Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

Background

Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies.

Conclusions

The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

     

Evaluation effects of allopurinol and FSH on reduction of ischemia–reperfusion injury and on preservation of follicle after heterotopic auto-transplantation of ovarian tissue in mouse

Purpose

Allopurinol and FSH injection are applied to reduce ischemia–reperfusion injury and to increase survival rate for ovarian follicles after ovarian heterotopic autotransplantation in mice.

Methods

Ovarian tissues from 6-week-old mice were grafted into back muscle then collected after 3 weeks. A total of five groups were included in this experiment as follows: control group (n = 5), sham-operated group (n = 5), allopurinol treatment group (AP) (n = 5), follicle stimulating hormone (FSH) treatment group (n = 5), as well as, allopurinol and FSH treatment group (APF) (n = 5). We investigated survival, number and development of follicles, vaginal cytology along with plasma malondialdehyde (MDA) concentration in grafted ovary.

Results

Total follicles count significantly increased in APF group compared with other treatment groups (p < 0.05). MDA concentration significantly decreased in AP group and APF treatment group compared with sham-operated group. In AP group, vaginal smears showed presence of cornified epithelial cells three–five day after surgery.

Conclusions

We demonstrated that allopurinol, as a XO inhibitor, plays an important role in order to decrease ischemia injury and to increase survival rate for follicles. Also, FSH, as a folliculogenesis and angiogenesis factor, increases development of follicles. It seems that allopurinol can cause re-establishing hypothalamus–pituitary axis and finally can restore estrous cycle earlier than for the sham operated group, so it explains the increasing survival rate for follicles.     

Effectiveness of Group Resiliency Training on Anxiety,Depression, and Marital Satisfaction in Mothers of Children with Attention Deficit Hyperactivity Disorder

Many studies have been reported that higher levels of depression and anxiety in parents of children with attention deficit hyperactivity disorder. The objective of this study was to evaluate the effectiveness of group resiliency training on anxiety, depression, and marital satisfaction in mothers of children with attention deficit hyperactivity disorder. This study was an experimental, pretest—post-test study with control group. Participants included 54 mothers of children with attention deficit hyperactivity disorder. Mothers were randomly divided to experimental and control groups. The experimental group received 8 group resiliency training sessions and then compared in changes in Beck depression and anxiety scale and the Enrich marital satisfaction scale. Results of multivariate analysis of covariance showed significant change in depression, anxiety, and marital satisfaction. Our study indicates that resiliency training can be considered as one the effective intervention for anxiety, depression, and marital satisfaction in these mothers.     

Solubilization of an amphiphilic drug by poly(ethylene oxide)-block-poly(ester) micelles.

The purpose of this study was to investigate the solubilization of an amphiphilic drug, i.e, amiodarone (AMI) in methoxy poly(ethylene oxide)-block-poly(ester) micelles of different core structure. The effect of core-forming block structure as well as molecular weight, applied drug to polymer ratios and assembly condition on AMI solubilization; stability of the solubilized formulation upon dilution in phosphate buffer and the hemolytic activity of solubilized AMI against rat red blood cells were assessed and compared to those parameters for the commercial intravenous formulation of AMI. In general, polymeric micelles of different core structure were found to be more efficient in retaining their AMI content upon dilution than surfactant micelles in the commercial formulation of AMI for injection. Micelles with a poly(epsilon-caprolactone) (PCL) core were more efficient than poly(D,L-lactide) and poly(L-lactide) cores in the solubilization and stabilization of encapsulated AMI within the carrier. Encapsulation of AMI by methoxy poly(ethylene oxide)-block-poly(epsilon-caprolactone) (MePEO-b-PCL) micelles having higher PCL chains increased the level of AMI solubilization and decreased its hemolytic activity. Compared to O/W emulsion, application of solvent evaporation method led to higher encapsulation efficiency and lower hemolytic activity for AMI in micelles. An increase in the level of AMI added to the co-solvent evaporation process led to an increase in the solubilized AMI levels, but made the formulation more hemolytic. In conclusion, PEO-b-PCL micelles, particularly those with longer PCL chains, were found to be efficient carriers in encapsulating amphiphilic AMI, retaining encapsulated AMI within the carrier and reducing its hemolytic activity.     

Vascular involvement in the prognosis of primary cutaneous melanoma

OBJECTIVE: To examine the role of vascular invasion as a prognostic factor in melanoma. DESIGN: Retrospective survival analysis. SETTING: Academic medical center. PATIENTS: A total of 526 patients with primary cutaneous melanoma from the University of California, San Francisco, Melanoma Center database with 2 years of follow-up or documented relapse. MAIN OUTCOME MEASURES: (1) Presence of vascular involvement defined as vascular invasion with tumor cells within blood or lymphatic vessels; or uncertain vascular invasion, with melanoma cells immediately adjacent to the endothelium. (2) Percentage with metastasis or death and relapse-free and overall survival. RESULTS: The presence of either type of vascular involvement significantly increased the risk of relapse and death and reduced the survival associated with melanoma. The impact of vascular involvement on these outcomes was similar to that of ulceration. In a multivariate analysis, vascular involvement was the second most important factor (after tumor thickness) in the primary tumor in predicting survival. CONCLUSIONS: Vascular involvement is an important independent predictor of metastasis and survival in melanoma. The phenomenon of uncertain vascular invasion describes an earlier step than definite vascular invasion in tumor progression.     

Efficacy of a telephone-based intervention among patients with type-2 diabetes; a randomized controlled trial in pharmacy practice

Background Pharmacists’ interventions to improve outcomes of diabetes management have been promising. However, evidence on using telephone-based interventions in pharmacy practice are limited, particularly in developing countries. Objective To evaluate the efficacy of a telephone-based intervention to improve care and clinical outcomes in type-2 diabetes. Setting A referral community pharmacy and drug information center. Method We conducted a two-armed randomized controlled trial on 100 patients with type-2 diabetes. The intervention consisted of 16 telephone calls in 3 month by a trained pharmacist working in an academic drug information center, while the control group received usual care. Before random allocation, patients attended a live education session delivered by pharmacists to learn the basics of diabetes care and to confirm the eligibility criteria. Assessments were performed at baseline, month-3 (after intervention), and month-9 (follow-up). Main outcome measure Hemoglobin A1c (HbA1c). Results Eighty four patient completed the trial. Baseline variables were comparable between the two groups and the baseline value of hemoglobin A1c was 8.00 ± 1.44 in the study population. HbA1c was significantly improved in both groups at month-3 (6.97 ± 1.41 vs. 7.09 ± 1.78) and remained steady at month-9 (6.96 ± 1.44 vs. 7.26 ± 1.85). Lipid profile showed small improvements in the intervention group but was not significant. The adherence score and self-care score improvement was significantly higher in the intervention group at month-3 and were maintained at month-9. Conclusion Medication adherence and self-care significantly improved in the telephone-based intervention group. However, the improvement of clinical outcomes might have been diluted due to the live diabetes education session.     

Association of ANGPTL3 polymorphisms with high‐density lipoprotein cholesterol uptake capacity in patients with cardiovascular disease

IntroductionPrevious studies have shown the importance of angiopoietin‐like 3 (ANGPTL3) as a modulator of lipid profiles. Cholesterol uptake capacity (CUC) is one means for assessing high‐density lipoprotein (HDL) functionality. This study for the first time has investigated the relationship between genetic ANGPTL3 polymorphism and CUC in patients with cardiovascular disease.MethodsFive hundred three subjects comprising 350 healthy subjects and 153 individuals who developed a cardiovascular disease (CVD) event during follow‐up were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) cohort study. A modified CUC method was used to determine the CUC of serum samples. Applied amplification refractory mutation system PCR was performed for ANGPTL3 variants genotyping including: rs10789117, rs1748195, and rs11207997. Sanger sequencing was applied to confirm the genotypes.ResultsThe results showed that there was a significant relationship between the rs1748195 genotypes and HDL concentration in the CVD group (p = 0.02). Moreover, individuals with a GG genotype of the rs1748195 were associated with a lower risk of CVD (OR = 0.49, 95% CI = 0.24–0.98, p = 0.04) compared with CC genotype in the CUC ≤ 1.7 a.u subgroup. Moreover, the CT genotype of rs11207997 was associated with a lower risk of CVD (OR = 0.74, 95% CI = 0.41–1.3, p = 0.01) compared with CC genotype in CUC > 1.7 a.u subgroup.ConclusionThe results showed that the CT genotype of the rs11207997 variant was associated with a lower risk of incident CVD in patients with higher HDL functionality. As well, the rs1748195 gene variant may contribute to a reduced risk of CVD.     

A Combination of Non-ablative Laser and Hyaluronic Acid Injectable for Postacne Scars: A Novel Treatment Protocol

BackgroundPostacne facial scars are often associated with significant patient distress. Energy-based devices, including non-ablative lasers, are commonly used for the treatment of postacne scarring. There is relatively limited data regarding the combination of non-ablative lasers with hyaluronic acid injections for postacne scarring.ObjectiveWe aimed to evaluate the efficacy of a non-ablative 1,540-nm erbium:glass laser combined with a hyaluronic acid injectable for the treatment of postacne scars.MethodsThis was a retrospective analysis of 12 patients who underwent the full treatment protocol. A before and after blinded clinical evaluation was performed independently by two dermatologists and graded on a scale from 0 (indicating a worsening of scarring) to 4 (indicating a 76–100% improvement in scarring). Pain perception, adverse effects, and patient satisfaction were evaluated.ResultsA mean correct blinded before and after evaluation by two dermatologists was 96 percent. Patients demonstrated mild to moderate improvement as assessed by a quartile scale of improvement (25–50%). Mild transient pain was reported by most patients. The satisfaction level of the patients was high (4 out of 5).LimitationsThe limitations of our study include the small cohort, retrospective design, and lack of a histological correlation.ConclusionOur results suggest that this combination treatment using 1,540-nm fractional erbium:glass laser and hyaluronic acid injections is both safe and effective for patients with postacne facial scars.