Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, ...small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
ABSTRACT
We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation‐carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer ...(EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%–50%) and 47% (36%–60%) for male carriers and 36% (25%–51%) and 37% (27%–50%) for female carriers. Corresponding EC risks were 18% (9.1%–34%) and 30% (18%–45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U‐shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%–10% and 18% have risks of 90%–100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.
Our estimates of colorectal and endometrial cancer risks for MLH1 and MSH2 mutation carriers are the most precise currently available. Average risks are similar for the two genes but there is so much individual variation about the average that a sizeable proportion of carries are almost certain to develop cancer whereas another sizeable proportion only have population‐level risks.
Air parcels with mixing ratios of high O3 and low H2O (HOLW) are common features in the tropical western Pacific (TWP) mid-troposphere (300-700 hPa). Here, using data collected during aircraft ...sampling of the TWP in winter 2014, we find strong, positive correlations of O3 with multiple biomass burning tracers in these HOLW structures. Ozone levels in these structures are about a factor of three larger than background. Models, satellite data and aircraft observations are used to show fires in tropical Africa and Southeast Asia are the dominant source of high O3 and that low H2O results from large-scale descent within the tropical troposphere. Previous explanations that attribute HOLW structures to transport from the stratosphere or mid-latitude troposphere are inconsistent with our observations. This study suggest a larger role for biomass burning in the radiative forcing of climate in the remote TWP than is commonly appreciated.
Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair gene mutation (Lynch syndrome).
To investigate the association ...between hormonal factors and endometrial cancer risk in Lynch syndrome.
A retrospective cohort study included 1128 women with a mismatch repair gene mutation identified from the Colon Cancer Family Registry. Data were analyzed with a weighted cohort approach. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand.
Age at menarche, first and last live birth, and menopause; number of live births; hormonal contraceptive use; and postmenopausal hormone use.
Self-reported diagnosis of endometrial cancer.
Endometrial cancer was diagnosed in 133 women (incidence rate per 100 person-years, 0.29; 95% CI, 0.24 to 0.34). Endometrial cancer was diagnosed in 11% (n = 70) of women with age at menarche greater than or equal to 13 years compared with 12.6% (n = 57) of women with age at menarche less than 13 years (incidence rate per 100 person-years, 0.27 vs 0.31; rate difference, -0.04 95% CI, -0.15 to 0.05; hazard ratio per year, 0.85 95% CI, 0.73 to 0.99; P = .04). Endometrial cancer was diagnosed in 10.8% (n = 88) of parous women compared with 14.4% (n = 40) of nulliparous women (incidence rate per 100 person-years, 0.25 vs 0.43; rate difference, -0.18 95% CI, -0.32 to -0.04; hazard ratio, 0.21 95% CI, 0.10 to 0.42; P < .001). Endometrial cancer was diagnosed in 8.7% (n = 70) of women who used hormonal contraceptives greater than or equal to 1 year compared with 19.2% (n = 57) of women who used contraceptives less than 1 year (incidence rate per 100 person-years, 0.22 vs 0.45; rate difference, -0.23 95% CI, -0.36 to -0.11; hazard ratio, 0.39 95% CI, 0.23 to 0.64; P < .001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use.
For women with a mismatch repair gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a mismatch repair gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.
DEPendency of association on the number of Top Hits (DEPTH) is an approach to identify candidate susceptibility regions by considering the risk signals from overlapping groups of sequential variants ...across the genome.
We applied a DEPTH analysis using a sliding window of 200 SNPs to colorectal cancer data from the Colon Cancer Family Registry (CCFR; 5,735 cases and 3,688 controls), and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO; 8,865 cases and 10,285 controls) studies. A DEPTH score > 1 was used to identify candidate susceptibility regions common to both analyses. We compared DEPTH results against those from conventional genome-wide association study (GWAS) analyses of these two studies as well as against 132 published susceptibility regions.
Initial DEPTH analysis revealed 2,622 (CCFR) and 3,686 (GECCO) candidate susceptibility regions, of which 569 were common to both studies. Bootstrapping revealed 40 and 49 candidate susceptibility regions in the CCFR and GECCO data sets, respectively. Notably, DEPTH identified at least 82 regions that would not be detected using conventional GWAS methods, nor had they been identified by previous colorectal cancer GWASs. We found four reproducible candidate susceptibility regions (2q22.2, 2q33.1, 6p21.32, 13q14.3). The highest DEPTH scores were in the human leukocyte antigen locus at 6p21 where the strongest associated SNPs were rs762216297, rs149490268, rs114741460, and rs199707618 for the CCFR data, and rs9270761 for the GECCO data.
DEPTH can identify candidate susceptibility regions for colorectal cancer not identified using conventional analyses of larger datasets.
DEPTH has potential as a powerful complementary tool to conventional GWAS analyses for discovering susceptibility regions within the genome.
Atmospheric circulation in a Snowball Earth is critical for determining cloud behavior, heat export from the tropics, regions of bare ice, and sea glacier flow. These processes strongly affect ...Snowball Earth deglaciation and the ability of oases to support photosynthetic marine life throughout a Snowball Earth. Here we establish robust aspects of the Snowball Earth atmospheric circulation by running six general circulation models with consistent Snowball Earth boundary conditions. The models produce qualitatively similar patterns of atmospheric circulation and precipitation minus evaporation. The strength of the Snowball Hadley circulation is roughly double modern at low CO2 and greatly increases as CO2 is increased. We force a 1‒D axisymmetric sea glacier model with general circulation model (GCM) output and show that, neglecting zonal asymmetry, sea glaciers would limit ice thickness variations to O(10%). Global mean ice thickness in the 1‒D sea glacier model is well‒approximated by a 0‒D ice thickness model with global mean surface temperature as the upper boundary condition. We then show that a thin‒ice Snowball solution is possible in the axysymmetric sea glacier model when forced by output from all the GCMs if we use ice optical properties that favor the thin‒ice solution. Finally, we examine Snowball oases for life using analytical models forced by the GCM output and find that conditions become more favorable for oases as the Snowball warms, so that the most critical time for the survival of life would be near the beginning of a Snowball Earth episode.
Key Points
Snowball Hadley cell is stronger than modern and increases with CO2 in six GCMs
GCMs produce a similar Snowball P-E pattern with net ablation in the tropics
Sea glacier thickness variations and oases are more favorable as Snowball ages
To survey urologists and family medicine physicians (FMPs) within a single institution to determine current vasectomy practice patterns and determine compliance with 2012 American Urological ...Association (AUA) vasectomy guidelines.
In 2016, a single-institution survey was conducted to understand the vasectomy practice patterns among urologists and nonurologists. The survey questions and 3 clinical scenarios were designed based on the 2012 AUA vasectomy guidelines. Results of the survey were compiled between urologists and nonurologists and then compared with the guideline recommendations.
A total of 23 FMPs and 6 urologists responded. Fewer prevasectomy counseling topics were discussed by FMPs compared with urologists. A variety of vasectomy techniques were used among FMPs. Vas deferens segments were more likely to be sent for histology by FMPs than urologists (65% vs 17%, P = .02). FMPs were more likely to send postvasectomy semen analyses earlier than urologists (P = .02) and more likely to send multiple postvasectomy semen analyses (P = .006) before forgoing alternative contraceptive methods. Regarding the clinical scenario questions, FMPs were more likely to answer discordantly from guideline recommendations compared with urologists.
Significant vasectomy practice pattern heterogeneity still exists among nonurologists surveyed within our institution. The 2012 AUA vasectomy guidelines have yet to be broadly implemented within nonurology practices. Further studies are warranted to investigate national trends in nonurologist vasectomy practice patterns and determine how the guidelines can be better implemented in nonurologic practices.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder in humans which results in the loss of motor neurons. It is caused by reduced levels of the survival motor neuron (SMN) protein as a ...result of loss or mutation of the SMN1 gene. SMN is encoded by two genes, SMN1 and SMN2, which essentially differ by a single nucleotide in exon 7. As a result, the majority of the transcript from SMN2 lacks exon 7 (SMNΔ7). SMNΔ7 may be toxic and detrimental in SMA, which, if true, could lead to adverse effects with drugs that stimulate expression of SMN2. To determine the role of SMNΔ7 in SMA, we created transgenic mice expressing SMNΔ7 and crossed them onto a severe SMA background. We found that the SMNΔ7 is not detrimental in that it extends survival of SMA mice from 5.2 to 13.3 days. Unlike mice with selective deletion of SMN exon 7 in muscle, these mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. This indicates that low levels of FL-SMN as found in SMA patients and absence of FL-SMN in muscle tissue have different effects and raises the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMNΔ7 can associate with each other and we suggest that this association stabilizes SMNΔ7 protein turnover and ameliorates the SMA phenotype by increasing the amount of oligomeric SMN. The increased survival of the SMNΔ7 SMA mice we report will facilitate testing of therapies and indicates the importance of considering co-complexes of SMN and SMNΔ7 when analyzing SMN function.
Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between ...BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors.
This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models.
In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m(2); HR, 1.10; 95% CI, 1.06-1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSI-high and obese BMI (HR, 1.00; P value: 0.98).
High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype.
High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors.
PDF
