Imatinib Mesylate Inhibits Platelet-Derived Growth Factor Receptor Phosphorylation of Melanoma Cells But Does Not Affect Tumorigenicity In Vivo

Platelet-derived growth factor (PDGF) and its cognate receptor are widely expressed on melanomas. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. Imatinib mesylate was previously reported to have specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Melanoma cells express abundant levels of the PDGF receptor (PDGFR). Nevertheless, c-Kit expression is progressively lost as the cells take on a more highly metastatic phenotype. To investigate the potential of imatinib mesylate as a therapy for melanoma, we studied its effect on the growth of melanoma cells using an in vivo mouse model. Melanoma cells with high malignant potential (PDGFR-positive, c-Kit-negative) or low malignant potential (PDGFR-positive, c-Kit-positive) were injected subcutaneously into athymic nude mice. Mice were treated with imatinib mesylate (100 mg/kg three times weekly) or with phosphate-buffered saline for 4 to 6 wk. PDGFR-α and -β were expressed on all melanoma cell lines tested. The level of PDGFR expression correlated with the metastatic potential of the melanoma cells: higher levels of PDGFR-α were expressed on cells with higher metastatic potential, and higher levels of PDGFR-β were expressed on cells with lower metastatic potential. There was no significant difference in tumor size between treated and control mice. Immunohistochemical studies demonstrated inhibition of PDGFR phosphorylation on the tumors from mice treated with imatinib mesylate but not from control mice, suggesting that the receptors were functional and that the concentration of drug used was appropriate. Our data demonstrated that imatinib mesylate blocked both PDGFR-α and PDGFR-βin vivo. It did not, however, affect the growth of melanoma cells expressing PDGFR, regardless of whether the cells expressed c-Kit

Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC

Comparative effectiveness of intensity modulated radiation therapy to 3-dimensional conformal radiation in locally advanced lung cancer: pathological and clinical outcomes.

OBJECTIVE: Intensity-modulated radiotherapy (IMRT) has better normal-tissue sparing compared with 3-dimensional conformal radiation (3DCRT). We sought to assess the impact of radiation technique on pathological and clinical outcomes in locally advanced non-small cell lung cancer (LANSCLC) treated with a trimodality strategy. METHODS: Retrospective review of LANSCLC patients treated from August 2012 to August 2018 at Sheba Medical Center, Israel. The trimodality strategy consisted of concomitant chemoradiation to 60 Gray (Gy) followed by completion surgery. The planning target volume (PTV) was defined by co-registered PET/CT. Here we compare the pathological regression, surgical margin status, local control rates (LC), disease free (DFS) and overall survival (OS) between 3DCRT and IMRT. RESULTS: Our cohort consisted of 74 patients with mean age 62.9 years, male in 51/74 (69%), adenocarcinoma in 46/74 (62.1%), stage 3 in 59/74 (79.7%) and chemotherapy in 72/74 (97.3%). Radiation mean dose: 59.2 Gy (SD ± 3.8). Radiation technique : 3DCRT in 51/74 (68.9%), IMRT in 23/74 (31%). Other variables were similar between groups.Major pathological response (including pathological complete response or less than 10% residual tumor cells) was similar: 32/51 (62.7%) in 3DCRT and 15/23 (65.2%) in IMRT, p=0.83. Pathological complete response (pCR) rates were similar: 17/51 (33.3%) in 3DCRT and 8/23 (34.8%) in IMRT, p=0.9. Surgical margins were negative in 46/51 (90.1%) in 3DCRT vs. 17/19 (89.4%) in IMRT (p=1.0).The 2-year LC rates were 81.6% (95% CI 69-89.4%); DFS 58.3% (95% CI 45.5-69%) and 3-year OS 70% (95% CI57-80%). Comparing radiation techniques, there were no significant differences in LC (p=0.94), DFS (p=0.33) and OS (p=0.72). CONCLUSION: When used to treat LANSCLC in the neoadjuvant setting, both IMRT and 3DCRT produce comparable pathological and clinical outcomes. ADVANCES IN KNOWLEDGE: This study validates the real-world effectiveness of IMRT compared to 3DCRT

A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies

Vitamin D Supplementation in Chronic Schizophrenia Patients Treated with Clozapine:A Randomized, Double-Blind, Placebo-controlled Clinical Trial

Background: While accumulating evidence suggests that vitamin D deficiency may be involved in the risk to develop schizophrenia and its outcome, there are no studies on vitamin D supplementation in this context. We sought to assess the effect of vitamin D supplementation on psychiatric, cognitive and metabolic parameters in chronic clozapine-treated schizophrenia patients. Methods: This eight-week, randomized, double-blind, placebo-controlled clinical trial, recruited schizophrenia patients who had been maintained on clozapine treatment for at least 18 weeks and had low levels of vitamin D (<75 nmol/l) and total PANSS scores >70 (to ascertain the presence of residual symptoms). Patients were randomly allocated to either weekly oral drops of vitamin D (14,000 IU) or placebo and subsequently assessed at two-week intervals for psychosis severity, mood, cognition and metabolic profile. Results: Twenty four patients were randomly assigned to vitamin D (aged 39.4 ± 9.6 years, 75% males) and the other 23 patients to the placebo arm (aged 42.5 ± 11.2 years, 60.9% males). After eight weeks, the vitamin D group exhibited a significant increase in vitamin D levels (31.4 vs −0.4 nmol/l, p < 0.0001). There was no significant effect of vitamin D on psychotic, depressive or metabolic parameters. However, in the vitamin D group, there was a trend towards improved cognition (effect size = 0.17, significance lost following Bonferroni correction). Conclusions: Vitamin D supplementation was associated with a trend towards improved cognition, but did not affect psychosis, mood or metabolic status. It is possible that the robust decrease in the PANSS scores in both groups may have obscured an effect of vitamin D supplementation

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in the aqueous humour of patients with primary angle closure glaucoma - a quantitative study

BACKGROUND: Altered levels of specific matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in the aqueous humour of primary open-angle glaucoma (POAG) eyes have been described. In this study, levels of specific MMPs and TIMPs in the aqueous humour of primary angle-closure glaucoma (PACG) eyes were measured and compared with those of POAG as well as non-glaucoma control eyes. METHODS: Aqueous humour from 16 PACG, 28 POAG and 27 control eyes were sampled during intraocular surgery. Levels of total protein, MMP-2, MMP-3, TIMP-1 and TIMP-2 were quantified by protein assay and enzyme immunoassay. RESULTS: Total protein levels were significantly higher in PACG (0.426 ± 0.126 mg/ml, p = 0.043) and POAG (0.578 ± 0.360 mg/ml, p = 0.007) compared to controls (0.292 ± 0.192 mg/ml). The difference between PACG and POAG was not significant (p = 0.158). MMP-2 was significantly higher in PACG (p = 0.032) and POAG (p < 0.001) compared to controls. The difference between PACG and POAG was also not significant (p = 0.133). MMP-3 was significantly higher in POAG compared to controls (p = 0.002) and PACG (p = 0.029). The difference between PACG and controls was not significant (p = 0.962). TIMP-1 was significantly higher in PACG (p = 0.049) and POAG (p = 0.010) compared to controls. The difference between PACG and POAG was also not significant (p = 0.961). TIMP-2 was significantly higher in POAG (p = 0.004) compared to controls. The difference between PACG and either controls or POAG was not significant (p > 0.05). Although not statistically significant (p > 0.05), the MMP-2/TIMP-2 ratio was highest in PACG (2.83 ± 7.40), followed by POAG (1.38 ± 1.55) and controls (1.34 ± 3.05). Similarly, the MMP-2/TIMP-1 ratio was highest in PACG (1.50 ± 1.69), followed by POAG (1.40 ± 0.77) and controls (1.15 ± 0.92). The MMP-2 + MMP-3/TIMP-1 + TIMP-2 ratio was higher in PACG (0.83 ± 0.80) and POAG (0.82 ± 0.53) compared to controls (0.70 ± 0.63). In both POAG and PACG, there were no significant differences in the levels of total protein, MMP-2, MMP-3, TIMP-1 and TIMP-2 between patients on prostaglandin analogues and those not. CONCLUSION: We found altered levels of MMPs and TIMPs as well as imbalance of MMP:TIMP ratios in the aqueous humour of PACG eyes that were different from POAG and non-glaucoma control eyes

Workplace Wellness, Mental Health Literacy, and Usage Intention of E-Mental Health amongst Digital Workers during the COVID-19 Pandemic

The prevalence of mental health problems in both Malaysian and global workplaces has significantly increased due to the presence of the coronavirus disease (COVID-19) pandemic, globalization, technology advancement in Industry 4.0, and other contributing factors. The pervasiveness of the issue poses a huge challenge to improving the occupational safety and health (OSH) of workers in various industries, especially in the digital industry. The emergence of the innovative industry is evident mainly due to the rapid development of Industry 4.0 and the relevant demands of multiple businesses in the digital transformation. Nonetheless, limited studies and academic discussions were conducted on the OSH topic of digital employees. Hence, the current study serves to fill the existing gap and provide academic contributions by scrutinising the perceptions of digital workers regarding their workplace well-being, mental health literacy, and the impression of employing e-mental health. The objectives of this study are: 1) To examine the mental health literacy and workplace wellness of digital workers, 2) to explore the emental health usage intention and actual e-mental health utilization, and 3) to identify digital workers’ feedback on e-mental health. In the current context, e-mental health focuses on three dimensions, namely, 1) “health in our hand (HIOH)”, 2) “interacting for health (IFH)”, and 3) “data enabling health (DEH)”. The present study employed an online cross-sectional survey and received 326 digital workers’ completed responses. Variables, such as “mental health literacy (MHL)”, “workplace wellness (WW)”, and e-mental health intention and usage were explicated by analysing the data through descriptive statistics. The study results indicated a moderate to a high level of the MHL and the WW. More than half of the workers possessed a high intention level to employ e-mental health, with the HIOH dimension being the most prevalent domain. Nevertheless, the actual e-mental health usage was very low, owing to the online resources being a new concept amongst digital employees. Numerous confounding factors also existed in affecting the low usage, such as privacy concerns, data security levels, and health verification issues. In addition, the mental health issue has not been openly and widely discussed in Malaysian workplaces due to stigmatisation. As such, the current findings could provide additional insights into the OSH literature; it could serve as a guideline for the OSH decision-makers, employers, and eHealth developers when establishing a feasible framework for the practical adoption of e-mental health services by digital workers