Treatment-related cardiovascular events in patients with non-small cell lung cancer: Evidence from real-world data with a competing risks approach.

BACKGROUND: Understanding cancer treatment-related cardiovascular (CV) events is important for cancer care; however, comprehensive evaluation of CV events in patients with lung cancer is limited. This study aimed to assess the cumulative incidence and associated risks of various CV event types in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 7868 individuals aged 40 years and older, recently diagnosed with NSCLC (2007-2018), were assessed with data obtained from the National Cancer Center, Korea. This study included nine types of CV events. A 2-year cumulative incidence function (CIF) of CV events was estimated, with death as a competing event. The associated risks were assessed by subdistribution hazard ratio (sHR) in the Fine-Gray competing risks model. RESULTS: CV events were observed in 7.8% of patients with NSCLC, with the most frequently observed types being atrial fibrillation and flutter (AF) (2.7%), venous thromboembolic disease (2.0%), and cerebrovascular disease (CeVD) (1.5%). Overall, all CV events were highest in the group treated with systemic therapy (CIF, 10.6%; 95% confidence interval [CI], 9.5%-11.8%), followed by those treated with surgery (CIF, 10.0%; 95% CI, 8.6%-11.6%); the incidence of AF (CIF, 5.7%; 95% CI, 4.6%-7.0%) was highest in patients treated with surgery. Individuals treated with systemic therapy were found to exhibit a higher CeVD risk than those treated with surgery (sHR, 4.12; 95% CI, 1.66-10.23). Among the patients who underwent surgery, those with lobectomy and pneumonectomy had a higher AF risk (vs. wedge resection/segmentectomy; sHR, 7.79; 95% CI, 1.87-32.42; sHR, 8.10; 95% CI, 1.60-40.89). CONCLUSIONS: These findings revealed treatment-related CV event risks in patients with NSCLC, which suggests that the risk of AF in surgery and CeVD in systemic therapy should be paid more attention to achieve a better prognosis and improve cancer survivorship outcomes. PLAIN LANGUAGE SUMMARY: Atrial fibrillation and flutter (AF) is the most common cardiovascular event, particularly at a high risk in patients with non-small cell lung cancer (NSCLC) undergoing surgery. Patients receiving surgery with poor performance status, diagnosed with regional stage, and undergoing lobectomy or pneumonectomy are at a high risk of AF. Systemic/radiotherapy is associated with cerebrovascular and ischemic heart disease in patients with NSCLC.

Seasonal influences on the efficacy of anti-programmed cell death (ligand) 1 inhibitors in lung cancer.

BACKGROUND: Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy. METHODS: A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed. RESULTS: A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n = 173) had a significantly lower risk of progression or death from immunotherapy than the other group (n = 311) (PFS: hazard ratio [HR], 0.77 [95% confidence interval (CI), 0.62-0.96]; p = .018; OS: HR, 0.77 [95% CI, 0.1-0.98]; p = .032). In a propensity score-matched population, the winter group (n = 162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p = .009) than the other group (n = 162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p = .012). The trend toward longer survival in the winter group continued in subgroup analyses. CONCLUSIONS: Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons.

STK3 higher expression association with clinical characteristics in intrinsic subtypes of breast cancer invasive ductal carcinoma patients.

PURPOSE: STK3 has a central role in maintaining cell homeostasis, proliferation, growth, and apoptosis. Previously, we investigated the functional link between STK3/MST2, and estrogen receptor in MCF-7 breast cancer cells. To expand the investigation, this study evaluated STK3's higher expression and associated genes in breast cancer intrinsic subtypes using publicly available data. METHODS: The relationship between clinical pathologic features and STK3 high expression was analyzed using descriptive and multivariate analysis. RESULTS: Increased STK3 expression in breast cancer was significantly associated with higher pathological cancer stages, and a different expression level was observed in the intrinsic subtypes of breast cancer. Kaplan-Meier analysis showed that breast cancer with high STK3 had a lower survival rate in IDC patients than that with low STK3 expression (p < 0.05). The multivariate analysis unveiled a strong correlation between STK3 expression and the survival rate among IDC patients, demonstrating hazard ratios for lower expression. In the TCGA dataset, the hazard ratio was 0.56 (95% CI 0.34-0.94, p = 0.029) for patients deceased with tumor, and 0.62 (95% CI 0.42-0.92, p = 0.017) for all deceased patients. Additionally, in the METABRIC dataset, the hazard ratio was 0.76 (95% CI 0.64-0.91, p = 0.003) for those deceased with tumor. From GSEA outcomes 7 gene sets were selected based on statistical significance (FDR < 0.25 and p < 0.05). Weighted Sum model (WSM) derived top 5% genes also have higher expression in basal and lower in luminal A in association with STK3. CONCLUSION: By introducing a novel bioinformatics approach that combines GSEA and WSM, the study successfully identified the top 5% of genes associated with higher expression of STK3.

Blood Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Promising Screening Biomarkers for Brain Metastases in Patients with Lung Cancer.

The diagnosis of brain metastases (BMs) in patients with lung cancer (LC) predominantly relies on magnetic resonance imaging (MRI), a method that is constrained by high costs and limited accessibility. This study explores the potential of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) as screening biomarkers for BMs in LC patients. We conducted a retrospective analysis of 700 LC cases at the National Cancer Center, Korea, from July 2020 to June 2022, measuring sNfL and sGFAP levels at initial LC diagnosis. The likelihood of BM was evaluated using multivariate analysis and a predictive nomogram. Additionally, we prospectively monitored 177 samples from 46 LC patients initially without BM. Patients with BMs (n= 135) had significantly higher median sNfL (52.5 pg/mL) and sGFAP (239.2 pg/mL) levels compared to those without BMs (n = 565), with medians of 17.8 pg/mL and 141.1 pg/mL, respectively (p < 0.001 for both). The nomogram, incorporating age, sNfL, and sGFAP, predicted BM with an area under the curve (AUC) of 0.877 (95% CI 0.84-0.914), showing 74.8% sensitivity and 83.5% specificity. Over nine months, 93% of samples from patients without BM remained below the cutoff, while all patients developing BMs showed increased levels at detection. A nomogram incorporating age, sNfL, and sGFAP provides a valuable tool for identifying LC patients at high risk for BM, thereby enabling targeted MRI screenings and enhancing diagnostic efficiency.

A randomized Phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation.

BACKGROUND: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: This is an open-label, multicenter, randomized Phase 2 study in South Korea. Chemonaïve patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. RESULTS: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty-nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression-free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51-1.08; p = .119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31-0.95; p = .032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. CONCLUSIONS: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. PLAIN LANGUAGE SUMMARY: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression-free survival compared with the erlotinib alone. However, the progression-free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects.

Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer.

BACKGROUND: In EGFR-mutant and MET-amplified lung cancer resistant to EGFR inhibitors, double blockade of EGFR and MET is considered as a reasonable strategy despite increasing toxicity. This study evaluated the single MET inhibition in these specific tumours. METHODS: We investigated the efficacy of a single MET inhibitor in EGFR-mutant, MET-amplified lung cancer cells (HCC827GR) and the matched clinical cases and patient-derived cells. Acquired resistance mechanisms to single MET inhibitor were further explored. RESULTS: Single MET inhibitor sufficiently inhibited the EGFR downstream signalling and proliferation in the HCC827GR cells. The MET-inhibitor-sensitive clones had similar EGFR mutation allele frequency as the MET-inhibitor-resistant clones. The patients with EGFR-mutant, MET-amplified lung cancer resistant to EGFR inhibitors showed definite response to single MET inhibitor but the response duration was not durable. The MET gene copy number in their plasma circulating tumour DNA was significantly decreased during the treatment and was not re-increased after progression. In the cells resistant to single MET inhibitor, the EGFR pathway was reactivated, and gefitinib alone successfully suppressed their growth. CONCLUSIONS: Single MET inhibition produced a short-lived response in EGFR-mutant and MET-amplified lung cancer. A further study of a novel combination therapy schedule is needed to achieve long-lasting efficacy and less toxicity.

Versatile Mechanochromic Sensor based on Highly Stretchable Chiral Liquid Crystalline Elastomer.

A mechanochromic strain sensor that is capable of distinguishing the orientation, the location, and the degree of deformation based on the highly stretchable membrane of main-chain chiral liquid crystalline elastomer (MCLCE) is proposed. The MCLCE film is designed to exhibit uniform and significant color shift upon the small strain by using step-growth polymerization of liquid crystal (LC) oligomer and its phase-stabilization in solvent mesogen. As conformally placed on the bottom elastomer sheet, the MCLCE film shows multimodal, instantaneous color change for sensing arbitrary in-plane deformation, out-of-plane bending, and nonzero Gaussian deformation. Based on high freedom in the device design, it is also demonstrated that this sensor can display color patterns or encrypted images in response to the localized weight or strain. The simple and straightforward concept proposed here can be applicable in the fields of wearable devices, displays, and soft robotics.

Broadband and pixelated camouflage in inflating chiral nematic liquid crystalline elastomers.

Living organisms such as fishes1, cephalopods2 and clams3 are cryptically coloured with a wide range of hues and patterns for camouflage, signalling or energy regulation. Despite extensive efforts to create colour-changing materials and devices4, it is challenging to achieve pixelated structural coloration with broadband spectral shifts in a compact space. Here, we describe pneumatically inflating thin membranes of main-chain chiral nematic liquid crystalline elastomers that have such properties. By taking advantage of the large elasticity anisotropy and Poisson's ratio (>0.5) of these materials, we geometrically program the size and the layout of the encapsulated air channels to achieve colour shifting from near-infrared to ultraviolet wavelengths with less than 20% equi-biaxial transverse strain. Each channel can be individually controlled as a colour 'pixel' to match with surroundings, whether periodically or irregularly patterned. These soft materials may find uses in distinct applications such as cryptography, adaptive optics and soft robotics.

Phase 1 trial of 4-1BB-based adoptive T-cell therapy targeting human telomerase reverse transcriptase in patients with advanced refractory solid tumors.

BACKGROUND AIMS: Human telomerase reverse transcriptase (hTERT) is an attractive target for anti-cancer therapies. We developed an effective method for generating hTERT-specific CD8+ T cells (hTERT-induced natural T cells [TERTiNTs]) using peripheral blood mononuclear cells (PBMCs) from patients with solid cancers and investigated their feasibility and safety. METHODS: This was a single-center phase 1 trial using a 3 + 3 dose escalation design to evaluate six dose levels of TERTiNTs. PBMCs from each patient were screened using an hTERT peptide panel to select those that stimulated CD8+ T cells. The four most stimulatory peptides were used to produce autologous CD8+ T cells from patients refractory or intolerant to standard therapies. Eligible patients received a single intravenous infusion of TERTiNTs at different dose levels (4 × 108 cells/m2, 8 × 108 cells/m2 and 16 × 108 cells/m2). Pre-conditioning chemotherapy, including cyclophosphamide alone or in combination with fludarabine, was administered to induce lymphodepletion. RESULTS: From January 2014 to October 2019, a total of 24 patients with a median of three prior lines of therapy were enrolled. The most common adverse events were lymphopenia (79.2%), nausea (58.3%) and neutropenia (54.2%), mostly caused by pre-conditioning chemotherapy. The TERTiNT infusion was well tolerated, and dose-limiting toxicities were not observed. None of the patients showed objective responses. Seven patients (30.4%) achieved stable disease with a median progression-free survival of 3.9 months (range, 3.2-11.3). At the highest dose level (16 × 108 cells/m2), four of five patients showed disease stabilization. CONCLUSIONS: The generation of TERTiNTs was feasible and safe and provided an interesting disease control rate in heavily pre-treated cancer patients.

Long-term outcomes in patients with advanced and/or metastatic non-small cell lung cancer who completed 2 years of immune checkpoint inhibitors or achieved a durable response after discontinuation without disease progression: Multicenter, real-world data (KCSG LU20-11).

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown significant improvements in patients with advanced non-small cell lung cancer (NSCLC). One of the major issues with ICIs is determining the optimal treatment duration. METHODS: This multicenter, retrospective study analyzed clinical outcomes in patients with NSCLC who completed 2 years of ICI therapy or were treated for more than 6 months and then discontinued ICIs without disease progression at 11 medical centers in Korea between August 2017 and December 2020. RESULTS: Ninety-six patients who completed 2 years of ICIs were reviewed. The median durations of treatment and follow-up were 24.0 and 33.9 months, respectively. The objective response rate (ORR) was 85.4%. The median progression-free survival (PFS) and overall survival (OS) periods were not reached. After completion, the PFS and OS rates were 81.1% and 96.4%, respectively, at 12 months. Forty-three patients were identified who discontinued ICIs without disease progression: 26 (60.5%) for adverse events and 17 (39.5%) for other causes. The median durations of treatment and follow-up were 10.5 and 21.2 months, respectively. The ORR was 90.7%. The median PFS and OS periods were not reached. After discontinuation, the PFS and OS rates were 71.0% and 90.0%, respectively, at 12 months. CONCLUSIONS: A significantly high proportion of patients who completed 2 years of ICI therapy continued to experience long-term PFS. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long-term survival. LAY SUMMARY: The optimal treatment duration for immune checkpoint inhibitors (ICIs) remains to be determined. This study reports the long-term outcomes of patients with non-small cell lung cancer who completed 2 years of ICI therapy or achieved a durable response after the discontinuation of ICIs without disease progression in real-world practice. A significantly high proportion of patients who completed 2 years of ICIs continued to experience long-term progression-free survival. In addition, even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long-term survival.

Hypoxic induction of apoptosis occurs through HIF-1α and accompanies mammalian sterile 20-like kinase 2 cleavage in human endometrial adenocarcinoma Ishikawa cells.

The incidence of endometrial cancer is increasing worldwide. One of the main causes of this cancer is a hormone imbalance; progesterone derivatives have been used for treatment. However, reports have shown that hypoxia plays important and possibly beneficial roles in endometrial function. Here, we show the effect of hypoxia on the proliferation of human endometrial adenocarcinoma Ishikawa cells. Hypoxia induced caspase-dependent apoptosis in Ishikawa cells. Overexpression and siRNA-mediated knockdown of hypoxia-inducible factor-1α (HIF-1α) confirmed that HIF-1α accelerates hypoxia-induced cell death. Treatment with dimethyloxalglycine, which stabilizes HIF-1α, suppressed cell proliferation. Kaplan-Meier analysis showed that the expression level of HIF-1α has a significant positive effect on the survival rate of endometrial cancer patients. In our search for cellular targets involved in hypoxic apoptosis, we noticed that mammalian sterile 20-like kinase 2 (MST2), a member of the Hippo pathway, was positively correlated with HIF-1α expression in 176 endometrial cancer patients extracted from the TCGA database. Hypoxia induced caspase-dependent MST2 cleavage. In addition, a MST2 inhibitor suppressed HIF-1α-mediated reporter activity. These results suggest HIF-1α and the Hippo signaling pathway are involved in endometrial cancer.

Class II Division 1 Adolescent Treatment with Twin Block and Fixed Orthodontic Appliances: 3-Dimensional Changes of the Temporomandibular Joint.

INTRODUCTION: Skeletal Class II division 1 malocclusions with a retrognathic mandible can be treated with Twin Block and fixed orthodontic appliances in growing adolescent patients. OBJECTIVE: The aim of this case report was to show successful treatment results following step-by-step procedures determined by visualizing the changes of the temporomandibular joint (TMJ) area using cone-beam computed tomography (CBCT) images. CASE REPORT: A 10-year, 8-month-old female adolescent with skeletal Class II division 1 (ANB, 6.2°), severe overjet (8.4 mm), and overbite (7.8 mm) was treated with Twin Block and fixed orthodontic appliances. After wearing an active plate for 4 months, a Twin Block appliance for 9 months, a retainer with an inclined plane for 13 months, and fixed orthodontic treatment for 17 months, her skeletal Class II was corrected. After 39 months of posttreatment retention, good treatment results were maintained with favorable occlusion and facial balance. Acceptable 3-dimensional changes of the TMJ area were identified using cone-beam computed tomography images. CONCLUSION: A female adolescent patient with skeletal Class II division 1 malocclusion, severe overjet and overbite, and mandibular retrusion was treated using Twin Block and fixed orthodontic appliances. Acceptable 3-dimensional changes in the TMJ area and 2-dimensional growth of the mandible were identified using CBCT and cephalometric images.

One-Step Polymerase Chain Reaction-Free Nanowire-Based Plasma Cell-Free DNA Assay to Detect EML4-ALK Fusion and to Monitor Resistance in Lung Cancer.

BACKGROUND: Next-generation sequencing has mostly been used for genotyping cell-free DNA (cfDNA) in plasma. However, this assay has several clinical limitations. We evaluated the clinical utility of a novel polymerase chain reaction-free nanowire (NW)-based plasma cfDNA assay for detecting ALK fusion and mutations. PATIENTS, MATERIALS, AND METHODS: We consecutively enrolled 99 patients with advanced non-small cell lung cancer undergoing a fluorescence in situ hybridization (FISH) test for ALK fusion; ALK-positive (n = 36). The NW-based assay was performed using 50-100 µL of plasma collected at pretreatment and every 8 weeks during ALK inhibitor treatment. RESULTS: There was high concordance between the NW-based assay and the FISH test for identification of ALK fusion (94.9% with a kappa coefficient value of 0.892, 95% confidence interval [CI], 0.799-0.984). There was no difference in the response rate to the first anaplastic lymphoma kinase inhibitor between the ALK-positive patients identified by the NW-based assay and by the FISH test (73.5% vs. 72.2%, p = .931). In the ALK variant analysis, variants 1 and 3 subgroups were detected in 27 (75.0%) and 8 (22.2%) patients, respectively. Among 24 patients treated with crizotinib, variant 3 subgroup was associated with worse median overall survival than variant 1 subgroup (36.5 months; 95% CI, 0.09-87.6 vs. 19.8 months; 95% CI, 9.9-not reached, p = .004]. A serial assessment identified that ALK L1196M resistance mutation emerged before radiologic progression during crizotinib treatment. CONCLUSION: The newly developed simple NW-based cfDNA assay may be clinically applicable for rapid diagnosis of ALK fusion with its variant forms and early detection of resistance. IMPLICATIONS FOR PRACTICE: The authors developed a novel one-step polymerase chain reaction-free nanowire (NW)-based plasma cell-free DNA (cfDNA) assay. This study evaluated the clinical utility of this novel method for the diagnosis of EML4-ALK fusion in advanced non-small cell lung cancer (NSCLC). The NW-based assay and FISH test showed high concordance rate in 99 patients with advanced NSCLC. Serial cfDNA assessment demonstrated this method provided early detection of resistance before radiologic progression during crizotinib treatment. Taken together, plasma cfDNA genotyping by the NW-based cfDNA assay may be useful for the rapid diagnosis of ALK fusion, classifying variants, and early detection of resistance.

Increased Lipid Accumulation under Hypoxia in SZ95 Human Sebocytes.

BACKGROUND: Excessive sebum is produced by specialized cells called sebocytes and is considered a cause or consequence of acne, sebaceous cysts, hyperplasia, and sebaceous adenoma. OBJECTIVE: To report changes in lipid accumulation in human sebocytes under hypoxia, which occurs under conditions of seborrhea. METHODS: Sebocytes from the immortalized human gland cell line SZ95 were cultured under conditions of hypoxia for 48 h; lipid formation was confirmed by Nile red and Oil Red O staining. To investigate whether HIF-1α plays a role in lipid accumulation, SZ95 cells transfected or treated with dimethyloxalylglycine (DMOG) were assessed by Nile red. For protein expression of the sterol regulatory element-binding protein-1 (SREBP-1) and perilipin 2 (PLIN2), Western blot analysis was performed. Differentially expressed genes (DEGs) in SZ95 sebocytes under hypoxia were revealed by RNA-Seq analyses, and the statistical significance of the correlation between hypoxic and acne/non-acne skin was evaluated using gene set enrichment analysis. RESULTS: Hypoxia induces lipid accumulation in SZ95 sebocytes. In addition, the levels of SREBP-1 and PLIN2 were regulated by HIF-1α in SZ95 sebocytes under hypoxia. RNA-Seq analyses of DEGs in SZ95 sebocytes under hypoxia revealed 256 DEGs, including several lipid droplet-associated genes. DEGs between acne and non-acne skin are significantly enriched in hypoxia gene sets. We also detected 93 differentially expressed inflammatory mediators. CONCLUSIONS: To the best of our knowledge, this study is the first to show that a hypoxic microenvironment can increase lipogenesis and provides a link between seborrhea and inflammation.

MST2 silencing induces apoptosis and inhibits tumor growth for estrogen receptor alpha-positive MCF-7 breast cancer.

Mammalian sterile 20-like kinase 1/2 (MST1/2) plays an important role in cell growth and apoptosis and functions as a tumor suppressor. Previously, we showed that MST2 overexpression activates Estrogen receptor alpha (ERα) in human breast cancer MCF-7 cells in the absence of a ligand. Here, we examined the role of MST2 in the growth of ER-positive MCF-7 cells. Cell cycle, apoptosis, and mammosphere formation assay method were implemented to detect the biological effects of MST2 ablation on the growth of MCF-7 cells in vitro. The effect of MST2-siRNA on MCF-7 cells tumor growth in vivo was studied in tumor-bearing mouse model. Kaplan-Meier plotter analysis was used to determine the effect of MST2 on overall survival in breast cancer patients. MST2 overexpression increased cell viability marginally. The ablation of MST2 using siRNA dramatically suppressed the viability of the MCF-7 cells, but not ER-negative MDA-MB-231 breast cancer cells. Furthermore, MST2 knockdown increased caspase-dependent apoptosis and led to decreased mammosphere formation. Treatment of MCF-7 tumor-bearing mice with MST2 siRNA significantly inhibited tumor growth. The tumor weight was reduced further when tamoxifen was added. Patients with ER-positive breast cancer with low MST2 expression had better overall survival than did those with high MST2 expression in Kaplan-Meier survival analyses using public datasets. Our results provide new insight into the role of MST2, a key component of the Hippo signaling pathway, in mediating breast cancer progression.

Individual Disaster Assistance For Socially Vulnerable People: Lessons Learned From the Pohang Earthquake in the Republic of Korea.

The Republic of Korea has been considered to be relatively safe from earthquake hazards because of the geological location of the Korean Peninsula, which has a low level of intraplate seismic activity. However, an earthquake with a moment magnitude of 5.4 struck the city of Pohang on November 15, 2017, causing 90 casualties and 52 million USD in property losses. During the recovery process after the earthquake, the Korean government provided individual disaster assistance to victims who reported their damages. However, the government disaster assistance could have been unfairly distributed among the socially vulnerable victims who essentially relied on that assistance. This study identifies whether the government disaster assistance was fairly distributed to socially vulnerable victims using a statistical model based on the data from the Pohang earthquake that occurred in 2017 in Korea. A conceptual model was constructed using a structural equation model (SEM) of three factors-social vulnerability, physical vulnerability, and the amount paid out in individual disaster assistance. Furthermore, interviews with and a survey of the victims were conducted to verify the problems identified by the conceptual model. This study found that socially vulnerable victims were less likely to take advantage of the government disaster assistance program.

Energy-Efficient Wearable EPTS Device Using On-Device DCNN Processing for Football Activity Classification.

This paper presents an energy-optimized electronic performance tracking system (EPTS) device for analyzing the athletic movements of football players. We first develop a tiny battery-operated wearable device that can be attached to the backside of field players. In order to analyze the strategic performance, the proposed wearable EPTS device utilizes the GNSS-based positioning solution, the IMU-based movement sensing system, and the real-time data acquisition protocol. As the life-time of the EPTS device is in general limited due to the energy-hungry GNSS sensing operations, for the energy-efficient solution extending the operating time, in this work, we newly develop the advanced optimization methods that can reduce the number of GNSS accesses without degrading the data quality. The proposed method basically identifies football activities during the match time, and the sampling rate of the GNSS module is dynamically relaxed when the player performs static movements. A novel deep convolution neural network (DCNN) is newly developed to provide the accurate classification of human activities, and various compression techniques are applied to reduce the model size of the DCNN algorithm, allowing the on-device DCNN processing even at the memory-limited EPTS device. Experimental results show that the proposed DCNN-assisted sensing control can reduce the active power by 28%, consequently extending the life-time of the EPTS device more than 1.3 times.

Small Hepatocellular Carcinoma With Low Tumor Marker Expression Benefits More From Anatomical Resection Than Tumors With Aggressive Biology.

OBJECTIVE: We assessed prognostic advantage of anatomical resection (AR) over nonanatomical resection (NAR) for hepatocellular carcinoma (HCC) according to multiplication of α-fetoprotein, des-γ-carboxyprothrombin, and tumor volume (ADV) scores. BACKGROUND: Superiority of AR over NAR is debated. ADV score is surrogate marker of postresection prognosis for solitary HCC. METHODS: This study included 1572 patients who underwent curative resection for solitary HCC of 2.0 to 5.0 cm between 2006 and 2014. RESULTS: Preoperative patient profiles were not statistically different between AR and NAR groups. In 1324 naïve patients without preoperative treatment, AR group showed lower recurrence rates (P = 0.003) and higher patient survival rates (P = 0.012) than NAR group. AR group showed lower recurrence rates in patients with ADV ≤5 log (P ≤ 0.046). ADV scores >4 log and >3 log were independent risk factors for tumor recurrence and patient survival in treatment-naïve patients, respectively. In treatment-naïve group with preserved hepatic functional reserve, AR group showed lower recurrence rates in patients with ADV ≤4 log (P = 0.026). Absence of microvascular invasion also showed lower recurrence rates (P = 0.007) in AR group. In 248 patients with preoperative treatment, AR group showed lower recurrence rates (P = 0.001) and higher patient survival rates (P = 0.006). AR group showed lower recurrence rates in patients with ADV ≤4 log (P < 0.001) and higher survival rates in patients with ADV ≤5 log (P ≤ 0.043). CONCLUSIONS: Prognostic benefit of AR was evident in patients with ADV score ≤4 log or absence of microvascular invasion. Patients with less aggressive tumor biology benefit more from AR than NAR, thus being reasonably indicated for AR.

MST2 kinase regulates osteoblast differentiation by phosphorylating and inhibiting Runx2 in C2C12 cells.

The mammalian Ste20-like kinase (MST) pathway or Hippo pathway plays essential roles in cell proliferation, apoptosis, organ size control, and development. Runx2 is a key transcription factor in osteoblast differentiation. The objective of this study was to investigate whether the MST pathway could modulate Runx2 and osteoblast differentiation. First, we found that Runx2 interacted with MST2 and SAV1 via the WW domain of SAV1 and amino acid 292-445 of Runx2 containing a PY motif. Results of OSE luciferase reporter assay revealed that co-expression of MST2 and SAV1 inhibited the transcriptional activity of Runx2 whereas siRNA-mediated down-regulation of Mst1 and Mst2 increased its activity. MST2 and SAV1 significantly reduced mRNA levels of osteoblast differentiation marker genes such as alkaline phosphatase and osteocalcin in differentiating C2C12 cells. MST2 and SAV1 also hampered osteoblast differentiation of C2C12 cells induced by Runx2 as shown by alkaline phosphatase activity assay and Alizarin Red staining. Mass spectrometric analysis of immunoprecipitated Runx2 protein from HEK293 cells overexpressing MST2 and SAV1 revealed two novel phosphorylation sites at Ser-339 and Ser-370 residues of mouse Runx2 protein. Mutation of both serine residues to alanine interfered with the inhibitory effect of MST2 and SAV1 on the transcriptional activity of Runx2 and osteoblast differentiation induced by Runx2. Our results suggest that the MST kinase pathway can directly regulate osteoblast differentiation by modulating Runx2 activity through phosphorylation.

Mammalian Hippo kinase pathway is downregulated by BCL-2 via protein degradation.

Mammalian ste20-like kinase (MST) signaling pathway plays a significant part in control of cell death and cell cycle. It was originally found as Hippo pathway in Drosophila and composed of MST kinase and Salvador-1 (SAV1), a scaffold protein. In mammalian cells, MST pathway induces cell-cycle exit and apoptosis in response to various signals. BCL-2, an anti-apoptotic protein, inhibits cell death and plays an important part in tumorigenesis. In the present report, we present evidence showing that BCL-2 is a new regulator of MST pathway. First, protein levels of MST2 and SAV1 were reduced significantly by co-expression of BCL-2. Physical interaction of BCL-2 with SAV1 was correlated with proteasomal degradation of SAV1 and MST2 proteins. In SH-SY5Y neuroblastoma cell line expressing a high level of BCL-2 but low levels of MST2 and SAV1, siRNA-induced knockdown of BCL-2 restored the expression of MST2 and SAV1. Inhibition of BCL-2 with BAD or ABT-737, a BCL-2 inhibitor, reversed its effect on MST2 and SAV1 proteins. ABT737 increased HEK293 cell death significantly when both MST2 and SAV1 were co-expressed. These results suggest that cancer cells may avoid cell death through enhanced expression of BCL-2 which down-regulates the pro-apoptotic MST pathway.