple index of baseline risk marker imbalance in the observational studies appeared to explain much of the heterogeneity in the observational data (R2meta = 46.2%; P < .001). CONCLUSIONS AND RELEVANCE: Use of IABP was not found to improve mortality among patients with acute myocardial infarction in the RCTs, regardless of whether patients had cardiogenic shock. The observational studies showed a variety of mutually contradictory associations between IABP therapy and mortality, much of which was explained by the differences between studies in the balance of risk factors between IABP and non-IABP groups.
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in ...inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
Mining for novel antibiotics Randall, Justin R; Davies, Bryan W
Current opinion in microbiology,
10/2021, Letnik:
63
Journal Article
Recenzirano
Odprti dostop
•Exploration of new microbial habitats provides opportunity for antibiotic discovery.•Computational approaches advance detection of hidden antibiotic sources.•Large datasets provide opportunity for ...in silico antibiotic development.•Antibody-based approaches expand options to fight bacterial infection.
Colorectal cancer is common. As many patients present with advanced disease, an effective screening test would have substantial clinical benefits. Recent progress in understanding the biology of ...colorectal cancer (and of cancer cells in general) has led to possible new approaches to screening. In particular, there are prospects of developing tests based on analysis of stool, which promise improved accuracy, safety, affordability and patient compliance.
The total synthesis of (−)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed 4 + 3 cycloaddition between a vinylcarbenoid and a diene to rapidly ...generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The 4 + 3 cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh2(S-PTAD)4.
Purpose
There is no consensus in the literature regarding the association between operative blood loss and postoperative outcomes in colorectal surgery, despite evidence suggesting a link. Therefore, ...this systematic review assesses the association between operative blood loss, perioperative and long-term outcomes after colorectal surgery.
Methods
A literature search of MEDLINE, EMBASE, Science Citation Index Expanded and Cochrane was performed to identify studies reporting on operative blood loss in colorectal surgery.
Results
The review included forty-nine studies reporting on 61,312 participants, with a mean age ranging from 53.4 to 78.1 years. The included studies demonstrated that major operative blood loss was found to be a risk factor for mortality, anastomotic leak, presacral abscess, and postoperative ileus, leading to an increased duration of hospital stay. In the long term, the studies suggest that significant blood loss was an independent risk factor for future small bowel obstruction due to colorectal cancer recurrence and adhesions. Studies found that survival was significantly reduced, whilst the risk of colorectal cancer recurrence was increased. Reoperation and cancer-specific survival were not associated with major blood loss.
Conclusion
The results of this systematic review suggest that major operative blood loss increases the risk of perioperative adverse events and has short and long-term repercussions on postoperative outcomes. Laparoscopic and robotic surgery, vessel ligation technology and anaesthetic considerations are essential for reducing blood loss and improving outcomes. This review highlights the need for further high quality, prospective, multicentre trials with a greater number of participants, and accurate and standardised methods of measuring operative blood loss.
Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to ...addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.
PDF
![Asymmetric [4 + 3] Cycloadd...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0002-7863_1943-2984_1520-5126/small "Asymmetric [4 + 3] Cycloadditions between Vinylcarbenoids and Dienes: Application to the Total Synthesis of the Natural Product (−)-5-epi-Vibsanin E")
