AMBMP activates WNT pathway and alleviates stress-induced behaviors in maternal separation and chronic stress models.

Depressive disorders are both prevalent and debilitating, and a proportion of patients have treatment resistance to classic antidepressants. Recent evidence has implicated the intracellular WNT signaling pathway as having a key role in the pathogenesis of major depressive disorder. In the present study, we investigated the role of ß-catenin and transcription factor-4 (TCF4) in the depression-like and anxiety-like behaviors exhibited by mice exposed to maternal separation, or chronic mild stress. Both rodent models of childhood and adulthood stress showed depression and anxiety-like behaviors. During the last three weeks of medication, we applied AMBMP (2-Amino-4-[3,4- (methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine) to the maternal separation and chronic stress model for the first time. The drug alleviated the depression-like index in saccharin preference test (SPT) and forced swim test (FST), and anxiety-like index in open field test (OFT) and elevated-plus maze (EPM), and reversed the disruption of ß-catenin and TCF4 in stressed mice by upregulating the WNT pathway specifically. Therefore, the WNT pathway may be involved in the mediation of patient recovery and could be a target for novel antidepressants.

Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair.

BACKGROUND: BRCA germline mutations are being targeted for development of PARP inhibitors. BRCA genes collaborate with several others in the Fanconi Anemia (FA) pathway. We screened cancer patients' tumors for FA functional defects then aimed to establish the safety/feasibility of administering PARP inhibitors as monotherapy and combined with a DNA-breaking agent. METHODS: Patients underwent FA functional screening for the presence (or lack) of tumor FancD2 nuclear foci formation on their archival tumor material, utilizing a newly developed method (Fanconi Anemia triple-stain immunofluorescence [FATSI]), performed in a Clinical Laboratory Improvement Amendments-certified laboratory. FATSI-negative patients were selected for enrollment in a two-arm dose escalation trial of veliparib, or veliparib/mitomycin-C (MMC). RESULTS: One hundred eighty-five of 643 (28.7%) screened patients were FATSI-negative. Sixty-one received veliparib or veliparib/MMC through 14 dose levels. Moderate/severe toxicities included fatigue (DLT at veliparib 400mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300mg BID veliparib and veliparib 200mg BID for 21 days following 10mg/m(2) MMC every 28 days. Six antitumor responses occurred, five in the combination arm (3 breast, 1 ovarian, 1 endometrial [uterine], and 1 non-small cell lung cancer). Two patients have received 36 and 60 cycles to date. BRCA germline analysis among 51 patients revealed five deleterious mutations while a targeted FA sequencing gene panel showed missense/nonsense mutations in 29 of 49 FATSI-negative tumor specimens. CONCLUSIONS: FATSI screening showed that a substantial number of patients' tumors have FA functional deficiency, which led to germline alterations in several patients' tumors. Veliparib alone or with MMC was safely administered to these patients and produced clinical benefit in some. However, a better understanding of resistance mechanisms in this setting is needed.

Cognitive impairment and its relation to imaging measures in multiple sclerosis: a study using a computerized battery.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) is an important component of multiple sclerosis (MS) disability. A complex biological interplay between white matter (WM) and gray matter (GM) disease likely sustains CI. This study aims to address this issue by exploring the association between the extent of normal WM and GM disease and CI. METHODS: Cognitive function of 24 MS patients and 24 healthy volunteers (HVs) was studied using the Automated Neuropsychological Assessment Metrics (ANAM) battery. WM focal lesions and normal appearing WM (NAWM) volume in patients, cortical thickness (CTh) and deep GM structure volumes in both patients and HVs were measured by high field strength (3.0-Tesla; 3T) imaging. RESULTS: An analysis of covariance showed that patients performed worse than HVs on Code Substitution Delayed Memory (P = .04) and Procedural Reaction Time (P = .05) indicative of reduced performance in memory, cognitive flexibility, and processing speed. A summary score (Index of Cognitive Efficiency) indicating global test battery performance was also lower for the patient group (P = .04). Significant associations, as determined by the Spearman rank correlation tests, were noted between each of these 3 cognitive scores and measures of NAWM volume [CDD-TP1(r = .609; P = .0035), PRO-TP1 (r = .456; P = .029) and ICE (r = .489; P = .0129)], CTh (r = .5; P ≤ .05) and volume of subcortical normal appearing GM (NAGM) structures (r = .4; P≤ .04), but not WM lesions. CONCLUSIONS: Both NAWM and NAGM volumes are related to CI in MS. The results highlight once again the urgent need to develop pharmacological strategies protecting patients from widespread neurodegeneration as possible preventive strategies of CI development.

Clinical efficacy of butylphthalide in the treatment of acute cerebral infarction and its effect on serum C-reactive protein / 中国基层医药

Objective To observe the clinical efficacy of butylphthalide in the treatment of acute cerebral infarction and its effect on serum C-reactive protein(CRP).Methods A total of 120 inpatients with acute cerebral infarction were randomly assigned into control group (n =60) and observation group (n =60) by the digital table method.The control group was treated with Xueshuantong injection,inhibiting blood platelet and improving brain metabolism.The observation group was treated with butylphthalide based on the treatment of the control group.The changes in serum CRP and clinical efficacy were compared between the two groups 2 weeks after treatment.Results After treatment,the CRP level was decreased greatly in the observation group,but the CRP level was reduced slightly in the control group compared with before treatment,the CRP level in the observation group was (2.54 ± 0.79) mg/L,which was significantly lower than (5.66 ± 1.78) mg/L in the control group (t =12.41,P ＜ 0.05).The total effective rate in the observation group was 75.00％,which was significantly higher than 53.33％ in the control group (x2 =6.13,P ＜ 0.05).The 3-day NIHSS score [(8.62 ± 1.89) points],1-week NIHSS score [(4.21 ± 1.76) points],and 2-week NIHSS score [(5.79 ± 1.36) points] after treatment were significantly lower in the observation group compared with the control group (t =2.84,11.93,6.67,all P ＜ 0.05).Conclusion Based on conventional treatment,butylphthalide injection in the treatment of acute cerebral infarction can remarkably reduce CRP level,alleviate inflammatory reactions,improve cerebral infarction condition and prognosis,exert obvious effect and it is worthy of clinical promotion.