Wideband PRM: Highly Accurate and Sensitive Method for High-Throughput Targeted Proteomics.

Targeted mass spectrometry (MS) approaches, which are powerful methods for uniquely and confidently quantifying a specific panel of proteins in complex biological samples, play a crucial role in validating and clinically translating protein biomarkers discovered through global proteomic profiling. Common targeted MS methods, such as multiple reaction monitoring (MRM) and parallel-reaction monitoring (PRM), employ specific mass spectrometric technologies to quantify protein levels by comparing the transitions of surrogate endogenous (ENDO) peptides with those of stable isotope-labeled (SIL) peptide counterparts. These methods utilizing amino acid analyzed (AAA) SIL peptides warrant sensitive and precise measurements required for targeted MS assays. Compared with MRM, PRM provides higher experimental throughput by simultaneously acquiring all transitions of the target peptides and thereby compensates for different ion suppressions among transitions of a target peptide. However, PRM still suffers different ion suppressions between ENDO and SIL peptides due to spray instability, as the ENDO and SIL peptides were monitored at different liquid chromatography (LC) retention times. Here we introduce a new targeted MS method, termed wideband PRM (WBPRM), that is designed for high-throughput targeted MS analysis. WBPRM employs a wide isolation window for simultaneous fragmentation of both ENDO and SIL peptides along with multiplexed single ion monitoring (SIM) scans for enhanced MS sensitivity of the target peptides. Compared with PRM, WBPRM was demonstrated to provide increased sensitivity, precision, and reproducibility of quantitative measurements of target peptides with increased throughput, allowing more target peptide measurements in a shortened experiment time. WBPRM is a straightforward adaptation to a manufacturer-provided MS method, making it an easily implementable technique, particularly in complex biological samples where the demand for higher precision, sensitivity, and efficiency is paramount.

Synthesis of S-Carbamidomethyl Cysteine and Its Use for Quantification of Cysteinyl Peptides by Targeted Proteomics.

Proteomics has played a central role in the identification of reliable disease biomarkers, which are the basis of precision medicine, a promising approach for tackling recalcitrant diseases such as cancer, that elude conventional treatments. Among proteomic methodologies, targeted proteomics employing stable isotope-labeled (SIL) internal standards is particularly suited for the clinical translation of biomarker information owing to its high throughput and accuracy in the quantitative analysis of patient-derived proteomes. Using SIL internal standards ensures the utmost level of confidence in detection and precision in targeted MS experiments. For successfully establishing assays based on targeted proteomics, it is crucial to secure broad coverage when selecting the SIL standard peptide panel. However, cysteinyl peptides have often been excluded because of cysteine's high chemical reactivity. To address this limitation, a new cysteine building block was developed by incorporating a sulfhydryl group configured with an S-carbamidomethyl group, which is commonly used in proteome sampling. This compound was found to be chemically stable and applicable to a variety of solid-phase peptide synthesis (SPPS) campaigns. Furthermore, a direct comparison of the synthesized SIL peptides and tryptic endogenous peptides demonstrated the potential utility of an SPPS flow based on the new cysteine building block for improving the success of targeted proteomic applications.

Exchange Bias in Weakly Interlayer-Coupled van der Waals Magnet Fe3GeTe2.

van der Waals (vdW) magnetic materials provide an ideal platform to study low-dimensional magnetism. However, observations of magnetic characteristics of these layered materials truly distinguishing them from conventional magnetic thin film systems have been mostly lacking. In an effort to investigate magnetic properties unique to vdW magnetic materials, we examine the exchange bias effect, a magnetic phenomenon emerging at the ferromagnetic-antiferromagnetic interface. Exchange bias is observed in the naturally oxidized vdW ferromagnet Fe3GeTe2, owing to an antiferromagnetic ordering in the surface oxide layer. Interestingly, the magnitude and thickness dependence of the effect is unlike those expected in typical thin-film systems. We propose a possible mechanism for this behavior, based on the weak interlayer magnetic coupling inherent to vdW magnets, demonstrating the distinct properties of these materials. Furthermore, the robust and sizable exchange bias for vdW magnets persisting up to relatively high temperatures presents a significant advance for realizing practical two-dimensional spintronics.

Chrysin-Induced G Protein-Coupled Estrogen Receptor Activation Suppresses Pancreatic Cancer.

Pancreatic cancer (PC) has a high mortality rate due to its poor prognosis and the possibility of surgical resection in patients with the disease. Importantly, adjuvant chemotherapy is necessary to improve PC prognosis. Chrysin, a natural product with anti-inflammatory, antioxidant, and anticancer properties, has been studied for several years. Our previous study demonstrated that chrysin induced G protein-coupled estrogen receptor (GPER) expression and regulated its activity in breast cancer. Herein, we investigated whether chrysin-induced GPER activation suppresses PC progression in MIA PaCa-2 cells and a xenograft model. To determine its mechanism of action, cytotoxicity and clonogenic assays, a FACS analysis, and Western blotting were performed. Furthermore, the delay in tumor growth was evaluated in the MIA PaCa-2-derived xenograft model. Tumor tissues were investigated by Western blotting, immunohistochemistry, and a proteomic analysis. Chrysin caused cell cycle arrest and significantly decreased cell viability. Following co-treatment with chrysin and 17ß-estradiol, the inhibitory effect of chrysin on cell proliferation was enhanced. In the xenograft model, chrysin and G1 (a GPER agonist) significantly delayed tumor growth and reduced both Ki-67 (a proliferation marker) and c-Myc expressions in tumor tissues. The proteomic analysis of tumor tissues identified that rho-associated coiled-coil containing protein kinase 1 (ROCK1), transgelin 2 (TAGLN2), and FCH and Mu domain containing endocytic adaptor 2 (FCHO2) levels were significantly reduced in chrysin-treated tumor tissues. High ROCK1, TAGLN2, and FCHO2 expressions were indicative of low overall PC survival as found using the Kaplan-Meier plotter. In conclusion, our results suggest that chrysin suppresses PC progression through the activation of GPER and reductions in ROCK1, TAGLN2, and FCHO2 expressions.

Clinical Significance of Ventricular Premature Contraction Provoked by the Treadmill Test.

Background and Objectives: The treadmill test (TMT) is a predictive tool for myocardial ischemia. Recently, exercise-provoked ventricular premature contracture (VPC) during TMT was shown to have a relation with coronary artery disease and cardiovascular mortality. Therefore, we evaluate clinical correlates of exercise-provoked VPC and compare the predictive power for myocardial ischemia and cardiovascular events. Method: Data of 408 patients (≥18 years of age) who underwent TMT for work up of angina, palpitation, dyspnea, syncope, or arrhythmia between February 2015, and January 2016, were collected with consent at Samsung Medical Center, Seoul, Republic of Korea. Among total of 408 patients, 208 were excluded according to the previous history of PCI or CABG, previous MI, decreased left ventricular ejection fraction lower than 50%, arrhythmia that could affect ST-segment change on ECG. Results: Among 200 patients, 32 (16.0%) developed exercise-provoked VPC (21 patients in the exercise phase, 20 patients in the recovery phase). Of them, 20 patients (10.0%) showed positive TMT, and 4 patients (2.0%) underwent revascularization after TMT. Among 21 patients showing exercise phase VPC, 5 (23.8%) showed positive TMT results. In patients younger than 65 years, exercise phase VPC was associated with positive TMT (odds ratio 6.879, 1.458-32.453) considering demographics and previous medical history in multivariable analysis. Among the 20 patients showing recovery phase VPC, 2 (10.0%) underwent revascularization after TMT. In multivariable analysis, recovery phase VPC was associated with revascularization (odds ratio 9.381, 1.144-76.948) considering age, sex, BMI, and TMT result. Conclusion: VPC during the treadmill test was a useful predictor of myocardial ischemia in this study.

Estimation of the reproduction number of influenza A(H1N1)pdm09 in South Korea using heterogeneous models.

BACKGROUND: The reproduction number is one of the most crucial parameters in determining disease dynamics, providing a summary measure of the transmission potential. However, estimating this value is particularly challenging owing to the characteristics of epidemic data, including non-reproducibility and incompleteness. METHODS: In this study, we propose mathematical models with different population structures; each of these models can produce data on the number of cases of the influenza A(H1N1)pdm09 epidemic in South Korea. These structured models incorporating the heterogeneity of age and region are used to estimate the reproduction numbers at various terminal times. Subsequently, the age- and region-specific reproduction numbers are also computed to analyze the differences illustrated in the incidence data. RESULTS: Incorporation of the age-structure or region-structure allows for robust estimation of parameters, while the basic SIR model provides estimated values beyond the reasonable range with severe fluctuation. The estimated duration of infectious period using age-structured model is around 3.8 and the reproduction number was estimated to be 1.6. The estimated duration of infectious period using region-structured model is around 2.1 and the reproduction number was estimated to be 1.4. The estimated age- and region-specific reproduction numbers are consistent with cumulative incidence for corresponding groups. CONCLUSIONS: Numerical results reveal that the introduction of heterogeneity into the population to represent the general characteristics of dynamics is essential for the robust estimation of parameters.

Electrocardiographic predictors of early recurrence of atrial fibrillation.

BACKGROUND: Electrical cardioversion (ECV) is an effective method for restoring sinus rhythm after atrial fibrillation (AF). However, early recurrence of AF occurs in a significant number of patients after ECV. This study aimed to identify electrocardiographic (ECG) predictors of early AF recurrence after ECV. METHODS: A total of 272 patients with persistent AF undergoing successful ECV were consecutively enrolled in this study. We investigated clinical, echocardiographic, and ECG data. The 12-lead ECG parameters were measured during sinus rhythm right after ECV using a digital caliper. The early AF recurrence was defined as recurrence within 2 months. RESULTS: Of the 272 patients, 165 patients (60.7%) experienced an early AF recurrence. Maximum P-wave duration (PWD) in limb leads (OR: 1.086; 95% CI: 1.019-1.157; p = .012) and P-terminal force (PTF) in V1 (OR: 1.019; 95% CI: 1.004-1.033; p = .011) were independent predictors of early AF recurrence after ECV. The optimal cutoff value of the maximum PWD in limb leads for predicting early AF recurrence was 134 ms, characterized by 90.3% sensitivity and 72.0% specificity. Likewise, the optimal cutoff value of PTF in V1 was 50 ms × mm, characterized by 80.0% sensitivity and 64.5% specificity. CONCLUSION: A longer PWD (>134 ms) and a larger PTF (>50 ms × mm) were useful predictors of early recurrence of AF after successful ECV in clinical practice. A more effective rhythm control therapy such as catheter ablation or rate control strategy rather than a repeat ECV should be considered.

Effectiveness of the Early Staged Hybrid Approach for Treatment of Symptomatic Atrial Fibrillation: the Electrophysiology Study Could Be Deferred?

BACKGROUND: The efficacy of catheter ablation for persistent atrial fibrillation (AF) remains suboptimal. A hybrid approach of catheter ablation combined with totally thoracoscopic surgical ablation can improve outcomes. In this study, we evaluated the efficacy of the early staged hybrid procedure in hospital stay after totally thoracoscopic ablation compared to the stand-alone totally thoracoscopic ablation. METHODS: Patients who underwent totally thoracoscopic ablation from February 2012 to December 2018 were included in this study. We compared the outcomes of the totally thoracoscopic ablation only group versus the early staged hybrid procedure group. The primary outcome was recurrence of atrial tachyarrhythmia after three months of blanking period. The secondary outcome was repeated unplanned additional electrophysiology study and catheter ablation due to atrial tachyarrhythmia recurrence. RESULTS: A total of 306 patients (mean age, 56.8 ± 8.5 years; 278 [90.8%] males) was included in the study, with 81 patients in the early staged hybrid group and 225 patients in the stand-alone totally thoracoscopic ablation only group. The mean follow-up duration was 30.0 months. Overall arrhythmia-free survival showed no significant difference between the two groups (log-rank P = 0.402). There was no significant difference in the rate of repeat procedure between the two groups (log-rank = 0.11). CONCLUSION: The early staged hybrid procedure after thoracoscopic ablation could not improve the outcome of recurrence of atrial tachyarrhythmia. The second stage of electrophysiology study could be deferred to patients with recurrence of atrial tachyarrhythmia during follow up after totally thoracoscopic ablation.

Efficient and Privacy-Preserving Energy Trading on Blockchain Using Dual Binary Encoding for Inner Product Encryption.

The rapidly increasing expansion of distributed energy resources (DER), such as renewable energy systems and energy storage systems into the electric power system and the integration of advanced information and communication technologies enable DER owners to participate in the electricity market for grid services. For more efficient and reliable power system operation, the concept of peer-to-peer (P2P) energy trading has recently been proposed. The adoption of blockchain technology in P2P energy trading has been considered to be the most promising solution enabling secure smart contracts between prosumers and users. However, privacy concerns arise because the sensitive data and transaction records of the participants, i.e., the prosumers and the distribution system operator (DSO), become available to the blockchain nodes. Many efforts have been made to resolve this issue. A recent breakthrough in a P2P energy trading system on an Ethereum blockchain is that all bid values are encrypted using functional encryption and peer matching for trading is performed securely on these encrypted bids. Their protocol is based on a method that encodes integers to vectors and an algorithm that securely compares the ciphertexts of these vectors. However, the comparison method is not very efficient in terms of the range of possible bid values because the amount of computation grows linearly according to the size of this range. This paper addresses this challenge by proposing a new bid encoding algorithm called dual binary encoding, which dramatically reduces the amount of computation as it is only proportional to the square of the logarithm of the size of the encoding range. Moreover, we propose a practical mechanism for rebidding the remaining amount caused when the amounts from the two matching peers are not equal. Finally, the feasibility of the proposed method is evaluated by using a virtual energy trade testbed and a private Ethereum blockchain platform.

Clinical Factors Associated with Renal Outcome After Heart Transplantation.

Cardiorenal syndrome (CRS) frequently occurs in end-stage heart failure patients waiting for heart transplantation (HT). Decision-making regarding simultaneous heart and kidney transplantation is an unresolved issue in these patients. We investigated clinical factors associated with renal outcome after HT. A total of 180 patients who received HT from 1996 to 2015 were included. Factors associated with early post-HT chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] < 60 mL/minute/1.73 m2 within 1 year post-HT), post-HT end-stage kidney disease (ESKD), and significant renal function improvement (%ΔeGFR > 15%) at 1 year post-HT were analyzed. Early post-HT CKD and post-HT ESKD developed in 61 (33.9%) and 8 (4.4%) of 180 patients, respectively. Old age was only independently associated with early post-HT CKD and preexisting CKD tended to be associated with early post-HT CKD. Old age and preexisting CKD were independently associated with post-HT ESKD. Low pre-HT eGFR and preoperative renal replacement therapy were not associated with early post-HT CKD or post-HT ESKD. Young age, low pre-HT eGFR, and high %ΔeGFR 1 month post-HT were independently associated with significant renal function improvement. Preoperative renal function, including preoperative RRT, was not associated with post-HT mortality. In conclusion, preexisting CKD may impact renal outcomes after HT, but preoperative severe renal dysfunction, even that severe enough to require RRT, may not be a contraindication for HT alone. Our data suggest the necessity of early HT in end-stage heart failure patients with CRS and the importance of careful management during the early postoperative period.

Radiofrequency vs. Cryoballoon vs. Thoracoscopic Surgical Ablation for Atrial Fibrillation: A Single-Center Experience.

Background and Objectives: Cryoballoon ablation (CBA) and totally thoracoscopic surgical ablation (TTA) have emerged as alternatives to radiofrequency catheter ablation (RFCA) for atrial fibrillation. In this study, we describe our experience comparing patient characteristics and outcomes of RFCA, CBA, and TTA. Materials and Methods: We retrospectively analyzed data from patients who underwent RFCA, CBA, or TTA. Both atrial fibrillation (AF)- and atrial tachyarrhythmia (ATa)-free survival rates were compared using time to recurrence after a 3-month blanking period (defined by a duration of more than 30 s). All patients were regularly followed using 12-lead ECGs or Holter ECG monitoring. Results: Of 354 patients in this study, 125 underwent RFCA, 97 underwent CBA and 131 underwent TTA. The TTA group had more patients with persistent AF, a larger LA diameter, and a history of stroke. The CBA group showed the shortest procedure time (p < 0.001). The CBA group showed significantly lower AF-free survival at 12 months than the RFCA and TTA groups (RFCA 84%, CBA 74% and TTA 85%, p = 0.071; p = 0.859 for TTA vs. RFCA, p = 0.038 for RFCA vs. CBA and p = 0.046 for TTA vs. CBA). There were no significant differences in ATa-free survival among the three groups (p = 0.270). There were no procedure-related adverse events in the RFCA group, but some complications occurred in the CBA group and the TTA group (6% and 5%, respectively). Conclusions: RFCA and CBA are effective and safe as first-line treatments for paroxysmal and persistent AF. In some high-risk stroke patients, TTA may be a viable option. It is important to consider patient characteristics when selecting an ablation method for AF.

Comparison of three neutralizing broths for environmental sampling of low levels of Listeria monocytogenes desiccated on stainless steel surfaces and exposed to quaternary ammonium compounds.

BACKGROUND: An effective environmental sampling method involves the use of a transport/neutralizing broth with the ability to neutralize sanitizer residues that are collected during sampling and to maintain viability of stressed Listeria monocytogenes (Lm) cells. RESULTS: We applied Lm onto stainless steel surfaces and then subjected Lm to desiccation stress for 16-18 h at room temperature (RT, 21-24 °C). This was followed by the subsequent application of Whisper™ V, a quaternary ammonium compound (QAC)-based sanitizer, diluted to 400 ppm and 8000 ppm of active quat, for 6 h. We then sampled Lm with sponges pre-moistened in three transport broths, Dey/Engley (D/E) broth, Letheen broth and HiCap™ broth, to generate environmental samples that contained sanitizer residues and low levels of stressed Lm, which were subsequently analyzed by an enrichment-based method. This scheme conformed with validation guidelines of AOAC International by using 20 environmental test portions per broth that contained low levels of Lm such that not all test portions were positive (i.e., fractional positive). We showed that D/E broth, Letheen broth and HiCap™ broth performed similarly when no quat or 400 ppm of quat was applied to the Lm contaminating stainless steel surfaces. However, when 8000 ppm of quat was applied, Letheen broth did not effectively neutralize the QAC in the samples. These comparisons were performed on samples stored under three conditions after collection to replicate scenarios of sample transport, RT for 2 h, 4 °C for 24 h and 4 °C for 72 h. Comparisons under the three different scenarios generally reached the same conclusions. In addition, we further demonstrated that storing Letheen and HiCap™ broths at RT for two months before sampling did not reduce their capacity to neutralize sanitizers. CONCLUSIONS: We developed a scheme to evaluate the ability of transport broths to neutralize QAC sanitizers. The three transport broths performed similarly with a commonly used concentration of quat, but Letheen broth could not effectively neutralize a very high concentration of QAC. The performance of transport broths was not significantly affected under the assessed pre-sampling and post-sampling storage conditions.

Effects of chronic intermittent hypoxia caused by obstructive sleep apnea on lipopolysaccharide-induced acute lung injury.

AIM OF THE STUDY: Obstructive sleep apnea (OSA) is a common disease associated with significant morbidity and mortality. Sleep quality is an important issue; some patients with acute lung injury (ALI) have underlying OSA. However, the potential influences of OSA on ALI have not been reported until now. In this study, we evaluated the impact of preceding intermittent hypoxia (IH), a typical characteristic of OSA, on lipopolysaccharide (LPS)-induced ALI in a mouse model. METHODS: C57BL/6J mice were randomly divided into four groups: room air-control (RA-CTL), intermittent hypoxia-control (IH-CTL), room air-lipopolysaccharide (RA-LPS), and intermittent hypoxia-lipopolysaccharide (IH-LPS) groups. The mice were exposed to RA or IH (20 cycles/h, FiO2 nadir 7 ± 0.5%, 8 h/day) for 30 days. The LPS groups received intratracheal LPS on day 28. RESULTS: The IH-LPS group tended to exhibit more severe inflammation, fibrosis, and oxidative stress compared to the other groups, including the RA-LPS group. Total cell, neutrophil, and eosinophil counts in bronchoalveolar lavage fluid increased significantly in the IH-LPS group compared to the RA-LPS group. Compared to the RA-LPS group, the hydroxyproline level increased significantly in the IH-LPS group. In addition, the IH-LPS group exhibited significantly more terminal deoxynucleotidyl transferase dUTP nick end labeled-positive cells compared to the RA-LPS group. CONCLUSIONS: We found that prior IH may negatively impact LPS-induced ALI in a mouse model. This result suggests that ALI in patients with OSA may be more of a concern. Further research into the mechanisms underlying the effects of IH on ALI is needed.

Effectiveness and safety of high-power and short-duration ablation for cavotricuspid isthmus ablation in atrial flutter.

BACKGROUND: Despite many studies on new tools and strategies for cavotricuspid isthmus (CTI) ablation, there is an unmet need to improve the CTI ablation procedure. Recently, high-power short-duration (HPSD) ablation has been widely used for pulmonary vein (PV) isolation in atrial fibrillation. We evaluated the effectiveness and safety of HPSD for CTI ablation in atrial flutter (AFL). METHODS: Eighty-four patients who underwent CTI ablation with or without simultaneous PV isolation between January 2018 and February 2019 were enrolled in this prospective cohort study. We compared procedural characteristics, periprocedural complications, and recurrence of atrial tachyarrhythmia (ATa) between the HPSD group (50 W for 15 s) and conventional group (30 W for 60 s). RESULTS: A total of 84 patients were divided into the HPSD (n = 42) and conventional (n = 42) groups. Bidirectional CTI block was achieved in all patients and 95% achieved bidirectional block after the first-line ablation in both groups. Although there was no difference in the total number of ablation lines between the two groups (1.17 ± 0.7 vs 1.38 ± 0.8, P = .067), HPSD ablation significantly reduced total ablation time compared to the conventional group (236.0 ± 85.6 vs 534.2 ± 235.2 s, P < .001). One pericardial tamponade was reported in the HPSD group. During the mean follow-up of 9.3 ± 4.8 months, CTI-dependent AFL recurrence occurred in one patient in the HPSD group. Recurrence of ATa developed in 14 patients with no significant difference between the groups. CONCLUSION: Our study demonstrates that HPSD CTI ablation is safe and can shorten procedure time.

Remote Management of Poststroke Patients With a Smartphone-Based Management System Integrated in Clinical Care: Prospective, Nonrandomized, Interventional Study.

BACKGROUND: Advances in mobile health (mHealth) have enabled systematic and continuous management of patients with chronic diseases. OBJECTIVE: We developed a smartphone-based mHealth system and aimed to evaluate its effects on health behavior management and risk factor control in stroke patients. METHODS: With a multifaceted stroke aftercare management system that included exercise, medication, and educational materials, we performed a 12-week single-arm intervention among eligible poststroke patients in the stroke clinic from September to December 2016. The intervention consisted of (1) regular blood pressure (BP), blood glucose, and physical activity measurements; (2) stroke education; (3) an exercise program; (4) a medication program; and (5) feedback on reviewing of records by clinicians. Clinical assessments consisted of the stroke awareness score, Beck Depression Inventory-II (BDI), EuroQol-5 Dimensions (EQ-5D), and BP at visit 1 (baseline), visit 2 (4 weeks), and visit 3 (12 weeks). Temporal differences in the parameters over 12 weeks were investigated with repeated-measures analysis of variance. Changes in medication adherence at visit 1-2 (from visit 1 to visit 2) and visit 2-3 (from visit 2 to visit 3) were compared. System satisfaction was evaluated with a self-questionnaire using a 5-point Likert scale at visit 3. RESULTS: The study was approved by the Institutional Review Board in September 2016, and participants were enrolled from September to December 2016. Among the 110 patients enrolled for the study, 99 were included in our analyses. The mean stroke awareness score (baseline: 59.6 [SD 18.1]; 4 weeks: 67.6 [SD 16.0], P<.001; 12 weeks: 74.7 [SD 14.0], P<.001) and BDI score (baseline: 12.7 [SD 10.1]; 4 weeks: 11.2 [SD 10.2], P=.01; 12 weeks: 10.7 [SD 10.2], P<.001) showed gradual improvement; however, no significant differences were found in the mean EQ-5D score (baseline: 0.66 [SD 0.33]; 4 weeks: 0.69 [SD 0.34], P=.01; 12 weeks: 0.69 [SD 0.34], P<.001). Twenty-six patients who had uncontrolled BP at baseline had -13.92 mmHg (P=.001) and -6.19 mmHg (P<.001) reductions on average in systolic and diastolic BP, respectively, without any antihypertensive medication change. Medication compliance was better at visit 2-3 (60.9% [SD 37.2%]) than at visit 1-2 (47.8% [SD 38.7%], P<.001). CONCLUSIONS: Awareness of stroke, depression, and BP was enhanced when using the smartphone-based mHealth system. Emerging mHealth techniques have potential as new nonpharmacological secondary prevention methods because of their ubiquitous access, near real-time responsiveness, and comparatively lower cost.

Treatment response to intravitreal bevacizumab in small pigmented choroidal lesions with subretinal fluid.

BACKGROUND: To describe the effects of intravitreal bevacizumab injection (IVB) and/or transpupillary thermotherapy (TTT) in the treatment of small pigmented choroidal lesions with subfoveal fluid (SFF), and to investigate prognostic value of the therapeutic response in future tumor growth. METHODS: Retrospective chart review of 19 patients, who were diagnosed with choroidal neovascularization (CNV)-free small pigmented choroidal lesions and treated with IVB and/or TTT, was performed. RESULTS: Complete resolution of SFF was achieved in two eyes (2/14; 14.3%) after IVB, and in three eyes (3/4; 75%) after TTT. Best corrected visual acuity was improved in two eyes (2/9; 22%) after IVB, and in three eyes (3/4; 75%) after TTT. Among five patients who underwent TTT after IVB, four patients (4/5; 80%) demonstrated additional advantage. All IVBs could not reduce tumor sizes. Rather, tumor growth was detected in seven out of 14 eyes (7/14; 50%) that underwent IVB. None of the patients who underwent TTT showed tumor growth. The lack of treatment response to IVB was suggestive of malignancy, as most small pigmented lesions that had no response to IVB showed tumor growth (86%, p = 0.010). CONCLUSION: IVB was not effective in reducing tumor size and subfoveal fluid in small pigmented choroidal lesions. Therapeutic response to IVB can be used as an indicator between melanoma and nevus in small pigmented choroidal lesion.

Prognostic Value of Tumor-Infiltrating Lymphocyte Density Assessed Using a Standardized Method Based on Molecular Subtypes and Adjuvant Chemotherapy in Invasive Breast Cancer.

BACKGROUND: This study investigated the prognostic value of tumor-infiltrating lymphocyte (TIL) density as determined by molecular subtype and receipt of adjuvant chemotherapy in invasive breast cancer (IBC). METHODS: Stromal TIL densities were evaluated in 1489 IBC samples using recommendations proposed by the International TILs Working Group. Cases were allocated to high- and low-TIL density groups using a cutoff of 10%. RESULTS: Of the 1489 IBC patients, 427 (28.7%) were assigned to the high-TIL group and 1062 (71.3%) to the low-TIL group. High TIL density was found to be significantly associated with large tumor size (p = 0.001), high histologic grade (p < 0.001), and high Ki-67 labeling index (p < 0.001). Triple-negative and human epidermal growth factor receptor 2 (HER2)-positive subtypes had significantly higher TIL densities than luminal A or B (HER2-negative) subtypes (p < 0.001). High TIL density was significantly associated with prolonged disease-free survival (DFS) by univariate (p < 0.001) and multivariate (p < 0.001) analyses. In the low-TIL-density group, the patients who did not receive adjuvant chemotherapy showed better DFS (p < 0.001), but no such survival difference was observed in the high-TIL group (p = 0.222). For the patients who received adjuvant anthracycline, high-TIL density was found to be an independent prognostic factor of favorable DFS in the luminal B (HER2-negative; p = 0.003), HER2-positive (p = 0.019), and triple-negative (p = 0.017) subtypes. CONCLUSION: Measurements of TIL density in routine clinical practice could give useful prognostic information for the triple-negative, HER2-positive, and luminal B (HER2-negative) IBC subtypes, especially for patients administered adjuvant anthracycline.

Interleukin-13 receptor alpha 2 expression in tumor cells is associated with reduced disease-free survival in patients with luminal subtype invasive breast cancer.

Interleukin-13 receptor alpha 2 is one of the subunits of transmembrane receptor for interleukin-13. The aim of this study was to investigate the prognostic value of interleukin-13 receptor alpha 2 expression in invasive breast cancer. Interleukin-13 receptor alpha 2 expressions were assessed by immunohistochemistry in tissue microarrays of 1283 invasive breast cancer samples, and associations between these expressions and clinicopathological variables and clinical outcomes were investigated. Interleukin-13 receptor alpha 2 expression was observed in 138 (10.8%) samples, and found to be associated with positive estrogen receptor (p < 0.001) and progesterone receptor (p < 0.001) and with the luminal subtype (p < 0.001). No significant association was found between interleukin-13 receptor alpha 2 expression and other clinicopathological variables including age, tumor size, lymph node metastasis, histologic types, histologic grade, HER2 status, Ki-67 labeling index, or tumor-infiltrating lymphocytes levels. Patients with interleukin-13 receptor alpha 2 expression tended to have poorer disease-free survival, but the difference was not statistically significant (p = 0.069). Subgroup analysis showed luminal breast cancer patients positive for interleukin-13 receptor alpha 2 expression had significantly poorer disease-free survival (p = 0.018) than luminal breast cancer patients negative for interleukin-13 receptor alpha 2 expression. However, no association between interleukin-13 receptor alpha 2 expression and clinical outcome was observed in HER2-positive and triple-negative subgroups (p = 0.574 and p = 0.936, respectively). Multivariate analysis showed interleukin-13 receptor alpha 2 expression was an independent poor prognostic factor for luminal breast cancer (p = 0.03). This study shows interleukin-13 receptor alpha 2 expression could be a useful prognostic marker for selecting patients with luminal breast cancer likely to follow a clinically aggressive course despite receiving systemic therapy.

Correction to: Regulation of SIRT1/AMPK axis is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in hepatocellular carcinoma cells.

This article contains an error.

Regulation of SIRT1/AMPK axis is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with high mortality worldwide. Here the underlying antitumor mechanism of gallotannin was elucidated in HCC cells. Gallotannin suppressed viability and colony formation, increased subG1 portion and also induced senescence via upregulation of p21, G0/G1 arrest and higher SA-ß-gal activity in HepG2 and SK-Hep1 cells. However, pan-caspase inhibitor Z-VAD-FMK reversed the ability of gallotannin to activate caspase 3 at 48 h after treatment in two HCC cells. Of note, gallotannin also induced autophagic features by increasing LC3 punctae, LC3B-II conversion, autophagic vacuoles and decreasing the expression of Beclin1 in two HCC cells. Furthermore, autophagy flux assay using GFP-mRFP-LC3 plasmid revealed increased yellowish color and late autophagy inhibitor CQ or NH4Cl enhanced cytotoxicity, LC3B-II conversion, and LC3 punctae in gallotannin-treated HepG2 and SK-Hep1 cells compared to early autophagy inhibitor 3-MA or wortmannin. Interestingly, gallotannin attenuated the expression of SIRT1 and mTOR and activated phosphorylation of AMPK in two HCC cells. Furthermore, AMPK activator AICAR significantly enhanced SA-ß-gal activity and antiproliferation induced by gallotannin, while AMPK inhibitor compound C did not in two HCC cells. Consistently, LC3B-II conversion by gallotannin was not shown in AMPKα1 -/- MEF cells compared to WT AMPK +/+ MEF cells. Consistently, gallotannin reduced in vivo growth of HepG2 cells implanted in NCr nude mice along with decreased expression of PCNA and SIRT1 and increased AMPKα1 and TUNEL. Overall, these findings highlight evidence that regulation of SIRT1/AMPK is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in HCC cells.