Gi and RGS proteins provide biochemical control of androgen receptor nuclear exclusion

Nuclear localization of androgen receptors (ARs) is essential for their activity. Melatonin induces AR nuclear exclusion via increase in cGMP, calcium, and protein kinase C (PKC) activation, presumably through G-protein(s). The effects of regulators of G-protein signaling (RGS) on AR localization were studied in AR-expressing PC3 cells. Gi-specific RGS10 inhibited melatonin but not cGMP-induced AR nuclear exclusion, independent of androgen. No evidence for Gq activation by melatonin was found. However, Gi/Gq-selective RGS4 inhibited AR nuclear exclusion downstream of PKC activation—an effect that was abrogated by constitutively active Gq. RGS10 and RGS4, but not RGS2, ablated the inhibitory effects of melatonin on AR reporter gene activity. For the first time, these data show regulation by Gi and Gi-specific RGS protein-mediated AR nuclear exclusion, which is potentially important in the treatment of AR-dependent cancers and neurodegenerative disorders. They also reveal a role for a Gq protein downstream of PKC activation in AR nuclear localization.     

Transcranial Magnetic Stimulation at M1 disrupts cognitive networks in schizophrenia

Transcranial Magnetic Stimulation (TMS) is rapidly gaining acceptance as a non-invasive probe into brain functionality. We utilize TMS to study the connectivity of a simple motor network in patients of schizophrenia (N=19), and in healthy control subjects (N=9). TMS was used in an externally paced finger tapping task, perturbing the internal network oscillations invoked by the finger motion as it keeps pace with a metronome. TMS perturbations were synchronized to the metronome and applied to the network at the level of the primary motor cortex (M1). Contrary to initial expectations, TMS did not affect the sensorimotor synchronization of subjects with schizophrenia or their tapping accuracy. TMS did cause extreme deviations in the finger's trajectory, and altered the timing perceptions of subjects with schizophrenia. Additionally, it invoked high-level deficiencies related to attention and volition in the form of lapses, implying that the connectivity between modules in the brain that underlie motor control, sensorimotor synchronization, timing perception and awareness of action, can be disrupted by TMS in subjects with schizophrenia, but not in healthy subjects. The ability to disrupt high level network functions with perturbations to the lower level of M1 supports models describing deficits in connectivity of distributed networks in the brains of schizophrenia patients. It also demonstrates the use of TMS to probe connectivity between components of such networks.     

Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam

In 42 alcoholic inpatients we performed an open randomized study to compare the effects of diazepam and gamma-hydroxybutyrate (GHB) on the suppression of severe alcohol withdrawal syndrome and hypercortisolism. Both diazepam (.5 mg/kg bodyweight, q.i.d.) and GHB (50 mg/kg bodyweight, q.i.d.) were orally administered for three weeks. During all study period, GHB was more able than diazepam in reducing both withdrawal syndrome and hypercortisolism. These effects were evident during the first week of treatment and persisted throughout the study period. The results confirm a strict correlation between high levels of plasma cortisol and alcohol withdrawal symptoms and they show a slight superiority of GHB over diazepam in the suppression of both ethanol withdrawal and hypercortisolism. Taken together, our data suggest that GHB may act as potent anti-withdrawal agent in severe abstinent alcoholics.     

A prospective, controlled study of the botanical compound mixture LCS101 for chemotherapy-induced hematological complications in breast cancer

Background.

This prospective, controlled study evaluated the safety, tolerability, and efficacy of the mixture of botanical compounds known as LCS101 in preventing chemotherapy-induced hematological toxicity in breast cancer patients.

Methods.

Female patients diagnosed with localized breast cancer were randomly allocated to receive treatment with either LCS101 or placebo capsules, in addition to conventional chemotherapy. The study intervention was initiated 2 weeks prior to the initiation of chemotherapy and continued until chemotherapy was completed, with participants receiving 2 g of LCS101 capsules thrice daily. Subjects were assessed for the development of hematological and nonhematological toxicities, as well as the tolerability and safety of the study intervention.

Results.

Sixty-five breast cancer patients were recruited, with 34 allocated to LCS101 and 31 allocated to placebo treatment. Patients in the treatment group developed significantly less severe (grades 2–4) anemia (p < .01) and leukopenia (p < .03) when comparing grades 0–1 with grades 2–4, with significantly less neutropenia (p < .04) when comparing grades 0–2 with grades 3–4. This effect was more significant among patients undergoing a dose-dense regimen. No statistically significant effect was found with respect to nonhematological toxicities, and side effect rates were not significantly different between the groups, with no severe or life-threatening events observed in either group.

Conclusion.

The addition of LCS101 to anthracycline- and taxane-based chemotherapy is safe and well tolerated, and may significantly prevent some chemotherapy-induced hematological toxicities in early breast cancer patients. These results should encourage further larger and more extensive clinical trials.     

Malignant gastroparesis: pathogenesis and management of an underrecognized disorder

Gastroparesis is a disorder of the stomach caused by delayed gastric emptying in the absence of mechanical obstruction. Symptoms of gastroparesis include nausea, vomiting, early satiety, bloating, and abdominal discomfort. Gastroparesis has been described as a complication of several malignancies, including gastric, pancreatic, gallbladder, esophageal, and lung cancers, as well as leiomyosarcoma.The prevalence of malignant gastroparesis (MG) is unknown, and this entity is widely underrecognized and undertreated. Diabetes mellitus is the most common identifiable cause of benign gastroparesis, ie, gastroparesis occurring in the absence of an underlying malignant pathology. In the setting of malignancy, gastroparesis may result from the cancer itself or may be a complication of its treatment with such modalities as surgery, radiation therapy, or chemotherapy. Coexisting conditions, including diabetes, hypothyroidism, and neurologic diseases, may further exacerbate MG. The pathogenesis of MG is not clearly understood at present. However, mechanisms suggested in the literature include postvagotomy syndrome, malignant infiltration of the autonomic nervous system, and paraneoplastic dysmotility with autoantibody-mediated destruction of the enteric nervous system (the interstitial cells of Cajal, also called the intrinsic pacemaker of the gastrointestinal tract, or the myenteric plexus). Appropriate treatment of MG may help to avoid serious consequences, such as cancer cachexia, intolerance of oral anticancer agents, dehydration, and hospitalization. In this article, we will describe our institutional experience with MG and will provide a concise review of the literature. Guidelines for management will be suggested.     

Therapeutic capacity of the synthetic peptide-based vaccine against Taenia solium cysticercosis in pigs

The S3Pvac synthetic vaccine composed of three peptides (GK1, KETc1 and KETc12) effectively protect against pig cysticercosis. Preliminary results point to an additional cysticidal capacity induced by S3Pvac or GK1 immunization. Herein, clear evidences of the cysticidal effect of S3Pvac but not of GK1 are presented. S3Pvac immunization of already experimentally infected pigs induced a reduction in the parasite load, in the vesicular cysticerci and in their viability. It also substantially increases the percent of histological damaged cysticerci more importantly in muscles than in brains, with a concomitant reduction in the antibody levels. Thus, S3Pvac represents a powerful means of controlling cysticercosis infection in pigs.