Distinct limbic dopamine regulation across olfactory-tubercle subregions through integration of in vivo fast-scan cyclic voltammetry and optogenetics.

The olfactory tubercle (OT), an important component of the ventral striatum and limbic system, is involved in multi-sensory integration of reward-related information in the brain. However, its functional roles are often overshadowed by the neighboring nucleus accumbens. Increasing evidence has highlighted that dense dopamine (DA) innervation of the OT from the ventral tegmental area (VTA) is implicated in encoding reward, natural reinforcers, and motivated behaviors. Recent studies have further suggested that OT subregions may have distinct roles in these processes due to their heterogeneous DA transmission. Currently, very little is known about regulation (release and clearance) of extracellular DA across OT subregions due to its limited anatomical accessibility and proximity to other DA-rich brain regions, making it difficult to isolate VTA-DA signaling in the OT with conventional methods. Herein, we characterized heterogeneous VTA-DA regulation in the medial (m) and lateral (l) OT in "wild-type," urethane-anesthetized rats by integrating in vivo fast-scan cyclic voltammetry with cell-type specific optogenetics to stimulate VTA-DA neurons. Channelrhodopsin-2 was selectively expressed in the VTA-DA neurons of wild-type rats and optical stimulating parameters were optimized to determine VTA-DA transmission across the OT. Our anatomical, neurochemical, and pharmacological results show that VTA-DA regulation in the mOT is less dependent on DA transporters and has greater DA transmission than the lOT. These findings establish the OT as a unique, compartmentalized structure and will aid in future behavioral characterization of the roles of VTA-DA signaling in the OT subregions in reward, drug addiction, and encoding behavioral outputs necessary for survival.

Lung Cancer in Pregnancy: An Unusual Case of Complete Response to Chemotherapy.

The diagnosis of lung cancer in pregnancy is rare. Most cases are quite advanced and have dismal outcomes despite treatment. We present the case of a 26-year-old woman who was diagnosed with Stage IIIA (T3N2M0) squamous-cell carcinoma of the lung with lymphoepithelioma-like features at the 18(th) week of pregnancy. A chest CT revealed a large right hilar mass with obliteration of the right main bronchus and resulting collapse of the right lung with mediastinal shift to the right. A transbronchial biopsy of the mass and a subcarinal lymph node confirmed poorly differentiated squamous cell carcinoma with lymphoepithelioma-like features. Brain MRI, PET, and CT scans were negative for distant metastasis. The patient received four cycles of neoadjuvant cisplatin and docetaxel with a complete radiographic response. She delivered a healthy baby girl at 35 weeks gestation. Post-partum, she received radiation to the right hilum and mediastinum as consolidation. The patient continues to remain free of disease more than 16 months after initial diagnosis. To our knowledge, this is the only reported case of lung cancer in pregnancy where there is a complete response to chemotherapy. The histology is also distinct from other reported cases. In addition, this case exemplifies the relative safety and efficacy of chemotherapy during the later stages of pregnancy. As long as a patient is beyond the first trimester of pregnancy, platinum-based doublet chemotherapy may be considered as a feasible treatment option.

Synthesis and in vitro evaluation of novel 1,2,3,4-tetrahydroisoquinoline derivatives as potent antiglioma agents.

Glioblastoma Multiforme (GBM) continues to demand improved chemotherapeutic solutions. In order to discover novel chemotherapeutic agents for GBM, we identified novel tetrahydroisoquinoline (THI) analogs as antiglioma agents. The present study reports the design, synthesis and in vitro evaluation of new THI derivatives in four established human glioma cell lines (T98, U87, LN18 and A172). Our structure activity relationship (SAR) studies revealed that the important modification of the carbon linker between the biphenyl and THI ring yielded EDL-360 (12) as a potent antiglioma agent (LN18; IC50: 5.42 ± 0.06 µM) and is considered to be our new lead drug candidate for further preclinical studies.