Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation

Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50 = 11.9 nM) than digitoxin (IC50 = 90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.     

The frequency and biodiversity of poliovirus and non-polio enterovirus strains isolated from healthy children living in a limited area in Romania

The risk of importation and transmission of poliovirus strains to small susceptible groups within populations will remain until polio is eradicated globally. We investigated the circulation and biodiversity of enteroviruses in a group of children under 6 years of age with low vaccine coverage against polio. Only vaccine Sabin strains and viruses of the human enterovirus species B were isolated from the group. Evidence of inter-human circulation of Sabin strains was found.     

Neurocognitive outcomes at kindergarten entry after liver transplantation at <3 yr of age

This prospective inception cohort study determines kindergarten‐entry neurocognitive abilities and explores their predictors following liver transplantation at age <3 yr. Of 52 children transplanted (1999–2008), 33 (89.2%) of 37 eligible survivors had psychological assessment at age 54.7 (8.4) months: 21 with biliary atresia, seven chronic cholestasis, and five acute liver failure. Neurocognitive scores (mean [s.d.], 100 [15]) as tested by a pediatric‐experienced psychologist did not differ in relation to age group at transplant (≤12 months and >12 months): FSIQ, 93.9 (17.1); verbal (VIQ), 95.3 (16.5); performance (PIQ), 94.3 (18.1); and VMI, 90.5 (15.9), with >70% having scores ≥85, average or above. Adverse predictors from the pretransplant, transplant, and post‐transplant (30 days) periods using univariate linear regressions for FSIQ were post‐transplant use of inotropes, p = 0.029; longer transplant warm ischemia time, p = 0.035; and post‐transplant highest serum creatinine, (p = 0.04). For PIQ, they were pretransplant encephalopathy, p = 0.027; post‐transplant highest serum creatinine, p = 0.034; and post‐transplant inotrope use, p = 0.037. For VMI, they were number of post‐transplant infections, p = 0.019; post‐transplant highest serum creatinine, p = 0.025; and lower family socioeconomic index, p = 0.039. Changes in care addressing modifiable predictors, including reducing acute post‐transplant illness, pretransplant encephalopathy, transplant warm ischemia times, and preserving renal function, may improve neurocognitive outcomes.     

Rare renal tumor--mucinous tubular and spindle cell carcinoma

We report a rare case of renal tumor--mucinous tubular and spindle cell carcinoma in a 65-year-old man. The tumor, located in the right kidney, was well circumscribed. Microscopically, the tumoral proliferation was composed of cuboidal cells arranged in tubules, with abrupt transition to spindle cell morphology in a myxoid stroma. Because of the favorable prognosis with this type of tumor, mucinous tubular and spindle cell carcinoma must be differentiated from papillary renal cell carcinoma, especially the variant with sarcomatoid dedifferentiation.     

Modulatory Effects of Deltamethrin on Antioxidant Defense Mechanisms and Lipid Peroxidation in Carassius auratus gibelio Liver and Intestine

Pyrethroids, such as deltamethrin, are toxic substances that lead to generation of reactive oxygen species, which harm living organisms. We assessed the level and patterns of imbalance evolved by a single dose of 2 μg/L deltamethrin on the lipid peroxidation (LPO) and the antioxidant defense system of Carassius auratus gibelio liver and intestine, and monitored the recovery dynamics of these parameters during a 14-day post-exposure period. LPO and antioxidative defense mechanisms displayed different responses in the investigated tissues. Sudden increase of LPO in the liver, persisting at this elevated level throughout the test period, was observed on the third day post-exposure, while in the intestine significant enhancement of this parameter was recorded from the seventh day. Reduced glutathione (GSH) showed a transient increase in the liver, and was depleted in the intestine by the second day of exposure, with signs of recovery by the end of the experimental tenure. In the liver of fish a temporary inhibition of superoxide dismutase (SOD) and catalase (CAT) activity, and activation of glutathione peroxidase (GPX), glutathione transferase (GST), and glutathione reductase (GR) enzymes was observed, with maximum thresholds recorded on the third and second days, respectively. In the intestine a relevant increase in CAT and GST activity up to the second day and almost complete recovery by the end of the experiment was recorded, while for GR a continuous enhancement was apparent.     

A Prospective Outcome Study on the Effects of Facet Joint Radiofrequency Denervation on Pain, Analgesic Intake, Disability, Satisfaction, Cost, and Employment

Burnham RS, Holitski S, Dinu I. A prospective outcome study on the effects of facet joint radiofrequency denervation on pain, analgesic intake, disability, satisfaction, cost, and employment.

Objective

To assess the effect of radiofrequency denervation (RFD) on patients with chronic low back pain (LBP) of facet joint origin.

Design

Prospective cohort study.

Setting

Interventional pain management program.

Participants

Consecutive subjects (N=44; 101 facet joints) over 2 years with chronic refractory mechanical LBP of facet origin established by 2 local anesthetic blocks (medial branch ± intra-articular) resulting in more than 50% pain relief.

Intervention

RFD of the symptomatic lumbar facet joints.

Main Outcome Measures

Self-reported pain intensity, frequency, bothersomeness, analgesic intake, satisfaction, disability, back pain-related costs, and employment twice prior to and at 1, 3, 6, 9, and 12 months post-RFD.

Results

Post-RFD, significant improvements in pain, analgesic requirement, satisfaction, disability, and direct costs occurred. They peaked at 3 to 6 months and gradually diminished thereafter. Satisfaction with medical care and living with current symptoms improved similarly. Overall, satisfaction with the RFD procedure was high, and no complications were reported.

Conclusions

RFD provides safe and significant short-term improvement in pain, analgesic requirements, function, satisfaction, and direct costs in patients with chronic LBP of facet origin.