Gambling and the Role of Resilience in an International Online Sample of Current and Ex-serving Military Personnel as Compared to the General Population.

Compared to the general population, military personnel are particularly vulnerable to developing gambling problems. The present study examined the presentation of gambling-including gambling frequency, personal thoughts on reducing gambling and recommendations from others to reduce gambling-across these populations. Additionally, the study measured the association between gambling and various psychosocial risk and protective factors-including psychological distress, suicidal ideation, external encouragement to reduce substance use, days out of role, personal wellbeing, resilience, social support and intimate bonds. Data was extracted from the Global Health & Wellbeing Survey, an online self-report survey conducted in Australia, Canada, New Zealand, the United Kingdom and the United States. Of the 10,765 eligible respondents, 394 were military veterans and 337 were active military personnel. Consistent with previous research, a higher proportion of gambling behaviours were observed in both current and ex-serving military samples, compared to the general population. To varying degrees, significant associations were found between the different gambling items and all psychosocial risk and protective factors in the general population sample. However, the military sample yielded only one significant association between gambling frequency and the protective factor 'resilience'. A post hoc stepwise linear regression analysis demonstrated the possible mediating role resilience plays between gambling frequency and other psychosocial risk (psychological distress, and suicidal thoughts and behaviour) and protective factors (personal wellbeing) for the military sample. Given the findings, it is recommended that routine screening tools identifying problem gambling are used within the military, and subsequent resilience focused interventions are offered to at risk personnel.

The Relationship Between Ambient Air Pollution and Acute Ischemic Stroke: A Time-Stratified Case-Crossover Study in a City-State With Seasonal Exposure to the Southeast Asian Haze Problem.

STUDY OBJECTIVE: Studies are divided on the short-term association of air pollution with stroke. Singapore is exposed to seasonal transboundary haze. We aim to investigate the association between air pollution and stroke incidence in Singapore. METHODS: We performed a time-stratified case-crossover analysis on all ischemic stroke cases reported to the Singapore Stroke Registry from 2010 to 2015. Exposure on days was compared with control days on which exposure did not occur. Control days were chosen on the same day of the week earlier and later in the same month in the same year. We fitted a conditional Poisson regression model to daily stroke incidence that included Pollutant Standards Index and environmental confounders. The index was categorized according to established classification (0 to 50=good, 51 to 100=moderate, and ≥101=unhealthy). We assessed the relationship between stroke incidence and Pollutant Standards Index in the entire cohort and in predetermined subgroups of individual-level characteristics. RESULTS: There were 29,384 ischemic stroke cases. Moderate and unhealthy Pollutant Standards Index levels showed association with stroke occurrence, with incidence risk ratio 1.10 (95% confidence interval 1.06 to 1.13) and 1.14 (95% confidence interval 1.03 to 1.25), respectively. Subgroup analyses showed generally significant association, except in Indians and nonhypertensive patients. The association was significant in subgroups aged 65 years or older, women, Chinese, nonsmokers and those with history of diabetes, hypertension, and hyperlipidemia. Stratified by age and smoking, the risk diminished in smokers of all ages. Risk remained elevated for 5 days after exposure. CONCLUSION: We found a short-term elevated risk of ischemic stroke after exposure to air pollution. These findings have public health implications for stroke prevention and emergency health services delivery.

The NOAA NCEI marine microplastics database.

Microplastics (<5 mm) pollution is a growing problem affecting coastal communities, marine ecosystems, aquatic life, and human health. The widespread occurrence of marine microplastics, and the need to curb its threats, require expansive, and continuous monitoring. While microplastic research has increased in recent years and generated significant volumes of data, there is a lack of a robust, open access, and long-term aggregation of this data. The National Oceanic and Atmospheric Administration (NOAA) National Centers for Environmental Information (NCEI) now provides a global open access to marine microplastics data on an easily discoverable and accessible GIS web map and data portal ( https://www.ncei.noaa.gov/products/microplastics ). The objective of this data portal is to develop a repository where microplastics data are aggregated, archived, and served in a user friendly, consistent, and reliable manner. This work contributes to NCEI's efforts towards data standardization, integration, harmonization, and interoperability among national and international collaborators for monitoring global marine microplastics. This paper describes the NOAA NCEI global marine microplastics database, its creation, quality control procedures, and future directions.

Latent Transformer Models for out-of-distribution detection.

Any clinically-deployed image-processing pipeline must be robust to the full range of inputs it may be presented with. One popular approach to this challenge is to develop predictive models that can provide a measure of their uncertainty. Another approach is to use generative modelling to quantify the likelihood of inputs. Inputs with a low enough likelihood are deemed to be out-of-distribution and are not presented to the downstream predictive model. In this work, we evaluate several approaches to segmentation with uncertainty for the task of segmenting bleeds in 3D CT of the head. We show that these models can fail catastrophically when operating in the far out-of-distribution domain, often providing predictions that are both highly confident and wrong. We propose to instead perform out-of-distribution detection using the Latent Transformer Model: a VQ-GAN is used to provide a highly compressed latent representation of the input volume, and a transformer is then used to estimate the likelihood of this compressed representation of the input. We demonstrate this approach can identify images that are both far- and near- out-of-distribution, as well as provide spatial maps that highlight the regions considered to be out-of-distribution. Furthermore, we find a strong relationship between an image's likelihood and the quality of a model's segmentation on it, demonstrating that this approach is viable for filtering out unsuitable images.

Fluid overload in children with pediatric acute respiratory distress syndrome: A retrospective cohort study.

OBJECTIVES: To assess the association of cumulative fluid overload (FO) up to 14 days from the diagnosis of pediatric acute respiratory syndrome (PARDS) with pediatric intensive care unit (PICU) mortality, 28-day mechanical ventilation free days (VFD), and 28-day intensive care unit free days (IFD). We hypothesized that fluid overload, even beyond the acute period, would be associated with increased morbidity and mortality. METHODS: We conducted a retrospective cohort study of PARDS patients admitted to PICU from 2009 to 2015. For repeated admissions, we considered the admission with the highest oxygenation index (OI). Daily FO (%) was calculated as (intake - output)/weight at PICU admission × 100. Peak cumulative FO (CFO) was the highest CFO from the diagnosis of PARDS to Day 14 or to PICU discharge or mortality, whichever was earliest. Rate to peak CFO was the peak CFO divided by the number of days to reach that highest CFO. The association of FO with mortality, VFD and IFD were analyzed with logistic and linear regression models, with the following covariates: Pediatric Index of Mortality 2 score, PARDS severity, and the presence of acute kidney injury (AKI). RESULTS: There were 165 patients included in this study, with a mortality rate of 45.5% (75/165), median age 3.2 years (interquartile range [IQR] 0.7-9.9) and OI 15.8 (IQR 9.5-27.9). Seventy-three (44.2%) patients had severe PARDS and 64 (38.8%) had AKI. AKI (aOR [adjusted odds ratio] 3.19, 95% CI [confidence interval] 1.43-7.09, p = 0.004) and rate to peak cumulative FO (aOR 1.23, 95% CI 1.07-1.42, p = 0.004) were associated with mortality. AKI and peak cumulative FO were associated with decreased VFD and IFD. CONCLUSION: The rate to peak CFO over the first 14 days of PARDS was associated with mortality and peak CFO was associated with decreased VFD and IFD.

Genetic associated complications of type 2 diabetes mellitus.

According to the International Diabetes Federation, the number of adults (age of 20-79) being diagnosed with diabetes mellitus (DM) have increased from 285 million in year 2009 to 463 million in year 2019 which comprises of 95% type 2 DM patient (T2DM). Research have claimed that genetic predisposition could be one of the factors causing T2DM complications. In addition, T2DM complications cause an incremental risk to mortality. Therefore, this article aims to discuss some complications of T2DM in and their genetic association. The complications that are discussed in this article are diabetic nephropathy, diabetes induced cardiovascular disease, diabetic neuropathy, diabetic foot ulcer (DFU) and Alzheimer's disease (AD). According to the information obtained, genes associated with diabetic nephropathy (DN) are gene GABRR1 and ELMO1 that cause injury to glomerular. Replication of genes FRMD3, CARS and MYO16/IRS2 shown to have link with DN. The increase of gene THBS2, NGAL, PIP, TRAF6 polymorphism, ICAM-1 encoded for rs5498 polymorphism and C667T increase susceptibility towards DN in T2DM patient. Genes associated with cardiovascular diseases are adiponectin gene (ACRP30) and apolipoprotein E (APOE) polymorphism gene with ξ2 allele. Haptoglobin (Hp) 1-1 genotype and mitochondria superoxide dismutase 2 (SOD2) plays a role in cardiovascular events. As for genes related to diabetic neuropathy, janus kinase (JAK), mutation of SCN9A and TRPA1 gene and destruction of miRNA contribute to pathogenesis of diabetic neuropathy among T2DM patients. Expression of cytokine IL-6, IL-10, miR-146a are found to cause diabetic neuropathy. Besides, A1a16Va1 gene polymorphism, an oxidative stress influence was found as one of the gene factors. Diabetic retinopathy (DR) is believed to have association with monocyte chemoattractant protein-1 (MCP-1) and insulin-like growth factor 1 (IGF1). Over-expression of gene ENPP1, IL-6 pro-inflammatory cytokine, ARHGAP22's protein rs3844492 polymorphism and TLR4 heterozygous genotype are contributing to significant pathophysiological process causing DR, while research found increases level of UCP1 gene protects retina cells from oxidative stress. DFU is manifested by slowing in re-epithelialization of keratinocyte, persistence wound inflammation and healing impairment. Re-epithelialization disturbance was caused by E2F3 gene, reduction of Tacl gene encoded substance P causing persistence inflammation while expression of MMp-9 polymorphism contributes to healing impairment. A decrease in HIF-1a gene expression leads to increased risk of pathogenesis, while downregulation of TLR2 increases severity of wound in DFU patients. SNPs alleles has been shown to have significant association between the genetic dispositions of T2DM and AD. The progression of AD can be due to the change in DNA methylation of CLOCK gene, followed with worsening of AD by APOE4 gene due to dyslipidemia condition in T2DM patients. Insulin resistance is also a factor that contributes to pathogenesis of AD.

Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Primary results from PALOMA-4.

BACKGROUND: The cyclin-dependent kinase 4/6 inhibitor palbociclib has demonstrated efficacy and a manageable safety profile in combination with endocrine therapy in women with oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in international phase 3 trials. The phase 3 PALOMA-4 trial evaluated the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole in Asian women with ER+/HER2- ABC. METHODS: Postmenopausal women (n = 340) with no prior systemic treatment for advanced disease were randomised 1:1 to palbociclib (125 mg/d orally; 3 weeks on, 1 week off) plus letrozole (2.5 mg/d orally; continuously) or placebo plus letrozole. The primary end-point was investigator-assessed progression-free survival (PFS). Secondary end-points included tumour response and safety. RESULTS: Median (95% CI) PFS was 21.5 (16.6-24.9) months with palbociclib plus letrozole and 13.9 (13.7-16.6) months with placebo plus letrozole (hazard ratio, 0.68 [95% CI, 0.53-0.87]; P = 0.0012). Consistent with the established safety profile, the most common adverse events (AEs) with palbociclib plus letrozole were neutropenia, leukopenia, thrombocytopaenia, and anaemia. Grade 3/4 neutropenia was reported in 84.5% of patients in the palbociclib arm versus 1.2% in the placebo arm. One serious AE of febrile neutropenia in the palbociclib group was reported. CONCLUSIONS: Findings from PALOMA-4 support the efficacy and safety of first-line palbociclib plus letrozole in postmenopausal Asian women with ER+/HER2- ABC. No new safety concerns of palbociclib plus letrozole were identified. TRIAL REGISTRATION: Clinicaltrials. gov, NCT02297438.

Identification of microRNA-mRNA modules using microarray data.

BACKGROUND: MicroRNAs (miRNAs) are post-transcriptional regulators of mRNA expression and are involved in numerous cellular processes. Consequently, miRNAs are an important component of gene regulatory networks and an improved understanding of miRNAs will further our knowledge of these networks. There is a many-to-many relationship between miRNAs and mRNAs because a single miRNA targets multiple mRNAs and a single mRNA is targeted by multiple miRNAs. However, most of the current methods for the identification of regulatory miRNAs and their target mRNAs ignore this biological observation and focus on miRNA-mRNA pairs. RESULTS: We propose a two-step method for the identification of many-to-many relationships between miRNAs and mRNAs. In the first step, we obtain miRNA and mRNA clusters using a combination of miRNA-target mRNA prediction algorithms and microarray expression data. In the second step, we determine the associations between miRNA clusters and mRNA clusters based on changes in miRNA and mRNA expression profiles. We consider the miRNA-mRNA clusters with statistically significant associations to be potentially regulatory and, therefore, of biological interest. CONCLUSIONS: Our method reduces the interactions between several hundred miRNAs and several thousand mRNAs to a few miRNA-mRNA groups, thereby facilitating a more meaningful biological analysis and a more targeted experimental validation.

Lumbar spine bone mineral density predicts endothelial reactivity in patients with systemic lupus erythematosus.

OBJECTIVES: To explore whether endothelial function is related to bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive adult SLE patients and age-, sex-, BMI- and smoking-status-matched healthy controls were studied. Subjects with hypertension, hyperlipidemia, diabetes mellitus, renal impairment, dysthyroidism, history of or treatment for cardiovascular and cerebrovascular disorders, antiphospholipid syndrome, positive antiphospholipid antibodies or bone loss were excluded. Endothelial function was assessed by measuring flow-mediated dilatation (FMD) at the brachial artery and carotid intima-media thickness (IMT) by ultrasound. Lumbar and hip BMD were measured by dual-energy x-ray absorptiometry. Fasting blood samples were assayed for atherogenic index and high sensitivity C-reactive protein (hsCRP). Regression models were constructed to study the relationship between FMD and BMD. RESULTS: One hundred and ten subjects (55 SLE and 55 matched healthy controls) were studied. While there were no differences between SLE patients and controls in menopausal status, blood pressure, atherogenic index, carotid IMT and BMD, SLE patients had significantly poorer FMD even after adjustment for age, gender, smoking and baseline brachial artery diameter. Also, SLE patients with lumbar osteopenia had significantly lower FMD than those with normal BMD. Multivariate regression revealed that lower FMD was associated with lower lumbar BMD and higher serum hsCRP in SLE patients, but these relationships were absent amongst healthy controls. CONCLUSIONS: Lumbar vertebral BMD predicted endothelial reactivity in SLE patients without clinically-overt bone loss and atherosclerosis. Thus, early atherosclerotic disease should be considered in lupus patients especially if vertebral bone loss is evident.

Inverse association between hepatic stellate cell apoptosis and fibrosis in chronic hepatitis C virus infection.

Perisinusoidal hepatic stellate cells (HSC) are the principal fibrogenic cells in the liver. In animal models, HSC apoptosis is the predominant clearance mechanism of activated HSC, although data evaluating whether the same processes occur in humans are limited. We conducted a cross-sectional study to evaluate the association between HSC apoptosis and fibrosis stage in subjects with chronic hepatitis C virus (HCV) infection (n = 44) and HCV-negative controls with normal liver histology (n = 9). We used immunohistochemical techniques to identify activated (alpha-smooth muscle actin+), proliferative (Ki-67+) and apoptotic (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick end-labelling+) HSC in liver biopsy specimens from all subjects. The same pathologist enumerated positive cells per high-power field (HPF, x 200) in 20 periportal/lobular areas. HSC apoptosis was decreased in HCV-positive subjects compared with controls (median 0.4, range 0.0-3.1 vs 1.1, 0.2-3.5 cells/HPF, P = 0.02). Among HCV-positive subjects, HSC apoptosis was decreased in those with moderate to advanced fibrosis (P = 0.04) compared with those with mild fibrosis. By multivariate analysis, HSC apoptosis decreased by an average of 0.14 cells/HPF (95% confidence interval 0.01-0.28 cells/HPF) per increase in fibrosis stage (P = 0.04). While the number of activated and proliferative HSC was significantly increased in HCV-infected subjects compared with that in uninfected controls, the numbers of these cells did not differ between HCV-infected subjects with mild vs moderate/advanced fibrosis. In conclusion, the number of apoptotic HSC was significantly decreased in HCV-infected subjects with advanced fibrosis. In chronic HCV infection, inhibition of HSC apoptosis may be one mechanism by which fibrosis progresses.

Mucinous cancer of the appendix: challenges in diagnosis and treatment.

The authors report and discuss a case of a mucinous carcinoma of the appendix, a rare entity with a distinct natural history that poses diagnostic and therapeutic challenges. Mucinous peritoneal carcinomatosis is most commonly associated with primary tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, while tumor markers (CEA and CA19.9) may be surrogates for extent of disease. Treatment consists of surgical debulking, sometimes coupled with intraperitoneal drug delivery, but recurrence is universal. New treatment approaches are needed. Mucin genes are regulated in part by epidermal growth factor receptor signaling. Therefore, we initiated a phase II study of cetuximab for mucinous peritoneal carcinomatosis, that was part of this patient's treatment.

NADPH Oxidase-4 Driven Cardiac Macrophage Polarization Protects Against Myocardial Infarction-Induced Remodeling.

The reactive oxygen species-generating enzyme NADPH oxidase 4 (Nox4) is up-regulated in the heart after myocardial infarction (MI). Mice with cardiomyocyte-targeted Nox4 overexpression (TG) displayed increased macrophages in the heart at baseline, with skewing toward an M2 phenotype compared with wild-type controls (WT). After MI, TG mice had a higher proportion of M2 macrophages along with higher survival, decreased cardiac remodeling, and better contractile function than wild-type mice. The post-MI increase in cardiac matrix metalloproteinase-2 activity was substantially blunted in TG mice. These results indicate that cardiomyocyte Nox4 modulates macrophage polarization toward an M2 phenotype, resulting in improved post-MI survival and remodeling, likely through the attenuation of cardiac matrix metalloproteinase-2 activity.

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.

Analysis of a splice array experiment elucidates roles of chromatin elongation factor Spt4-5 in splicing.

Splicing is an important process for regulation of gene expression in eukaryotes, and it has important functional links to other steps of gene expression. Two examples of these linkages include Ceg1, a component of the mRNA capping enzyme, and the chromatin elongation factors Spt4-5, both of which have recently been shown to play a role in the normal splicing of several genes in the yeast Saccharomyces cerevisiae. Using a genomic approach to characterize the roles of Spt4-5 in splicing, we used splicing-sensitive DNA microarrays to identify specific sets of genes that are mis-spliced in ceg1, spt4, and spt5 mutants. In the context of a complex, nested, experimental design featuring 22 dye-swap array hybridizations, comprising both biological and technical replicates, we applied five appropriate statistical models for assessing differential expression between wild-type and the mutants. To refine selection of differential expression genes, we then used a robust model-synthesizing approach, Differential Expression via Distance Synthesis, to integrate all five models. The resultant list of differentially expressed genes was then further analyzed with regard to select attributes: we found that highly transcribed genes with long introns were most sensitive to spt mutations. QPCR confirmation of differential expression was established for the limited number of genes evaluated. In this paper, we showcase splicing array technology, as well as powerful, yet general, statistical methodology for assessing differential expression, in the context of a real, complex experimental design. Our results suggest that the Spt4-Spt5 complex may help coordinate splicing with transcription under conditions that present kinetic challenges to spliceosome assembly or function.

A fast pathway for fear in human amygdala.

A fast, subcortical pathway to the amygdala is thought to have evolved to enable rapid detection of threat. This pathway's existence is fundamental for understanding nonconscious emotional responses, but has been challenged as a result of a lack of evidence for short-latency fear-related responses in primate amygdala, including humans. We recorded human intracranial electrophysiological data and found fast amygdala responses, beginning 74-ms post-stimulus onset, to fearful, but not neutral or happy, facial expressions. These responses had considerably shorter latency than fear responses that we observed in visual cortex. Notably, fast amygdala responses were limited to low spatial frequency components of fearful faces, as predicted by magnocellular inputs to amygdala. Furthermore, fast amygdala responses were not evoked by photographs of arousing scenes, which is indicative of selective early reactivity to socially relevant visual information conveyed by fearful faces. These data therefore support the existence of a phylogenetically old subcortical pathway providing fast, but coarse, threat-related signals to human amygdala.

A comparison of liver transplantation outcomes in the pre- vs. post-MELD eras.

BACKGROUND: The model for end stage liver disease (MELD)-based organ allocation system is designed to prioritize orthotopic liver transplantation (OLT) for patients with the most severe liver disease. However, there are no published data to confirm whether this goal has been achieved or whether the policy has affected long-term post-OLT survival. AIM: To compare pre-OLT liver disease severity and long-term (1 year) post-OLT survival between the pre- and post-MELD eras. METHODS: Using the United Network of Organ Sharing database, we compared two cohorts of adult patients undergoing cadaveric liver transplant in the pre-MELD (n = 3857) and post-MELD (n = 4245) eras. We created multivariable models to determine differences in: (i) pre-OLT liver disease severity as measured by MELD; and (ii) 1-year post-OLT outcomes. RESULTS: Patients undergoing OLT in the post-MELD era had more severe liver disease at the time of transplantation (mean MELD = 20.5) vs. those in the pre-MELD era (mean MELD = 17.0). There were no differences in the unadjusted patient or graft survival at 1 year post-OLT. This difference remained insignificant after adjusting for a range of prespecified recipient, donor, and transplant centre-related factors in multivariable survival analysis. CONCLUSIONS: Although liver disease severity is higher in the post- vs. pre-MELD era, there has been no change in long-term post-OLT patient or graft survival. These results indicate that the MELD era has achieved its primary goals by allocating cadaveric livers to the sickest patients without compromising post-OLT survival.

Inhibition of thrombin activatable fibrinolysis inhibitor by cysteine derivatives.

Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a basic carboxypeptidase that functions as a fibrinolysis inhibitor through the cleavage of C-terminal lysine on partially degraded fibrin. Modulation of TAFI activity provides a potential therapy for thrombosis complications by potentiating fibrinolysis. In our study, we identified three novel TAFI inhibitors containing a cysteine backbone. Three cysteine derivatives, guanidinyl-L-cysteine, glycyl-L-cysteine, and glycyl-glycyl-L-cysteine were tested in TAFI substrate assays and showed K(app)(i)=0.08, 0.14, and 0.99 microM, respectively. Subsequent fibrinolysis assays confirmed their TAFI inhibitory activities. Guanidinyl-L-cysteine showed inhibitory activity in a human plasma clot lysis assay (IC(50)=9.4 microM). Identification of these cysteine derivatives represents an opportunity to develop potent and specific TAFI inhibitors.

Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice.

The lack of tumor models that can reliably predict for response to anticancer agents remains a major deficiency in the field of experimental cancer therapy. Although heterotransplants of certain human solid tumors can be successfully grown in nude mice, they have never been appropriately explored for prediction of in vivo chemosensitivity to anticancer agents. We determined the tumor response rate and studied the influence of several biological and molecular tumor parameters on the in vivo sensitivity to paclitaxel in a series of heterotransplanted human non-small cell lung cancer (NSCLC) tumors. One hundred consecutive resected NSCLC tumors were heterotransplanted s.c. in nude mice. The in vivo sensitivity to i.v. paclitaxel (60 mg/kg every 3 weeks) was studied in 34 successfully grown heterotransplants. Treatment started when the tumors reached a size of 5 mm in diameter, and strict standard clinical criteria (>50% shrinkage in tumor weight or cross-sectional surface) were used to define tumor response. Baseline multidrug resistance protein (MRP), Her-2/neu, and epidermal growth factor receptor (EGFR) expression, and pre- and posttherapy bax and bcl-2 expression were determined by Western blot analysis. p53 status was determined by sequencing. The overall take rate was 46% (95% confidence interval, 36-56%) and was significantly higher (P < 0.05) for squamous carcinoma tumors (75%) than for adenocarcinoma tumors (30%) and bronchoalveolar tumors (23%). The heterotransplants were morphologically very similar to the original tumors. The response rate to paclitaxel was 21% (95% confidence interval, 9-38%). Baseline tumor parameters associated with response were no Her-2/neu expression (none of the responding tumors expressed Her-2/neu versus 48% of the nonresponding tumors, P = 0.05) and baseline bcl-2 expression (all responding tumors expressed bcl-2 versus only 43% of the nonresponding tumors, P = 0.02). There was a trend toward a higher response rate in bax-positive tumors, and MRP- and EGFR-negative tumors, but it was not statistically significant. The response was independent of baseline p53 status and baseline mitotic index. Responding tumors had a higher bax/bcl-2 ratio 24 h after therapy, but the difference was only marginally significant (2.8 for responding tumors versus 1.1 for nonresponding tumors, P = 0.07). The extent of mitotic arrest at 24 h after therapy was not associated with response. Human NSCLC heterotransplants are morphologically identical to the original tumors and have a response rate to paclitaxel that is equivalent to that reported in Phase II studies in patients with advanced NSCLC treated with single-agent paclitaxel. NSCLC heterotransplants deserve to be explored to evaluate new agents for lung cancer and to predict clinical response on an individual basis in selected groups of patients.

Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy.

PURPOSE: Neoadjuvant chemotherapy for breast cancer creates new possibilities for the analysis of biological factors in the tumor and/or host, which may play a role in the response to treatment. In this study we analyzed whether changes in local antitumor immunity take place after neoadjuvant paclitaxel therapy and if they correlate with response to treatment. EXPERIMENTAL DESIGN: Neoadjuvant chemotherapy (paclitaxel, 200 mg/m2 q2w, 4 treatments) was followed by definitive surgical management. Histological sections from the pre- and post-treatment surgical specimens of 25 patients were analyzed for the extent of lymphocytic infiltration and presence of tumor infiltrating lymphocytes (TILs). The cumulative apoptotic response in the tumor after the first dose of paclitaxel was also studied in 10 of 25 patients. RESULTS: Pretreatment lymphocytic infiltrate in the tumor was minimal in the majority of patients and showed no relationship with clinical response. In the patients without TILs before treatment, development of TILs after treatment was noted in 0/3 (0%) patients with stable disease, 3/12 (25%) patients with clinical partial response, and 4/6 (67%) patients with clinical complete response and pathological residual disease. These correlated with the tumor cell apoptotic response to the first dose of paclitaxel. CONCLUSIONS: These results suggest that development of TILs after treatment correlates with clinical response to neoadjuvant paclitaxel therapy. The possible mechanism(s) whereby neoadjuvant chemotherapy may lead to induction of antitumor T cells is discussed. Immunological processes may influence the response of breast cancer patients to neoadjuvant treatment.