Morusin induces cell death through inactivating STAT3 signaling in prostate cancer cells

STAT3 has been recognized as an efficacious drug target for prostate cancer because of its constitutive activation in this fatal disease. We recently identified the root bark of Morus alba Linn. as a potential STAT3 inhibitor among 33 phytomedicines traditionally used in Korea. Morusin, an active compound isolated from the root bark of Morus alba, has shown anti-oxidant and anti-inflammatory effects. In the present study, we examined whether morusin has a potential as an anti-cancer agent in prostate cancer. We found that morusin suppressed viability of prostate cancer cells, but little effect in normal human prostate epithelial cells. Morusin also reduced STAT3 activity by inhibiting its phosphorylation, nuclear accumulation, and DNA binding activity. In addition, morusin down-regulated expression of STAT3 target genes encoding Bcl-xL, Bcl-2, Survivin, c-Myc and Cyclin D1, which are involved in regulation of apoptosis and cell cycle. Furthermore, morusin induced apoptosis in human prostate cancer cells by reducing STAT3 activity. Taken together, these results suggest that morusin could be a potentially therapeutic agent for prostate cancer by reducing STAT3 activity and inducing apoptosis.     

Fluid administration in severe sepsis and septic shock,patterns and outcomes: an analysis of a large national database

Purpose

The optimal strategy of fluid resuscitation in the early hours of severe sepsis and septic shock is controversial, with both an aggressive and conservative approach being recommended.

Methods

We used the 2013 Premier Hospital Discharge database to analyse the administration of fluids on the first ICU day, in 23,513 patients with severe sepsis and septic shock, who were admitted to an ICU from the emergency department. Day 1 fluid was grouped into categories 1 L wide, starting with 1–1.99 L up to ≥9 L, to examine the effect of day 1 fluids on patient mortality. We built binary response models for hospital mortality and the propensity for receiving more than 5 L of fluids on day 1, using patient age and acute conditions present on admission. Patients were grouped by the requirement for mechanical ventilation and the presence or absence of shock. We assessed trends in the difference between actual and expected mortality, in the low fluid range (1–5 L day 1 fluids) and the high fluid range (5 to ≥9 L day 1 fluids) categories, using weighted linear regression controlling for the effects of sample size and variation within the day 1 fluid category.

Results

Day 1 fluid administration averaged 4.4 L being lowest in the group with no mechanical ventilation and no shock (3.6 L) and highest (5.4 L) in the group receiving mechanical ventilation and in shock. The administration of day 1 fluids was remarkably consistent on the basis of hospital size, teaching status, rural/urban location, and region of the country. The hospital mortality in the entire cohort was 25.8%, with a mean ICU and hospital length of stay of 5.1 and 9.1 days, respectively. In the entire cohort, low volume resuscitation (1–4.99 L) was associated with a small but significant reduction in mortality, of ?0.7% per litre (95% CI ?1.0%, ?0.4%; p = 0.02). However, in patients receiving high volume resuscitation (5 to ≥9 L), the mortality increased by 2.3% (95% CI 2.0, 2.5%; p = 0.0003) for each additional litre above 5 L. Total hospital cost increased by $999 for each litre of fluid above 5 L (adjusted R ² = 92.7%, p = 0.005).

Conclusion

The mean amount of fluid administered to patients with severe sepsis and septic shock in the USA during the first ICU day is less than that recommended by the Surviving Sepsis Campaign guidelines. The administration of more than 5 L of fluid during the first ICU day is associated with a significantly increased risk of death and significantly higher hospital costs.

     

Low-level laser therapy prevents severe oral mucositis in patients submitted to hematopoietic stem cell transplantation: a randomized clinical trial

Purpose

The purpose of this study is to evaluate the effectiveness of low-level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation.

Methods

This is a randomized, parallel, superiority trial including 35 patients divided into the following: laser (n?=?17) and sham (n?=?18). The variables assessed were oral mucositis (grade 2 of the World Health Organization oral toxicity scale), severe oral mucositis (grade 3 or 4), and pain (according to a visual analogue scale). In the laser group, a InGaAlP laser, wavelength of 650 nm, power 100 mW, energy per point of 2 J, time 20 s by point, extremity fiber optic 0.028 cm², and energy density 70 J/cm², was used, applied the first day of conditioning until D + 5, while the sham group received simulated laser over the same period.

Results

No statistically significant difference was found in the incidence of oral mucositis (p?=?0.146). Severe mucositis was found in 40 % of the patients (14/35), 3 in the intervention group (17.65 %) and 11 in the sham group (61.11 %) (p?=?0.015). The cumulative probability of survival with respect to the development of severe oral mucositis was >0.6 for the intervention group and 0 for the control group (p?=?0.0397). On the day on which pain was considered the worst, patients in the sham group were more likely to classify their pain as severe compared to those in the laser group (p?=?0.041).

Conclusion

Low-level laser therapy proved effective for the prevention of severe oral mucositis and intense oral pain in patients submitted to hematopoietic stem cell transplantation.

     

Preperitoneal fat thickness by ultrasonography and obesity-related disorders

Purpose To determine optimal cutoff values for preperitoneal fat thickness measured by ultrasonography as indicators for obesity-related disorders. Methods We studied 276 men aged 60 ± 13 years and 307 women aged 64 ± 11 years. Participants were consecutively enrolled from inpatients aged ≤75 years. Demographic data were collected and maximal preperitoneal fat thickness (PFT_max) and carotid intima-media thickness were evaluated on B-mode ultrasonography. Receiver operating characteristic (ROC) curve analysis was performed to determine optimal cutoff values for PFT_max. Results Multiple regression analysis using one or more obesity-related disorders as an objective variable showed that the tertile on the basis of PFT_max was a significant independent contributing factor in both men and women. Receiver operating characteristic curve analysis identified the cutoff points of 6.1 mm for PFT_max in men (sensitivity, 66.7%; specificity, 62.5%) and 8.7 mm for PFT_max in women (sensitivity, 56.6%; specificity, 63.6%) as discriminator values corresponding to the presence of one or more obesity-related disorders. Using the new criteria to diagnose visceral obesity, we found that adjusted carotid intima-media thickness was significantly higher in men and women with visceral obesity and two or more obesity-related disorders than in those without them. Conclusions These findings suggested that PFT_max measured on ultrasonography was useful in screening for indicators of cardiovascular risk factors.     

Management of Peripheral Arterial Disease of the Lower Extremities

Smoking should be stopped and hypertension, diabetes mellitus, dyslipidemia, and hypothyroidism treated in patients with peripheral arterial disease (PAD) of the lower extremities. Statins decrease the incidence of intermittent claudication and improve exercise duration until the onset of intermittent claudication in persons with PAD and hypercholesterolemia. Antiplatelet drugs such as aspirin or clopidogrel, especially clopidogrel, angiotensin-converting enzyme inhibitors, and statins should be given to all persons with PAD. Beta blockers should be given if coronary artery disease is present. Exercise rehabilitation programs and cilostazol increase exercise time until intermittent claudication develops. Chelation therapy should be avoided. Indications for lower extremity percutaneous transluminal angioplasty or bypass surgery are (1) incapacitating claudication in persons interfering with work or lifestyle, (2) limb salvage in persons with limb-threatening ischemia as manifested by rest pain, nonhealing ulcers, and/or infection or gangrene, and (3) vasculogenic impotence. Dr. Aronow has no real or apparent conflicts of interest relating to the subject under discussion.     

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.     

Deep Brain Stimulation and Motor Cortical Stimulation for Neuropathic Pain

Deep brain stimulation (DBS) is an important treatment option for neuropathic pain. DBS has a considerable history, and it can be used successfully for a wide number of pain syndromes. Epidural motor cortex stimulation (MCS) also is a treatment option for neuropathic pain. Less invasive than DBS, MCS has been rapidly adopted and studied since first described in 1991. A growing body of literature supports the use of MCS for facial pain, though further study to better define the mechanism of action and the most appropriate patient populations is ongoing.     

Mitochondrial disease and epilepsy

Mitochondrial diseases are a group of diseases caused by dysfunctional mitochondria, organelles that generate energy for the cell. Mitochondrial diseases are often caused by mutations, acquired, or inherited in the mitochondrial DNA or nuclear genes that code for respiratory chain complexes in the mitochondrion. Mitochondrial diseases involve multiple organs and show heterogeneous and unpredictable progression. The most common clinical presentation of mitochondrial diseases is encephalomyopathy, and epileptic seizures can frequently occur as a presenting sign of mitochondrial encephalopathy. While whether mitochondrial dysfunction or epilepsy is the cause or consequence is still debatable, they may be interrelated to create a vicious cycle. Epileptic phenotypes vary in different mitochondrial diseases. At present, there are no curative treatments for mitochondrial diseases, and the efficacy of many anticonvulsants, vitamins, nutritional supplements, and the ketogenic diet remain to be proven. Understanding the pathophysiology of mitochondrial diseases may further facilitate effective diagnostic and therapeutic approaches to these diseases.