We describe five cases of headache due to spontaneous liquoral hypotension, the syndrome comprising sudden, intense and oppressive orthostatic holocranial headache. The headache improved in the recumbent position and was accompanied by nausea and sometimes vomiting. There was no history of lumbar puncture or previous trauma. CSF tension was low or negative. The CSF showed a raised protein content and increased red and white cell counts. CT scan was normal or showed a slit ventricular system. Improvement was complete three to eight weeks from onset. The treatment consisted of bed rest and oral and parenteral fluid replacement. An isotope cisternography carried out in all patients while the headache was present showed a cisternographic pattern characterized by a combination of premature elimination and failure to detect the isotope at the cerebral convexity. Scan images did not show CSF leakage at any site. This stereotyped reaction pattern suggests that CSF hyperabsorption is the most likely pathophysiological mechanism of this entity.

We previously developed cell-based vaccines as therapeutics for metastatic cancers. The vaccines were aimed at activating type I CD4+T cells and consisted of tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated invariant chain. The vaccines showed some efficacy in mice with sarcoma, melanoma, and breast cancer and activated MHC class II syngeneic T cells from breast, lung, and melanoma patients. During the course of the vaccine studies, we observed that CD80 not only costimulated naïve T cells, but also bound to PD-L1 and prevented tumor cell-expressed PD-L1 from binding to its receptor PD-1 on activated T cells. A soluble form of CD80 (CD80-Fc) had the same effect and sustained IFNγ production by both human and murine PD-1+ activated T cells in the presence of PD-L1+ human or mouse tumor cells, respectively. In vitro studies with human tumor cells indicated that CD80-Fc was more effective than antibodies to either PD-1 or PD-L1 in sustaining T cell production of IFNγ. Additionally, in vivo studies with a murine tumor demonstrated that CD80-Fc was more effective than antibodies to PD-L1 in extending survival time. Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation. These results suggest that CD80-Fc may be a useful monotherapy that minimizes PD-1 pathway immune suppression while simultaneously activating tumor-reactive T cells.

Summary The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.

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This paper reviews the goals of the Domoweb project and the solutions adopted to achieve them. As a result we enjoy a great support to develop smart home techniques and solutions. As a consequence of the acquired experiences a Smart home model is proposed as a division of four main categories. In relation with the smart home model, we show the essential features a smart environment prediction algorithm should satisfy and a procedure to select relevant information from the model to achieve artificial intelligence based solutions.