Differential Sensitivity to Ionizing Radiation in Gemcitabine-Resistant and Paclitaxel-Resistant Pancreatic Cancer Cells.

PURPOSE: Chemoresistance remains a major challenge in treating pancreatic ductal adenocarcinoma (PDAC). Although chemoradiation has proven effective in other tumor types, such as head and neck squamous cell carcinoma, its role in PDAC and effect on acquired chemoresistance have yet to be fully explored. In this study, we investigated the sensitivity of gemcitabine-resistant (GR) and paclitaxel-resistant (PR) PDAC cells to ionizing radiation (IR) and their underlying mechanisms. METHODS AND MATERIALS: GR and PR clones were generated from PANC-1, PATU-T, and SUIT2-007 pancreatic cancer cell lines. Cell survival after radiation was assessed using clonogenic assay, sulforhodamine B assay, apoptosis, and spheroid growth by bioluminescence. Radiation-induced DNA damage was assessed using Western blot, extra-long polymerase chain reaction, reactive oxygen species production, and immunofluorescence. Autophagy and modulation of the Hippo signaling pathway were investigated using proteomics, Western blot, immunofluorescence, and reverse-transcription quantitative polymerase chain reaction. RESULTS: In both 2- and 3-dimensional settings, PR cells were more sensitive to IR and showed decreased ß-globin amplification, indicating more DNA damage accumulation compared with GR or wild-type cells after 24 hours. Proteomic analysis of PR PATU-T cells revealed that the protein MST4, a kinase involved in autophagy and the Hippo signaling pathway, was highly downregulated. A differential association was found between autophagy and radiation treatment depending on the cell model. Interestingly, increased yes-associated protein nuclear localization and downstream Hippo signaling pathway target gene expression were observed in response to IR. CONCLUSIONS: This was the first study investigating the potential of IR in targeting PDAC cells with acquired chemoresistance. Our results demonstrate that PR cells exhibit enhanced sensitivity to IR due to greater accumulation of DNA damage. Additionally, depending on the specific cellular context, radiation-induced modulation of autophagy and the Hippo signaling pathway emerged as potential underlying mechanisms, findings with potential to inform personalized treatment strategies for patients with acquired chemoresistance.

Prognostic and predictive value of human equilibrative nucleoside transporter 1 (hENT1) in extrahepatic cholangiocarcinoma: a translational study.

Introduction: Effective (neo) adjuvant chemotherapy for cholangiocarcinoma is lacking due to chemoresistance and the absence of predictive biomarkers. Human equilibrative nucleoside transporter 1 (hENT1) has been described as a potential prognostic and predictive biomarker. In this study, the potential of rabbit-derived (SP120) and murine-derived (10D7G2) antibodies to detect hENT1 expression was compared in tissue samples of patients with extrahepatic cholangiocarcinoma (ECC), and the predictive value of hENT1 was investigated in three ECC cell lines. Methods: Tissues of 71 chemonaïve patients with histological confirmation of ECC were selected and stained with SP120 or 10D7G2 to assess the inter-observer variability for both antibodies and the correlation with overall survival. Concomitantly, gemcitabine sensitivity after hENT1 knockdown was assessed in the ECC cell lines EGI-1, TFK-1, and SK-ChA-1 using sulforhodamine B assays. Results: Scoring immunohistochemistry for hENT1 expression with the use of SP120 antibody resulted in the highest interobserver agreement but did not show a prognostic role of hENT1. However, 10D7G2 showed a prognostic role for hENT1, and a potential predictive role for gemcitabine sensitivity in hENT1 in SK-ChA-1 and TFK-1 cells was found. Discussion: These findings prompt further studies for both preclinical validation of the role of hENT1 and histochemical standardization in cholangiocarcinoma patients treated with gemcitabine-based chemotherapy.

Prediction Model for Early-Stage Pancreatic Cancer Using Routinely Measured Blood Biomarkers.

Importance: Accurate risk prediction models using routinely measured biomarkers-eg, carbohydrate antigen 19-9 (CA19-9) and bilirubin serum levels-for pancreatic cancer could facilitate early detection of pancreatic cancer and prevent potentially unnecessary diagnostic tests for patients at low risk. An externally validated model using CA19-9 and bilirubin serum levels in a larger cohort of patients with pancreatic cancer or benign periampullary diseases is needed. Objective: To assess the discrimination, calibration, and clinical utility of a prediction model using readily available blood biomarkers (carbohydrate antigen 19-9 [CA19-9] and bilirubin) to distinguish early-stage pancreatic cancer from benign periampullary diseases. Design, Setting, and Participants: This diagnostic study used data from 4 academic hospitals in Italy, the Netherlands, and the UK on adult patients with pancreatic cancer or benign periampullary disease treated from 2014 to 2022. Analyses were conducted from September 2022 to February 2023. Exposures: Serum levels of CA19-9 and bilirubin from samples collected at diagnosis and before start of any medical intervention. Main Outcomes and Measures: Discrimination (measured by the area under the curve [AUC]), calibration, and clinical utility of the prediction model and the biomarkers, separately. Results: The study sample comprised 249 patients in the development cohort (mean [SD] age at diagnosis, 67 [11] years; 112 [45%] female individuals), and 296 patients in the validation cohort (mean [SD] age at diagnosis, 68 [12] years; 157 [53%] female individuals). At external validation, the prediction model showed an AUC of 0.89 (95% CI, 0.84-0.93) for early-stage pancreatic cancer vs benign periampullary diseases, and outperformed CA19-9 (difference in AUC [ΔAUC], 0.10; 95% CI, 0.06-0.14; P < .001) and bilirubin (∆AUC, 0.07; 95% CI, 0.02-0.12; P = .004). In the subset of patients without elevated tumor marker levels (CA19-9 <37 U/mL), the model showed an AUC of 0.84 (95% CI, 0.77-0.92). At a risk threshold of 30%, decision curve analysis indicated that performing biopsies based on the prediction model was equivalent to reducing the biopsy procedure rate by 6% (95% CI, 1%-11%), without missing early-stage pancreatic cancer in patients. Conclusions and Relevance: In this diagnostic study of patients with pancreatic cancer or benign periampullary diseases, an easily applicable risk score showed high accuracy for distinguishing early-stage pancreatic cancer from benign periampullary diseases. This model could be used to assess the added diagnostic and clinical value of novel biomarkers and prevent potentially unnecessary invasive diagnostic procedures for patients at low risk.

New Pharmacological Strategies against Pancreatic Adenocarcinoma: The Multifunctional Thiosemicarbazone FA4.

A new sigma-2 (σ2) receptor ligand (FA4) was efficiently synthesized and evaluated for cytotoxic, proapoptotic, and antimigratory activity on pancreatic ductal adenocarcinoma (PDAC) primary cell cultures, which restrained the aggressive and chemoresistant behavior of PDAC. This compound showed relevant antiproliferative activity with half maximal inhibitory concentration (IC50) values ranging from 0.701 to 0.825 µM. The cytotoxic activity was associated with induction of apoptosis, resulting in apoptotic indexes higher than those observed after exposure to a clinically relevant concentration of the gemcitabine, the first-line drug used against PDAC. Interestingly, FA4 was also able to significantly inhibit the migration rate of both PDAC-1 and PDAC-2 cells in the scratch wound-healing assay. In conclusion, our results support further studies to improve the library of thiosemicarbazones targeting the σ-2 receptor for a deeper understanding of the relationship between the biological activity of these compounds and the development of more efficient anticancer compounds against PDAC.

The Diagnostic Value of the CA19-9 and Bilirubin Ratio in Patients with Pancreatic Cancer, Distal Bile Duct Cancer and Benign Periampullary Diseases, a Novel Approach.

Distinction of pancreatic ductal adenocarcinoma (PDAC) in the head of the pancreas, distal cholangiocarcinoma (dCCA), and benign periampullary conditions, is complex as they often share similar clinical symptoms. However, these diseases require specific management strategies, urging improvement of non-invasive tools for accurate diagnosis. Recent evidence has shown that the ratio between CA19-9 and bilirubin levels supports diagnostic distinction of benign or malignant hepatopancreaticobiliary diseases. Here, we investigate the diagnostic value of this ratio in PDAC, dCCA and benign diseases of the periampullary region in a novel fashion. To address this aim, we enrolled 265 patients with hepatopancreaticobiliary diseases and constructed four logistic regression models on a subset of patients (n = 232) based on CA19-9, bilirubin and the ratio of both values: CA19-9/(bilirubin-1). Non-linearity was investigated using restricted cubic splines and a final model, the 'Model Ratio', based on these three variables was fitted using multivariable fractional polynomials. The performance of this model was consistently superior in terms of discrimination and calibration compared to models based on CA19-9 combined with bilirubin and CA19-9 or bilirubin alone. The 'Model Ratio' accurately distinguished between malignant and benign disease (AUC [95% CI], 0.91 [0.86-0.95]), PDAC and benign disease (AUC 0.91 [0.87-0.96]) and PDAC and dCCA (AUC 0.83 [0.74-0.92]) which was confirmed by internal validation using 1000 bootstrap replicates. These findings provide a foundation to improve minimally-invasive diagnostic procedures, ultimately ameliorating effective therapy for PDAC and dCCA.

Weight loss support seeking on twitter: the impact of weight on follow back rates and interactions.

People seek weight loss support on online social networks, but little is known about how to build a supportive community. We created four Twitter accounts portraying women interested in weight loss (two obese, two normal weight/overweight) and followed health care professional and peer accounts for 2-5 weeks. We examined follow back rates, interactions, and organic follows from professionals and peers by weight status. Follow back rates did not differ by weight status when following professionals (6.8 % normal weight/overweight vs 11.0 % for obese; p = 0.4167) or peers (6.7 % for normal weight/overweight vs 10.8 % for obese; p = 0.1548). Number of interactions and organic followers also did not differ by weight status. Peers interacted with study accounts significantly more than professionals (p = 0.0138), but interactions were infrequent. Women seeking weight loss support on Twitter may need to be present for more than 5 weeks to build an interactive weight loss community.

Immunosuppressive therapy after solid-organ transplantation: does the INTERMED identify patients at risk of poor adherence?

Background: Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT) recipients. Objective: This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20) might have lower medication adherence than noncomplex patients (INTERMED≤20). Methods: Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20). Results: Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11) and noncomplex patients (N=21) were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value). Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. Conclusion: Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly morbid patients who have complex social and psychological characteristics (AU)

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Substance Use and Mental Health Stigma in Veterans With Co-Occurring Disorders.

OBJECTIVE: This pilot study examined whether substance use or mental illness was more stigmatizing among individuals with co-occurring mental health and substance abuse problems. METHODS: This study included 48 individuals with co-occurring substance use and mental health problems enrolled in a Substance Abuse and Mental Health Services funded treatment program. Subjects received a baseline assessment that included addiction, mental health, and stigma measures. RESULTS: The sample consisted primarily of White males with an average age of 38 years. Substance abuse was found to be more stigmatizing than mental illness, F(1, 47) = 14.213, p < .001, and stigma varied across four different levels of stigma (Aware, Agree, Apply, and Harm), F(2.099, 98.675) = 117.883, p < .001. The interaction between type and level of stigma was also significant, F(2.41, 113.284) = 20.250, p < .001, indicating that differences in reported stigma between types varied across levels of stigma. Post hoc tests found a significant difference between all levels of stigma except for the comparison between Apply and Harm. Reported stigma was significantly higher for substance abuse than mental illness at the Aware and Agree levels. In addition, pairwise comparisons found significant differences between all levels of stigma with the exception of the comparison between Apply and Harm, indicating a pattern whereby reported stigma generally decreased from the first level (Aware stage) to subsequent levels. CONCLUSIONS: These results have important implications for treatment, suggesting the need to incorporate anti-stigma interventions for individuals with co-occurring disorders with a greater focus on substance abuse.

Immunosuppressive therapy after solid-organ transplantation: does the INTERMED identify patients at risk of poor adherence?

BACKGROUND: Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT) recipients. OBJECTIVE: This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20) might have lower medication adherence than noncomplex patients (INTERMED≤20). METHODS: Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20). RESULTS: Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11) and noncomplex patients (N=21) were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value). Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. CONCLUSION: Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly morbid patients who have complex social and psychological characteristics.

Using Mixed Methods to Examine the Role of Veterans' Illness Perceptions on Depression Treatment Utilization and HEDIS Concordance.

BACKGROUND: Although depression screening occurs annually in the Department of Veterans Affairs (VA) primary care, many veterans may not be receiving guideline-concordant depression treatment. OBJECTIVES: To determine whether veterans' illness perceptions of depression may be serving as barriers to guideline-concordant treatment. RESEARCH DESIGN: We used a prospective, observational design involving a mailed questionnaire and chart review data collection to assess depression treatment utilization and concordance with Healthcare Effectiveness Data and Information Set guidelines adopted by the VA. The Self-Regulation Model of Illness Behavior guided the study. SUBJECTS: Veterans who screened positive for a new episode of depression at 3 VA primary care clinics in the US northeast. MEASURES: The Illness Perceptions Questionnaire-Revised, measuring patients' perceptions of their symptoms, cause, timeline, consequences, cure or controllability, and coherence of depression and its symptoms, was our primary measure to calculate veterans' illness perceptions. Treatment utilization was assessed 3 months after the positive depression screen through chart review. Healthcare Effectiveness Data and Information Set (HEDIS) guideline-concordant treatment was determined according to a checklist created for the study. RESULTS: A total of 839 veterans screened positive for a new episode of depression from May 2009-June 2011; 275 (32.8%) completed the survey. Ninety-two (33.9%) received HEDIS guideline-concordant depression treatment. Veterans' illness perceptions of their symptoms, cause, timeline, and controllability of depression predicted receiving guideline-concordant treatment. CONCLUSIONS: Many veterans are not receiving guideline-concordant treatment for depression. HEDIS guideline measures may not be assessing all aspects of quality depression care. Conversations about veterans' illness perceptions and their specific needs are encouraged to ensure that appropriate treatment is achieved.

Early-treatment weight loss predicts 6-month weight loss in women with obesity and depression: implications for stepped care.

OBJECTIVE: Some adults with comorbid depression and obesity respond well to lifestyle interventions while others have poor outcomes. The objective of this study was to evaluate whether early-treatment weight loss progress predicts clinically significant 6-month weight loss among women with obesity and depression. METHODS: We conducted a secondary analysis of data from 75 women with obesity and depression who received a standard lifestyle intervention. Relative risks (RRs) and 95% confidence intervals (CIs) for achieving ≥5% weight loss by 6 months were calculated based on whether they achieved ≥1 lb/week weight loss in weeks 2-8. Among those on target at week 3, we examined potential subsequent time points at which weight loss progress might identify additional individuals at risk for treatment failure. RESULTS: At week 2, women who averaged ≥1 lb/week loss were twice as likely to achieve 5% weight loss by 6 months than those who did not (RR=2.40; 95% CI: 2.32-4.29); weight loss at weeks 3-8 was similarly predictive (RRs=2.02-3.20). Examining weight loss progress at week 3 and subsequently at a time point during weeks 4-8, 52-67% of participants were not on target with their weight loss, and those on target were 2-3 times as likely to achieve 5% weight loss by 6 months (RRs=1.82-2.92). CONCLUSION: Weight loss progress as early as week 2 of treatment predicts weight loss outcomes for women with comorbid obesity and depression, which supports the feasibility of developing stepped care interventions that adjust treatment intensity based on early progress in this population.

The role of coping in depression treatment utilization for VA primary care patients.

OBJECTIVE: To examine the impact of Veterans' coping strategies on mental health treatment engagement following a positive screen for depression. METHODS: A mixed-methods observational study using a mailed survey and semi-structured interviews. Sample included 271 Veterans who screened positive for depression during a primary care visit at one of three VA medical centers and had not received a diagnosis of depression or prescribed antidepressants 12 months prior to screening. A subsample of 23 Veterans was interviewed. RESULTS: Logistic regression models showed that Veterans who reported more instrumental support and active coping were more likely to receive depression or other mental health treatment within three months of their positive depression screen. Those who reported emotional support or self-distraction as coping strategies were less likely to receive any treatment in the same time frame. Qualitative analyses revealed that how Veterans use these and other coping strategies can impact treatment engagement in a variety of ways. CONCLUSIONS: The relationship between Veterans' use of coping strategies and treatment engagement for depression may not be readily apparent without in-depth exploration. PRACTICE IMPLICATIONS: In VA primary care clinics, nurse care managers and behavioral health providers should explore how Veterans' methods of coping may impact treatment engagement.

A pilot study of Qigong for reducing cocaine craving early in recovery.

OBJECTIVES: This pilot study examined the feasibility, preliminary efficacy, and determined the effect sizes of external qigong therapy (EQT) in reducing cue-elicited cocaine craving and associated symptoms among recently abstinent cocaine-dependent (CD) individuals. METHODS: This study randomized 101 CD subjects to either a real EQT (n=51) or sham EQT control (n=50) group. Subjects underwent a baseline assessment and a weekly cue-exposure session for 2 weeks. Total EQT or sham treatments ranged from 4 to 6 sessions in 2 weeks. RESULTS: EQT-treated subjects displayed a greater reduction in cue-elicited craving (p=0.06) and symptoms of depression (p<0.05) with medium effect sizes. CONCLUSIONS: This study demonstrated the feasibility of delivering EQT among CD individuals early in residential treatment. Future research should include a larger sample and examine the mechanisms and potential longitudinal benefits of EQT.

A wraparound treatment engagement intervention for homeless veterans with co-occurring disorders.

This article reports the results of a low-intensity wraparound intervention, Maintaining Independence and Sobriety through Systems Integration, Outreach, and Networking (MISSION), to augment Treatment as Usual (TAU) and engage and retain homeless veterans with a co-occurring disorder (COD) in care. Using a quasi-experimental design, 333 homeless veterans were enrolled, 218 who received MISSION along with TAU and 115 who received TAU alone. Group assignment was based on MISSION treatment slot availability at time of enrollment. Compared with TAU alone, individuals receiving MISSION demonstrated greater outpatient session attendance within the 30 days before the 12-month follow up assessment and a larger decline from baseline in the number of psychiatric hospitalization nights. Individuals in the MISSION and TAU-only groups both showed statistically significant improvements in substance use and related problems at 12 months, with those in MISSION less likely to drink to intoxication and experience serious tension or anxiety. Although this study confirmed that compared with TAU alone, MISSION along with TAU is effective in augmenting usual care and engaging and retaining homeless veterans in treatment, some caution is warranted as this study did not involve random assignment. These results, however, are similar to a recent study involving a briefer version of the intervention which included random assignment. Based on these findings, MISSION is being further studied in the joint Department of Housing and Urban Development (HUD) - Department of Veterans Affairs (VA) Supportive Housing (HUD-VASH) program, which offers rapid housing placement and case management to aid in housing maintenance.

Commentary on the shifting processes model: a conceptual model for weight management.

Macchi and colleagues propose a theoretical model that merges concepts from the biopsychosocial model and family systems theory to produce a broader framework for understanding weight loss and maintenance (see record 2013-28564-001). The Shifting Processes Model views individual weight loss and maintenance in the context of family dynamics, including family eating and exercise habits, home environment, and family relationships. The authors reason that traditional models put the burden of change on the individual rather than the family system, when the latter is an important context of individual behavior.

Serum water analysis in normal pregnancy and preeclampsia.

Hemodilution and hemoconcentration affect hematology measurements and serum analyte concentrations but whether a given blood sample is hemodiluted or hemoconcentrated is frequently not known. Preeclampsia (PE) is a serious pregnancy complication and samples obtained from PE patients may be relatively hemoconcentrated when compared to those of normal pregnancy, where hemodilution is the norm. Laboratory test results may appear similar when values would differ if adjusted for hemodilution and hemoconcentration. We sought to determine if serum water (SW) content analysis can facilitate differentiation of the hemodilution of normal pregnancy from the hemoconcentration of PE, within the broader search of a clinical laboratory method to potentially correct for pregnancy-related, sample concentration variations. Serum samples from 59 non-pregnant, 64 normal pregnant, 23 mild PE, and 8 severe PE patients were tested for SW content. The mean results in g/100g were as follows: 91.15, 91.86, 92.00, and 92.46 respectively. SW data were also compared with corresponding total protein (TP), serum albumin (SA), and hematocrit (HCT) results. The t-test was significant (p= <0.001) for TP, SA, HCT, and SW in group-by-group comparisons. SA and SW were significantly, inversely correlated in the normal pregnant and severe PE groups, while TP and SW were significantly, inversely correlated in all groups. Correlation coefficients were stronger in the pregnancy groups than the non-pregnant group. This study demonstrates differences in the SW content between: non-pregnant, normal pregnant, mild PE, and severe PE patient sera.

Incremental efficacy of adding bupropion to the nicotine patch for smoking cessation in smokers with a recent history of alcohol dependence: results from a randomized, double-blind, placebo-controlled study.

AIMS: The primary aim of this study was to compare the efficacy of smoking cessation treatment using a combination of nicotine patch and bupropion vs. nicotine patch and placebo bupropion. A secondary aim was to investigate whether the efficacy of bupropion is moderated by belief about whether one is receiving active or placebo medication. METHODS: Participants were recruited from a residential substance abuse treatment program and the community. We randomly assigned 148 smokers with between 2 and 12 months of alcohol abstinence to nicotine patch plus bupropion or nicotine patch plus placebo. All participants also received seven counseling sessions. RESULTS: At follow up, differences between medication conditions were not significant. Seven-day point prevalence quit rates in the patch plus bupropion vs. patch plus placebo conditions at week 24 were 6% and 11%, respectively. Differences between groups on prolonged abstinence and time to first smoking lapse were also not significant. However, among participants who received bupropion, those who accurately "guessed" that they were receiving bupropion were more likely to remain abstinent than those who incorrectly believed they were receiving placebo. CONCLUSIONS: Findings do not support combining nicotine patch and bupropion for smoking cessation in this population. However, findings support previous studies suggesting the importance of assessing the blind in smoking cessation studies and its possible moderating effect on medication efficacy. Future directions for enhancing smoking cessation outcome in these smokers include investigations of intensive behavioral and pharmacological interventions, including studies of potential interactions between individual genetic differences and medication efficacy.

Impact of traumatic and violent victimization experiences in individuals with schizophrenia and schizoaffective disorder.

Individuals with schizophrenia or schizoaffective disorder (SZ) experience more violent victimization and noninterpersonal traumatic experiences than the general population. Earlier studies, however, have generally excluded one or grouped together victimization and trauma experiences into single outcome variables, which may obscure their contributory role to SZ symptoms. This issue is important because there is some evidence that intentionally induced violence produces higher rates of psychopathology than nonintentional traumatic experiences. We examined the independent contribution of both types of victimization experiences on SZ patients' symptomatology. We were also interested in determining whether SZ patients' pattern of acute symptom presentation could discriminate between SZ patients with and without posttraumatic stress disorder (PTSD) comorbidity. SZ inpatients (n = 70) were assessed for the presence of comorbid PTSD diagnosis, violent victimization, and noninterpersonal traumatic experiences. Patients were also rated on SZ symptom severity and general psychopathology measures. Past violent victimization experiences predicted severity of dysphoria and anxiety in SZ. Past traumatic experiences, however, predicted severity of psychosis. Victimization predicted severity of patients' autistic/cognitive symptoms. SZ patients with comorbid PTSD presented with significantly more anxiety and dysphoria symptoms and SZ illness chronicity than their non-PTSD counterparts. Discriminant function analysis revealed that the severity of positive, dysphoric, autistic/cognitive, and anxiety symptoms differentiated comorbid PTSD patients from their non-PTSD counterparts, with an overall 72.9% classification rate. Past traumatic and victimization experiences are significantly associated with SZ patients' symptom severity and illness course in partially overlapping domains. Use of common assessment strategies may be employed to increase detection of PTSD in SZ patients presenting for acute treatment.

Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.

BACKGROUND: Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants. METHODS: We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors. RESULTS: In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P=0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P=0.02) and death that was not related to relapse (35% vs. 22%, P=0.02). CONCLUSIONS: This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.

A common human TLR1 polymorphism regulates the innate immune response to lipopeptides.

Toll-like receptors (TLR) are critical mediators of the immune response to pathogens and human polymorphisms in this gene family regulate inflammatory pathways and are associated with susceptibility to infection. Lipopeptides are present in a wide variety of microbes and stimulate immune responses through TLR1/2 or TLR2/6 heterodimers. It is not currently known whether polymorphisms in TLR1 regulate the innate immune response. We stimulated human whole blood with triacylated lipopeptide, a ligand for TLR1/2 heterodimers, and found substantial inter-individual variation in the immune response. We sequenced the coding region of TLR1 and found a non-synonymous polymorphism, I602S (base pair T1805G), that regulated signalling. In comparison to TLR1_602S, the 602I variant mediated substantially greater basal and lipopeptide-induced NF-kappaB signalling in transfected HEK293 cells. These signalling differences among TLR1 variants were also found with stimulation by extracts of Mycobacterium tuberculosis. Furthermore, individuals with the 602II genotype produced substantially more IL-6 than those with the 602SS variant in a lipopeptide-stimulated whole-blood cytokine assay. Together, these observations demonstrate that variation in the inflammatory response to bacterial lipopeptides is regulated by a common TLR1 transmembrane domain polymorphism that could potentially impact the innate immune response and clinical susceptibility to a wide spectrum of pathogens.