Audit and Inventory of Federal Law Enforcement Agency Tactical Medic Bags.

Separate evidence-based, best practice guidelines and recommendations exist for the prehospital management of traumatic injuries sustained in combat settings and those encountered during high-threat civilian operational incidents. The Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) Tactical Medic Program is a mature operational medicine asset supporting high-threat federal law enforcement operations. The ATF conducted an audit of its agency-issued tactical medic bags with regards to completeness, as defined by authorized medical protocols, which are aligned with current Tactical Combat Casualty Care and Tactical Emergency Casualty Care guidelines.

Nonsense-Mediated Decay Targeted RNA (ntRNA): Proposal of a ntRNA-miRNA-lncRNA Triple Regulatory Network Usable as Biomarker of Prognostic Risk in Patients with Kidney Cancer.

The most prevalent subtype of renal cell carcinoma (RCC), kidney renal clear cell carcinoma (KIRC) may be associated with a poor prognosis in a high number of cases, with a stage-specific prognostic stratification currently in use. No reliable biomarkers have been utilized so far in clinical practice despite the efforts in biomarker research in the last years. Nonsense-mediated mRNA decay (NMD) is a critical safeguard against erroneous transcripts, particularly mRNA transcripts containing premature termination codons (called nonsense-mediated decay targeted RNA, ntRNA). In this study, we first characterized 296 differentially expressed ntRNAs that were independent of the corresponding gene, 261 differentially expressed miRNAs, and 4653 differentially expressed lncRNAs. Then, we constructed a hub ntRNA-miRNA-lncRNA triple regulatory network associated with the prognosis of KIRC. Moreover, the results of immune infiltration analysis indicated that this network may influence the changes of the tumor immune microenvironment. A prognostic model derived from the genes and immune cells associated with the network was developed to distinguish between high- and low-risk patients, which was a better prognostic than other models, constructed using different biomarkers. Additionally, correlation of methylation and ntRNAs in the network suggested that some ntRNAs were regulated by methylation, which is helpful to further study the causes of abnormal expression of ntRNAs. In conclusion, this study highlighted the possible clinical implications of ntRNA functions in KIRC, proposing potential significant biomarkers that could be utilized to define the prognosis and design personalized treatment plans in kidney cancer management in the next future.

NEPA efficacy and tolerability during (neo)adjuvant breast cancer chemotherapy with cyclophosphamide and doxorubicin.

OBJECTIVES: This is a prospective study evaluating NEPA in patients with breast cancer (the NEPA group), who received (neo)adjuvant AC chemotherapy (consisting of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2). The primary objectives were to assess the efficacy and safety of NEPA in controlling chemotherapy-induced nausea and vomiting (CINV). The secondary objectives were to compare CINV between the NEPA group and historical controls (the APR group) who received aprepitant in an earlier prospective randomised study. PATIENTS AND METHODS: 60 patients participated in the NEPA group; 62 were in the APR group. Eligibility criteria of both groups were similar, that is, Chinese patients with breast cancer who were treated with (neo)adjuvant AC. NEPA group received NEPA and dexamethasone; APR group received aprepitant, ondansetron and dexamethasone. Individuals filled in self-reported diary, visual analogue scale for nausea and Functional Living Index-Emesis questionnaire. RESULTS: Within the NEPA group, 70.0%, 85.7% and 60.0%, respectively reported complete response in the acute, delayed and overall phases in cycle 1 AC. When compared with the historical APR group during cycle 1 AC, NEPA group achieved significantly higher rates of complete response, complete protection, total control, 'no significant nausea' and 'no nausea' in the delayed phase; similar findings were noted in the overall phase with significantly better quality of life. Superior efficacy of NEPA was maintained over multiple cycles. Both antiemetic regimens were well tolerated. CONCLUSION: In this study on Chinese patients with breast cancer who were uniformly receiving AC, NEPA was effective in controlling CINV. TRIAL REGISTRATION NUMBER: NCT03386617.

Differential Effects of Estrogen Receptor Alpha and Beta on Endogenous Ligands of Peroxisome Proliferator-Activated Receptor Gamma in Papillary Thyroid Cancer.

Purpose: The inhibition of estrogen receptor alpha (ERα) or the activation of ERß can inhibit papillary thyroid cancer (PTC), but the precise mechanism is not known. We aimed to explore the role of ERα and ERß on the production of endogenous peroxisome proliferator-activated receptor gamma (PPARγ) ligands in PTC. Methods: 2 PTC cell lines, 32 pairs of PTC tissues and matched normal thyroid tissues were used in this study. The levels of endogenous PPARγ ligands 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), and15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) were measured by ELISA. Results: The levels of PGJ2 and 15(S)-HETE were significantly reduced in PTC, but 13(S)-HODE was not changed. Activation of ERα or inhibition of ERß significantly downregulated the production of PGJ2, 15(S)-HETE and 13(S)-HODE, whereas inhibition of ERα or activation of ERß markedly upregulated the production of these three ligands. Application of endogenous PPARγ ligands inhibited growth, induced apoptosis of cancer cells, and promoted the efficacy of chemotherapy. Conclusion: The levels of endogenous PPARγ ligands PGJ2 and 15(S)-HETE are significantly decreased in PTC. The inhibition of ERα or activation of ERß can inhibit PTC by stimulating the production of endogenous PPARγ ligands to induce apoptosis in cancer cells.

Direct Measurement of B Lymphocyte Gene Expression Biomarkers in Peripheral Blood Transcriptomics Enables Early Prediction of Vaccine Seroconversion.

Peripheral blood transcriptome is a highly promising area for biomarker development. However, transcript abundances (TA) in these cell mixture samples are confounded by proportions of the component leukocyte subpopulations. This poses a challenge to clinical applications, as the cell of origin of any change in TA is not known without prior cell separation procedure. We developed a framework to develop a cell-type informative TA biomarkers which enable determination of TA of a single cell-type (B lymphocytes) directly in cell mixture samples of peripheral blood (e.g., peripheral blood mononuclear cells, PBMC) without the need for subpopulation separation. It is applicable to a panel of genes called B cell informative genes. Then a ratio of two B cell informative genes (a target gene and a stably expressed reference gene) obtained in PBMC was used as a new biomarker to represent the target gene expression in purified B lymphocytes. This approach, which eliminates the tedious procedure of cell separation and directly determines TA of a leukocyte subpopulation in peripheral blood samples, is called the Direct LS-TA method. This method is applied to gene expression datasets collected in influenza vaccination trials as early predictive biomarkers of seroconversion. By using TNFRSF17 or TXNDC5 as the target genes and TNFRSF13C or FCRLA as the reference genes, the Direct LS-TA B cell biomarkers were determined directly in the PBMC transcriptome data and were highly correlated with TA of the corresponding target genes in purified B lymphocytes. Vaccination responders had almost a 2-fold higher Direct LS-TA biomarker level of TNFRSF17 (log 2 SMD = 0.84, 95% CI = 0.47-1.21) on day 7 after vaccination. The sensitivity of these Direct LS-TA biomarkers in the prediction of seroconversion was greater than 0.7 and area-under curves (AUC) were over 0.8 in many datasets. In this paper, we report a straightforward approach to directly estimate B lymphocyte gene expression in PBMC, which could be used in a routine clinical setting. Moreover, the method enables the practice of precision medicine in the prediction of vaccination response. More importantly, seroconversion could now be predicted as early as day 7. As the acquired immunology pathway is common to vaccination against influenza and COVID-19, these biomarkers could also be useful to predict seroconversion for the new COVID-19 vaccines.

Genome-Wide Search for SNP Interactions in GWAS Data: Algorithm, Feasibility, Replication Using Schizophrenia Datasets.

In this study, we looked for potential gene-gene interaction in susceptibility to schizophrenia by an exhaustive searching for SNP-SNP interactions in 3 GWAS datasets (phs000021:phg000013, phs000021:phg000014, phs000167) using our recently published algorithm. The search space for SNP-SNP interaction was confined to 8 biologically plausible ways of interaction under dominant-dominant or recessive-recessive modes. First, we performed our search of all pair-wise combination of 729,454 SNPs after filtering by SNP genotype quality. All possible pairwise interactions of any 2 SNPs (5 × 1011) were exhausted to search for significant interaction which was defined by p-value of chi-square tests. Nine out the top 10 interactions, protein coding genes were partnered with non-coding RNA (ncRNA) which suggested a new alternative insight into interaction biology other than the frequently sought-after protein-protein interaction. Therefore, we extended to look for replication among the top 10,000 interaction SNP pairs and high proportion of concurrent genes forming the interaction pairs were found. The results indicated that an enrichment of signals over noise was present in the top 10,000 interactions. Then, replications of SNP-SNP interaction were confirmed for 14 SNPs-pairs in both replication datasets. Biological insight was highlighted by a potential binding between FHIT (protein coding gene) and LINC00969 (lncRNA) which showed a replicable interaction between their SNPs. Both of them were reported to have expression in brain. Our study represented an early attempt of exhaustive interaction analysis of GWAS data which also yield replicated interaction and new insight into understanding of genetic interaction in schizophrenia.

Ambient Temperature is A Strong Selective Factor Influencing Human Development and Immunity.

Solar energy, which is essential for the origin and evolution of all life forms on Earth, can be objectively recorded through attributes such as climatic ambient temperature (CAT), ultraviolet radiation (UVR), and sunlight duration (SD). These attributes have specific geographical variations and may cause different adaptation traits. However, the adaptation profile of each attribute and the selective role of solar energy as a whole during human evolution remain elusive. Here, we performed a genome-wide adaptation study with respect to CAT, UVR, and SD using the Human Genome Diversity Project-Centre Etude Polymorphism Humain (HGDP-CEPH) panel data. We singled out CAT as the most important driving force with the highest number of adaptive loci (6 SNPs at the genome-wide 1 × 10-7 level; 401 at the suggestive 1 × 10-5 level). Five of the six genome-wide significant adaptation SNPs were successfully replicated in an independent Chinese population (N = 1395). The corresponding 316 CAT adaptation genes were mostly involved in development and immunity. In addition, 265 (84%) genes were related to at least one genome-wide association study (GWAS)-mapped human trait, being significantly enriched in anthropometric loci such as those associated with body mass index (χ2; P < 0.005), immunity, metabolic syndrome, and cancer (χ2; P < 0.05). For these adaptive SNPs, balancing selection was evident in Euro-Asians, whereas obvious positive and/or purifying selection was observed in Africans. Taken together, our study indicates that CAT is the most important attribute of solar energy that has driven genetic adaptation in development and immunity among global human populations. It also supports the non-neutral hypothesis for the origin of disease-predisposition alleles in common diseases.

Reference intervals of spot urine copper excretion in preschool children and potential application in pre-symptomatic screening of Wilson disease.

The objectives were to determine the reference intervals of spot urine copper excretion indexes in pre-school children and to evaluate their utility in screening for Wilson disease (WD). With spot urine collected from a control sample of preschool children (aged 3-7 years, n=153), the reference intervals of spot urine copper excretion indexes and their biological variation were defined. In order to investigate their utility performance in screening for WD in this age group, multiple spot urine samples from six WD patients who were diagnosed at presymptomatic stage were also analysed and compared. Cut-off values useful for detection of WD were defined by receiver operator curve (ROC) analysis. Biological (inter-individual) variation of spot urine copper indexes expressed as coefficient of variation (CVg) were around 60% at this age group, which was moderate and similar to other clinically useful urine tests, such as urine albumin excretion ratio. Spot urine copper excretion strongly correlated with both urine creatinine and osmolality. Linear regression against both creatinine and osmolality showed that ∼94% of data points in healthy preschool children fell within the prediction interval, suggesting that both were useful normalisation factors. ROC showed that copper to osmolality ratio was the best index with an area under curve (AUC) greater than 0.98. Cut-off values of 0.5 µmol/L, 0.1 µmol/mmol and 0.00085 µmol/mOsmol (32 µg/L, 56 µg/g creatinine and 0.054 µg/mOsmol, respectively, in conventional units) for spot urine copper concentration, copper to creatinine ratio and copper to osmolality ratio, respectively, have potential application in the differentiation of WD patients. Based on the data, a new WD screening strategy targeting preschool children is proposed. Application of a bivariate screening strategy using spot urine copper concentration and urine osmolality may be useful in a population-wide screening program for WD among preschool children.

A randomized study of olanzapine-containing versus standard antiemetic regimens for the prevention of chemotherapy-induced nausea and vomiting in Chinese breast cancer patients.

OBJECTIVES: Chemotherapy-induced nausea and vomiting (CINV) are distressing symptoms. This randomized study evaluated the antiemetic efficacies of standard antiemetic regimen with/without olanzapine. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive Chinese breast cancer patients who were planned for (neo)adjuvant doxorubicin/cyclophosphamide. Antiemetic regimen for all studied population included aprepitant, ondansetron and dexamethasone; patients were randomized to Olanzapine (with olanzapine) or Standard arms (without olanzapine). Patients filled in self-reported diaries and completed visual analogue scales for nausea, as well as Functional Living Index-Emesis questionnaires. Blood profiles including fasting glucose and lipids were monitored. RESULTS: 120 patients were randomized. In Cycle 1 doxorubicin/cyclophosphamide, the Olanzapine arm had significantly higher rates of "Complete Response" than the Standard arm: 65.0% vs 38.3% in the overall period (p = 0.0035), 70.0% vs 51.7% in the acute period (p = 0.0397) and 92.9% vs 74.2% in the delayed period (p = 0.0254). Olanzapine arm also had significantly higher rates of "No significant nausea" and "No nausea" during all 3 time-frames and better QOL. Similar findings were also revealed throughout multiple cycles. Pre-study abnormalities in glucose and lipids occurred in 39.7% and 34.2% of the studied population respectively; there were no differences in these parameters between the two arms at end-of-study assessment. CONCLUSION: The addition of olanzapine to standard aprepitant-based antiemetic regimen provides clinically meaningful improvement in controlling CINV. This was associated with a positive impact on QOL and tolerable toxicity profiles among Chinese breast cancer patients receiving doxorubicin/cyclophosphamide chemotherapy. Further studies on metabolic profiles of breast cancer patients are warranted.

Status of inflammation in relation to health related quality of life in hepatocellular carcinoma patients.

PURPOSE: Both Inflammation and health-related quality of life (HRQoL) are independent prognosticators in HCC patients. We hypothesized that inflammation can cause impairment in HRQoL and investigated the correlation between inflammatory status and HRQoL in HCC patients. METHODS: Clinical, laboratory and HRQoL (using EORTC QLQ-C30, QLQ-HCC18, C30 and HCC18 index-scores) data were prospectively collected from HCC patients at diagnosis. Correlation analyses were performed between HRQoL and inflammation-based markers including C-reactive protein (CRP), CRP/albumin ratio (CRP/alb), Glasgow Prognostic Score (GPS), Inflammation-Based Index (IBI) and Prognostic Index (PI). RESULTS: Among 445 HCC patients, higher inflammatory states were significantly correlated with worse HRQoL. For CRP and CRP/alb ratio, the HRQoL factors with higher correlations included C30 and HCC18 index-scores, certain QLQ-C30 domains and items ('physical functioning', 'role functioning', 'fatigue', 'pain', 'appetite loss') and QLQ-HCC18 items ('fatigue', 'body image', 'nutrition' and 'abdominal swelling'), where the Pearson's correlation coefficients were up to 0.416. Multivariate analyses indicated that worse HRQoL factors were significantly correlated with worse scores in GPS, IBI and PI. CONCLUSION: In HCC patients, inflammatory status correlates with HRQoL at presentation. In particular, relatively stronger correlations with CRP-based markers have been observed in HRQoL scales that assess constitutional symptoms (QLQ-C30 'physical functioning', 'role functioning', 'fatigue', 'appetite loss' and QLQ-HCC18 'fatigue' and 'nutrition') and tumor burden (QLQ-C30 'pain' and QLQ-HCC18 'abdominal swelling' and 'body image'). Future studies are warranted to evaluate whether intervention that reduces inflammation could improve HRQoL in HCC patients.

The association of liver function and quality of life of patients with liver cancer.

BACKGROUND: Quality of life (QOL) assessments with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-HCC18, C30 and HCC18 index scores have been shown to be prognostic factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC), independent of disease stage and liver function. Liver function parameters (including bilirubin, albumin, international normalized ratio [INR], Child-Pugh class, ALBI grade, MELD, alkaline phosphatase [ALP]-to-platelet ratio, albumin-to-ALP ratio) have also been found to be independent prognostic factors for OS in HCC patients. There has been scanty data on whether QOL and baseline liver function per se are correlated in HCC patients. This study investigates the correlations between baseline QOL data and liver function variables in HCC patients. METHODS: From 2007 to 2011, 517 patients were enrolled. Baseline QOL was assessed at diagnosis using the EORTC QLQ-C30 and QLQ-HCC18; thereafter C30 and HCC18 index scores were derived. Clinical and laboratory data were collected. For liver function assessment, Child-Pugh class, ALBI grade, MELD, ALP-to-platelet ratio and albumin-to-ALP ratio were derived. Correlation analyses were performed between QOL and liver function data. RESULTS: Complete QOL data were available in 472 HCC patients. After adjusting for clinical variables, significant correlations were found between QOL (QLQ-C30 and QLQ-HCC18) and dichotomized liver function variables (including Child-Pugh class, ALBI grade and the presence of ascites). It was demonstrated that QOL had significant and potentially clinically important correlations with continuous liver function variables (albumin, bilirubin, ALP and albumin-to-ALP ratio), with the highest Spearman's rank correlation coefficient (rho) exceeding 0.4. HCC18 and C30 index scores were also significantly correlated with these liver function variables. HCC18 index score, which had rho up to 0.37, generally performed better than C30 index score, which had rho up to 0.33. CONCLUSIONS: In HCC patients, baseline QOL assessment (using EORTC QLQ-C30, QLQ-HCC18, C30 index-score or HCC18 index-score) is significantly correlated with liver function. Based on the findings of this study, future trials are warranted to assess whether treatment to enhance liver function could improve HCC patients' QOL.

Correlations of health-related quality of life with serum inflammatory indicators IL-8 and mIBI in patients with hepatocellular carcinoma.

PURPOSE: Health-related quality of life (HRQoL) is a significant prognostic factor for overall survival in hepatocellular carcinoma (HCC) patients, and this is independent of stage and liver function. Inflammation plays a significant role in HCC development and progression. It was hypothesized that the inflammatory status of HCC patients may affect their HRQoL. The relationship between HRQoL and inflammatory status was explored using indicators IL-8 level and modified inflammation-based index (mIBI, based on IL-8, C-reactive protein, and albumin). METHODS: From 2007-2011, HCC patients were enrolled prospectively. Baseline HRQoL assessment utilized the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-HCC18; clinical and laboratory data were collected at diagnosis. Two summary indices, C30 and HCC18 index-scores, were calculated. Correlation analyses were performed between HRQoL and inflammatory markers. RESULTS: In the 445 patients studied, significant correlations were found between IL-8 levels and EORTC QLQ-C30, QLQ-HCC18, C30, and HCC18 index-scores. The strongest correlated factors were those reflective of constitutional symptoms, namely QLQ-C30 "appetite loss" (with Pearson's correlation coefficient, r=0.322, P<0.0001); QLQ-C30 "fatigue" (r=0.311, P<0.0001); QLQ-C30 "role functioning" (r=-0.305, P<0.0001); QLQ-HCC18 "nutrition" (r=0.317, P<0.0001); and QLQ-HCC18 "fatigue" (r=0.306, P<0.0001). In addition, moderate but significant correlations were also observed with HCC18 index score (r=0.321, P<0.0001), and C30 index score (r=0.306, P<0.0001). HRQoL factors were also significantly correlated with mIBI. CONCLUSION: Baseline HRQoL using the conventional assessments of EORTC QLQ-C30 and QLQ-HCC18, as well as C30 and HCC18 index-scores, significantly correlated with inflammatory indicators (IL-8 level and mIBI) in HCC patients. Among the strongest correlations were those between IL-8 level and the two index-scores, as well as HRQoL aspects that represent constitutional symptoms. When paralleled with molecular findings, traditional HRQoL assessment in HCC has gained a new level of understanding: pattern recognition within an HRQoL instrument could potentially identify patients with more severe inflammatory state.

Discovering Genetic Factors for psoriasis through exhaustively searching for significant second order SNP-SNP interactions.

In this paper, we aim at discovering genetic factors of psoriasis through searching for statistically significant SNP-SNP interactions exhaustively from two real psoriasis genome-wide association study datasets (phs000019.v1.p1 and phs000982.v1.p1) downloaded from the database of Genotypes and Phenotypes. To deal with the enormous search space, our search algorithm is accelerated with eight biological plausible interaction patterns and a pre-computed look-up table. After our search, we have discovered several SNPs having a stronger association to psoriasis when they are in combination with another SNP and these combinations may be non-linear interactions. Among the top 20 SNP-SNP interactions being found in terms of pairwise p-value and improvement metric value, we have discovered 27 novel potential psoriasis-associated SNPs where most of them are reported to be eQTLs of a number of known psoriasis-associated genes. On the other hand, we have inferred a gene network after selecting the top 10000 SNP-SNP interactions in terms of improvement metric value and we have discovered a novel long distance interaction between XXbac-BPG154L12.4 and RNU6-283P which is not a long distance haplotype and may be a new discovery. Finally, our experiments with the synthetic datasets have shown that our pre-computed look-up table technique can significantly speed up the search process.

Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians.

Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB, ATP6V0C, ATG4D, and WIPI1, could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1, Atg18a, extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.

Profiles of lipids, blood pressure and weight changes among premenopausal Chinese breast cancer patients after adjuvant chemotherapy.

BACKGROUND: Adjuvant chemotherapy improves outcome of patients with early breast cancer. However, chemotherapy may be associated with long term toxicities. In this retrospective cohort study, the objectives were to determine body weight, body mass index (BMI), blood pressure and fasting lipids levels of young premenopausal Chinese breast cancer patients after adjuvant chemotherapy. Potential factors associated with these parameters were identified. METHODS: Eligibility criteria include premenopausal Chinese patients who were diagnosed to have stage I-III breast cancer within 3-10 years, age < 45 and having received adjuvant chemotherapy at the time of breast cancer diagnosis. Information at initial breast cancer diagnosis were retrieved from patients' medical records and include age at diagnosis, tumor characteristics, anti-cancer treatments, blood pressure and body weight and height. At study entry, all patients had additional background demographics collected, as well as blood pressure, body weight and fasting serum lipid profiles measured. Incidence of chemotherapy-related amenorrhoea (CRA) and menopause were determined. Factors associated with weight gain, hypertension and dyslipidaemias were analyzed. RESULTS: Two hundred and eighty patients were studied. The median age at breast cancer diagnosis was 41 years (range: 24-45). The median time from breast cancer diagnosis to study entry was 5.0 years. The median age at study entry was 46.5 years (range: 28-54). 91.1% developed CRA; 48.9% had become menopausal and 10% were peri-menopausal. Between initial breast cancer diagnosis and the time of study entry, the median weight gain was 1.8 kg; 63.2% gained weight by >2%; 52.1% were overweight/obese; 30.7% had hypertension. Abnormal total-cholesterol and LDL-cholesterol occurred in 34.3% and 56.1% respectively. On multivariate analyses, older age was associated with reduced risk while occurrence of CRA and having received taxane-containing regimens were associated with increased risk of weight gain. Oestrogen-receptor positivity was associated with reduced risk while overweight/obese statuses were associated with increased risk of hypertension. Use of tamoxifen was associated with reduced risk of abnormal LDL-cholesterol. Weight gain, overweight/obese, older age, progression to post/peri-menopausal status at study entry, having received corticosteroid premedication before adjuvant chemotherapy and having received taxane-containing adjuvant chemotherapy were associated with increased risk of dyslipidaemias. CONCLUSION: Among young premenopausal Chinese breast cancer patients who had received adjuvant chemotherapy, the current study has revealed that although there was only a median weight gain of 1.8 kg, there was a nearly 60% increase in abnormal BMI. Further, a significant proportion of patients were detected to have hypertension and dyslipidaemias. Interventional studies with lifestyle modifications are warranted.

BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity.

Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, Aldh2 gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits in vivo the growth of BRCA1/2-deficient tumors and ex vivo in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors.

VCNet: vector-based gene co-expression network construction and its application to RNA-seq data.

MOTIVATION: Building gene co-expression network (GCN) from gene expression data is an important field of bioinformatic research. Nowadays, RNA-seq data provides high dimensional information to quantify gene expressions in term of read counts for individual exons of genes. Such an increase in the dimension of expression data during the transition from microarray to RNA-seq era made many previous co-expression analysis algorithms based on simple univariate correlation no longer applicable. Recently, two vector-based methods, SpliceNet and RNASeqNet, have been proposed to build GCN. However, they failed to work when sample size is less than the number of exons. RESULTS: We develop an algorithm called VCNet to construct GCN from RNA-seq data to overcome this dimensional problem. VCNet performs a new statistical hypothesis test based on the correlation matrix of a gene-gene pair using the Frobenius norm. The asymptotic distribution of the new test is obtained under the null model. Simulation studies demonstrate that VCNet outperforms SpliceNet and RNASeqNet for detecting edges of GCN. We also apply VCNet to two expression datasets from TCGA database: the normal breast tissue and kidney tumour tissue, and the results show that the GCNs constructed by VCNet contain more biologically meaningful interactions than existing methods. CONCLUSION: VCNet is a useful tool to construct co-expression network. AVAILABILITY AND IMPLEMENTATION: VCNet is open source and freely available from https://github.com/wangzengmiao/VCNet under GNU LGPL v3. CONTACT: dengmh@pku.edu.cn or nelsontang@cuhk.edu.hk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genome-wide association study identifies novel susceptible loci and highlights Wnt/beta-catenin pathway in the development of adolescent idiopathic scoliosis.

The genetic architecture of adolescent idiopathic scoliosis (AIS) remains poorly understood. Here we present the result of a 4-stage genome-wide association study composed of 5,953 AIS patients and 8,137 controls. Overall, we identified three novel susceptible loci including rs7593846 at 2p14 near MEIS1 (Pcombined = 1.19 × 10-13, OR = 1.21, 95% CI = 1.10-1.32), rs7633294 at 3p14.1 near MAGI1 (Pcombined = 1.85 × 10-12, OR = 1.20, 95% CI = 1.09-1.32), and rs9810566 at 3q26.2 near TNIK (Pcombined = 1.14 × 10-11, OR = 1.19, 95% CI = 1.08-1.32). We also confirmed a recently reported region associated with AIS at 20p11.22 (Pcombined = 1.61 × 10-15, OR = 1.22, 95% CI = 1.12-1.34). Furthermore, we observed significantly asymmetric expression of Wnt/beta-catenin pathway in the bilateral paraspinal muscle of AIS patients, including beta-catenin, TNIK, and LBX1. This is the first study that unveils the potential role of Wnt/beta-catenin pathway in the development of AIS, and our findings may shed new light on the etiopathogenesis of AIS.

Prognostic values of EORTC QLQ-C30 and QLQ-HCC18 index-scores in patients with hepatocellular carcinoma - clinical application of health-related quality-of-life data.

BACKGROUND: Health-related quality-of-life (HRQOL) assessment with EORTC QLQ-C30 was prognostic for overall survival (OS) in patients with advance-stage hepatocellular carcinoma (HCC), but no data existed for early-stage patients. The HCC-specific QLQ-HCC18 has not been evaluated for prognostic value in HCC patients. Utilization of raw HRQOL data in clinical setting has been impractical and non-meaningful. Therefore we developed index scores of QLQ-C30 and QLQ-HCC18 in an attempt to enable clinical utilization of these HRQOL measurements. This study investigates the prognostic significance of QLQ-C30, QLQ-HCC18 and C30/HCC18 index-scores in patients with newly diagnosed HCC which encompasses all stages. METHODS: From 2007-2011, 517 patients were prospectively recruited. HRQOL was assessed at diagnosis using QLQ-C30 and QLQ-HCC18; C30 and HCC18 index-scores were calculated from raw HRQOL data. Cox regression was performed using continuous, dichotomized QLQ-C30 and QLQ-HCC18 variables, or index-scores, together with clinical factors to identify independent factors for OS. Various multivariate models were validated with c-index and bootstrapping for 1000 replications. RESULTS: Four hundred and seventy two patients had complete HRQOL data. Their median OS was 8.6 months. In multivariate analysis, independent prognostic HRQOL variables for OS were QLQ-C30 pain (HR 1.346 [1.092-1.661], p = 0.0055), QLQ-C30 physical functioning (HR 0.652 [0.495-0.860], p = 0.0024); QLQ-HCC18 pain (HR 1.382 [1.089-1.754], p = 0.0077) and QLQ-HCC18 fatigue (HR 1.441 [1.132-1.833], p = 0.0030). C30 index-score (HR 2.143 [1.616-2.841], p < 0.0001) and HCC18 index-score (HR 1.957 [1.411-2.715], p < 0.0001) were highly significant factors for OS. The median OS of patients with C30 index-score of 0-20, 21-40, 41-60, 61-100 were 16.4, 7.3, 3.1, 1.8 months respectively (p < 0.0001); while for HCC18 index-score: 16.4, 6.0, 2.8, 1.8 months respectively (p < 0.0001). All the multivariate models were validated, with mean optimism <0.01. The bootstrap validated c-index was 0.78. CONCLUSIONS: QLQ-C30 and QLQ-HCC18 were prognostic for OS in patients with newly diagnosed HCC irrespective of stage. Both C30 and HCC18 index-scores were highly significant prognostic factors for OS in newly diagnosed HCC patients. Index-scoring provides an effective way to summarize, analyze and interpret raw HRQOL data, and renders QLQ-C30 and QLQ-HCC18 meaningful and communicable in clinical practice. Index-scores could potentially serve as a standardized tool for future HRQOL research.

CrossNorm: a novel normalization strategy for microarray data in cancers.

Normalization is essential to get rid of biases in microarray data for their accurate analysis. Existing normalization methods for microarray gene expression data commonly assume a similar global expression pattern among samples being studied. However, scenarios of global shifts in gene expressions are dominant in cancers, making the assumption invalid. To alleviate the problem, here we propose and develop a novel normalization strategy, Cross Normalization (CrossNorm), for microarray data with unbalanced transcript levels among samples. Conventional procedures, such as RMA and LOESS, arbitrarily flatten the difference between case and control groups leading to biased gene expression estimates. Noticeably, applying these methods under the strategy of CrossNorm, which makes use of the overall statistics of the original signals, the results showed significantly improved robustness and accuracy in estimating transcript level dynamics for a series of publicly available datasets, including titration experiment, simulated data, spike-in data and several real-life microarray datasets across various types of cancers. The results have important implications for the past and the future cancer studies based on microarray samples with non-negligible difference. Moreover, the strategy can also be applied to other sorts of high-throughput data as long as the experiments have global expression variations between conditions.