Dezocine Alleviates Morphine-Induced Dependence in Rats.

BACKGROUND: Opioid dependence is a major public health issue without optimal therapeutics. This study investigates the potential therapeutic effect of dezocine, a nonaddictive opioid, in opioid dependence in rat models. METHODS: Dezocine was administered intraperitoneally to a morphine-dependent rat model to investigate its effect on withdrawal and conditioned place preference (CPP). Effect of dezocine on morphine withdrawal syndrome and CPP was analyzed using 2-way analysis of variance (ANOVA) followed by Tukey's post hoc test. Buprenorphine and vehicle solution containing 20% (v/v) dimethyl sulfoxide were used for positive and negative control, respectively. The astrocytes activation in nucleus accumbens was assessed by immunofluorescence assay of glial fibrillary acidic protein. Effect of dezocine and buprenorphine on the internalization of κ opioid receptor (KOR) was investigated using Neuro2A expressing KOR fused to red fluorescent protein tdTomato (KOR-tdT). Buprenorphine and dezocine were screened against 44 G-protein-coupled receptors, ion channels, and transporter proteins using radioligand-binding assay to compare the molecular targets. RESULTS: The mean withdrawal score was reduced in rats treated with 1.25 mg·kg dezocine compared to vehicle-treated control animals starting from the day 1 (mean difference: 7.8; 95% confidence interval [CI], 6.35-9.25; P < .0001 by 2-way ANOVA). Significance was observed at all treatment days, including day 7 (mean difference: 2.13; 95% CI, 0.68-3.58; P < .001 by 2-way ANOVA). Furthermore, dezocine inhibited the reinstatement of morphine-induced CPP (mean difference: 314; 95% CI, 197.9-430.1; P < .0001 by 2-way ANOVA) compared to the control group. Chronic morphine administration induced astrocytes activation in nucleus accumbens, which was attenuated by dezocine. Dezocine blocked the agonist-induced KOR internalization in vitro, 1 of the mechanisms involved in the downstream signaling and development of opioid dependence. Dezocine had affinity to norepinephrine and serotonin transporters and sigma-1 receptor, whereas buprenorphine showed no activity against these targets. CONCLUSIONS: Dezocine could potentially be used to alleviate opioid dependence. Due to the unique molecular target profile different from buprenorphine, it might have important value in studying the mechanisms of morphine dependence and developing novel therapeutic approaches.

HHLA2 is a novel immune checkpoint protein in pancreatic ductal adenocarcinoma and predicts post-surgical survival.

HHLA2 is a newly identified member of the B7 immune checkpoint family, but its function and crosstalk with immune cells is not fully understood. To gain insights into the HHLA2 expression profile and to determine the clinical significance and function of HHLA2 in pancreatic cancer, we performed immunohistochemistry (IHC) analyses on tissue microarrays (TMAs) of pancreatic ductal adenocarcinoma (PDAC, n = 92) with matched peritumoral tissues as well as in cohorts of precancerous lesions: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). We found that HHLA2 was rarely detected in normal acinar, islet, and ductal cells but widely expressed from early pancreatic precancerous lesions to invasive PDAC. The overall HHLA2 positivity was 95% (19/20) in low grade PanIN and 70.73% (29/41) in IPMN. HHLA2 expression was detected in 77.17% (71/92) of the PDAC cases and was significantly associated with better prognosis in this cohort. Our findings suggest that HHLA2 may behave as a costimulatory ligand in pancreatic cancer, which differs from other B7 family members that are largely characterized as checkpoint inhibitors. Further investigation of the HHLA2 signaling pathway and its receptors is warranted by our data and may lead to novel therapeutic interventions.

Altered expression of CD226 and CD96 on natural killer cells in patients with pancreatic cancer.

The progression of pancreatic cancer (PC) is significantly associated with tumor immune escape, which may be associated with nature killer (NK) cell dysfunction. CD226, CD96, and TIGIT, which share the ligand CD155, play important roles in the regulation of NK cell function. The present study was conducted to investigate the roles of these molecules in NK cells from PC patients. Expression of these molecules on NK cells was detected from samples of 92 pancreatic cancer patients and 40 healthy controls. The expression of CD155 was also evaluated by immunohistochemistry in 88 pancreatic cancer tissues. The percentage of CD226+ and CD96+ NK cells was significantly lower in PC patients than in the healthy controls; however, the mean fluorescence intensity of CD226 and CD96 was not significantly different between the two groups. TIGIT expression on NK cells from PC patients was similar to that in the healthy controls. Additionally, the expression of CD226 was positively correlated with CD96. Further analysis demonstrated that the decrease in the percentage of CD226+ and CD96+ NK cells was associated with tumor histological grade and lymph node metastasis. Moreover, the CD155 levels in PC tissues were significantly higher than those in adjacent tissues. Our results suggest that a lower percentage of CD226+ and CD96+ NK cells may contribute to tumor immune escape in PC patients; moreover, the use of NK cells with high CD226 and CD96 expression to treat PC cells with high CD155 expression may have potential and should be explored in the future.

Faux pas deficits in people with medial frontal lesions as related to impaired understanding of a speaker's mental state.

This study examined the nature of deficits in mentalizing, the ability to read the mental state of other people, as measured by a faux pas task in people with medial frontal lesions. A total of 56 Mandarin-speaking Chinese individuals participated (9 participants with medial frontal lesions, 12 participants with lateral frontal lesions, 5 participants with non-frontal lesions, and 30 healthy controls). The faux pas test ascertained the participants' ability to identify and understand a social faux pas, and to understand the mental states of the characters (the speaker and the recipient in a conversation with a social faux pas). Although the participants with medial frontal lesions performed less well than the other clinical participants and the control participants on all aspects of the faux pas test, the most significant deficit was observed in understanding mental states and hence inferring the speaker's intentions. The performance on the various aspects of decoding a social faux pas by people with medial frontal lesions suggests that the cognitive processes, and hence the respective neural correlates subserving these various processes, may be different. Our results add to existing literature and illustrate the very nature of deficits of mentalizing, measured by a faux pas test, experienced by people with medial frontal lesions. The data have also prompted that future behavioral and neuroimaging studies may be applied to further decode both the neural mechanisms and the cognitive variables affecting "mentalizing".

[Diagnosis and surgical treatment for non-functional islet cell tumor: a retrospective analysis of 44 cases].

OBJECTIVE: To evaluate the methods of diagnosis and surgical treatment for nonfunctional islet cell tumor (NICT). METHODS: Forty-four patients with non-functional islet cell tumor treated at the First Affiliated Hospital of Nanjing Medical University during January 1968 to June 2008 were analyzed retrospectively. There were 9 males and 35 females, aged from 7- to 70-years-old. Clinical manifestation: 15 cases (34.1%) of abdominal masses, 17 patients (38.6%) with epigastric or back pain, 5 cases of jaundice, 5 cases (11.4%) for upper abdominal fullness or vomiting, 10 cases (22.7%) of pancreatic tumor noticed by routine health checkups or imaging examinations. Imaging examination: CT scan, sonography, ERCP, MRI, upper GI series were performed in 33 (75.0%), 16 (36.4%), 6 (13.6%), 2 (4.5%), and 10 cases (22.7%) respectively. Operation methods: 39 patients (88.6%) underwent surgical resection and the other 5 patients did not. COMPLICATIONS: pancreatic fistula in 7 patients (15.9%), intra-abdominal bleeding in 4 (9.1%), gastrojejunal anastomosis outlet obstruction in 1 (2.3%), biliary fistula in 2 (4.5%) and incisional infection in 3 (6.8%). Surgery related mortality happened in 2 patients (4.5%), both treated before 1999. Twenty-five patients underwent operation between January 1999 and June 2008 were followed up for 6 to 108 months. All survive except one died 75 months after the surgery for unknown reason. CONCLUSIONS: No specific clinical manifestation is recognized for non-functional islet cell tumor. Spiral CT is an optimal diagnostic method, while surgery is the first choice for treatment. Middle segmental pancreatectomy has become an alternative surgical protocol for NICT.

[The deficit of decision-making in Parkinson's disease].

OBJECTIVE: To investigate the characteristics of decision-making impairment in Parkinson's disease (PD) patients. METHODS: A total of 20 individuals with idiopathic PD were compared with matched health controls on the Iowa Gambling Task, A series of battery including the assessment working memory, visual spatial ability and verbal fluency was also administered. The severity of disease was assessed based on the Hohen and Yahr scale. RESULTS: The results showed that PD group impaired on verbal fluency, working memory and decision-making task. In Iowa gambling task, the PD group selected more disadvantageous cards than health controls (51.6 +/- 5.8, 46.8 +/- 8.2 respectively), the difference between two groups is significant (t((38)) = 2.12, P = 0.04). A 2 (group) x 5 (block) ANOVA (analysis of variance) on the scores of advantageous from the gambling task revealed a significant main effect of group (F((1, 38)) = 6.16, P = 0.01). The ANOVA also revealed a significant main effect of block (F((4, 152)) = 2.43, P = 0.04). The results showed that health controls gradually shifted their selections toward the good decks as the game progresses, but the PD group did not exhibit this stable advantageous shift in decision-making. Meanwhile, the study indicated the total number of disadvantageous cards for PD was positive correlation to the degrees of severity to clinical symptom. CONCLUSION: The present study suggests that the decision-making impairment might be in early PD. The deficit of decision-making for PD might be attributed to the dysfunction of the orbito-frontal cortex.

Prefrontal cortex involvement in the event-based prospective memory: evidence from patients with lesions in the prefrontal cortex.

PRIMARY OBJECTIVE: The aim of the present study was to investigate the event-based prospective memory (EBPM) and time-based prospective memory (TBPM) in patients with lesion in prefrontal cortex (PFC) and test the hypothesis that the prefrontal cortex is involved in the prospective memory (PM) network. RESEARCH DESIGN: The performance of patients with lesion in PFC (n = 30) was compared with that of a demographically matched control group (n = 30). METHODS AND PROCEDURES: A neuropsychological battery of tests including EBPM and TBPM tasks were administered to both groups. MAIN OUTCOME AND RESULTS: The group with lesion in PFC were significantly impaired in EBPM, but insignificantly impaired in TBPM tasks. There was no difference in performance of EBPM and TBPM tasks between the patients with lesion in the left and the right PFC. CONCLUSIONS: These results suggest that the patients with lesion in PFC were impaired in EBPM, but not in TBPM, implying that EBPM and TBPM may have different neural substrates. It is possible that PFC is more selectively involved in EBPM, but less in TBPM.

[Deficit in risk-taking decision-making of patients with lesions of prefrontal cortex].

OBJECTIVE: To investigate the influence of injury of prefrontal cortex on the risk-taking decision-making and to test the hypothesis that the orbitofrontal area is involved in the special network of risk-taking decision-making. METHODS: 47 patients with lesions in the prefrontal lobe, 21 in the orbitofrontal area (OBF) and 19 in the dorsolateral prefrontal cortex (DLF), and 40 healthy controls (HC group) were administered with a risk-taking task. RESULTS: The risky response rate after punishment of the HC group was 0.54 +/- 0.23, significantly fewer than before punishment (t = -3.82, P < 0.01), and the risky response rate after punishment of the DLF injury group was 0.68 +/- 0.16, significantly fewer than before punishment too (t = -2.32, P < 0.05). The risky response rate after reward of the patients with lesions in OBF areas was 0.79 +/- 0.19, significantly higher than that of the HC group (0.68 +/- 0.16, P < 0.05), and the risky response rate after punishment of the patients with lesions in OBF areas was 0.82 +/- 0.18, significantly higher than that of the HC group (0.54 +/- 0.23, P < 0.05). The risky response rates after reward and after punishment of the DLP group were 0.72 +/- 0.22 and 0.63 +/- 0.25 respectively, both not significantly different from those of the HC group (both P > 0.05). CONCLUSION: The patients with lesions in the orbitofrontal area, not in the dorsolateral prefrontal cortex, have a specific deficit in risk-taking decision-making, i.e. an inhibition effect of punishment, reduced sensitivity to punishment but increased sensitivity to reward. The orbitofrontal areas play an important role in risk-taking decision-making processes.