Prolonged exposure therapy for PTSD in individuals with opioid use disorder: A randomized pilot study.

OBJECTIVE: Nearly all individuals with opioid use disorder (OUD) report lifetime trauma exposure and one-third meet diagnostic criteria for posttraumatic stress disorder (PTSD). Although prolonged exposure (PE) therapy is a first-line treatment for PTSD, little is known about the effects of PE in individuals with co-occurring OUD. Furthermore, its efficacy is commonly undermined by poor therapy attendance. This pilot study evaluated the feasibility and initial efficacy of a novel PE protocol for improving PE attendance and PTSD symptoms among buprenorphine- or methadone-maintained adults with PTSD. METHOD: Thirty participants with co-occurring PTSD and OUD were randomized to receive either: (a) continued medications for OUD (MOUD) treatment as usual (TAU), (b) Prolonged Exposure therapy (PE), or (c) PE with financial incentives delivered contingent upon PE session attendance (PE+). Primary outcomes included PE session attendance, PTSD symptom severity, and use of opioids other than prescribed MOUD. RESULTS: PE+ participants attended significantly more therapy sessions vs. PE (87% vs. 35%; p <.0001). PTSD symptom reductions were also significantly greater in the PE+ vs. TAU group (p =.046). Participants in the two PE conditions submitted significantly fewer urine samples that tested positive for opioids than TAU participants (0% vs. 22%; p =.007). CONCLUSIONS: These findings provide preliminary support for the efficacy of PE+ for improving PE attendance and PTSD symptoms without prompting opioid relapse in individuals with co-occurring PTSD and OUD. These promising results justify a larger scale randomized clinical trial to more rigorously evaluate this novel treatment approach.

Recidivism prevention for impaired driving: Longitudinal 5-year outcomes from Quebec's severity-based intervention assignment program.

INTRODUCTION: Driving while impaired by alcohol (DWI) is a persistent problem. Tailoring intervention modality to client risk and needs (i.e., risk/needs) is posited to both reduce recidivism more efficiently than uniform approaches and circumvent overtreatment or undertreatment. DWI drivers in Quebec must participate in a severity-based intervention assignment program to be relicensed, but like most tailoring programs it has yet to undergo systematic scrutiny. The current longitudinal cohort study tests two main hypotheses underpinning this approach: 1) drivers classified at higher recidivism risk based on their arrest characteristics (DWIR) show poorer outcomes over up to 5-years postassessment compared to drivers classified at lower risk (DWIF); and 2) for both DWIR and DWIF groups, assignment of drivers with greater risk/needs to intensive intervention (II) will be advantageous for reducing recidivism risk compared to assignment into brief intervention (BI) for those with lower risk/needs. METHODS: Drivers who entered the program from 2012 to 2016 were followed to the end of 2018 (N = 37,612). Survival analysis examined the predictive validity of the initial classification into DWIR or DWIF groups for documented recidivism over a follow-up of up to 5 years. Logistic regression discontinuity evaluated the relative outcomes of drivers who were assigned to either BI or II. The study explored interaction effects between classification and intervention assignment with age and sex. RESULTS: In line with the hypothesis, the average hazard of recidivism was 58 % greater in DWIR drivers compared to DWIF drivers. In both DWIF and DWIR drivers, assignment of drivers with greater risk/needs to II was associated with reduced recidivism compared to assignment of drivers with lower risk/needs to BI, with 57 % and 35 % decreased probability of recidivism, respectively. Younger age was more strongly associated with recidivism risk in DWIF drivers than in DWIR drivers. CONCLUSIONS: The current study found that Quebec's severity-based intervention assignment approach accurately identifies DWI drivers who: i) by their arrest characteristics pose a greater risk for recidivism, which may require expeditious exposure to preventative countermeasures; and ii) as a function of their greater risk/needs, benefit from assignment to more intensive intervention to mitigate their recidivism risk.

Posttraumatic stress disorder in individuals seeking treatment for opioid use disorder in Vermont.

Posttraumatic stress disorder (PTSD) and opioid use disorder (OUD) may be associated with poor outcomes in rural areas where access to mental health services and opioid agonist treatment (OAT) is limited. This study examined the characteristics associated with a history of PTSD among a sample of individuals seeking buprenorphine treatment for OUD in Vermont, the second-most rural state in the US. Participants were 89 adults with OUD who participated in one of two ongoing randomized clinical trials examining the efficacy of an interim buprenorphine dosing protocol for reducing illicit opioid use during waitlist delays to OAT. Thirty-one percent of participants reported a history of PTSD. Those who did (PTSD+; n = 28) and did not (PTSD-; n = 61) report a history of PTSD were similar on sociodemographic and drug use characteristics. However, the PTSD+ group was less likely to have received prior OUD treatment compared to the PTSD- group (p = .02) despite being more likely to have a primary care physician (p = .009) and medical insurance (p = .002). PTSD+ individuals also reported greater mental health service utilization, more severe psychiatric, medical and drug use consequences, and greater pain severity and interference vs. PTSD- individuals (ps < 0.05). These findings indicate that a history of PTSD is prevalent and associated with worse outcomes among individuals seeking treatment for OUD in Vermont. Dissemination of screening measures and targeted interventions may help address the psychiatric and medical needs of rural individuals with OUD and a history of PTSD.

Cortisol stress response predicts 9-year risky driving convictions in male first-time driving-while-impaired offenders.

BACKGROUND: With driving while impaired by alcohol (DWI) representing a persistent burden on global health, better understanding and prevention of recidivism following a first-time DWI conviction are needed. Progress towards these goals is challenged by the marked heterogeneity in offender characteristics and a traffic safety literature that relies on subjective self-report measures and cross-sectional study designs. The present study tested the hypothesis that an objective neurobiological marker of behavioural maladjustment, the cortisol stress response (CSR), predicts future DWI and other traffic convictions over a 9-year follow-up period. METHODS: One hundred thirty-two male first-time DWI offenders and 31 non-offender comparators were recruited and assessed at intake for their substance use, psychosocial and psychological characteristics and CSR. Traffic conviction data were obtained from provincial driving records. Survival analysis estimated the association between CSR and risk of a traffic conviction over time. RESULTS: In support of our hypothesis, blunted CSR predicted traffic convictions during the follow-up duration. This effect generalized to both DWI offenders and non-DWI drivers. While CSR was lower in DWI offenders compared to non-offenders, it did not specifically predict recidivism in DWI offenders. Modelling results indicated that blunted CSR, along with DWI offender group membership, experience seeking and drug use frequency, may demarcate a high-risk driver phenotype. CONCLUSIONS: CSR is a neurobiological marker of a driver phenotype with elevated generalized driving risk. For drivers with characteristics consistent with this phenotype, expanding the focus of intervention to address multiple forms of risky driving may be necessary to curb their overall threat to traffic safety.

The Role of Behavioral Phenotypes on Impaired Driving Recidivism Risk and Treatment Response to Brief Intervention: A Preliminary Study.

BACKGROUND: Heterogeneity in the driving while impaired (DWI) offender population and modest outcomes from remedial programs are fueling interest in clarifying clinically significant DWI subtypes to better assess recidivism risk and target interventions. Our previous research identified 2 putative behavior phenotypes of DWI offenders with distinct behavioral, personality, cognitive, and neurobiological profiles: (i) offenders primarily engaging in DWI (pDWI); and (ii) offenders engaging in DWI and other traffic violations (MIXED). Here, we evaluate these phenotypes' clinical significance for prediction of recidivism and intervention targeting. METHODS: DWI recidivists participating in a previous randomized controlled trial (N = 184 comparing brief motivational interviewing (BMI) and an information and advice control condition (IA) were retrospectively classified as either pDWI (n = 97) or MIXED (n = 87). Secondary analyses then evaluated the effect of this phenotypic classification on self-reported 6- and 12-month alcohol misuse outcomes and documented 5-year DWI recidivism violations, and in response to either BMI or IA (i.e., pDWI-BMI, n = 46; MIXED-BMI, n = 45; pDWI-IA, n = 51; MIXED-IA, n = 42). Two hypotheses were tested: (i) MIXED classification is associated with poorer alcohol misuse outcomes and recidivism outcomes than pDWI classification; and (ii) pDWI paired with BMI is associated with better outcomes compared to MIXED paired with BMI. RESULTS: MIXED classification was associated with significantly greater risk of recidivism over the 5-year follow-up compared to pDWI classification. Moreover, the pDWI-BMI pairing was associated with significantly decreased recidivism risk compared to the MIXED-BMI pairing. Analyses of 6- and 12-month alcohol use outcomes produced null findings. CONCLUSIONS: The clinical significance of phenotypic classification for risk assessment and targeting intervention was partially supported with respect to recidivism risk. Prospective investigation of this and other behavioral phenotypes is indicated.

Lack of p53 Augments Antitumor Functions in Cytolytic T Cells.

Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and antitumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS-dependent JNK activation that leads to its activation-induced cell death. Because tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor-mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor-reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope-reactive T cells developed on p53 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNγ secretion, cytolytic capacity, expression of stemness gene signature, and decreased TGF-ß signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR-transduced T cells using a combination of p53 inhibitors also potentiated the T-cell effector function and improved persistence. Thus, our data highlight the key role of p53 in regulating the tumor-reactive T-cell response and that targeting this pathway could have potential translational significance in adoptive T-cell therapy. Cancer Res; 76(18); 5229-40. ©2016 AACR.

Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies.

Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2-restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self-MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540-51. ©2016 AACR.

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors.

The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), which does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease are highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high-affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.

Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity.

Hepatitis C Virus (HCV) is a major public health concern, with no effective vaccines currently available and 3% of the world's population being infected. Despite the existence of both B- and T-cell immunity in HCV-infected patients, chronic viral infection and HCV-related malignancies progress. Here we report the identification of a novel HCV TCR from an HLA-A2-restricted, HCV NS3:1073-1081-reactive CTL clone isolated from a patient with chronic HCV infection. We characterized this HCV TCR by expressing it in human T cells and analyzed the function of the resulting HCV TCR-transduced cells. Our results indicate that both the HCV TCR-transduced CD4(+) and CD8(+) T cells recognized the HCV NS3:1073-1081 peptide-loaded targets and HCV(+) hepatocellular carcinoma cells (HCC) in a polyfunctional manner with cytokine (IFN-gamma, IL-2, and TNF-alpha) production as well as cytotoxicity. Tumor cell recognition by HCV TCR transduced CD8(-) Jurkat cells and CD4(+) PBL-derived T cells indicated this TCR was CD8-independent, a property consistent with other high affinity TCRs. HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections.

ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase.

Cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH, ALDH1L1) is an abundant enzyme of folate metabolism. It converts 10-formyltetrahydrofolate to tetrahydrofolate and CO(2) in an NADP(+)-dependent reaction. We have identified a gene at chromosome locus 12q24.11 of the human genome, the product of which has 74% sequence similarity with cytosolic FDH. This protein has an extra N-terminal sequence of 22 amino acid residues, predicted to be a mitochondrial translocation signal. Transfection of COS-7 or A549 cell lines with a construct in which green fluorescent protein was introduced between the leader sequence and the rest of the putative mitochondrial FDH (mtFDH) has demonstrated mitochondrial localization of the fusion protein, suggesting that the identified gene encodes a mitochondrial enzyme. Purified pig liver mtFDH displayed dehydrogenase/hydrolase activities similar to cytosolic FDH. Real-time PCR performed on an array of human tissues has shown that although cytosolic FDH mRNA is highest in liver, kidney, and pancreas, mtFDH mRNA is most highly expressed in pancreas, heart, and brain. In contrast to the cytosolic enzyme, which is not detectable in cancer cells, the presence of mtFDH was demonstrated in several human cancer cell lines by conventional and real-time PCR and by Western blot. Analysis of genomes of different species indicates that the mitochondrial enzyme is a later evolutionary product when compared with the cytosolic enzyme. We propose that this novel mitochondrial enzyme is a likely source of CO(2) production from 10-formyltetrahydrofolate in mitochondria and plays an essential role in the distribution of one-carbon groups between the cytosolic and mitochondrial compartments of the cell.