Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake.

BACKGROUND: Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified. METHODS: The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay. RESULTS: During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse. CONCLUSIONS: The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction.

Brief Report: Tyrosine Kinase Inhibitors for Lung Cancers That Inhibit MATE-1 Can Lead to "False" Decreases in Renal Function.

INTRODUCTION: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon. METHODS: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR). RESULTS: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations. CONCLUSIONS: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.

Tumor-agnostic genomic and clinical analysis of BRAF fusions identify actionable targets.

BACKGROUND: Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course. PATIENTS/METHODS: We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, intact BRAF kinase domain). RESULTS: We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. 39 fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. 24 patients spanning multiple histologies were treated with MAPK-directed therapies of which 20 were evaluable for RECIST. Best response was partial response (N=2), stable disease (N=11), and progressive disease (N=7). The median time on therapy was 1 month with MEK plus BRAF inhibitors ([N=11], range 0-18 months) and 8 months for MEK inhibitors ([N=14], range 1-26 months). 9 patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N=6), Erdheim-Chester disease (N=1), extraventricular neurocytoma (N=1), melanoma (N=1)]. Fifteen patients had acquired BRAF fusions. CONCLUSIONS: BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy underscoring the importance of post-progression biopsies to optimize treatment at relapse in these patients.

Central Nervous System Disease in Patients With RET Fusion-Positive NSCLC Treated With Selpercatinib.

INTRODUCTION: Central nervous system (CNS) metastases develop in nearly half of patients with RET fusion-positive NSCLCs and cause morbidity and mortality. The selective RET inhibitor selpercatinib treats existing intracranial disease, but no studies have investigated whether early initiation of selpercatinib is associated with decreased development of CNS metastases. METHODS: A total of 61 patients with RET fusion-positive advanced NSCLC with and without CNS metastases treated with selpercatinib on the LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 expanded access program (NCT03906331) were identified. Cumulative incidence rates (CIRs) for CNS metastases were assessed as an event of interest; systemic progression of disease and death were considered competing risks. RESULTS: The median age was 65 years, and the most common 5' fusion partners were KIF5B (67%) and CCDC6 (18%). There were 24 patients (39%) who received prior platinum chemotherapy and 20 patients (33%) who received prior multikinase inhibition. The median time on selpercatinib was 21.8 months. Furthermore, 30 patients (49%) had CNS disease at baseline and 31 patients (51%) had no baseline CNS disease. CIRs of CNS progression among patients with baseline CNS disease were 3% (95% confidence interval [CI]: 0%-10%), 10% (95% CI: 0%-22%), 17% (3%-30%), 17% (3%-30%), and 20% (5%-35%) at 6, 12, 18, 24, and 36 months, respectively. CIR for CNS progression among patients without baseline CNS disease was 0% at 6, 12, 18, 24, and 36 months (95% CI: 0%-0%). CONCLUSIONS: CNS progression was not observed with selpercatinib therapy in patients without baseline CNS disease. CNS progression on selpercatinib was rare in patients with baseline CNS disease. Early initiation of selpercatinib is associated with decreased rates of CNS metastasis formation and progression and may play a preventive role.

Deep Learning of Cell Spatial Organizations Identifies Clinically Relevant Insights in Tissue Images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a novel cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (i.e. the cell spatial distribution, morphology, proximity, and interactions) derived from pathology images. Ceograph identifies key cell spatial organization features by accurately predicting their influence on patient clinical outcomes. In patients with oral potentially malignant disorders, our model highlights reduced structural concordance and increased closeness in epithelial substrata as driving features for an elevated risk of malignant transformation. In lung cancer patients, Ceograph detects elongated tumor nuclei and diminished stroma-stroma closeness as biomarkers for insensitivity to EGFR tyrosine kinase inhibitors. With its potential to predict various clinical outcomes, Ceograph offers a deeper understanding of biological processes and supports the development of personalized therapeutic strategies.

Deep learning of cell spatial organizations identifies clinically relevant insights in tissue images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (for example,. the cell spatial distribution, morphology, proximity, and interactions) derived from pathology images. Ceograph identifies key cell spatial organization features by accurately predicting their influence on patient clinical outcomes. In patients with oral potentially malignant disorders, our model highlights reduced structural concordance and increased closeness in epithelial substrata as driving features for an elevated risk of malignant transformation. In lung cancer patients, Ceograph detects elongated tumor nuclei and diminished stroma-stroma closeness as biomarkers for insensitivity to EGFR tyrosine kinase inhibitors. With its potential to predict various clinical outcomes, Ceograph offers a deeper understanding of biological processes and supports the development of personalized therapeutic strategies.

Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.

Acute ethanol does not always affect delay discounting in rats selected to prefer or avoid ethanol.

AIMS: The purpose of this study was to determine whether animals predisposed to prefer alcohol possess an altered acute response to alcohol on a delay discounting task relative to animals predisposed to avoid alcohol. METHODS: We used rats selected to prefer or avoid alcohol to assess whether genotype moderates changes in delay discounting induced by acute ethanol exposure. Selectively bred rat lines of Sardinian alcohol-preferring (sP; n = 8) and non-preferring (sNP; n = 8) rats, and alko alcohol (AA, n = 8) and alko non-alcohol (ANA, n = 8) rats were trained in an adjusting amount task to assess delay discounting. RESULTS: There were no significant effects of line on baseline discounting; however, both lines of alcohol-preferring rats exhibit slowed reaction times. Acute ethanol (0, 0.25, 0.5 g/kg) treatment also had no effect on delay discounting in any of the selectively bred rat lines. CONCLUSION: Our data indicate that in these lines of animals, alcohol preference or avoidance has no impact on delay discounting following acute ethanol exposure. It is possible that other genetic models or lines may be differentially affected by alcohol and exhibit qualitatively and quantitatively different responses in delay discounting tasks.

Bioinformatically Expanded Next-Generation Sequencing Analysis Optimizes Identification of Therapeutically Relevant MET Copy Number Alterations in >50,000 Tumors.

PURPOSE: Clinical relevance thresholds and laboratory methods are poorly defined for MET amplification, a targetable biomarker across malignancies. EXPERIMENTAL DESIGN: The utility of next-generation sequencing (NGS) in assessing MET copy number alterations was determined in >50,000 solid tumors. Using fluorescence in situ hybridization as reference, we validated and optimized NGS analysis. RESULTS: Incorporating read-depth and focality analyses achieved 91% concordance, 97% sensitivity, and 89% specificity. Tumor heterogeneity, neoplastic cell proportions, and genomic focality affected MET amplification assessment. NGS methodology showed superiority in capturing overall amplification status in heterogeneous tumors and defining amplification focality among other genomic alterations. MET copy gains and amplifications were found in 408 samples across 23 malignancies. Total MET copy number inversely correlated with amplified segment size. High-level/focal amplification was enriched in certain genomic subgroups and associated with targeted therapy response. CONCLUSIONS: Leveraging our integrated bioinformatic approach, targeted therapy benefit was observed across diverse MET amplification contexts.

Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy.

INTRODUCTION: Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs). METHODS: This multicenter, retrospective study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated. RESULTS: A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL [interquartile range: 304-4000] versus 3786 mg/dL [interquartile range: 842-6596], p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5-undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2-14.9). CONCLUSIONS: Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

NTRK fusions in lung cancer: From biology to therapy.

Fusions involving TRK protein tyrosine kinases are oncogenic drivers in a variety of tumors in children and adults, with a prevalence of ∼0.2% in non-small cell lung cancer. Diagnosis can be challenging due to structural features such as NTRK intron length, but next-generation sequencing (NGS), including RNA-based NGS, increases detection. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Furthermore, the first-generation TRK inhibitors are well tolerated. Care should be taken, however, to monitor on-target adverse events, such as dizziness, weight gain, paresthesias, and withdrawal pain. On-target and off-target mechanisms mediating TRK inhibitor resistance may occur. Next-generation TRK inhibitors, such as selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer.

Allele-Specific Role of ERBB2 in the Oncogenic Function of EGFR L861Q in EGFR-Mutant Lung Cancers.

INTRODUCTION: Unlike common EGFR mutations, many less common EGFR mutations remain poorly characterized in terms of oncogenic function and drug sensitivity. Here, we characterize the subset of lung adenocarcinoma harboring EGFR L861Q through both preclinical and clinical investigations. METHODS: We reviewed clinical and genomic data from patients with EGFR-mutant lung cancer. We established cells expressing EGFR mutations and performed functional analysis of L861Q in comparison with common EGFR mutations. RESULTS: Among the patients with lung cancer, 3.4% (47 of 1367) possess an EGFR L861Q mutation. Of the patients with L861Q, 23.4% (11 of 47) had a concurrent exon 18 mutation (typically involving G719). In vitro studies revealed that the oncogenic activity of L861Q is dependent on asymmetric dimerization. Cells expressing L861Q were less sensitive to EGFR-specific inhibitors compared with cells expressing L858R but were similarly sensitive to pan-ERBB inhibitors. In cells expressing L861Q, ERBB2 phosphorylation was markedly higher compared with cells expressing L858R, and an enhanced interaction between EGFR and ERBB2 was observed in coimmunoprecipitation studies. In addition, treatment with osimertinib enhanced expression of the antiapoptotic protein MCL1, and knockdown of ERBB2 suppressed the expression of MCL1 in L861Q, raising the possibility of differential allele-specific cross-phosphorylation of ERBB2. Moreover, compared with EGFR-specific inhibitors, pan-ERBB inhibitors exerted superior growth inhibitory effects on cells expressing compound L861Q/G719X mutations. CONCLUSIONS: Our results suggest that ERBB2 plays a previously unrecognized role in EGFR L861Q-driven tumorigenesis, and pan-ERBB inhibitors are likely to be more effective than selective EGFR tyrosine kinase inhibitors in this setting.

Strain differences in behavioral inhibition in a Go/No-go task demonstrated using 15 inbred mouse strains.

BACKGROUND: High levels of impulsivity have been associated with a number of substance abuse disorders including alcohol abuse. Research has not yet revealed whether these high levels predate the development of alcohol abuse. METHODS: The current study examined impulsivity in 15 inbred strains of mice (A/HeJ, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C57L/J, C58/J, CBA/J, DBA/1J, DBA/2J, NZB/B1NJ, PL/J, SJL/J, SWR/J, and 129P3/J) using a Go/No-go task, which was designed to measure a subject's ability to inhibit a behavior. Numerous aspects of response to ethanol and other drugs of abuse have been examined in these strains. RESULTS: There were significant strain differences in the number of responses made during the No-go signal (false alarms) and the extent to which strains responded differentially during the Go and No-go signals (d'). The rate of responding prior to the cue did not differ among strains, although there was a statistically significant correlation between false alarms and precue responding that was not related to basal activity level. Interstrain correlations suggested that false alarms and rate of responding were associated with strain differences in ethanol-related traits from the published literature. CONCLUSIONS: The results of this study do support a link between innate level of impulsivity and response to ethanol and are consistent with a genetic basis for some measures of behavioral inhibition.

Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain.

In utero alcohol exposure can cause fetal alcohol spectrum disorders (FASD), characterized by structural brain abnormalities and long-lasting behavioral and cognitive dysfunction. Neuronal plasticity is affected by in utero alcohol exposure and can be modulated by extracellular proteolysis. Plasmin is a major extracellular serine-protease whose activation is tightly regulated by the plasminogen activator (PA) system. In the present study we explored the effect of ethanol on the expression of the main components of the brain PA system in sex-specific cortical astrocyte primary cultures in vitro and in the cortex and hippocampus of post-natal day (PD) 9 male and female rats. We find that ethanol alters the PA system in astrocytes and in the developing brain. In particular, the expression of tissue-type PA (tPA), encoded by the gene Plat, is consistently upregulated by ethanol in astrocytes in vitro and in the cortex and hippocampus in vivo. Astrocytes exhibit endogenous plasmin activity that is increased by ethanol and recombinant tPA and inhibited by tPA silencing. We also find that tPA is expressed by astrocytes of the developing cortex and hippocampus in vivo. All components of the PA system investigated, with the exception of Neuroserpin/Serpini1, are expressed at higher levels in astrocyte cultures than in the developing brain, suggesting that astrocytes are major producers of these proteins in the brain. In conclusion, astrocyte PA system may play a major role in the modulation of neuronal plasticity; ethanol-induced upregulation of tPA levels and plasmin activity may be responsible for altered neuronal plasticity in FASD.

Sex differences in the association of alcohol with cognitive decline and brain pathology in a cohort of octogenarians.

RATIONALE: The beneficial effects of moderate alcohol may differ in aging men versus women. OBJECTIVES: Cognitive and functional decline and neuropathology were investigated in a cohort of aging men and women with diverse alcohol histories. METHODS: Non-demented (Clinical Dementia Rating (CDR) of ≤ 0.5 and a Mini-Mental State Examination (MMSE) score of > 24), autonomously living participants were tracked in longitudinal aging studies to examine self-report and objective tests of rates of decline in a cohort (n = 486) of octogenarians. Neurofibrillary tangles (NFTs; Braak stage) and neuritic plaques (NPs) were staged at autopsy in a subset of participants (n = 149) using current standard neuropathologic diagnostic criteria. RESULTS: Moderate drinking men had an attenuated rate of decline compared to rare/never drinkers and women on the MMSE and CDR sum of boxes. In contrast, moderate drinking women had a reduced rate of decline only in the Logical Memory Delayed Recall Test (LMDR) compared to rare/never drinkers and men. Moderate alcohol consumption was associated with a reduction in the incidence of advanced (stages 5-6) Braak NFT stage in men (p < 0.05), with no effect in women. CONCLUSIONS: In this cohort, men experienced a broader range of beneficial effects associated with alcohol. Alcohol's effects may differ in men and women in important ways that suggest a narrower beneficial window.

Peripheral immune factors are elevated in women with current or recent alcohol dependence and associated with altered mood and memory.

BACKGROUND: The adverse effects of alcohol on brain function result, in part, from inflammatory processes. The sex-specific neuropsychiatric consequences and inflammatory status of active alcohol dependence and early remission from dependence have not been investigated. METHODS: Neuropsychiatric symptoms, inflammatory factors, and liver enzymes were compared in a prospective cohort study of adults with (n=51) or without (n=31) a current or recent history of alcohol dependence. RESULTS: Neuropsychiatric profiles were similar in adults with current or recent alcohol dependence regardless of sex. In male and female participants measures of depression (female p<0.05, male p<0.001), anxiety (female p<0.001, male p<0.001), and memory complaints (female p<0.001, male p<0.05) were elevated, relative to non-dependent controls. Significant sex×alcohol dependence history interactions were observed for plasma levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) and brain derived neurotrophic factor (BDNF), with women in the alcohol dependent group exhibiting increased levels of both analytes (p<0.05) relative to controls. Positive correlations between TIMP-1 levels and measures of depression (r2=0.35, p<0.01), anxiety (r2=0.24, p<0.05) and memory complaints (r2=0.44, p<0.01) were found in female, but not male, participants. CONCLUSIONS: Though neuropsychiatric profiles were similar for men and women with current or recent alcohol dependence, plasma factors associated with increases in depression, anxiety, and memory impairment differed and support the need to tailor treatments based on sex.

A neurotoxic alcohol exposure paradigm does not induce hepatic encephalopathy.

Alcohol abuse is associated with neurological dysfunction, brain morphological deficits and frank neurotoxicity. Although these disruptions may be a secondary effect due to hepatic encephalopathy, no clear evidence of causality is available. This study examined whether a 72h period of alcohol intoxication known to induce physical dependence, followed by a single withdrawal, was sufficient to induce signs of hepatic encephalopathy in male and female mice. Animals were continuously intoxicated via alcohol vapor inhalation, a procedure previously shown to induce significant neurotoxicity in female mice. At peak synchronized withdrawal (8h following the end of alcohol exposure), blood samples were taken and levels of several liver-regulated markers and brain swelling were characterized. Glutathione levels were also determined in the medial frontal cortex (mFC) and hippocampus. Results revealed elevated levels of cholesterol, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and decreased levels of blood urea nitrogen and total bilirubin in alcohol-exposed male and female groups compared to controls. Brain water weight was not affected by alcohol exposure, though males tended to have slightly more water weight overall. Alcohol exposure led to reductions in tissue levels of glutathione in both the hippocampus and mFC which may indicate increased oxidative stress. Combined, these results suggest that hepatic encephalopathy does not appear to play a significant role in the neurotoxicity observed following alcohol exposure in this model.