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"I doubt not that there is some order throughout, from the warning to the end of the post paroxysmal stage."1 With these words John Hughlings Jackson, in 1880, discussed the results of his exhaustive clinical studies of epileptic patients whose symptoms comprised a number or a series of consecutive or simultaneous alterations of thought, emotion, sensation, and behavior. Thus he indicated his confidence that the varied manifestations of each epileptic attack, whether "dreamy state," uncinate fit, hallucination, or complex automatism, were consistent within the framework of the attack, if only the framework itself could be discerned. The present study is a direct outgrowth of lengthy clinical and electroencephalographic investigation carried out on a group of epileptic patients in collaboration with Drs. Paul MacLean and Gilbert Glaser.2In the course of these studies, we were repeatedly struck by the frequency of association of certain groups of symptoms within the
2539 Background: BPM 31510 is a small molecule that targets the metabolic machinery of the cancer microenvironment to create a hallmark shift from lactate dependency towards mitochondrial oxidative phosphorylation, reversing the Warburg effect. Preclinical data indicate BPM 31510 causes this shift resulting in tumor regression and enhances the antitumor activity in combination with chemotherapy agents in a priming schedule. This is the first clinical study to evaluate BPM 31510 at a 4-days (d) continuous infusion in four arms; as a single agent, and in combination with Gemcitabine, 5-FU or Docetaxel. Methods: Eligible patients (pts) (aged ≥ 18 y) had previously treated relapsed/refractory ST. Pts in the monotherapy arm received IV BPM 31510 for 4 d in continuous infusion in 28-d cycles. Pts in the combination arms were primed for 3 wks and then started in a weekly dosing (either gemcitabine, 5-FU or docetaxel) after the BPM 31510 infusion in a 6-wk cycle. Doses were escalated in a 3+3 schema. Phase I endpoints were safety, PK and Multi-Omics based pharmacodynamics. Tumor response is evaluated at wk 2 and every 4 -6 wks. Results: As of 01 Dec 2014, 56 pts have been enrolled. Pts have been treated at 3 dose levels up to 137 mg/kg. No DLTs or treatment‐related SAEs have been reported. MTD has not yet been established. Most frequently reported related AEs in all 4 arms were grade 1-2 INR prolongation that resolved after Vitamin K administration. No bleeding reported. Grade 1-2 thrombocytopenia has been seen in the Gemcitabine arm requiring dose modification. PK data indicated linear distribution. 12/25 pts (48%) that are evaluable for efficacy after cycle 2 showed various responses including: tumor reductions, decrease FDG, arrested tumor progression, stable disease, decrease in tumor markers, QOL improvements. Integrated multi-omics technology showed reversal of the Warburg effect in selected pts. Conclusions: Emerging data from this study suggest that BPM 31510 is well tolerated in monotherapy or in combination with chemotherapy agents. Early anti-tumor activity is seen. Dose-escalation on a 6-day infusion schedule is ongoing to determine the recommended phase II dose Clinical trial information: NCT01957735.
OBJECTIVE: Onset of schizophrenia occurs during the reproductive period in more than 80% of those affected. The author reviews neuroendocrine and physiologic events that occur in the basal forebrain at the initiation of and throughout the reproductive period and proposes their possible relationship to the onset of schizophrenia. METHOD: The neuroendocrine changes that occur in specific areas of the anterior basal forebrain during the reproductive period are reviewed and analyzed in relation to reported anatomic, molecular, and biochemical pathologies of schizophrenia. RESULTS: The reproductive period is associated with development of regular pulsatile release in the brain and bloodstream of gonadotropic releasing hormones from the hypothalamus, luteinizing and follicle stimulating hormones from the pituitary, and gonadal hormones from the ovaries and testes. In addition to being concentrated in the hypothalamus, brain receptors for gonadotropic and gonadal hormones are concentrated in specific subcortical forebrain nuclei of the limbic system that project to the thalamus and to cortical and subcortical structures that subserve perception, cognition, and behavior. CONCLUSIONS: There is a flood of estrogen and testosterone to the brain and body during puberty and throughout the reproductive period. To avoid hyperexcitability and seizures, the surge of these excitatory hormones must be counterbalanced by appropriate inhibitory factors. Excessive focal inhibition may be induced by increased release of or increased receptors for one or more inhibitory transmitters, e.g., dopamine, serotonin, and γ-aminobutyric acid in the anterior basal forebrain. Further investigation of the physiology and pathology of this brain region, where abnormal electrical activity was recorded from individuals with schizophrenia many years ago and where dopamine D2 and dopamine D3 receptors targeted by the most effective antipsychotic agents are maximally expressed, could lead to greater understanding of the critical pathophysiology for development of schizophrenia.
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