A stereocontrolled total synthesis of the indole diterpenoid natural product paspaline is described. Key steps include a highly diastereoselective enzymatic desymmetrization, substrate-directed ...epoxidation, Ireland-Claisen rearrangement, and diastereotopic group selective C–H acetoxylation to assemble the target with excellent stereofidelity. The route and results described herein outline complementary conceptual disconnections in the arena of steroid natural product synthesis.
An enantioselective synthesis of the indole diterpenoid natural product paspaline is disclosed. Critical to this approach was the implementation of stereoselective desymmetrization reactions to ...assemble key stereocenters of the molecule. The design and execution of these tactics are described in detail, and a thorough analysis of observed outcomes is presented, ultimately providing the title compound in high stereopurity. This synthesis provides a novel template for preparing key stereocenters in this family of molecules, and the reactions developed en route to paspaline present a series of new synthetic disconnections in preparing steroidal natural products.
Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), ...candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1).
Endpoints based on RECISTv1.1 objective response rate (ORR)/progression-free survival (PFS) or irRECIST immune-related ORR (irORR)/immune-related PFS (irPFS) were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 IHC, and by multiplex immunofluorescence for CD8, PD-1, TIM-3, and LAG-3. T-cell activation signatures were assessed by RNA sequencing.
Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR, but immune-related progressive disease (irPD) rate was significantly lower than progressive disease (PD) rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR, but patients with TC PD-L1 ≥1% had longer median irPFS and higher irORR. High percentage of CD8
tumor-infiltrating cells (TIC) that are PD-1
TIM-3
LAG-3
(% CD8
PD-1
TIM-3
LAG-3
TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8
PD-1
TIM-3
LAG-3
TIC identified three groups of patients for which irPFS and irORR were significantly different.
Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared with RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8
TIC may predict outcome on nivolumab in mccRCC.
Medicinal application of many complex natural products is precluded by the impracticality of their chemical synthesis. Pactamycin, the most structurally intricate aminocydopentitol antibiotic, ...displays potent antiproliferative properties across multiple phylogenetic domains, but it is highly cytotoxic. A limited number of analogs produced by genetic engineering technologies show reduced cytotoxicity against mammalian cells, renewing promise for therapeutic applications. For decades, an efficient synthesis of pactamycin amenable to analog derivatizations has eluded researchers. Here, we present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction and symmetry-breaking reduction sequence was designed to enable assembly of the entire carbon core skeleton in under five steps and control critical three-dimensional (stereochemical) functional group relationships. This modular route totals 15 steps and is immediately amenable for structural analog synthesis.
Brian Dickson Sharpe, Robert J; Roach, Kent
Brian Dickson,
2003, 20150201, 2003, 2003-12-15
eBook
"When Brian Dickson was appointed in 1973 to the Supreme Court of Canada, it was largely preoccupied with run-of-the-mill disputes. By the time he retired as chief justice in 1990, the Court had ...become a major national institution, very much in the public eye. The Court's decisions, particularly those concerned with reforming large areas of private and public law under the Charter of Rights and Freedoms, were the subject of intense public interest and concern." "Brian Dickson played a leading role in this transformation. In this biography, Robert Sharpe and Kent Roach trace Dickson's life from a Depression-era boyhood in Saskatchewan, to the battlefields of Normandy, the boardrooms of corporate Canada, and high judicial office during a critical period in the history of the Supreme Court. Dickson played an important part in the evolution of the Canadian judiciary and of Canada itself. Engaging and incisive, Brian Dickson: A Judge's Journey presents a compelling study of one of Canada's greatest legal figures while offering new insights into the work of Canada's highest court."--Jacket.
Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable ...aromatic energies inherent to these building blocks limit the available product types. In this paper, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N-hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso Diels–Alder cycloaddition. The reaction chemistry of the derived 2.2.2-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. The methodology allows for the expeditious synthesis of a functionalized intermediate bearing structural and stereochemical features in common with the complex alkaloid tetrodotoxin.
OBJECTIVE. Healthcare-acquired infections (HAIs) cause substantial patient morbidity and mortality. Items in the environment harbor microorganisms that may contribute to HAIs. Reduction in surface ...bioburden may be an effective strategy to reduce HAIs. The inherent biocidal properties of copper surfaces offer a theoretical advantage to conventional cleaning, as the effect is continuous rather than episodic. We sought to determine whether placement of copper alloy-surfaced objects in an intensive care unit (ICU) reduced the risk of HAI. DESIGN. Intention-to-treat randomized control trial between July 12, 2010, and June 14, 2011. SETTINg. The ICUs of 3 hospitals. PATIENTS. Patients presenting for admission to the ICU. METHODS. Patients were randomly placed in available rooms with or without copper alloy surfaces, and the rates of incident HAI and/or colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) in each type of room were compared. RESULTS. The rate of HAI and/or MRSA or VRE colonization in ICU rooms with copper alloy surfaces was significantly lower than that in standard ICU rooms (0.071 vs 0.123; P = .020). For HAI only, the rate was reduced from 0.081 to 0.034 (P = .013). CONCLUSIONs. Patients cared for in ICU rooms with copper alloy surfaces had a significantly lower rate of incident HAI and/or colonization with MRSA or VRE than did patients treated in standard rooms. Additional studies are needed to determine the clinical effect of copper alloy surfaces in additional patient populations and settings.
Background
Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to ...insulin resistance and is associated with an increased biochemical risk profile for cardiovascular disease and an increased prevalence of diabetes mellitus. Insulin‐sensitising agents such as metformin may be effective in treating PCOS‐related anovulation. This is an update of Morley 2017 and only includes studies on metformin.
Objectives
To evaluate the effectiveness and safety of metformin in combination with or in comparison to clomiphene citrate (CC), letrozole and laparoscopic ovarian drilling (LOD) in improving reproductive outcomes and associated gastrointestinal side effects for women with PCOS undergoing ovulation induction.
Search methods
We searched the following databases from inception to December 2018: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies.
Selection criteria
We included randomised controlled trials of metformin compared with placebo, no treatment, or in combination with or compared with CC, letrozole and LOD for women with PCOS subfertility.
Data collection and analysis
Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes and ovulation. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes and reproductive outcomes using GRADE methodology.
Main results
We included 41 studies (4552 women). Evidence quality ranged from very low to moderate based on GRADE assessment. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency.
Metformin versus placebo or no treatment
The evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51; I2 = 0%; 4 studies, 435 women; low‐quality evidence). For a live birth rate of 19% following placebo, the live birth rate following metformin would be between 19% and 37%. The metformin group probably experiences more gastrointestinal side effects (OR 4.00, 95% CI 2.63 to 6.09; I2 = 39%; 7 studies, 713 women; moderate‐quality evidence). With placebo, the risk of gastrointestinal side effects is 10% whereas with metformin this risk is between 22% and 40%. There are probably higher rates of clinical pregnancy (OR 1.98, 95% CI 1.47 to 2.65; I2 = 30%; 11 studies, 1213 women; moderate‐quality evidence). There may be higher rates of ovulation with metformin (OR 2.64, 95% CI 1.85 to 3.75; I2 = 61%; 13 studies, 684 women; low‐quality evidence). We are uncertain about the effect on miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35; I2 = 0%; 4 studies, 748 women; low‐quality evidence).
Metformin plus CC versus CC alone
We are uncertain if metformin plus CC improves live birth rates compared to CC alone (OR 1.27, 95% CI 0.98 to 1.65; I2 = 28%; 10 studies, 1219 women; low‐quality evidence), but gastrointestinal side effects are probably more common with combined therapy (OR 4.26, 95% CI 2.83 to 6.40; I2 = 8%; 6 studies, 852 women; moderate quality evidence). The live birth rate with CC alone is 24%, which may change to between 23% to 34% with combined therapy. With CC alone, the risk of gastrointestinal side effects is 9%, which increases to between 21% to 37% with combined therapy. The combined therapy group probably has higher rates of clinical pregnancy (OR 1.62, 95% CI 1.32 to 1.99; I2 = 31%; 19 studies, 1790 women; moderate‐quality evidence). The combined group may have higher rates of ovulation (OR 1.65, 95% CI 1.35 to 2.03; I2 = 63%;21 studies, 1568 women; low‐quality evidence). There was no clear evidence of an effect on miscarriage (OR 1.35, 95% CI 0.91 to 2.00; I2 = 0%; 10 studies, 1206 women; low‐quality evidence).
Metformin versus CC
When all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01; I2 = 86%; 5 studies, 741 women; very low‐quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52; 2 studies, 500 women), while the non‐obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94; I2 = 78%, 3 studies, 241 women; very low‐quality evidence). However, due to the very low quality of the evidence we cannot draw any conclusions. Among obese women taking metformin there may be lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55; I2 = 0%; 2 studies, 500 women; low‐quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43; I2 = 0%; 2 studies, 500 women; low‐quality evidence) while among non‐obese women, the metformin group may have more pregnancies (OR 1.56, 95% CI 1.06 to 2.29; I2 = 26%; 6 studies, 530 women; low‐quality evidence) and no clear difference in ovulation rates (OR 0.80, 95% CI 0.52 to 1.25; I2 = 0%; 5 studies, 352 women; low‐quality evidence). We are uncertain whether there is a difference in miscarriage rates between the groups (overall: OR 0.92, 95% CI 0.51 to 1.66; I2 = 36%; 6 studies, 781 women; low‐quality evidence) and no studies reported gastrointestinal side effects.
Authors' conclusions
Our updated review suggests that metformin may be beneficial over placebo for live birth however, more women probably experience gastrointestinal side effects. We are uncertain if metformin plus CC improves live birth rates compared to CC alone, but gastrointestinal side effects are probably increased with combined therapy. When metformin was compared with CC, data for live birth were inconclusive, and the findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. No studies reported gastrointestinal side effects in this comparison. Due to the low quality of the evidence, we are uncertain of the effect of metformin on miscarriage in all three comparisons.
An asymmetric total synthesis of the aminocyclopentitol pactamycin is described. The title compound is delivered in 15 steps from 2,4-pentanedione. Critical to this approach was the exploitation of a ...complex symmetry-breaking reduction strategy to assemble the C1, C2, and C7 relative stereochemistry within the first four steps of the synthesis. Multiple iterations of this reduction strategy are described, and a thorough analysis of stereochemical outcomes is detailed. In the final case, an asymmetric Mannich reaction was developed to install a protected amine directly at the C2 position. Symmetry-breaking reduction of this material gave way to a remarkable series of stereochemical outcomes leading to the title compound without recourse to nonstrategic downstream manipulations. This synthesis is immediately accommodating to the preparation of structural analogs.
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