Identifying the complete repertoire of genes that drive cancer in individual patients is crucial for precision oncology. Most established methods identify driver genes that are recurrently altered ...across patient cohorts. However, mapping these genes back to patients leaves a sizeable fraction with few or no drivers, hindering our understanding of cancer mechanisms and limiting the choice of therapeutic interventions.
We present sysSVM2, a machine learning software that integrates cancer genetic alterations with gene systems-level properties to predict drivers in individual patients. Using simulated pan-cancer data, we optimise sysSVM2 for application to any cancer type. We benchmark its performance on real cancer data and validate its applicability to a rare cancer type with few known driver genes. We show that drivers predicted by sysSVM2 have a low false-positive rate, are stable and disrupt well-known cancer-related pathways.
sysSVM2 can be used to identify driver alterations in patients lacking sufficient canonical drivers or belonging to rare cancer types for which assembling a large enough cohort is challenging, furthering the goals of precision oncology. As resources for the community, we provide the code to implement sysSVM2 and the pre-trained models in all TCGA cancer types ( https://github.com/ciccalab/sysSVM2 ).
Understanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to ...leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 individuals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4312 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 92 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases.
Despite many systematic reviews and meta-analyses examining the associations of pregnancy complications with risk of type 2 diabetes mellitus (T2DM) and hypertension, previous umbrella reviews have ...only examined a single pregnancy complication. Here we have synthesised evidence from systematic reviews and meta-analyses on the associations of a wide range of pregnancy-related complications with risk of developing T2DM and hypertension.
Medline, Embase and Cochrane Database of Systematic Reviews were searched from inception until 26 September 2022 for systematic reviews and meta-analysis examining the association between pregnancy complications and risk of T2DM and hypertension. Screening of articles, data extraction and quality appraisal (AMSTAR2) were conducted independently by two reviewers using Covidence software. Data were extracted for studies that examined the risk of T2DM and hypertension in pregnant women with the pregnancy complication compared to pregnant women without the pregnancy complication. Summary estimates of each review were presented using tables, forest plots and narrative synthesis and reported following Preferred Reporting Items for Overviews of Reviews (PRIOR) guidelines.
Ten systematic reviews were included. Two pregnancy complications were identified. Gestational diabetes mellitus (GDM): One review showed GDM was associated with a 10-fold higher risk of T2DM at least 1 year after pregnancy (relative risk (RR) 9.51 (95% confidence interval (CI) 7.14 to 12.67) and although the association differed by ethnicity (white: RR 16.28 (95% CI 15.01 to 17.66), non-white: RR 10.38 (95% CI 4.61 to 23.39), mixed: RR 8.31 (95% CI 5.44 to 12.69)), the between subgroups difference were not statistically significant at 5% significance level. Another review showed GDM was associated with higher mean blood pressure at least 3 months postpartum (mean difference in systolic blood pressure: 2.57 (95% CI 1.74 to 3.40) mmHg and mean difference in diastolic blood pressure: 1.89 (95% CI 1.32 to 2.46) mmHg). Hypertensive disorders of pregnancy (HDP): Three reviews showed women with a history of HDP were 3 to 6 times more likely to develop hypertension at least 6 weeks after pregnancy compared to women without HDP (meta-analysis with largest number of studies: odds ratio (OR) 4.33 (3.51 to 5.33)) and one review reported a higher rate of T2DM after HDP (hazard ratio (HR) 2.24 (1.95 to 2.58)) at least a year after pregnancy. One of the three reviews and five other reviews reported women with a history of preeclampsia were 3 to 7 times more likely to develop hypertension at least 6 weeks postpartum (meta-analysis with the largest number of studies: OR 3.90 (3.16 to 4.82) with one of these reviews reporting the association was greatest in women from Asia (Asia: OR 7.54 (95% CI 2.49 to 22.81), Europe: OR 2.19 (95% CI 0.30 to 16.02), North and South America: OR 3.32 (95% CI 1.26 to 8.74)).
GDM and HDP are associated with a greater risk of developing T2DM and hypertension. Common confounders adjusted for across the included studies in the reviews were maternal age, body mass index (BMI), socioeconomic status, smoking status, pre-pregnancy and current BMI, parity, family history of T2DM or cardiovascular disease, ethnicity, and time of delivery. Further research is needed to evaluate the value of embedding these pregnancy complications as part of assessment for future risk of T2DM and chronic hypertension.
is an oral bacterium. Recent studies suggest that
may be involved in human gastric diseases. The mechanisms, however, by which
causes human gastric diseases have not been investigated. Here we ...examined the gastric epithelial pathogenicity of
using a cell culture model. Six
strains and the human gastric epithelial cell line AGS cells were used. IL-8 produced by AGS cells after incubation with
was measured using enzyme-linked immunosorbent assay (ELISA), and AGS cell apoptosis was determined by caspase 3/7 activities. The effects of
on actin arrangement in AGS cells was determined using fluorescence staining. The effects of
on global gene expression in AGS cells was determined by transcriptomic analysis and quantitative real-time PCR (qRT-PCR). The role of the upregulated
gene in gastric cancer survival was assessed using the Kaplan-Meier method.
induced production of IL-8 by AGS cells with strain variation. Significantly increased caspase 3/7 activities were observed in AGS cells incubated with
strains when compared to AGS cells without bacteria.
induced actin re-arrangement in AGS cells.
upregulated 30 genes in AGS cells and the upregulation of
gene was confirmed by qRT-PCR. The Kaplan-Meier analysis showed that upregulation of
gene is associated with worse survival in gastric cancer patients. Our findings suggest that
may play a role in gastric inflammation and the progression of gastric cancer. Further investigation in clinical studies is warranted.
Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. ...However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.
The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study ...aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy.
A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy.
During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57), belonging to an ethnic minority group aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women and smoking or previously smoking aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06). Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy.
The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.
A rise in Ca
2+
i provides the trigger for neurotransmitter release at neuronal boutons. We have used confocal microscopy and Ca
2+ sensitive dyes to directly measure the action potential-evoked Ca
...2+
i in the boutons of Schaffer collaterals. This reveals that the trial-by-trial amplitude of the evoked Ca
2+ transient is bimodally distributed. We demonstrate that “large” Ca
2+ transients occur when presynaptic NMDA receptors are activated following transmitter release. Presynaptic NMDA receptor activation proves critical in producing facilitation of transmission at theta frequencies. Because large Ca
2+ transients “report” transmitter release, their frequency on a trial-by-trial basis can be used to estimate the probability of release, p
r. We use this novel estimator to show that p
r increases following the induction of long-term potentiation.
► NMDA receptors contribute to the AP-evoked Ca
2+ rise at hippocampal boutons ► Presynaptic NMDA receptors are autoreceptors that facilitate transmitter release ► Glutamate photolysis at boutons produces a rapid NMDAR
u current ► Autoreceptor activation “reveals” that p
r increases with the induction of LTP
Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more ...long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland).
Pregnant women aged 15-49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians.
The prevalence of multimorbidity was 44.2% (95% CI 43.7-44.7%), 46.2% (45.6-46.8%) and 19.8% (18.8-20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% 23.8-24.6%, 23.5% 23.0-24.0% and 17.0% 16.0 to 17.9% in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% 30.8-31.8%). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 95% CI 1.04-3.17 45-49 years vs 15-19 years), multigravid (1.68 1.50-1.89 gravidity ≥ five vs one), have raised body mass index (1.59 1.44-1.76, body mass index 30+ vs body mass index 18.5-24.9) and smoked preconception (1.61 1.46-1.77) vs non-smoker).
Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.
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