Smoking history is associated with reduced efficacy of neoadjuvant therapy in pancreatic adenocarcinoma.

BACKGROUND: Differential responses to neoadjuvant therapy (NAT) exist in pancreatic ductal adenocarcinoma (PDAC); however, contributing factors are poorly understood. Tobacco smoke is a common risk factor for PDAC, with nicotine-induced chemoresistance observed in other cancers. This study aimed to explore the potential association between tobacco use and NAT efficacy in PDAC. METHODS: A single-center, retrospective analysis was conducted that included all consecutive patients with PDAC who underwent surgical resection after NAT with a documented smoking history (N = 208). NAT response was measured as percentage fibrosis in the surgical specimen. Multivariable models controlled for covariates and survival were modeled using the Kaplan-Meier method. RESULTS: Postoperatively, major responses to NAT (>95% fibrosis) were less frequently observed in smokers than in nonsmokers (13.7% vs 30.4%, respectively; P = .021). Pathologic complete responses were similarly less frequent in smokers than in nonsmokers (2.1% vs 9.9%, respectively; P = .023). On multivariate analysis controlling for covariates, smoking history remained independently associated with lower odds of major fibrosis (odds ratio [OR], 0.25; 95% CI, 0.10-0.59; P = .002) and pathologic complete response (OR, 0.21; 95% CI, 0.03-0.84; P = .05). The median overall survival was significantly longer in nonsmokers than in smokers (39.1 vs 26.6 months, respectively; P = .05). CONCLUSION: Tobacco use was associated with diminished pathologic responses to NAT. Future research to understand the biology underlying this observation is warranted and may inform differential NAT approaches or counseling among these populations.

Type of neoadjuvant treatment strategy is associated with differential pathologic responses in pancreatic ductal adenocarcinoma.

BACKGROUND: Tumor fibrosis after neoadjuvant treatment (NAT) for pancreatic ductal adenocarcinoma (PDAC) correlates with treatment response. Herein we assessed how different NAT strategies influence pathologic responses and survival. METHODS: Patients with surgically resected PDAC who received NAT (1991-2020) were included. Descriptive statistics compared outcomes amongst fibrosis groups (none, minor <50 â€‹%, partial 51%-94 â€‹%, major ≥95 â€‹%) and NAT (chemotherapy alone, chemoradiation, or chemotherapy â€‹+ â€‹chemoradiation (total neoadjuvant therapy, TNT)). RESULTS: Patients with major fibrosis most often received TNT (65.8 â€‹%, p â€‹< â€‹0.001). Major fibrosis was associated with the greatest rate of downstaging (77.8 â€‹%, p â€‹< â€‹0.001), highest R0 margin rate (100 â€‹%, p â€‹< â€‹0.01), and lowest mean positive lymph node ratio (0.80, p â€‹< â€‹0.01). Amongst complete responders, 11/14 (78.6 â€‹%) received TNT. Median overall (66.3 months, p â€‹= â€‹0.003) and disease-free (54.7months, p â€‹= â€‹0.05) survival were highest with major fibrosis. CONCLUSIONS: Major fibrosis and complete pathologic responses after NAT are most frequent with a TNT strategy and are associated with improved outcomes.

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory.

Epigenetic remodeling contributes to synaptic plasticity via modification of gene expression, which underlies cocaine-induced long-term memory. A prevailing hypothesis in drug addiction is that drugs of abuse rejuvenate developmental machinery to render reward circuitry highly plastic and thus engender drug memories to be highly stable. Identification and reversal of these pathological pathways are therefore critical for cocaine abuse treatment. Previous studies revealed an interesting finding in which the mRNA of histone lysine demethylase, KDM6B, is upregulated in the medial prefrontal cortex (mPFC) during early cocaine withdrawal. However, whether and how it contributes to drug-seeking behavior remain unknown. Here we used a conditioned place preference paradigm to investigate the potential role of KDM6B in drug-associated memory. We found that KDM6B protein levels selectively increased in the mPFC during cocaine withdrawal. Notably, systemic injection of KDM6B inhibitor, GSK-J4, disrupted both reconsolidation of cocaine-conditioned memory and cocaine-primed reinstatement, suggesting dual effects of KDM6B in cocaine reward memory. In addition, we found that NMDAR expression and function were both enhanced during early cocaine withdrawal in mPFC. Injection of GSK-J4 selectively reversed this cocaine-induced increase of NR2A expression and synaptic function, suggesting that mal-adaptation of cocaine-induced synaptic plasticity in mPFC largely underlies KDM6B-mediated cocaine-associated memory. Altogether, these data suggest that KDM6B plays an essential role in cocaine-associated memory, which mainly acts through enhancing cocaine-induced synaptic plasticity in the mPFC. Our findings revealed a novel role of KDM6B in cocaine-associated memory and inhibition of KDM6B is a potential strategy to alleviate drug-seeking behavior.

Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity.

Considerable evidence supports a contributory role for leukocyte-type 12/15 Lipoxygenase (L-12/15 LO) in mediating hippocampal and cortical neuronal injury in models of Alzheimer's disease and stroke. Whether L-12/15 LO contributes to neuronal injury in a model of Huntington's disease (HD) has yet to be determined. HD is characterized by marked striatal neuronal loss, which can be mimicked in humans and animals by inhibition of mitochondrial complex II using 3-Nitropropionic acid (3-NP). Herein, we compared histological and behavioral outcomes between mice that were wild-type or null for L-12/15 LO following systemic injection of 3NP. We found that mice deficient in L-12/15 LO had a higher incidence of striatal lesions coincident with an increase in morbidity as compared to their wild-type littermate controls. This could not be explained by differential metabolism of 3-NP as striatal succinate dehydrogenase activity was inhibited to the same extent in both genotypes. The present results show that deleting L-12/15 LO is detrimental to the striatum in the setting of chronic, systemic 3-NP exposure and are consistent with the overall conclusion that region-specific effects may determine the ultimate outcome of L-12/15 LO activation in the setting of brain injury.