Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

OBJECTIVE: The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS: Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS: Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION: Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.

Decrease of thyroid function after ischemic stroke is related to stroke severity.

BACKGROUND: Thyroid hormones are of fundamental importance for brain function. While low triiodothyronine levels during acute ischemic stroke (AIS) are associated with worse clinical outcomes, dynamics of thyroid function after AIS remains unknown. Thus, we longitudinally evaluated thyroid hormones after stroke and related them to stroke severity. METHODS: We prospectively traced thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxin (fT4) levels from the hyper-acute (within 24 h) to acute (3-5 days) and chronic (3-6 months) stages of ischemic stroke using a mixed regression model. Then, we analyzed whether stroke severity at presentation, expressed by National Institute of Health Stroke Scale (NIHSS), is associated with change in thyroid function. RESULTS: Forty-five patients were evaluated in hyper-acute and acute stages, while 29 were followed through chronic stage. TSH levels decreased from hyper-acute (2.91 ± 0.65 µIU/mL) to acute (2.86 ± 0.46 µIU/mL) and chronic stages of stroke (1.93 ± 0.35 µIU/m, p = 0.95). fT3 levels decreased from hyper-acute (2.79 ± 0.09 pg/ml) to acute (2.37 ± 0.07 pg/ml) stages, but recovered in chronic stage (2.78 ± 0.10 pg/ml, p < 0.01). fT4 levels decreased from hyper-acute (1.64 ± 0.14 ng/dl) to acute (1.13 ± 0.03 ng/dl) stages, and increased in the chronic stage (1.16 ± 0.08 ng/dl, p = 0.02). One-unit increase in presenting NIHSS was associated with 0.04-unit decrease of fT3 from hyper-acute to the acute stage (p < 0.01). CONCLUSION: There is a transient decrease of thyroid hormones after ischemic stroke, possibly driven by stroke severity. Larger studies are needed to validate these findings. Correction of thyroid function in acute stroke may be investigated to improve stroke outcomes.

Post-Marketing Safety Surveillance of Tofacitinib over 9 Years in Patients with Psoriatic Arthritis and Rheumatoid Arthritis.

INTRODUCTION: The safety of tofacitinib in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) has been demonstrated in clinical studies of ≤ 4 and 9.5 years, respectively. Post-marketing surveillance (PMS) data for tofacitinib from spontaneous and voluntary adverse event (AE) reports have been published for RA, but not PsA. To inform the real-world safety profile of tofacitinib in PsA, we evaluated AE reports submitted to the Pfizer safety database (including RA data for context). METHODS: Endpoints included AEs, serious AEs (SAEs), AEs of special interest (AESIs; serious infections, herpes zoster, cardiovascular events, malignancies, venous thromboembolism), and fatal cases. Exposure was estimated using IQVIA global commercial sales data. Number, frequency, and reporting rates (RRs; number of events/100 patient-years' [PY] exposure) were summarized by indication and formulation (immediate release [IR] 5 or 10 mg twice daily], modified release [MR] 11 mg once daily, or all tofacitinib). The data-collection period differed by indication (PsA: 14 December 2017 [US approval, IR/MR] to 6 November 2021; RA: 6 November 2012 [US approval, IR] to 6 November 2021; MR approval, 24 February 2016). RESULTS: A total of 73,525 case reports were reviewed (PsA = 5394/RA = 68,131), with 20,706/439,370 PY (PsA/RA) of exposure. More AEs were reported for IR versus MR (IR/MR: PsA = 8349/7602; RA = 137,476/82,153). RRs for AEs (IR/MR: PsA = 59.6/113.4; RA = 44.0/64.8) and SAEs (PsA = 8.1/13.6; RA = 8.0/9.5) were higher with MR versus IR. AE RRs (RA) in the first 4 years after IR approval were 95.9 (IR; 49,439 PY) and 147.0 (MR; 2000 PY). Frequency of SAEs, AESIs, and fatal cases was mostly similar across formulations and indications. The most frequently-reported AE Preferred Terms (PsA/RA) included drug ineffective (20.0%/17.8%), pain (9.7%/10.6%), condition aggravated (9.9%/10.5%), headache (8.8%/7.9%) and, for PsA, off-label use (10.5%/3.4%). CONCLUSIONS: Tofacitinib PMS safety data from submitted AE reports were consistent between PsA and RA, and aligned with its known safety profile. Exposure data (lower MR versus IR; estimation from commercial sales data), reporting bias, reporter identity, and regional differences in formulation use limit interpretation.

Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial.

OBJECTIVES: To characterise infections in patients with rheumatoid arthritis (RA) in ORAL Surveillance. METHODS: In this open-label, randomised controlled trial, patients with RA aged≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times per day or a tumour necrosis factor inhibitor (TNFi). Incidence rates (IRs; patients with first events/100 patient-years) and hazard ratios (HRs) were calculated for infections, overall and by age (50-<65 years; ≥65 years). Probabilities of infections were obtained (Kaplan-Meier estimates). Cox modelling identified infection risk factors. RESULTS: IRs/HRs for all infections, serious infection events (SIEs) and non-serious infections (NSIs) were higher with tofacitinib (10>5 mg two times per day) versus TNFi. For SIEs, HR (95% CI) for tofacitinib 5 and 10 mg two times per day versus TNFi, respectively, were 1.17 (0.92 to 1.50) and 1.48 (1.17 to 1.87). Increased IRs/HRs for all infections and SIEs with tofacitinib 10 mg two times per day versus TNFi were more pronounced in patients aged≥65 vs 50-<65 years. SIE probability increased from month 18 and before month 6 with tofacitinib 5 and 10 mg two times per day versus TNFi, respectively. NSI probability increased before month 6 with both tofacitinib doses versus TNFi. Across treatments, the most predictive risk factors for SIEs were increasing age, baseline opioid use, history of chronic lung disease and time-dependent oral corticosteroid use, and, for NSIs, female sex, history of chronic lung disease/infections, past smoking and time-dependent Disease Activity Score in 28 joints, C-reactive protein. CONCLUSIONS: Infections were higher with tofacitinib versus TNFi. Findings may inform future treatment decisions. TRIAL REGISTRATION NUMBER: NCT02092467.

IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage.

Aberrant expression of GLI1 is responsible for aggressive tumor behavior and survival due to its effects on the DNA damage response (DDR). We investigated whether interleukin (IL)-24, a tumor suppressor, inhibits GLI1 and the associated DDR pathway in human NSCLCs. IL-24 treatment reduces mRNA and protein expression of GLI1 in lung tumor cells, but not in normal cells. GLI1 reporter assay and mRNA studies demonstrated that IL-24 regulates GLI1 at the post-transcriptional level by favoring mRNA degradation. Associated with GLI1 inhibition was marked suppression of the ATM-mediated DDR pathway resulting in increased DNA damage, as evidenced by γ-H2AX foci and Comet assay. Furthermore, attenuation of GLI1-associated DDR by IL-24 increased caspase-3 and PARP activity, resulting in cancer cell apoptosis. GLI1 inhibition and overexpression confirmed that IL-24-mediated anti-tumor effects involved the GLI-dependent pathway. Finally, we observed that IL-24-mediated alteration in GLI1 is independent of the canonical hedgehog-signaling pathway. Our study provides evidence that IL-24 treatment induces DNA damage, and reduces GLI1 expression and offers an opportunity for testing IL-24-based therapy for inhibiting GLI1 in lung cancer.

HuR Reduces Radiation-Induced DNA Damage by Enhancing Expression of ARID1A.

Tumor suppressor ARID1A, a subunit of the chromatin remodeling complex SWI/SNF, regulates cell cycle progression, interacts with the tumor suppressor TP53, and prevents genomic instability. In addition, ARID1A has been shown to foster resistance to cancer therapy. By promoting non-homologous end joining (NHEJ), ARID1A enhances DNA repair. Consequently, ARID1A has been proposed as a promising therapeutic target to sensitize cancer cells to chemotherapy and radiation. Here, we report that ARID1A is regulated by human antigen R (HuR), an RNA-binding protein that is highly expressed in a wide range of cancers and enables resistance to chemotherapy and radiation. Our results indicate that HuR binds ARID1A mRNA, thereby increasing its stability in breast cancer cells. We further find that ARID1A expression suppresses the accumulation of DNA double-strand breaks (DSBs) caused by radiation and can rescue the loss of radioresistance triggered by HuR inhibition, suggesting that ARID1A plays an important role in HuR-driven resistance to radiation. Taken together, our work shows that HuR and ARID1A form an important regulatory axis in radiation resistance that can be targeted to improve radiotherapy in breast cancer patients.

Treatment Outcomes of Hepatitis C-Infected Patients in Specialty Clinic vs. Primary Care Physician Clinic: A Comparative Analysis.

BACKGROUND: Oral direct-acting antivirals (DAAs) provide an exceptional opportunity to treat hepatitis C virus (HCV) infection. GOALS: We compared the treatment outcomes between specialty and primary care physician (PCP) clinics for patients treated with DAAs. METHODS: We performed a retrospective analysis of patients treated for HCV in our PCP clinics and specialty; liver and gastroenterology clinics and gastroenterology clinics. We used the two-sided t-test and the chi-square test to compare the means of continuous and categorical variables, respectively. RESULTS: Data from a total of 377 patients was analyzed (PCP clinic: n = 185 and specialty clinic: n = 192). There was no significant difference between age, race, and gender. Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores were comparable at baseline. Greater than 90% of the patients achieved sustained virological response (SVR) with no difference between the groups. CONCLUSIONS: Uncomplicated patients can be treated for hepatitis C by their PCPs with DAAs with similar treatment outcomes to specialty clinics. There should be explicit guidelines on patient eligibility for treatment by PCPs vs. specialists.

Socioeconomic differences in nicotine exposure and dependence in adult daily smokers.

BACKGROUND: Socioeconomic status (SES) is a major determinant of tobacco use but little is known whether SES affects nicotine exposure and the degree of nicotine dependence. METHODS: The Pennsylvania Adult Smoking Study is a cross-sectional study of smoke exposure and nicotine dependence among adults conducted in central Pennsylvania between June 2012 and April 2014. The study included several measures of SES, including assessments of education and household income, as well as occupation, home ownership, health insurance, household density and savings accounts. Measurements included saliva for the nicotine metabolites cotinine (COT), 3-'hydroxycotinine (3HC) and total metabolites (COT +3HC). Puffing behavior was determined using portable smoking topography devices. RESULTS: The income levels of lighter smokers (< 20 cigarettes per day) was $10,000 more than heavier smokers. Higher Fagerström Test for Nicotine Dependence scores were associated with lower income and job status, scores ranged from 5.4 in unemployed, 4.4 in blue-collar, and 3.8 in white-collar workers. In principal components analysis used to derive SES indicators, household income, number in household, and type of dwelling were the major SES correlates of the primary component. Job category was the major correlate of the second component. Lower SES predicted significantly higher adjusted total nicotine metabolite levels in the unemployed group. Job category was significantly associated with total daily puffs, with the highest level in the unemployed, followed by blue-collar workers, after adjustment for income. CONCLUSIONS: Among smokers, there was a relationship between lower SES and increased nicotine dependence, cigarettes per day and nicotine exposure, which varied by job type.

Smart Phone/Device Application to Improve Delivery of Enteral Nutrition in Adult Patients Admitted to the Medical Intensive Care Unit.

BACKGROUND: Resident physicians are frequently uncomfortable ordering enteral nutrition (EN) and are unaware of the variety of formulas and supplements available for different disease processes. Many depend on a clinical dietician to assist with recommending EN formulas and patient energy requirements that may not be readily available on patient admission. This creates a barrier to early initiation of EN and non-compliance with Society of Critical Care Medicine and American Society of Parenteral and Enteral Nutrition clinical guidelines. OBJECTIVE: Internal medicine resident physicians were provided an iPod with a smart phone/device application (EN application) to assist them in choosing EN formulas for patients during their intensive care unit (ICU) rotation. The primary outcome was improved initiation of EN within 24 hours of admission. Secondary outcomes included the following: time to initiate EN, goal calories reached, infections rates, length of stay, mortality, and concordance with clinical guidelines. DESIGN: The study is a quasi-experimental design to improve delivery of EN at an academic medical center in the medical ICU. Data were collected from a retrospective chart review to evaluate the impact of an EN application to assist resident physicians when ordering EN. RESULTS: Use of the EN application reduced the percent of patients with delayed initiation of EN from 61.2% prior to 37.5% (P < .01). The mean time to initiate EN also improved 44.5 vs 31.9 hours (P < .01). Patients were also more likely to achieve their daily caloric goal (P < .01). CONCLUSION: The use of an EN application to assist internal medicine residents when ordering EN reduced delays in initiation of EN and improved overall delivery of EN to medical ICU patients.

Nicotine metabolite ratio predicts smoking topography: The Pennsylvania Adult Smoking Study.

BACKGROUND: The nicotine metabolite ratio (NMR) as measured by the ratio of 3'hydroxycotinine to cotinine has been examined in relation to tobacco use patterns including cigarettes per day and quit success to determine its role in nicotine dependence. We examined the NMR in relation to smoking topography and tested the hypothesis that normal metabolizers have a greater total daily puff volume than slow metabolizers. METHODS: The Pennsylvania Adult Smoking Study (PASS) is a longitudinal study of 352 adults who smoked, on average, 17 cigarettes per day. Subjects used a portable smoking topography device over a two-day period at home and at work. We measured the ratio of 3'hydroxycotinine to cotinine in the saliva of the subjects. RESULTS: In multiple linear regression analyses, a higher rate of nicotine metabolism was significantly associated with increased daily puffs and total daily puff volume. In a mediation analysis, a significant, indirect effect of race on the relationship between NMR and puff volume was observed, with 22% of the effect mediated by white race. A higher NMR was also associated with female gender, white race, cigarettes per day and nicotine dependence measures. CONCLUSION: The NMR was associated with tobacco use patterns including smoking topography. Faster nicotine metabolism was associated with greater total daily puffs and puff volume.

Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment.

Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis-diamine platinum (CDDP) to folate receptor-α (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non-targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co-delivery of siRNA and chemotherapy agents in lung cancer cells.

Chemodrug delivery using integrin-targeted PLGA-Chitosan nanoparticle for lung cancer therapy.

In this study, we report the efficacy of RGD (arginine-glycine-aspartic acid) peptide-modified polylactic acid-co-glycolic acid (PLGA)-Chitosan nanoparticle (CSNP) for integrin αvß3 receptor targeted paclitaxel (PTX) delivery in lung cancer cells and its impact on normal cells. RGD peptide-modified chitosan was synthesized and then coated onto PTX-PLGA nanoparticles prepared by emulsion-solvent evaporation. PTX-PLGA-CSNP-RGD displayed favorable physicochemical properties for a targeted drug delivery system. The PTX-PLGA-CSNP-RGD system showed increased uptake via integrin receptor mediated endocytosis, triggered enhanced apoptosis, and induced G2/M cell cycle arrest and more overall cytotoxicity than its non-targeted counterpart in cancer cells. PTX-PLGA-CSNP-RGD showed less toxicity in lung fibroblasts than in cancer cells, may be attributed to low drug sensitivity, nevertheless the study invited close attention to their transient overexpression of integrin αvß3 and cautioned against corresponding uptake of toxic drugs, if any at all. Whereas, normal human bronchial epithelial (NHBE) cells with poor integrin αvß3 expression showed negligible toxicity to PTX-PLGA-CSNP-RGD, at equivalent drug concentrations used in cancer cells. Further, the nanoparticle demonstrated its capacity in targeted delivery of Cisplatin (CDDP), a drug having physicochemical properties different to PTX. Taken together, our study demonstrates that PLGA-CSNP-RGD is a promising nanoplatform for integrin targeted chemotherapeutic delivery to lung cancer.

HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells.

Human antigen (Hu) R is an RNA-binding protein whose overexpression in human cancer correlates with aggressive disease, drug resistance, and poor prognosis. HuR inhibition has profound anticancer activity. Pharmacologic inhibitors can overcome the limitations of genetic inhibition. In this study, we examined the antitumor activity of CMLD-2, a small-molecule inhibitor directed against HuR, using non-small cell lung cancer (NSCLC) as a model. CMLD-2 efficacy was tested in vitro using H1299, A549, HCC827, and H1975 NSCLC cells and MRC-9 and CCD-16 normal human fibroblasts. Treatment of NSCLC cells with CMLD-2 produced dose-dependent cytotoxicity, caused a G1 phase cell-cycle arrest and induced apoptosis. CMLD-2 decreased HuR mRNA and the mRNAs of HuR-regulated proteins (Bcl2 and p27) in tumor cells. Additionally, reduction in the expression of HuR, Bcl2, cyclin E, and Bcl-XL with increased expression of Bax and p27 in CMLD-2-treated NSCLC cells were observed. CMLD-2-treated normal cells, HuR-regulated mRNAs and proteins albeit showed some reduction were less compared to tumor cells. Finally, CMLD-2 treatment resulted in greater mitochondrial perturbation, activation of caspase-9 and -3 and cleavage of PARP in tumor cells compared to normal cells. Our proof-of concept study results demonstrate CMLD-2 represents a promising HuR-targeted therapeutic class that with further development could lead to advanced preclinical studied and ultimately for lung cancer treatment.

Sex/Gender Differences in Cotinine Levels Among Daily Smokers in the Pennsylvania Adult Smoking Study.

BACKGROUND: This study was conducted to determine sex/gender differences in smoke exposure and to quantify the role of potential predictors including puffing behaviors, nicotine dependence, and non-nicotinic factors. METHODS: The Pennsylvania Adult Smoking Study (PASS) of 332 adult cigarette smokers utilized portable handheld topography devices to capture the smokers' profiles in a naturalistic environment. Sex/gender differences in salivary biomarkers were modeled using ANCOVA to account for measures of dependence (Fagerstrom Test for Nicotine Dependence, nicotine metabolite ratio [3-hydroxycotinine/cotinine]), and nondependence covariates including anthropomorphic factors and stress. The Blinder-Oaxaca method was used to decompose the sex/gender differences in nicotine uptake due to covariates. RESULTS: Men had significantly higher cotinine levels (313.5 ng/mL vs. 255.8 ng/mL, p < 0.01), cotinine +3-hydroxycotinine levels, (0.0787 mol/L vs. 0.0675 mol/L, p = 0.01), puff volumes (52.95 mL vs. 44.77 mL, p < 0.01), and a lower nicotine metabolite ratio (0.396 vs. 0.475, p = 0.01) than women. The mean Fagerström Test for Nicotine Dependence score did not differ between men and women (p = 0.24). Women had a higher mean Hooked on Tobacco Checklist score than men (7.64 vs. 6.87, p < 0.01). In multivariate analysis, nicotine metabolite levels were not significantly different by sex. Decomposition results show that ten predictors can explain 83% of the sex/gender differences in cotinine uptake. Height was the greatest contributor to these differences, followed by average puff volume. Conclusion and Impact: The higher levels of nicotine metabolites in men, compared to women, can be explained by height, weight, puff volume, and nicotine metabolism.

Tumor-targeted Nanoparticle Delivery of HuR siRNA Inhibits Lung Tumor Growth In Vitro and In Vivo By Disrupting the Oncogenic Activity of the RNA-binding Protein HuR.

Selective downregulation of the human antigen R (HuR) protein by siRNA may provide a powerful approach for treating lung cancer. To this end, we investigated the efficacy of transferrin receptor-targeted liposomal nanoparticle-based HuR siRNA (HuR-TfNP) therapy and compared with control siRNA (C)-TfNP therapy both, in vitro and in vivo using lung cancer models. In vitro studies showed HuR-TfNP, but not C-TfNP, efficiently downregulated HuR and HuR-regulated proteins in A549, and HCC827 lung cancer cells, resulting in reduced cell viability, inhibition of cell migration and invasion, and induction of G1 cell-cycle arrest culminating in apoptosis. However, HuR-TfNP activity in normal MRC-9 lung fibroblasts was negligible. In vivo biodistribution study demonstrated that fluorescently labeled HuR-siRNA or ICG dye-loaded TfNP localized in tumor tissues. Efficacy studies showed intratumoral or intravenous administration of HuR-TfNP significantly inhibited A549 (>55% inhibition) and HCC827 (>45% inhibition) subcutaneous tumor growth compared with C-TfNP. Furthermore, HuR-TfNP treatment reduced HuR, Ki67, and CD31 expression and increased caspase-9 and PARP cleavage and TUNEL-positive staining indicative of apoptotic cell death in tumor tissues compared with C-TfNP treatment. The antitumor activity of HuR-TfNP was also observed in an A549-luc lung metastatic model, as significantly fewer tumor nodules (9.5 ± 3.1; P < 0.001; 88% inhibition) were observed in HuR-TfNP-treated group compared with the C-TfNP-treated group (77.7 ± 20.1). Significant reduction in HuR, Ki67, and CD31 expression was also observed in the tumor tissues of HuR-TfNP-treatment compared with C-TfNP treatment. Our findings highlight HuR-TfNP as a promising nanotherapeutic system for lung cancer treatment. Mol Cancer Ther; 16(8); 1470-86. ©2017 AACR.

Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells.

Successful chemotherapeutic intervention for management of lung cancer requires an efficient drug delivery system. Gold nanoparticles (GNPs) can incorporate various therapeutics; however, GNPs have limitations as drug carriers. Nano-sized cellular vesicles like exosomes (Exo) can ferry GNP-therapeutic complexes without causing any particle aggregation or immune response. In the present study, we describe the development and testing of a novel Exo-GNP-based therapeutic delivery system -'nanosomes'- for lung cancer therapy. This system consists of GNPs conjugated to anticancer drug doxorubicin (Dox) by a pH-cleavable bond that is physically loaded onto the exosomes (Exo-GNP-Dox). The therapeutic efficacy of Dox in nanosomes was assessed in H1299 and A549 non-small cell lung cancer cells, normal MRC9 lung fibroblasts, and Dox-sensitive human coronary artery smooth muscle cells (HCASM). The enhanced rate of drug release under acidic conditions, successful uptake of the nanosomes by the recipient cells and the cell viability assays demonstrated that nanosomes exhibit preferential cytotoxicity towards cancer cells and have minimal activity on non-cancerous cells. Finally, the underlying mechanism of cytotoxicity involved ROS-mediated DNA damage. Results from this study mark the establishment of an amenable drug delivery vehicle and highlight the advantages of a natural drug carrier that demonstrates reduced cellular toxicity and efficient delivery of therapeutics to cancer cells.

The Impact on Endoscopic Resource Utilization After a Targeted Intervention for Cost-Minimization of EGD and Colonoscopy.

OBJECTIVES: The need to define the cost of endoscopic procedures becomes increasingly important in an era of providing low-cost, high-quality care. We examined the impact of informing endoscopists of the cost of accessories and pathology specimens as a cost-minimization strategy. METHODS: We conducted a prospective observational cohort study of therapeutic outpatient esophagogastroduodenoscopy (EGD) and colonoscopy. During the pre-intervention phase (phase 1), the endoscopists were not briefed on the cost of accessories or pathology specimens obtained during the procedure. During a 3-week intervention phase and the post-intervention phase (phase 2) endoscopists were informed of the dollar value of accessories and pathology specimens after the completion of all procedures. In all cases the institutional costs (not charges) were used. The endoscopists were blinded to their observation. RESULTS: A total of 969 EGD, colonoscopy, and EGD+colonoscopy performed by 6 endoscopists were reviewed, 456 procedures in phase 1 and 513 procedures in phase 2. There was no significant difference between phases 1 and 2 in total device and pathology cost in dollars (188.8±151.4 vs. 188.9±151.8, P=0.99), total device cost (36.2±107.9 vs. 39.0±95.96, P=0.67) and total pathology cost (152.6±101.3 vs. 149.9±112.5, P=0.70). There was not a significant difference in total device and pathology cost when examined by specific procedures performed, or for any of the endoscopists between phases 1 and 2. CONCLUSIONS: Making endoscopists more cost conscious by informing them of the costs of each procedure during EGD and colonoscopy does not result in lower procedural costs. Analysis of cost-minimization strategies involving procedures in other health-care settings and procedures using high-cost accessories are warranted.