We investigated whether the perifornical-lateral hypothalamic area (PF-LHA), where the orexin neurons reside, is a central chemoreceptor site by microdialysis of artificial cerebrospinal fluid (aCSF) equilibrated with 25% CO2 into PF-LHA in conscious rats. This treatment is known to produce a focal tissue acidification like that associated with a 6 to 7 mm Hg increase in arterial P CO2. Such focal acidification in the PF-LHA significantly increased ventilation up to 15% compared with microdialysis of normal aCSF equilibrated with 5% CO2 only in wakefulness but not in sleep in both the dark (P=0.004) and light (P<0.001) phases of the diurnal cycle. This response was predominantly due to a significant increase in respiratory frequency (11%, P< 0.001). There were no significant effects on ventilation in the group with probes misplaced outside the PF-LHA. These results suggest that PF-LHA functions as a central chemoreceptor site in the central nervous system in a vigilant state dependent manner with predominant effects in wakefulness.

Melanin concentrating hormone (MCH), a neuropeptide produced mainly in neurons localized to the lateral hypothalamic area (LHA), has been implicated in the regulation of food intake, energy balance, sleep state, and the cardiovascular system. Hypothalamic MCH neurons also have multisynaptic connections with diaphragmatic motoneurons and project to many central chemoreceptor sites. However, there are few studies of MCH involvement in central respiratory control. To test the hypothesis that MCH plays a role in the central chemoreflex, we induced a down regulation of MCH in the central nervous system by knocking down the MCH precursor (pMCH) mRNA in the LHA using a pool of small interfering RNA (siRNA), and measured the resultant changes in breathing, metabolic rate, body weight, and blood glucose levels in conscious rats. The injections of pMCH-siRNA into the LHA successfully produced a ∼62% reduction of pMCH mRNA expression in the LHA and a ∼43% decrease of MCH levels in the cerebrospinal fluid relative to scrambled-siRNA treatment (P = 0.006 and P = 0.02 respectively). Compared to the pretreatment baseline and the scrambled-siRNA treated control rats, knockdown of MCH resulted in: 1) an enhanced hypercapnic chemoreflex (∼42 & 47% respectively; P < 0.05) only in wakefulness; 2) a decrease in body weight and basal glucose levels; and 3) an unchanged metabolic rate. Our results indicate that MCH participates not only in the regulation of glucose and sleep-wake homeostasis but also the vigilance-state dependent regulation of the central hypercapnic chemoreflex and respiratory control.

Accessory male breast cancer (BC) is a rare entity and is associated with poor outcome. We report a 76-year-old patient who was diagnosed with concurrent accessory breast and primary lung cancer, both were positive for somatic BRCA-2 (E1593D) mutation. He received concurrent radiation and platinum-based chemotherapy for lung cancer with good response, but breast cancer progressed in about 8 months, and further progressed after single agent anastrozole in 10 months. Next Generation Sequencing (NGS) of breast cancer was also positive for CCND1 (Cyclin D1) and FGFR1 amplifications. Despite a poor molecular profile of breast cancer, and progression following platinum-based chemotherapy and anastrozole, he was successfully treated with the Cyclin-dependent kinase (CKD) 4/6 inhibitor palbociclib, estrogen-receptor down-regulator fulvestrant and luteinizing hormone-releasing hormone (LHRH) agonist leuprolide with the duration of response of 21 months which has exceeded duration of response to prior treatments. This case is of interest given FDA expanded the approval of palbociclib in combination with AI or fulvestrant for male patients with HR–positive, HER2-negative metastatic breast cancer in Apr. 2019 based on real-world data from electronic health records.

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The coupling effect between the stress field formed by rock mass and the seepage field formed by groundwater has an important impact on the stability of underground engineering. In order to conduct the fluid-solid coupling physical model test in the laboratory, it is necessary to develop suitable analogous materials. In this study, a new type of analogous material reflecting the fluid-solid coupling effect is developed with iron powder, barite powder, and quartz sand as aggregates, white cement as a cementing agent, and silicone oil as a regulator. Through a large number of orthogonal experiments, the influence laws of different material contents on the mechanical properties and permeability characteristics of analogous materials are obtained. In addition, a method for quickly determining the proportion of components in fluid-solid coupling analogous materials is also proposed. The developed analogous material is employed in the fluid-solid coupling physical model test of a deep tunnel. The variation laws of rock stress, displacement, and seepage pressure around the tunnel during construction are obtained, which verifies the feasibility of the developed analogous material.