Successful lung transplantation for artificial stone-associated accelerated silicosis: a case report.

This report focuses on the occupational health risks associated with the use of artificial stones containing high levels of crystalline silica in the production of kitchen countertops. It presents the case of a 43-yr-old man who developed severe silicosis due to his occupation involving cutting and polishing quartz stone raw materials. A retrospective analysis of the patient's medical records and occupational history was conducted. The diagnosis of severe silicosis, moderate restrictive lung disease, and bilateral pneumothorax was based on clinical manifestations, pulmonary function test, radiological findings, and histological reports. The patient underwent lung transplantation, and his pulmonary function improved post-surgery. The study highlights the significant health risks associated with procedures involving artificial stones and emphasizes the importance of awareness and protective measures for employees and workers. Clinicians should be cautious when diagnosing respiratory symptoms in patients with a history of occupational exposure to artificial stones containing high levels of crystalline silica.

RNA-binding protein-regulated fibronectin is essential for EGFR-activated metastasis of head and neck squamous cell carcinoma.

There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the role of RNA-binding proteins (RBPs) in EGFR-associated metastasis of HNSCC remains unclear. In this study, we reveal that RBPs, specifically nucleolin (NCL) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), correlated with the mesenchymal phenotype of HNSCC. The depletion of RBPs significantly attenuated EGF-induced HNSCC metastasis. Intriguingly, the EGF-induced EMT markers, such as fibronectin, were regulated by RBPs through the ERK and NF-κB pathway, followed by the enhancement of mRNA stability of fibronectin through the 5' untranslated region (5'-UTR) of the gene. The upregulation of fibronectin triggered the integrin signaling activation to enhance tumor cells' attachment to endothelial cells and increase endothelial permeability. In addition, the concurrence of EGFR and RBPs or EGFR and fibronectin was associated with overall survival and disease-free survival of HNSCC. The in vivo study showed that depletion of NCL, hnRNPA2B1, and fibronectin significantly inhibited EGF-promoted extravasation of tumor cells into lung tissues. The depletion of fibronectin or treatment with integrin inhibitors dramatically attenuated EGF-induced HNSCC metastatic nodules in the lung. Our data suggest that the RBPs/fibronectin axis is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis.

Risk of NSAID-associated anastomosis leakage after colorectal surgery: a large-scale retrospective study using propensity score matching.

PURPOSE: NSAIDs are commonly used as opioid-sparing analgesics in colorectal surgery. Many efforts are made to elucidate the risk of NSAID-associated anastomotic leakage after colorectal surgery. However, these results still remain controversial. In this study, we applied large-scale retrospective analysis using propensity score matching to fully clarify the association between risk of anastomotic leakage and use of NSAID after colorectal surgery. METHODS: All colorectal cancer patients receiving operation during February 2008 to August 2018 in our multi-institution medical organization research database were enrolled. It is worthy to mention that only patients requiring re-operation within 21 days after colorectal surgery due to anastomotic leakage were counted as anastomosis leakage. Furthermore, a propensity score TriMatch analysis was performed to prevent from interference of confounding factors. RESULTS: A total of 10,584 patients were included in this study and divided into three groups, no NSAIDs group, non-selective NSAIDs group, and selective COX-2 inhibitors group, respectively. Before tri-matching analysis, significant differences in anastomotic leakage rate were observed. After propensity score matching analysis, the ratio of anastomotic leakage requiring re-operation occurred in 2.0%, 3.6%, and 2.0% in no NSAIDs, non-selective NSAIDs, and selective COX-2 inhibitors group, respectively. No significant difference was observed in these three groups. CONCLUSION: These results suggest that NSAIDs are not associated with incidence of anastomosis leakage following colorectal surgery. To our knowledge, it is the first study demonstrating that NSAIDs is not associated with incidence of anastomosis leakage following colorectal surgery using propensity score matching at a larger-scale retrospective study.

Extracorporeal Shock Wave Therapy Combined with Platelet-Rich Plasma during Preventive and Therapeutic Stages of Intrauterine Adhesion in a Rat Model.

Intrauterine adhesion (IUA) is caused by artificial endometrial damage during intrauterine cavity surgery. The typical phenotype involves loss of spontaneous endometrium recovery and angiogenesis. Undesirable symptoms include abnormal menstruation and infertility; therefore, prevention and early treatment of IUA remain crucial issues. Extracorporeal shockwave therapy (ESWT) major proposed therapeutic mechanisms include neovascularization, tissue regeneration, and fibrosis. We examined the effects of ESWT and/or platelet-rich plasma (PRP) during preventive and therapeutic stages of IUA by inducing intrauterine mechanical injury in rats. PRP alone, or combined with ESWT, were detected an increased number of endometrial glands, elevated vascular endothelial growth factor protein expression (hematoxylin-eosin staining and immunohistochemistry), and reduced fibrosis rate (Masson trichrome staining). mRNA expression levels of nuclear factor-kappa B, tumor necrosis factor-α, transforming growth factor-ß, interleukin (IL)-6, collagen type I alpha 1, and fibronectin were reduced during two stages. However, PRP alone, or ESWT combined with PRP transplantation, not only increased the mRNA levels of vascular endothelial growth factor (VEGF) and progesterone receptor (PR) during the preventive stage but also increased PR, insulin-like growth factor 1 (IGF-1), and IL-4 during the therapeutic stage. These findings revealed that these two treatments inhibited endometrial fibrosis and inflammatory markers, thereby inhibiting the occurrence and development of intrauterine adhesions.

Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2.

The proviral integration site for moloney murine leukemia virus 1 (Pim1) is a serine/threonine kinase and able to promote cell proliferation, survival and drug resistance. Overexpression of Pim1 has been observed in many cancer types and is associated with the poor prognosis of breast cancer. However, it remains unclear whether Pim1 kinase is a potential therapeutic target for breast cancer patients. In this study, we found that Pim1 expression was strongly associated with HER2 expression and that HER2-overexpressing breast cancer cells were more sensitive to Pim1 inhibitor-induced inhibitions of cell viability and metastatic ability. Mechanistically, Pim1 inhibitor suppressed the expression of HER2 at least in part through transcriptional level. More importantly, Pim1 inhibitor overcame the resistance of breast cancer cells to HER2 tyrosine kinase inhibitor lapatinib. In summary, downregulation of HER2 by targeting Pim1 may be a promising and effective therapeutic approach not only for anti-cancer growth but also for circumventing lapatinib resistance in HER2-positive breast cancer patients.

PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs.

The tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.

Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer.

BACKGROUND AND AIMS: Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. APPROACH AND RESULTS: HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. CONCLUSIONS: vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.

Proteasome Inhibitors Suppress ErbB Family Expression through HSP90-Mediated Lysosomal Degradation.

Although dual EGFR/HER2 tyrosine kinase inhibitor lapatinib has provided effective clinical benefits for HER2-positive breast cancer patients, acquired resistance to this drug remains a major concern. Thus, the development of alternative therapeutic strategies is urgently needed for patients who failed lapatinib treatment. Proteasome inhibitors have been reported to possess high anti-tumor activity to breast cancer cells. Therefore, this study aims to examine whether and how proteasome inhibitor bortezomib can overcome lapatinib resistance. Treatments with several proteasome inhibitors, including Bortezomib, MG132, and proteasome inhibitor I (PSI), as well as the viabilities of both HER2-positive breast cancer cell lines and their lapatinib-resistant clones, were inhibited. Importantly, the expressions of ErbB family were downregulated at both transcriptional and translational levels. Also, our results further indicated that proteasome inhibitors decreased ErbB family expression through lysosomal degradation pathway in a heat shock protein 90 (HSP90)-dependent manner. In this study, our data supported a potential approach to overcome the acquired resistance of HER2-overexpressing breast cancer patients to lapatinib using proteasome inhibitors.

Correlation of anti-acetylcholine receptor antibody levels and long-term outcomes of juvenile myasthenia gravis in Taiwan: a case control study.

BACKGROUND: Myasthenia gravis is the most common disease affecting the neuromuscular junction. The most common etiology among patients with juvenile myasthenia gravis is the production of antibodies against the acetylcholine receptor. However, the clinical outcome in relation to serum levels of anti-acetylcholine receptor antibodies in juvenile myasthenia gravis has rarely been discussed. We aimed to analyze the correlation between the presence of anti-acetylcholine receptor antibodies and outcome in juvenile myasthenia gravis. METHODS: Patients diagnosed with juvenile myasthenia gravis younger than of 20 years of age were retrospectively recruited from January 1995 to February 2017 in a tertiary referral medical center. According to the Myasthenia Gravis Foundation of America outcome scale, the primary outcome was complete symptom remission and cessation of medications for at least 1 year measured 2 years after diagnosis. Secondary outcome was complete symptom remission at the last outpatient clinic. RESULTS: A total of 54 patients were followed up for over 2 years. Nine patients (9/54, 16.7%) achieved complete remission without medication use at 2 years after diagnosis. Thirteen (24.1%) patients achieved complete remission during longer follow-up periods. Those with negative anti-acetylcholine receptor antibodies were more likely to achieve complete remission at 2 years (6/15 [40%] vs. 3/39 [7.7%], 95% Confidence interval [CI] 1.670 to 38.323) and at the last outpatient clinic follow-up (8/15 [53.3%] vs. 5/39 [12.8%], 95% CI 2.367 to 20.704). Thirteen patients with comorbid autoimmune thyroid diseases were older than those without disease (11.8 ± 5.8 years old vs. 8.0 ± 6.3 years old, 95% CI 0.018 to 7.33). Moreover, patients negative for anti-acetylcholine receptor antibodies were less likely comorbid with autoimmune thyroid disease (1/35 [2.9%] vs. 12/71 [16.9%], 95% CI 0.018 to 1.161). CONCLUSIONS: Juvenile myasthenia gravis patients without anti-acetylcholine antibodies exhibited significantly increased complete remission rates and a reduced likelihood of comorbid autoimmune thyroid diseases compared with those with anti-acetylcholine receptor antibodies among Chinese.

Chrysin-induced ERK1/2 Phosphorylation Enhances the Sensitivity of Human Hepatocellular Carcinoma Cells to Sorafenib.

BACKGROUND/AIM: Sorafenib is now standard treatment for advanced hepatocellular carcinoma (HCC). However, therapeutic efficacy is not as good as was predicted. Many efforts are being made to improve HCC sensitivity to sorafenib. Our previous study demonstrated that co-treatment with chrysin enhanced sorafenib sensitivity through inhibition of ATP-binding cassette super-family G member 2 (ABCG2). Whether there is another mechanism other than inhibition of ABCG2 underlying chrysin-mediated synergistic effect is still not completely elucidated. MATERIALS AND METHODS: Phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) was examined by western blot. Cell viability was examined by crystal violet staining. The importance of ERK1/2 phosphorylation was assessed by overexpression and blockage of mitogen-activated protein kinase kinase 1 (MEK1). RESULTS: Chrysin induced sustained ERK1/2 phosphorylation of HCC cells in both time- and dose-dependent manners. Overexpression of MEK1 enhanced, whereas blockage of MEK1 led to loss of chrysin-synergized sorafenib effect, through modulating ERK1/2 phosphorylation level. CONCLUSION: These results identify another novel mechanism underlying chrysin-mediated synergistic effect on sorafenib activity in HCC cells.

The C-Terminus of Hepatitis B Virus-encoded X Protein Is Required for Lapatinib Sensitivity in Hepatocellular Carcinoma Cells.

BACKGROUND/AIM: Hepatitis B virus-encoded X protein (HBx) plays a pivotal role in hepatocellular carcinoma (HCC) progression and treatment resistance. Interestingly, our previous study unexpectedly showed that full-length HBx sensitized HCC cells to lapatinib by up-regulating erb-b2 receptor tyrosine kinase 3 (ERBB3). We further aimed to map the exact motif within the HBx sequence responsible for lapatinib sensitization. MATERIALS AND METHODS: The exact motif responsible for the lapatinib sensitization was assessed by construction of various fragments of HBx. Cell viability was examined by the MTT assay and crystal violet staining. RESULTS: Our investigation found that lapatinib sensitivity and up-regulation of ERBB3 promoter activity were observed only in HCC cells expressing C-terminal residues of HBx. Furthermore, C-terminal HBx peptide induced ERBB3 protein expression and sensitivity to lapatinib. CONCLUSION: These results not only indicate that the C-terminus of HBx is required for lapatinib sensitivity, but also provide clues to developing a predictive biomarker for response of HCC to lapatinib in the future.

c-Met inhibition is required for the celecoxib-attenuated stemness property of human colorectal cancer cells.

Cyclooxygenase-2 (COX-2) is frequently overexpressed and enhances colorectal cancer (CRC) tumorigenesis, including cancer stem cell (CSC) regulation. Accordingly, nonsteroidal anti-inflammatory drugs (NSAIDs), inhibiting COX-1/2 activity, are viewed as potential drugs for CRC treatment. Accumulated evidence indicates that celecoxib has the most potency for antitumor growth among NSAIDs and the underlying mechanism is only partly dependent on COX-2 inhibition. However, the potency of these NSAIDs on CSC inhibition is still not known. In this study, we found that among these NSAIDs, celecoxib has the most potency for CSC inhibition of CRC cells, largely correlating to inhibition of c-Met, not COX-2. Further analysis reveals that c-Met activity was required for basal CSC property. Silence of c-Met blocked whereas overexpression of c-Met enhanced the celecoxib-inhibited CSC property. Collectively, these results not only first elucidate the mechanism underlying celecoxib-inhibited CSC but also indicate c-Met as a critical factor for the CSC property of CRC cells.

Immunotherapy for anti-NMDA receptor encephalitis: Experience from a single center in Taiwan.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an anti-neuronal antibody-mediated inflammatory brain disease that causes severe psychiatric and neurological deficits in previously healthy patients. The aims of this study were to demonstrate the clinical characteristics of patients diagnosed with anti-NMDA receptor encephalitis and to compare the different treatment strategies among these patients. METHODS: Patients presenting with newly acquired psychiatric and/or neurological deficits were studied retrospectively from 2009 to 2017. Patients with evidence of anti-NMDA receptor antibodies in serum and/or cerebrospinal fluid were enrolled. The modified Rankin scale was used to assess the initial status and outcomes of the enrolled patients. Details of the clinical presentations and results of investigations were analyzed. RESULTS: All (n = 24) of the patients received first-line immunotherapy (steroids, and/or intravenous immunoglobulin, and/or plasma exchange), and 14 patients received second-line immunotherapy (rituximab and/or cyclophosphamide). The mean time between the first- and second-line treatment was 13 days. During the first 6 months, 20 patients (20/24, 83%) achieved a good outcome (modified Rankin Scale score ≤2) and 15 patients (15/24, 62.5%) completely recovered. Four patients (17.7%) relapsed, and three patients (12.5%) had associated tumors. CONCLUSION: Immunotherapy is an effective treatment for anti-NMDA receptor encephalitis. Rituximab and/or cyclophosphamide are treatment options for those who cannot tolerate or do not respond to first-line immunotherapy. Prospective studies are necessary to investigate the role of rituximab and cyclophosphamide in anti-NMDA receptor encephalitis.

Growth hormone supplementation may improve the pregnancy rate and endometrial receptivity among women aged more than 40 years undergoing in vitro fertilization.

BACKGROUND: Growth hormone (GH) supplements have been shown to improve pregnancy and live-birth rates, suggesting that GH has a beneficial effect on oocyte quality. However, the effects of GH on implantation and receptivity remain unknown. This study evaluated the efficacy of GH in women aged more than 40 years participating in assisted reproductive technology (ART) programs. METHODS: Cycles of in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in women aged more than 40 years (range, 40-43 years) between January 2009 and March 2014 at a university-based reproductive center were reviewed. Women were divided into two groups, those with and without GH co-stimulation. ART outcomes were evaluated. RESULTS: Supplement of GH significantly lowered cycle cancellation rate by increasing the per cycle rates of harvesting at least one oocyte and transferring at least one embryo (80.2% vs. 69.4%). GH increased the per cycle clinical pregnancy (15.9% vs. 6.8%) and favorable ultrasonic endometrial pattern (60.9% vs. 39.3%) rates. GH also increased the per transfer clinical pregnancy (19.9% vs. 9.9%) and implantation (11.2% vs. 5.2%) rates and the rate of a favorable ultrasonic endometrial pattern (65.1% vs. 45.0%). CONCLUSION: GH supplementation reduces the cycle cancellation rate in women aged more than 40 years, and increases the favorable ultrasonic endometrial pattern, pregnancy, and implantation rates by its beneficial actions on embryo quality and endometrial receptivity.

Intravitreal aflibercept versus bevacizumab for treatment of myopic choroidal neovascularization.

The authors performed a retrospective and comparative study to compare the efficacy of intravitreal aflibercept and bevacizumab for patients with myopic choroidal neovascularization (mCNV). The patients with treatment-naïve mCNV received 1 + PRN intravitreal bevacizumab from March 2008 to February 2013, while from March 2013 to July 2016 patients were treated by 1 + PRN intravitreal aflibercept, all with monthly follow-up for 12 months. Primary outcome measures included change in central foveal thickness (CFT) in 1 mm by spectral-domain optic coherence tomography, and best corrected visual acuity (BCVA) at month 12. Complications after injections were recorded. The intra-group changes in CFT and BCVA were compared with Wilcoxon signed rank test, the between-group difference compared with Wilcoxon rank sum test. Fisher's exact test was used for categorical comparison between groups. Seventy-eight eyes of 78 patients were collected. There were 42 eyes in bevacizumab group, with mean age of 53.2 ± 5.4 years and 27 female patients of them. The mean BCVA significantly improved from baseline 0.56 ± 0.35 logMAR to 0.35 ± 0.35 logMAR at Month 12 after bevacizumab treatment (p < 0.001). The mean CFT significantly decreased from baseline 315.3 ± 25.6 µm to 253.7 ± 24.4 µm at Month 12 following intravitreal bevacizumab (p < 0.001). There were 36 eyes in aflibercept group, with mean age of 52.8 ± 6.8 years and 24 female patients of them. The mean BCVA significantly improved from baseline 0.61 ± 0.47 logMAR to 0.38 ± 0.41 logMAR at Month 12 after aflibercept treatment (p < 0.001). The mean CFT significantly decreased from baseline 328.2 ± 19.8 µm to 241.8 ± 27.2 µm at Month 12 following intravitreal aflibercept (p < 0.001). The baseline demographics, lens status, axial length, refractive errors, duration of symptoms, BCVA, and CFT did not differ significantly between groups (p > 0.05). There was no significant difference between bevacizumab and aflibercept groups in BCVA and CFT from Month 1 to Month 12 (p > 0.05). Injection number of aflibercept was 2.11 ± 0.41, less than that of bevacizumab (3.23 ± 0.38) during 12-month period (p = 0.01). There were no systemic thromboembolic event, elevated intraocular pressure, retinal detachment, or infectious endophthalmitis following injections in both groups. We concluded that both aflibercept and bevacizumab can effectively treat choroidal neovascularization in high myopes. Intravitreal aflibercept had similar efficacy but less treatment number than bevacizumab for mCNV during 12-month period.

Chrysin Attenuates Cell Viability of Human Colorectal Cancer Cells through Autophagy Induction Unlike 5-Fluorouracil/Oxaliplatin.

Chemotherapeutic 5-fluorouracil (5-FU) combined with oxaliplatin is often used as the standard treatment for colorectal cancer (CRC). The disturbing side effects and drug resistance commonly observed in chemotherapy motivate us to develop alternative optimal therapeutic options for CRC treatment. Chrysin, a natural and biologically active flavonoid abundant in propolis, is reported to have antitumor effects on a few CRCs. However, whether and how chrysin achieves similar effectiveness to the 5-FU combination is not clear. In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), western blotting, fluorescence microscopy, and reactive oxygen species (ROS) production were assayed. We found that chrysin exhibited similar inhibition of cell viability as the 5-FU combination in a panel of human CRC cells. Furthermore, the results showed that chrysin significantly increased the levels of LC3-II, an autophagy-related marker, in CRC cells, which was not observed with the 5-FU combination. More importantly, blockage of autophagy induction restored chrysin-attenuated CRC cell viability. Further mechanistic analysis revealed that chrysin, not the 5-FU combination, induced ROS generation, and in turn, inhibited the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Collectively, these results imply that chrysin may be a potential replacement for the 5-FU and oxaliplatin combination to achieve antitumor activity through autophagy for CRC treatment in the future.

Cigarette smoke enhances oncogene addiction to c-MET and desensitizes EGFR-expressing non-small cell lung cancer to EGFR TKIs.

Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke-derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine-derived nitrosamine ketone (NNK), reduced the sensitivity of wild-type EGFR-expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P-treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c-MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c-MET reduces B[α]P-induced Akt activation. The CSE-treated NSCLC cells are sensitive to the c-MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c-MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.

Comparison of efficacy of intravitreal ranibizumab between non-vitrectomized and vitrectomized eyes with diabetic macular edema.

PURPOSE: To compare the efficacy of intravitreal ranibizumab between non-vitrectomized and vitrectomized eyes with diabetic macular edema (DME). STUDY DESIGN: A retrospective, nonrandomized, and comparative study. METHODS: From May 2013 to March 2016, 148 eyes of 148 patients with treatment-naïve center-involving DME were reviewed in one institution. Forty-six eyes underwent prior vitrectomy at least 3 months ago, and 102 eyes did not receive any vitrectomy. Three monthly then PRN intravitreal ranibizumab treatments were performed in all the patients with monthly follow-up for 6 months. Primary outcome measures included change in central foveal thickness (CFT) and best-corrected visual acuity (BCVA) at month 6. RESULTS: The CFT significantly reduced, and the BCVA significantly improved 6 months after ranibizumab injections in either vitrectomized or non-vitrectomized groups (p < 0.05). There was no difference between vitrectomized and non-vitrectomized eyes in baseline characteristics. Significantly better final BCVA and visual gain were found in non-vitrectomized eyes than in vitrectomized eyes (p = 0.01 and 0.03, respectively). Final CFT and CFT decrease were significantly greater in non-vitrectomized group than in vitrectomized group (p = 0.02 and 0.006, respectively). Injection number of ranibizumab was 4.12 ± 0.58 in non-vitrectomized eyes, significantly less than that in vitrectomized eyes (5.05 ± 0.71) during 6-month period (p < 0.001). There were no severe systemic/ocular adverse effects in both groups. CONCLUSIONS: Intravitreal ranibizumab was helpful for either vitrectomized or non-vitrectomized eyes with DME in short-term follow-up. Anatomical and functional improvements were greater in non-vitrectomized patients than in vitrectomized cases.

Correction: Increased expression of SKP2 is an independent predictor of locoregional recurrence in cervical cancer via promoting DNA-damage response after irradiation.

[This corrects the article DOI: 10.18632/oncotarget.10057.].

SMYD3 Promotes Homologous Recombination via Regulation of H3K4-mediated Gene Expression.

SMYD3 is a methyltransferase highly expressed in many types of cancer. It usually functions as an oncogenic protein to promote cell cycle, cell proliferation, and metastasis. Here, we show that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination. Deficiency of SMYD3 induces DNA-damage hypersensitivity, decreases levels of repair foci, and leads to impairment of homologous recombination. Moreover, the regulation of homologous recombination-related genes is via the methylation of H3K4 at the target gene promoters. These data imply that, besides its reported oncogenic abilities, SMYD3 may maintain genome integrity by ensuring expression levels of HR proteins to cope with the high demand of restart of stalled replication forks in cancers.