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1.  Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study 
PLoS Medicine  2016;13(12):e1002162.
Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.
Methods and Findings
We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10−50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10−4) were associated with increased risk of distant metastasis. Our study’s limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.
These data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.
Maria Teresa Landi and colleagues report genomic tumor data for a cohort of patients with lung adenocarcinoma, focusing on implications for tumor initiation and distant metastasis.
Author Summary
Why Was This Study Done?
Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and causes more than half a million deaths worldwide annually.
Genomic studies of LUAD can shed light on tumor initiation and progression and identify potential targets for treatment.
What Did the Researchers Do and Find?
We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), DNA copy number and DNA methylation determination, and transcriptome sequencing in 101 LUAD samples. We replicated major findings using public genomic resources and combined all existing genomic data for an overall analysis of 825 LUAD samples.
We identified two novel driver genes and characterized the driver events and types of mutations that have a stronger role in tumor initiation versus tumor progression.
We found strong associations between DNA methylation and somatic mutation patterns.
The total number of somatic mutations and the fraction of C→T transitions were associated with increased risk of distant metastasis.
What Do These Findings Mean?
We characterized LUAD genomic architecture and linked major genomic features with clinical outcomes.
Tobacco smoking-related mutations appear to have a stronger role in tumor initiation, while mutations associated with endogenous processes are more prominent at a later stage of tumor development and are associated with tumor progression.
Our findings highlight the complexity and heterogeneity of LUAD. In addition to new driver genes, we found some tumors with no exonic mutations in known lung cancer driver genes. This suggests that there are further drivers (genetic or epigenetic) to be identified, and larger numbers of samples need to be studied to fully capture LUAD genomic characteristics.
PMCID: PMC5140047  PMID: 27923066
3.  Exercise Preconditioning Improves Traumatic Brain Injury Outcomes 
Brain research  2015;1622:414-429.
To determine whether 6 weeks of exercise performed prior to traumatic brain injury (TBI) could improve post-TBI behavioral outcomes in mice, and if exercise increases neuroprotective molecules (vascular endothelial growth factor-A [VEGF-A], erythropoietin [EPO], and heme oxygenase-1 [HO-1]) in brain regions responsible for movement (sensorimotor cortex) and memory (hippocampus).
120 mice were randomly assigned to one of four groups: 1) no exercise + no TBI (NOEX-NOTBI [n=30]), 2) no exercise + TBI (NOEX-TBI [n=30]), 3) exercise + no TBI (EX-NOTBI [n=30]), and 4) exercise + TBI (EX-TBI [n=30]). The gridwalk task and radial arm water maze were used to evaluate sensorimotor and cognitive function, respectively. Quantitative real time polymerase chain reaction and immunostaining were performed to investigate VEGF-A, EPO, and HO-1 mRNA and protein expression in the right cerebral cortex and ipsilateral hippocampus.
EX-TBI mice displayed reduced post-TBI sensorimotor and cognitive deficits when compared to NOEX-TBI mice. EX-NOTBI and EX-TBI mice showed elevated VEGF-A and EPO mRNA in the cortex and hippocampus, and increased VEGF-A and EPO staining of sensorimotor cortex neurons 1 day post-TBI and/or post-exercise. EX-TBI mice also exhibited increased VEGF-A staining of hippocampal neurons 1 day post-TBI/post-exercise. NOEX-TBI mice demonstrated increased HO-1 mRNA in the cortex (3 days post-TBI) and hippocampus (3 and 7 days post-TBI), but HO-1 was not increased in mice that exercised.
Improved TBI outcomes following exercise preconditioning are associated with increased expression of specific neuroprotective genes and proteins (VEGF-A and EPO, but not HO-1) in the brain.
PMCID: PMC4562892  PMID: 26165153
Exercise; Traumatic Brain Injury; Sensorimotor Function; Cognitive Function; Vascular Endothelial Growth Factor; Erythropoietin
4.  Computerized decision support systems: improving patient safety in nephrology 
Nature reviews. Nephrology  2011;7(6):348-355.
Incorrect prescription and administration of medications account for a substantial proportion of medical errors in the USA, causing adverse drug events (ADEs) that result in considerable patient morbidity and enormous costs to the health-care system. Patients with chronic kidney disease or acute kidney injury often have impaired drug clearance as well as polypharmacy, and are therefore at increased risk of experiencing ADEs. Studies have demonstrated that recognition of these conditions is not uniform among treating physicians, and prescribed drug doses are often incorrect. Early interventions that ensure appropriate drug dosing in this group of patients have shown encouraging results. Both computerized physician order entry and clinical decision support systems have been shown to reduce the rate of ADEs. Nevertheless, these systems have been implemented at surprisingly few institutions. Economic stimulus and health-care reform legislation present a rare opportunity to refine these systems and understand how they could be implemented more widely. Failure to explore this technology could mean that the opportunity to reduce the morbidity associated with ADEs is missed.
PMCID: PMC5048740  PMID: 21502973
5.  Improvements in US Breast Cancer Survival and Proportion Explained by Tumor Size and Estrogen-Receptor Status 
Journal of Clinical Oncology  2015;33(26):2870-2876.
Breast cancer mortality began declining in many Western countries during the late 1980s. We estimated the proportion of improvements in stage- and age-specific breast cancer survival in the United States explained by tumor size or estrogen receptor (ER) status.
We estimated hazard ratios for breast cancer–specific death from time of invasive breast cancer diagnosis in the National Cancer Institute's Surveillance, Epidemiology, and End Results 9 Registries Database from 1973 to 2010, with and without stratification by tumor size and ER status.
Hazards from breast cancer–specific death declined from 1973 to 2010, not only in the first 5 years after diagnosis, but also thereafter. Stratification by tumor size explained less than 17% of the improvements comparing 2005 to 2010 versus 1973 to 1979, except for women age ≥ 70 years with local (49%) or regional (38%) disease. Tumor size usually accounted for more of the improvement in the first 5 years after diagnosis than later. Additional adjustment for ER status (positive, negative, or unknown) from 1990 to 2010 did not explain much more of the improvement, except for women age ≥ 70 years within 5 years after diagnosis.
Most stage-specific survival improvement in women younger than age 70 years old is unexplained by tumor size and ER status, suggesting a key role for treatment. In the first 5 years after diagnosis, tumor size contributed importantly for women ≥ 70 years old with local and regional stage, and stratification by tumor size and ER status explained even more of the survival improvement among women age ≥ 70 years.
PMCID: PMC4554748  PMID: 26195709
6.  Can We Predict Individual Combined Benefit and Harm of Therapy? Warfarin Therapy for Atrial Fibrillation as a Test Case 
PLoS ONE  2016;11(8):e0160713.
To construct and validate a prediction model for individual combined benefit and harm outcomes (stroke with no major bleeding, major bleeding with no stroke, neither event, or both) in patients with atrial fibrillation (AF) with and without warfarin therapy.
Using the Kaiser Permanente Colorado databases, we included patients newly diagnosed with AF between January 1, 2005 and December 31, 2012 for model construction and validation. The primary outcome was a prediction model of composite of stroke or major bleeding using polytomous logistic regression (PLR) modelling. The secondary outcome was a prediction model of all-cause mortality using the Cox regression modelling.
We included 9074 patients with 4537 and 4537 warfarin users and non-users, respectively. In the derivation cohort (n = 4632), there were 136 strokes (2.94%), 280 major bleedings (6.04%) and 1194 deaths (25.78%) occurred. In the prediction models, warfarin use was not significantly associated with risk of stroke, but increased the risk of major bleeding and decreased the risk of death. Both the PLR and Cox models were robust, internally and externally validated, and with acceptable model performances.
In this study, we introduce a new methodology for predicting individual combined benefit and harm outcomes associated with warfarin therapy for patients with AF. Should this approach be validated in other patient populations, it has potential advantages over existing risk stratification approaches as a patient-physician aid for shared decision-making
PMCID: PMC4981352  PMID: 27513986
7.  Multicentre prospective cohort study of body mass index and postoperative complications following gastrointestinal surgery 
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The British Journal of Surgery  2016;103(9):1157-1172.
There is currently conflicting evidence surrounding the effects of obesity on postoperative outcomes. Previous studies have found obesity to be associated with adverse events, but others have found no association. The aim of this study was to determine whether increasing body mass index (BMI) is an independent risk factor for development of major postoperative complications.
This was a multicentre prospective cohort study across the UK and Republic of Ireland. Consecutive patients undergoing elective or emergency gastrointestinal surgery over a 4‐month interval (October–December 2014) were eligible for inclusion. The primary outcome was the 30‐day major complication rate (Clavien–Dindo grade III–V). BMI was grouped according to the World Health Organization classification. Multilevel logistic regression models were used to adjust for patient, operative and hospital‐level effects, creating odds ratios (ORs) and 95 per cent confidence intervals (c.i.).
Of 7965 patients, 2545 (32·0 per cent) were of normal weight, 2673 (33·6 per cent) were overweight and 2747 (34·5 per cent) were obese. Overall, 4925 (61·8 per cent) underwent elective and 3038 (38·1 per cent) emergency operations. The 30‐day major complication rate was 11·4 per cent (908 of 7965). In adjusted models, a significant interaction was found between BMI and diagnosis, with an association seen between BMI and major complications for patients with malignancy (overweight: OR 1·59, 95 per cent c.i. 1·12 to 2·29, P = 0·008; obese: OR 1·91, 1·31 to 2·83, P = 0·002; compared with normal weight) but not benign disease (overweight: OR 0·89, 0·71 to 1·12, P = 0·329; obese: OR 0·84, 0·66 to 1·06, P = 0·147).
Overweight and obese patients undergoing surgery for gastrointestinal malignancy are at increased risk of major postoperative complications compared with those of normal weight.
High BMI increases risk of complications
PMCID: PMC4973675  PMID: 27321766
8.  Investigation of the Association Between the Fecal Microbiota and Breast Cancer in Postmenopausal Women: a Population-Based Case-Control Pilot Study 
We investigated whether the gut microbiota differed in 48 postmenopausal breast cancer case patients, pretreatment, vs 48 control patients. Microbiota profiles in fecal DNA were determined by Illumina sequencing and taxonomy of 16S rRNA genes. Estrogens were quantified in urine. Case-control comparisons employed linear and unconditional logistic regression of microbiota α-diversity (PD_whole tree) and UniFrac analysis of β-diversity, with two-sided statistical tests. Total estrogens correlated with α-diversity in control patients (Spearman Rho = 0.37, P = .009) but not case patients (Spearman Rho = 0.04, P = .77). Compared with control patients, case patients had statistically significantly altered microbiota composition (β-diversity, P = .006) and lower α-diversity (P = .004). Adjusted for estrogens and other covariates, odds ratio of cancer was 0.50 (95% confidence interval = 0.30 to 0.85) per α-diversity tertile. Differences in specific taxa were not statistically significant when adjusted for multiple comparisons. This pilot study shows that postmenopausal women with breast cancer have altered composition and estrogen-independent low diversity of their gut microbiota. Whether these affect breast cancer risk and prognosis is unknown.
PMCID: PMC4554191  PMID: 26032724
9.  Clinical outcome prediction in aneurysmal subarachnoid hemorrhage – Alterations in brain–body interface 
Surgical Neurology International  2016;7(Suppl 18):S527-S537.
Brain–body associations are essential in influencing outcome in patients with ruptured brain aneurysms. Thus far, there is scarce literature on such important relationships.
The multicenter Tirilazad database (3551 patients) was used to create this clinical outcome prediction model in order to elucidate significant brain–body associations. Traditional binary logistic regression models were used.
Binary logistic regression main effects model included four statistically significant single prognostic variables, namely, neurological grade, age, stroke, and time to surgery. Logistic regression models demonstrated the significance of hypertension and liver disease in development of brain swelling, as well as the negative consequences of seizures in patients with a history of myocardial infarction and post-admission fever worsening neurological outcome.
Using the aforementioned results generated from binary logistic regression models, we can identify potential patients who are in the high risk group of neurological deterioration. Specific therapies can be tailored to prevent these detriments, including treatment of hypertension, seizures, early detection and treatment of myocardial infarction, and prevention of hepatic encephalopathy.
PMCID: PMC4982352  PMID: 27583179
Aneurysmal subarachnoid hemorrhage; brain-body interactions; clinical outcome prediction model
10.  Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features 
Genome Biology  2016;17:163.
The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients.
We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors.
Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1021-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4964003  PMID: 27468850
Air pollution; Tumor stage; 16S rRNA
11.  Risk factors for mortality in patients admitted to intensive care units with pneumonia 
Respiratory Research  2016;17:80.
Despite the high mortality in patients with pneumonia admitted to an ICU, data on risk factors for death remain limited.
In this secondary analysis of PROTECT (Prophylaxis for Thromboembolism in Critical Care Trial), we focused on the patients admitted to ICU with a primary diagnosis of pneumonia. The primary outcome for this study was 90-day hospital mortality and the secondary outcome was 90-day ICU mortality. Cox regression model was conducted to examine the relationship between baseline and time-dependent variables and hospital and ICU mortality.
Six hundred sixty seven patients admitted with pneumonia (43.8 % females) were included in our analysis, with a mean age of 60.7 years and mean APACHE II score of 21.3. During follow-up, 111 patients (16.6 %) died in ICU and in total, 149 (22.3 %) died in hospital. Multivariable analysis demonstrated significant independent risk factors for hospital mortality including male sex (hazard ratio (HR) = 1.5, 95 % confidence interval (CI): 1.1 - 2.2, p-value = 0.021), higher APACHE II score (HR = 1.2, 95 % CI: 1.1 - 1.4, p-value < 0.001 for per-5 point increase), chronic heart failure (HR = 2.9, 95 % CI: 1.6 - 5.4, p-value = 0.001), and dialysis (time-dependent effect: HR = 2.7, 95 % CI: 1.3 - 5.7, p-value = 0.008). Higher APACHE II score (HR = 1.2, 95 % CI: 1.1 - 1.4, p-value = 0.002 for per-5 point increase) and chronic heart failure (HR = 2.6, 95 % CI: 1.3 – 5.0, p-value = 0.004) were significantly related to risk of death in the ICU.
In this study using data from a multicenter thromboprophylaxis trial, we found that male sex, higher APACHE II score on admission, chronic heart failure, and dialysis were independently associated with risk of hospital mortality in patients admitted to ICU with pneumonia. While high illness severity score, presence of a serious comorbidity (heart failure) and need for an advanced life support (dialysis) are not unexpected risk factors of mortality, male sex might necessitate further exploration. More studies are warranted to clarify the effect of these risk factors on survival in critically ill patients admitted to ICU with pneumonia.
Trial registration Identifier: NCT00182143.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-016-0397-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4940754  PMID: 27401184
Pneumonia; Intensive care; Mortality; Risk factor
12.  Aneurysmal subarachnoid hemorrhage prognostic decision-making algorithm using classification and regression tree analysis 
Classification and regression tree analysis involves the creation of a decision tree by recursive partitioning of a dataset into more homogeneous subgroups. Thus far, there is scarce literature on using this technique to create clinical prediction tools for aneurysmal subarachnoid hemorrhage (SAH).
The classification and regression tree analysis technique was applied to the multicenter Tirilazad database (3551 patients) in order to create the decision-making algorithm. In order to elucidate prognostic subgroups in aneurysmal SAH, neurologic, systemic, and demographic factors were taken into account. The dependent variable used for analysis was the dichotomized Glasgow Outcome Score at 3 months.
Classification and regression tree analysis revealed seven prognostic subgroups. Neurological grade, occurrence of post-admission stroke, occurrence of post-admission fever, and age represented the explanatory nodes of this decision tree. Split sample validation revealed classification accuracy of 79% for the training dataset and 77% for the testing dataset. In addition, the occurrence of fever at 1-week post-aneurysmal SAH is associated with increased odds of post-admission stroke (odds ratio: 1.83, 95% confidence interval: 1.56–2.45, P < 0.01).
A clinically useful classification tree was generated, which serves as a prediction tool to guide bedside prognostication and clinical treatment decision making. This prognostic decision-making algorithm also shed light on the complex interactions between a number of risk factors in determining outcome after aneurysmal SAH.
PMCID: PMC4964664  PMID: 27512607
Aneurysmal subarachnoid hemorrhage; brain–body interactions; classification and regression tree analysis; prognostic decision making
13.  Intra-Parenchymal Renal Resistive Index Variation (IRRIV) Describes Renal Functional Reserve (RFR): Pilot Study in Healthy Volunteers 
An increase of glomerular filtration rate after protein load represents renal functional reserve (RFR) and is due to afferent arteriolar vasodilation. Lack of RFR may be a risk factor for acute kidney injury (AKI), but is cumbersome to measure. We sought to develop a non-invasive, bedside method that would indirectly measure RFR. Mechanical abdominal pressure, through compression of renal vessels, decreases blood flow and activates the auto-regulatory mechanism which can be measured by a fall in renal resistive index (RRI). The study aims at elucidating the relationship between intra-parenchymal renal resistive index variation (IRRIV) during abdominal pressure and RFR. In healthy volunteers, pressure was applied by a weight on the abdomen (fluid-bag 10% of subject's body weight) while RFR was measured through a protein loading test. We recorded RRI in an interlobular artery after application of pressure using ultrasound. The maximum percentage reduction of RRI from baseline was compared in the same subject to RFR. We enrolled 14 male and 16 female subjects (mean age 38 ± 14 years). Mean creatinine clearance was 106.2 ± 16.4 ml/min/1.73 m2. RFR ranged between −1.9 and 59.7 with a mean value of 28.9 ± 13.1 ml/min/1.73 m2. Mean baseline RRI was 0.61 ± 0.05, compared to 0.49 ± 0.06 during abdominal pressure; IRRIV was 19.6 ± 6.7%, ranging between 3.1% and 29.2%. Pearson's coefficient between RFR and IRRIV was 74.16% (p < 0.001). Our data show the correlation between IRRIV and RFR. Our results can lead to the development of a “stress test” for a rapid screen of RFR to establish renal susceptibility to different exposures and the consequent risk for AKI.
PMCID: PMC4933701  PMID: 27458386
renal functional reserve (RFR); renal resistive index (RRI); protein loading test; color doppler; intra-parenchymal renal resistive index variation (IRRIV); renal hemodynamics; renal blood flow; healthy volunteers
14.  Clinical adjudication in acute kidney injury studies: findings from the pivotal TIMP-2*IGFBP7 biomarker study 
Nephrology Dialysis Transplantation  2016;31(10):1641-1646.
The NEPROCHECK test (Astute Medical, San Diego, CA, USA) combines urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) to identify patients at high risk for acute kidney injury (AKI). In a US Food and Drug Administration registration trial (NCT01573962), AKI was determined by a three-member clinical adjudication committee. The objectives were to examine agreement among adjudicators as well as between adjudicators and consensus criteria for AKI and to determine the relationship of biomarker concentrations and adjudicator agreement.
Subjects were classified as AKI 3/3, 2/3, 1/3 or 0/3 according to the proportion of adjudicators classifying the case as AKI. Subjects were classified as Kidney Disease: Improving Global Outcomes (KDIGO) AKI(+) when stage 2 or 3 AKI criteria were met.
Concordance between adjudicators and between adjudicators and KDIGO criteria were lower for AKI than non-AKI subjects [78.9 versus 97.3% (P < 0.001) and 91.5 versus 97.9% (P = 0.01)]. Subjects who were AKI 3/3 or 2/3 but KDIGO AKI(−) had higher median [TIMP-2]•[IGFBP7] compared with those who were AKI-1/3 or 0/3 but KDIGO AKI(+) {2.78 [interquartile range (IQR) 2.33–3.56] versus 0.52 [IQR 0.26–1.64]; P = 0.008}. [TIMP-2]•[IGFBP7] levels were highest in patients with AKI 3/3 and lowest in AKI 0/3, whereas AKI 2/3 and 1/3 exhibited intermediate values.
In this analysis, urine [TIMP-2]•[IGFBP7] levels correlated to clinically adjudicated AKI better than to KDIGO criteria. Furthermore, in difficult cases where adjudicators overruled KDIGO criteria, the biomarker test discriminated well. This study highlights the importance of clinical adjudication of AKI for biomarker studies and lends further support for the value of urine [TIMP-2]•[IGFBP7].
PMCID: PMC5039343  PMID: 27342580
acute kidney injury; biomarkers; diagnosis; insulin-like growth factor binding protein 7; tissue inhibitor of metalloproteinases-2
15.  Lung Cancer Prognosis Before and After Recurrence in a Population-Based Setting 
Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management.
We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non–surgically treated patients.
Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non–small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients.
This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events.
PMCID: PMC4838060  PMID: 25802059
16.  Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories 
Nature Communications  2016;7:11475.
Fear can be highly adaptive in promoting survival, yet it can also be detrimental when it persists long after a threat has passed. Flexibility of the fear response may be most advantageous during adolescence when animals are prone to explore novel, potentially threatening environments. Two opposing adolescent fear-related behaviours—diminished extinction of cued fear and suppressed expression of contextual fear—may serve this purpose, but the neural basis underlying these changes is unknown. Using microprisms to image prefrontal cortical spine maturation across development, we identify dynamic BLA-hippocampal-mPFC circuit reorganization associated with these behavioural shifts. Exploiting this sensitive period of neural development, we modified existing behavioural interventions in an age-specific manner to attenuate adolescent fear memories persistently into adulthood. These findings identify novel strategies that leverage dynamic neurodevelopmental changes during adolescence with the potential to extinguish pathological fears implicated in anxiety and stress-related disorders.
Flexible fear-related responses may be advantageous in adolescence. Here the authors use microprisms to image prefrontal cortical spine maturation across development and report that plasticity in adolescent fear extinction responses is associated with dynamic reorganization in the amygdalahippocampal-PFC circuit.
PMCID: PMC4890178  PMID: 27215672
18.  Association between tobacco use and the upper gastrointestinal microbiome among Chinese men 
Cancer causes & control : CCC  2015;26(4):581-588.
Tobacco causes many adverse health conditions and may alter the upper gastrointestinal (UGI) microbiome. However, the few studies that studied the association between tobacco use and the microbiome were small and underpowered. Therefore, we investigated the association between tobacco use and the UGI microbiome in Chinese men.
We included 278 men who underwent esophageal cancer screening in Henan Province, China. Men were categorized as current, former, or never smokers from questionnaire data. UGI tract bacterial cells were characterized using the Human Oral Microbial Identification Microarray. Counts of unique bacterial species and genera estimated alpha diversity. For beta diversity, principal coordinate (PCoA) vectors were generated from an unweighted UniFrac distance matrix. Polytomous logistic regression models were used for most analyses.
Of the 278 men in this study, 46.8% were current smokers and 12.6% were former smokers. Current smokers tended to have increased alpha diversity (mean: 42.3 species) compared to never smokers (mean: 38.9 species). For a 10 species increase, the odds ratio (OR) for current smoking was 1.29 (95% CI: 1.04–1.62). Beta diversity was also associated with current smoking. The first two PCoA vectors were strongly associated with current smoking (PCoA1 OR 0.66; 95% CI: 0.51–0.87; PCoA2 OR 0.73; 95% CI: 0.56–0.95). Furthermore, Dialister invisus and Megasphaera micronuciformis were more commonly detected in current smokers than in never smokers.
Current smoking was associated with both alpha and beta diversity in the UGI tract. Future work should consider how the UGI microbiome is associated with smoking related diseases.
PMCID: PMC4852095  PMID: 25701246
China; microbiome; tobacco; upper gastrointestinal tract
19.  Chemistry and Biology of Resveratrol-Derived Natural Products 
Chemical Reviews  2015;115(17):8976-9027.
PMCID: PMC4566929  PMID: 25835567
20.  Beta-Diversity Metrics of the Upper Digestive Tract Microbiome are Associated with Body Mass Index 
Obesity (Silver Spring, Md.)  2015;23(4):862-869.
Studies of the fecal microbiome have implicated the gut microbiota in obesity, but few studies examined the microbial diversity at other sites. We explored the association between obesity and the upper gastrointestinal (UGI) microbial diversity.
The UGI microbiome of 659 healthy Chinese adults with a measured body mass index (BMI) range of 15.0 to 35.7 was characterized using the 16S rRNA gene DNA microarray (HOMIM).
In multivariate-adjusted models, alpha diversity was not associated with BMI. However, beta diversity, assessed by principal coordinate vectors generated from an unweighted unifrac distance matrix of pairwise comparisons, was associated with BMI (third and fourth vectors, p=0.0132 and p=0.0280, respectively). Moreover, beta diversity, assessed by cluster membership (3 clusters), was also associated with BMI; individuals in the first cluster (median BMI 22.35, odds ratio (OR)=0.48, 95% confidence interval (CI)=0.05–4.34) and second cluster (median BMI 22.55, OR=0.26, 95% CI=0.09–0.75) were significantly less likely to be obese (BMI ≥27.5) than those in the third cluster (median BMI 23.59).
A beta-diversity metric of the UGI microbiome is associated with a four-fold difference in obesity risk in this Asian population. Future studies should address whether the UGI microbiome plays a causal role in obesity.
PMCID: PMC4380747  PMID: 25755147
beta-diversity; body mass index; Chinese; microbiome; obesity; upper gastrointestinal tract
21.  A Scalable Biomimetic Synthesis of Resveratrol Dimers and Systematic Evaluation of their Antioxidant Activities** 
An efficient synthetic route to quadrangularin A and pallidol is reported, featuring a scalable biomimetic oxidative dimerization that proceeds in excellent yield and with complete regioselectivity. A systematic evaluation of the natural products and their synthetic precursors as radical-trapping antioxidants is presented, providing insight to the properties relevant to their purported biological activities.
PMCID: PMC4457443  PMID: 25650836
resveratrol; antioxidants; quinone methide; pallidol; quadrangularin A
22.  Risk factors for and prediction of mortality in critically ill medical–surgical patients receiving heparin thromboprophylaxis 
Previous studies have suggested that prediction models for mortality should be adjusted for additional risk factors beyond the Acute Physiology and Chronic Health Evaluation (APACHE) score. Our objective was to identify risk factors independent of APACHE II score and construct a prediction model to improve the predictive accuracy for hospital and intensive care unit (ICU) mortality.
We used data from a multicenter randomized controlled trial (PROTECT, Prophylaxis for Thromboembolism in Critical Care Trial) to build a new prediction model for hospital and ICU mortality. Our primary outcome was all-cause 60-day hospital mortality, and the secondary outcome was all-cause 60-day ICU mortality.
We included 3746 critically ill non-trauma medical–surgical patients receiving heparin thromboprophylaxis (43.3 % females) in this study. The new model predicting 60-day hospital mortality incorporated APACHE II score (main effect: hazard ratio (HR) = 0.97 for per-point increase), body mass index (BMI) (main effect: HR = 0.92 for per-point increase), medical admission versus surgical (HR = 1.67), use of inotropes or vasopressors (HR = 1.34), acetylsalicylic acid or clopidogrel (HR = 1.27) and the interaction term between APACHE II score and BMI (HR = 1.002 for per-point increase). This model had a good fit to the data and was well calibrated and internally validated. However, the discriminative ability of the prediction model was unsatisfactory (C index < 0.65). Sensitivity analyses supported the robustness of these findings. Similar results were observed in the new prediction model for 60-day ICU mortality which included APACHE II score, BMI, medical admission and invasive mechanical ventilation.
Compared with the APACHE II score alone, the new prediction model increases data collection, is more complex but does not substantially improve discriminative ability.
Trial registration: Identifier: NCT00182143
PMCID: PMC4769241  PMID: 26921148
Prediction model; Critical care; APACHE; Intensive care unit; Mortality
23.  Severe gangrene at the glans penis requiring penectomy as the first major complication of Buerger’s disease 
We report an interesting case of Buerger’s disease that manifested at the glans penis in a 56 year-old former smoker. Penile involvement in Buerger’s disease is rare. Our patient had no prior extremity or digit amputations in his 4-year history of Buerger’s disease. However, our patient did suffer from recurrent penile ulcers over an 8-week timeframe that ultimately progressed to a gangrenous, unsalvageable glans penis. He underwent a partial penectomy and urethral reconstruction with excellent post-operative results.
PMCID: PMC4749402  PMID: 27069957
Buerger’s disease; glans penis; penile involvement; penectomy; urethral reconstruction
24.  Emerging Therapeutic Targets of Sepsis-Associated Acute Kidney Injury 
Seminars in nephrology  2015;35(1):38-54.
Sepsis-associated acute kidney injury (SA-AKI) is linked to high morbidity and mortality. Thus far singular approaches to target specific pathways known to contribute to the pathogenesis of SA-AKI have failed. Because of the complexity of the pathogenesis of SA-AKI, a reassessment necessitates integrative approaches to therapeutics of SA-AKI that include general supportive therapies such as the use of vasopressors, fluids, antimicrobial and target specific and time dependent therapeutics. There has been recent progress in our understanding of the pathogenesis and treatment of SA-AKI including temporal nature of pro- and anti-inflammatory processes. In this review, we will discuss the clinical and experimental basis of emerging therapeutic approaches that focus on targeting early proinflammatory and late anti-inflammatory processes as well as therapeutics that may enhance cellular survival and recovery. Lastly we include ongoing clinical trials in sepsis.
PMCID: PMC4369320  PMID: 25795498
Inflammation; cytokines; therapeutics; septic shock
25.  Applications of time-series analysis to mood fluctuations in bipolar disorder to promote treatment innovation: a case series 
Translational Psychiatry  2016;6(1):e720-.
Treatment innovation for bipolar disorder has been hampered by a lack of techniques to capture a hallmark symptom: ongoing mood instability. Mood swings persist during remission from acute mood episodes and impair daily functioning. The last significant treatment advance remains Lithium (in the 1970s), which aids only the minority of patients. There is no accepted way to establish proof of concept for a new mood-stabilizing treatment. We suggest that combining insights from mood measurement with applied mathematics may provide a step change: repeated daily mood measurement (depression) over a short time frame (1 month) can create individual bipolar mood instability profiles. A time-series approach allows comparison of mood instability pre- and post-treatment. We test a new imagery-focused cognitive therapy treatment approach (MAPP; Mood Action Psychology Programme) targeting a driver of mood instability, and apply these measurement methods in a non-concurrent multiple baseline design case series of 14 patients with bipolar disorder. Weekly mood monitoring and treatment target data improved for the whole sample combined. Time-series analyses of daily mood data, sampled remotely (mobile phone/Internet) for 28 days pre- and post-treatment, demonstrated improvements in individuals' mood stability for 11 of 14 patients. Thus the findings offer preliminary support for a new imagery-focused treatment approach. They also indicate a step in treatment innovation without the requirement for trials in illness episodes or relapse prevention. Importantly, daily measurement offers a description of mood instability at the individual patient level in a clinically meaningful time frame. This costly, chronic and disabling mental illness demands innovation in both treatment approaches (whether pharmacological or psychological) and measurement tool: this work indicates that daily measurements can be used to detect improvement in individual mood stability for treatment innovation (MAPP).
PMCID: PMC5068881  PMID: 26812041

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