Housekeeping genes (HKG) are constitutively expressed in all tissues while tissue-enriched genes (TEG) are expressed at a much higher level in a single tissue type than in others. HKGs serve as ...valuable experimental controls in gene and protein expression experiments, while TEGs tend to represent distinct physiological processes and are frequently candidates for biomarkers or drug targets. The genomic features of these two groups of genes expressed in opposing patterns may shed light on the mechanisms by which cells maintain basic and tissue-specific functions.
Here, we generate gene expression profiles of 42 normal human tissues on custom high-density microarrays to systematically identify 1,522 HKGs and 975 TEGs and compile a small subset of 20 housekeeping genes which are highly expressed in all tissues with lower variance than many commonly used HKGs. Cross-species comparison shows that both the functions and expression patterns of HKGs are conserved. TEGs are enriched with respect to both segmental duplication and copy number variation, while no such enrichment is observed for HKGs, suggesting the high expression of HKGs are not due to high copy numbers. Analysis of genomic and epigenetic features of HKGs and TEGs reveals that the high expression of HKGs across different tissues is associated with decreased nucleosome occupancy at the transcription start site as indicated by enhanced DNase hypersensitivity. Additionally, we systematically and quantitatively demonstrated that the CpG islands' enrichment in HKGs transcription start sites (TSS) and their depletion in TEGs TSS. Histone methylation patterns differ significantly between HKGs and TEGs, suggesting that methylation contributes to the differential expression patterns as well.
We have compiled a set of high quality HKGs that should provide higher and more consistent expression when used as references in laboratory experiments than currently used HKGs. The comparison of genomic features between HKGs and TEGs shows that HKGs are more conserved than TEGs in terms of functions, expression pattern and polymorphisms. In addition, our results identify chromatin structure and epigenetic features of HKGs and TEGs that are likely to play an important role in regulating their strikingly different expression patterns.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The human papillomavirus (HPV) vaccine was introduced into Thailand's national immunization program in 2017 for 11-12 year old school girls. The objectives of this study were to examine the ...epidemiological consequences and cost-effectiveness of a routine quadrivalent HPV (4vHPV) vaccination and the routine 4vHPV vaccination plus 5-year catch-up vaccination by comparing with cervical cancer screening only (no vaccination) in Thailand.
A transmission dynamic model was used to assess the cost-effectiveness of the routine 4vHPV vaccination and the routine 4vHPV vaccination plus catch-up vaccination, compared with no vaccination (screening only) in Thai population. The vaccination coverage rate assumptions were 95% in 11-12-year-old girls for the routine vaccination and 70% in 13-24 year-old females for the 5-year catch-up vaccination. Vaccination costs, direct medical costs of HPV-related diseases, and the number of quality of life years (QALYs) gained were calculated for over a 100-year time horizon with discount rate of 3%.
The model indicated that the routine 4vHPV vaccination and the routine plus catch-up 4vHPV vaccination strategies could prevent approximately 434,130 and 472,502 cumulative cases of cervical cancer, 182,234 and 199,068 cumulative deaths from cervical cancer and 12,708,349 and 13,641,398 cumulative cases of HPV 6/11 related genital warts, respectively, when compared with no vaccination over 100 years. The estimated cost per QALY gained (ICER) when compared to no vaccination in Thailand was 8,370 THB/QALY for the routine vaccination and 9,650 THB/QALY for the routine with catch-up vaccination strategy.
Considering the recommended threshold of 160,000 THB/QALY for Thailand, the implementation of the routine 4vHPV vaccination either alone or plus the catch-up vaccination was cost-effective as compared to the cervical cancer screening only.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or ...other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0-0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.
Background
Health‐related quality of life (HRQoL) is an important outcome measure and prognostic indicator in hepatocellular carcinoma (HCC). KEYNOTE‐240 (NCT02702401) assessed the efficacy and ...safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with HCC who previously received sorafenib. This study presents the results of a prespecified exploratory analysis of patient‐reported outcomes.
Methods
Patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ‐C30) and its HCC supplement (EORTC QLQ‐HCC18) electronically at baseline; at weeks 2, 3, 4, 6, 9, 12, and 18; and then every 9 weeks until 1 year or end of treatment, and at the 30‐day safety follow‐up visit.
Results
The HRQoL population included 271 and 127 patients randomly assigned to pembrolizumab and placebo, respectively. From baseline to week 12, changes in both scores were similar between pembrolizumab and placebo; global health status/QoL scores were stable. The proportions of patients who improved, remained stable, or deteriorated across all functional domain and symptom scores were generally similar between pembrolizumab and placebo. Time to deterioration was similar between the 2 arms based on the prespecified analysis of EORTC QLQ‐HCC18 domains of abdominal swelling, fatigue, and pain.
Conclusion
Pembrolizumab preserved HRQoL during treatment for advanced HCC. Combined with efficacy and safety results from KEYNOTE‐240, these findings support a positive benefit/risk profile for pembrolizumab in a second‐line treatment setting for patients with HCC who previously received sorafenib.
Pembrolizumab preserves health‐related quality of life during treatment in patients with advanced hepatocellular carcinoma (HCC) who had progression during or after or were intolerant to sorafenib. The results of this prespecified exploratory analysis combined with efficacy and safety data from KEYNOTE‐240 support a favorable risk–benefit profile for pembrolizumab in a second‐line treatment setting for patients with HCC who previously received sorafenib.
Alternative pre-messenger RNA splicing influences development, physiology and disease, but its regulation in humans is not well understood, partially because of the limited scale at which the ...expression of specific splicing events has been measured. We generated the first genome-scale expression compendium of human alternative splicing events using custom whole-transcript microarrays monitoring expression of 24,426 alternative splicing events in 48 diverse human samples. Over 11,700 genes and 9,500 splicing events were differentially expressed, providing a rich resource for studying splicing regulation. An unbiased, systematic screen of 21,760 4-mer to 7-mer words for cis-regulatory motifs identified 143 RNA 'words' enriched near regulated cassette exons, including six clusters of motifs represented by UCUCU, UGCAUG, UGCU, UGUGU, UUUU and AGGG, which map to trans-acting regulators PTB, Fox, Muscleblind, CELF/CUG-BP, TIA-1 and hnRNP F/H, respectively. Each cluster showed a distinct pattern of genomic location and tissue specificity. For example, UCUCU occurs 110 to 35 nucleotides preceding cassette exons upregulated in brain and striated muscle but depleted in other tissues. UCUCU and UGCAUG seem to have similar function but independent action, occurring 5' and 3', respectively, of 33% of the cassette exons upregulated in skeletal muscle but co-occurring for only 2%.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Purpose We sought to establish which human papillomavirus (HPV) vaccine communication approaches by pediatricians were associated with same-day HPV vaccination of 11- to 12-year-olds by ...evaluating audio recordings of visits. Methods Verilogue, a market research company maintaining a panel of primary care pediatricians, provided audio recordings and transcriptions of well-child visits for 11- to 12-year-old patients from January through June 2013. Seventy-five transcripts from 19 pediatricians were coded for use of presumptive language (i.e., words conveying assumption of vaccine delivery), offer of delay, recommendation strength, and information provision. Using logistic regression, we evaluated the association between pediatrician communication approaches and agreement to same-day HPV vaccination. Generalized estimating equations accounted for clustering of patients within pediatricians. Results Same-day agreement to HPV vaccination occurred in 29% of encounters. Pediatricians in the sample often provided parents with inconsistent, mixed messages and sometimes offered information about HPV or HPV vaccination that was inaccurate. Pediatricians used presumptive language in only 11 of 75 encounters; when used, presumptive language was associated with higher odds of accepting HPV vaccine (73% vs. 22%; odds ratio = 8.96; 95% confidence interval = 2.32–34.70). Pediatricians offered or recommended delay in most encounters (65%). HPV vaccine acceptance occurred far more often when pediatricians did not mention delaying vaccination (82% vs. 6%; odds ratio = 80.84; 95% confidence interval = 15.72–415.67). Same-day vaccination was not associated with strength of recommendation or pediatrician reference to vaccinating their own children. Conclusions Our findings highlight the need to develop and evaluate physician-focused trainings on using presumptive language for same-day HPV vaccination.
H-1 parvovirus (H-1PV) is a promising anticancer therapy. However, in-depth understanding of its life cycle, including the host cell factors needed for infectivity and oncolysis, is lacking. This ...understanding may guide the rational design of combination strategies, aid development of more effective viruses, and help identify biomarkers of susceptibility to H-1PV treatment. To identify the host cell factors involved, we carry out siRNA library screening using a druggable genome library. We identify one crucial modulator of H-1PV infection: laminin γ1 (LAMC1). Using loss- and gain-of-function studies, competition experiments, and ELISA, we validate LAMC1 and laminin family members as being essential to H-1PV cell attachment and entry. H-1PV binding to laminins is dependent on their sialic acid moieties and is inhibited by heparin. We show that laminins are differentially expressed in various tumour entities, including glioblastoma. We confirm the expression pattern of laminin γ1 in glioblastoma biopsies by immunohistochemistry. We also provide evidence of a direct correlation between LAMC1 expression levels and H-1PV oncolytic activity in 59 cancer cell lines and in 3D organotypic spheroid cultures with different sensitivities to H-1PV infection. These results support the idea that tumours with elevated levels of γ1 containing laminins are more susceptible to H-1PV-based therapies.
In the phase III KEYNOTE-181 study (NCT02564263) of patients with advanced esophageal cancer (EC), pembrolizumab monotherapy prolonged overall survival versus chemotherapy as second-line therapy in ...patients with programmed death ligand 1 combined positive score (CPS) ≥ 10. We present the results of the prespecified health-related quality-of-life (HRQoL) analyses of the squamous cell carcinoma (SCC), CPS ≥ 10, and CPS ≥ 10 SCC populations.
HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC questionnaire (OES18), and EuroQol 5-dimension questionnaire (EQ-5D). Data were analyzed in patients who received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 9 least squares mean change in global health status/quality of life, functional or symptom subscales, and time to deterioration (≥ 10-point deterioration) for specific subscales.
The HRQoL population included 387 patients with SCC. Compliance and completion rates for all three questionnaires were similar in both treatment groups at baseline and week 9. No clinically meaningful differences in global health status/quality of life scores were observed between treatment groups from baseline to week 9 (least squares mean difference, 2.80; 95% CI, -1.48 to 7.08); patients in both treatment groups generally exhibited stable functioning and symptom scores of the QLQ-C30 and QLQ-OES18 from baseline to week 9. Time to deterioration for pain (hazard ratio HR, 1.22; 95% CI, 0.79 to 1.89), reflux (HR, 2.38; 95% CI, 1.33 to 4.25), and dysphagia (HR, 1.53; 95% CI, 1.02 to 2.31) subscales were similar between treatment groups. These findings were generally similar in the CPS ≥ 10 (n = 218) and CPS ≥ 10 SCC (n = 166) subgroups.
In patients with advanced EC, pembrolizumab monotherapy and chemotherapy maintained HRQoL in patients with SCC, CPS ≥ 10, and CPS ≥ 10 SCC.
This study aims to demonstrate the real-world experience of integrating multi-location high-granularity synchrophasor measurements and various data analysis techniques to perform disturbance analysis ...and enhance the situational awareness of a power grid. It describes the utilisation of box plots, correlation techniques, and clustering techniques. These are applied to synchrophasor measurements obtained from 400 kV substations of the Maharashtra State Electricity Transmission Company Limited in the western part of the Indian grid to elucidate the behaviour of the grid under ambient and disturbance/event conditions. The results illustrate how correlation technique can serve as important decision-making tool for system operators in managing the grid. The application of various clustering techniques (such as k-means clustering, hierarchical clustering, and partitioning around medoids) to synchrophasor data to determine the number of clusters formed is also discussed. Internal validation techniques are applied to verify the effectiveness of the clustering algorithms.
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Background
We investigated the association of body mass index (BMI) modeled as a continuous variable with survival outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune ...checkpoint inhibitors (ICI).
Methods
We performed a single-institution retrospective analysis of consecutively diagnosed locally advanced or metastatic NSCLC patients treated with single-agent ICI in the first line or recurrent setting. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and objective response rate (ORR). BMI was modeled using a four-knot restricted cubic spline. Multiple Cox regression was used for survival analysis.
Results
Two hundred patients were included (female 54%; never smoker 12%). Adenocarcinoma was the most common histology (61%). Median age was 67 years, median BMI was 25.9 kg/m
2
, and 65% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. On multivariable analysis, only BMI and ECOG PS were independently associated with OS (
p
< 0.01). Mortality risk decreased as the BMI increased from 20 to 30 kg/m
2
(HR 0.49, 95% CI 0.28–0.84); however, it was reversed as the BMI surpassed ~ 30 kg/m
2
. Compared to ECOG PS ≥ 2, patients with ECOG PS of 0–1 had a longer OS (HR 0.42, 95% CI 0.28–0.63). Similar trends were observed with PFS and ORR, but the strength of the association was weaker.
Conclusion
We observed a nonlinear association between BMI and OS following treatment with ICI in advanced NSCLC. Risk of death increases at both extremes of BMI with a nadir that exists around 30 kg/m
2
.
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