Dysfunctional neurotransmission within striatal networks is believed to underlie the pathophysiology of several neurological and psychiatric disorders. Nitric oxide (NO)-producing interneurons have been shown to play a critical role in modulating striatal synaptic transmission. These interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and may be regulated by DA receptor activation. In the current study, striatal NO efflux was measured in anesthetized male rats using an NO-selective electrochemical microsensor and the role of DA in modulating NO synthase (NOS) activity was assessed during electrical or chemical (bicuculline) stimulation of the substantia nigra (SN). Electrical stimuli were patterned to approximate the natural single spike or burst firing activity of midbrain DA neurons. Electrical stimulation of the SN at low frequencies induced modest increases in striatal NO efflux. In contrast, train stimulation of the SN robustly increased NO efflux in a stimulus intensity-dependent manner. NO efflux evoked by SN stimulation was similar in chloral hydrate-and urethane-anesthetized rats. The facilitatory effect of train stimulation on striatal NO efflux was transient and attenuated by systemic administration of the neuronal NOS inhibitor 7-nitroindazole and the nonselective NOS inhibitor methylene blue. Moreover, the increase in NO efflux observed during chemical and train stimulation of the SN was attenuated following systemic administration of the DA D 1/5 receptor antagonist SCH 23390. SCH 23390 also blocked NO efflux induced by systemic administration of the D 1/5 agonist SKF 81297. These results indicate that neuronal NOS is activated in vivo by nigrostriatal DA cell burst firing via a DA D 1/5 -like receptor-dependent mechanism.

Drug addiction results from a subversion of neural circuits that control motivation. Although the hedonic and addictive properties of psychostimulants and drugs of abuse are predominantly attributed to dopamine and glutamate, it is appreciated that other signaling molecules in the brain are important. This study suggests that cocaine-and amphetamine-regulated transcript (CART) peptides modulate the locomotor and motivational properties of psychostimulants. The behavioral effects of cocaine and amphetamine were examined in Cart tm1Amgen knockout (Cart KO) and wild-type (WT) mice. Acute amphetamine administration increased in locomotor activity in WT mice, but this response was attenuated in Cart KO mice. Repeated amphetamine produced locomotor sensitization in WT mice but hardly any in Cart KO mice. Amphetamine elicited conditioned place preference in both genotypes, but amphetamine's potency was reduced in the Cart KO mice. Intravenous cocaine self-administration was observed in both genotypes, but Cart KO mice consumed less cocaine and responded less for cocaine than WT mice. The behavioral effects of psychostimulants were reduced in the mutant Cart KO mice. By contrast, open field activity and sucrose preference of drug-naive mice WT and Cart KO mice were not significantly different. The attenuated effects of amphetamine and cocaine in Cart KO mice suggest a positive neuromodulatory role for CART peptides in the locomotor and motivational properties of psychostimulants and implicate CART peptides in psychostimulant addiction.

Expression of FGFR1 controls both myoblast proliferation and differentiation. The Krüppel-like transcription factor BTEB1 demonstrates bimodal, reciprocal activity by activating the FGFR1 promoter in proliferating myoblasts and repressing the same promoter via the same DNA-binding site in differentiated myotubes.

For patients ineligible for cisplatin with definitive radiotherapy (CP-CRT) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), concurrent cetuximab (C225-RT) is a popular substitute. Carboplatin-based chemoradiation (CB-CRT) is another option; however, relative efficacies of CP-CRT, CB-CRT and C225-RT are unclear, particularly in the human papillomavirus (HPV)-unrelated population. We identified 316 patients with stage III-IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225-RT (N = 61), CB-CRT (N = 74) or CP-CRT (N = 181). Kaplan-Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3-year cumulative incidences for CP-CRT, CB-CRT and C225-RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan-Meier estimates for 3 year OS were: CP-CRT: 71%; CB-CRT: 59% and C225-RT: 54%; p = 0.0094. CP-CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203-0.557, p < 0.01) and CB-CRT (HR 0.279; 95% CI 0.141-0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP-CRT (HR 0.548; 95% CI 0.355-0.845, p < 0.01) and CB-CRT (HR 0.549; 95% CI 0.334-0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB-CRT group compared to C225-RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB-CRT group *T.H.B. and C.B. are co-first authors † N.C. and A.D.B. are co-senior authors Cancer Therapy and Prevention compared to C225-RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB-CRT is an effective alternative to CP-CRT in HPV-unrelated LA-HNSCC with superior locoregional control and OS compared to C225-RT.What's new? While head and neck squamous cell carcinoma that are caused by human papillomavirus can be treated relatively well, virusnegative tumors have a poor prognosis. In this large multi-institutional study, the authors found that cisplatin-and carboplatin-based regimens-in concurrent chemoradiotherapy-were superior to antibody-based therapies, with carboplatinbased regimens representing a more tolerable alternative for patients with virus-negative tumors.