UBX-390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer.

The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic prostate cancer. The high global mortality burden of prostate cancer, despite medical treatments such as androgen deprivation or AR antagonist therapy, highlights the need to explore alternative strategies. One strategy involves the use of heterobifunctional degraders, also known as proteolysis-targeting chimeras, which are novel small-molecule therapeutics that inhibit amplified or mutated targets. Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.

EW-7197, transforming growth factor ß inhibitor, combined with irreversible electroporation for improving skin wound in a rat excisional model.

To evaluate the safety and efficacy of combining EW-7197 with irreversible electroporation (IRE) for improving wound healing, 16 male Sprague-Dawley rats were randomly divided into four groups of four rats each after dorsal excisional wound induction: sham control group; oral administration of EW-7197 for 7 days group; one-time application of IRE group; and one-time application of IRE followed by oral administration of EW-7197 for 7 days group. Measurement of wound closure rate, laser Doppler scanning, histological staining (hematoxylin and eosin and Masson's trichrome), and immunohistochemical analyses (Ki-67 and α-SMA) were performed to evaluate the efficacy. Fifteen of 16 rats survived throughout the study. Statistically significant differences in wound closure rates were observed between the combination therapy group and the other three groups (all P < 0.05). The degrees of inflammation, α-SMA, and Ki-67 were reduced in the EW-7197 and IRE monotherapy groups; however, not statistically significant. The fibrosis score exhibited significant reduction in all three treatment groups, with the most prominent being in the combination therapy group. This study concludes that oral administration of EW-7197 combined with IRE demonstrated effectiveness in improving skin wound in a rat excisional model and may serve as a potential alternative for promoting healing outcomes.

Impact of Incorporating Future Mandatory Price Reductions with Generic Drug Entry on the Cost-Effectiveness of New Drugs: A Policy Simulation Study of Dupilumab in Atopic Dermatitis Treatment.

The introduction of high-cost medications often poses challenges in achieving cost-effectiveness for drug insurance coverage. Incorporating future price reductions for these medications may enhance their cost-effectiveness. We examined the influence of future cost reductions mandated by the national insurer's equal pricing for equivalent drugs (EPED) policy on the cost-effectiveness of dupilumab, a biologic drug for moderate to severe atopic dermatitis in the Korean healthcare system. We conducted a policy simulation study using semi-Markovian cost utility analysis of dupilumab in combination with supportive care (SC) versus SC alone, with and without the EPED policy adjustment. The EPED would lower dupilumab's price to 70% following the entry of a biosimilar drug in 10.3 years. Scenario analyses quantified the impact of changing time to the EPED, chemical versus biological designation, response criteria, discount rates, and time horizons on the Incremental Cost-Effectiveness Ratio (ICER) and acceptability with and without EPED adjustment. The EPED adjustment of dupilumab's future price significantly improved its cost-effectiveness, with a 9.7% decrease in ICER and a substantial 14.6% increase in acceptability. Assuming EPED in 5 years, the ICER fell below the predefined willingness-to-pay threshold. If dupilumab were a chemical drug, EPED adjustment demonstrated a 19.1% increase in acceptability. Incorporating future cost reductions via the EPED system in economic evaluations is crucial, especially for drugs facing imminent generic entry. This study underscores the importance of EPED adjustment in the cost-effectiveness analysis of innovative medications, especially for those nearing willingness-to-pay thresholds.

Correction: Three-Day Monitoring of Adhesive Single-Lead Electrocardiogram Patch for Premature Ventricular Complex: Prospective Study for Diagnosis Validation and Evaluation of Burden Fluctuation.

[This corrects the article DOI: 10.2196/46098.].

Use of bio-information and communication technology shortens time to peak at a lower height of the epidemic curve: An alternative to flattening for countries with early COVID-19 outbreaks.

INTRODUCTION: The traditional approach to epidemic control has been to slow down the rate of infection while building up healthcare capacity, resulting in a flattened epidemic curve. Advancements in bio-information-communication technology (BICT) have enabled the preemptive isolation of infected cases through efficient testing and contact tracing. This study aimed to conceptualize the BICT-enabled epidemic control (BICTEC) and to document its relationships with epidemic curve shaping and epidemic mitigation performance. METHODS: Daily COVID-19 incidences were collected from outbreak to Aug. 12, 2020, for nine countries reporting the first outbreak on or before Feb. 1, 2020. Key epidemic curve determinants-peak height (PH), time to peak (TTP), and area under the curve (AUC)-were estimated for each country, and their relationships were analyzed to test if epidemic curves peak quickly at a shorter height. CFR (Case Fatality Rate) and CI (Cumulative Incidence) were compared across the countries to identify relationships between epidemic curve shapes and epidemic mitigation performance. RESULTS: China and South Korea had the quickest TTPs (40.70 and 45.37 days since outbreak, respectively) and the shortest PHs (2.95 and 4.65 cases per day, respectively). Sweden, known for its laissez-faire approach, had the longest TTP (120.36) and the highest PH (279.74). Quicker TTPs were correlated with shorter PHs (ρ = 0·896, p = 0·0026) and lower AUCs (0.790, p = 0.0028), indicating that epidemic curves do not follow a flattened trajectory. During the study period, countries with quicker TTPs tended to have lower CIs (ρ = .855, P = .006) and CFRs (ρ = 0.684, P = .061). For example, South Korea, with the second-quickest TTP, reported the second lowest CI and the lowest CFR. CONCLUSIONS: Countries that experienced early COVID-19 outbreaks demonstrated the epidemic curves that quickly peak at a shorter height, indicating a departure from the traditional flattened trajectory. South Korea's BICTEC was found to be at least as effective as most lockdowns in reducing CI and CFR.

Novel self-expandable stent-based endobiliary radiofrequency ablation for unresectable malignant biliary obstruction.

BACKGROUND AND AIMS: Endobiliary radiofrequency ablation (RFA) is an emerging endoscopic palliative adjunctive therapy used for the local treatment of unresectable malignant biliary obstruction (MBO). However, irregular ablation ranges caused by insufficient electrode-to-bile duct contact pose a significant obstacle. The aim was to investigate the feasibility of a self-expandable stent (SES)-based electrode with a customized RFA generator in the porcine liver and common bile duct (CBD). METHODS: A SES-RFA system with polarity-switching was developed to perform endobiliary RFA. The ablation ranges of 20 ablation protocols were evaluated to validate the feasibility of the newly developed RFA system in the porcine liver. Nine of the 20 ablation protocols were selected for evaluation in the porcine CBD with cholangiography, endoscopy, and histological and immunohistochemical analysis. RESULTS: The SES-RFA system with polarity-switching was successfully constructed and demonstrated high accuracy and reproducibility. The ablation area was clearly identified between the two SESs. The ablation ranges and degree of mucosal damage including TUNEL- and HSP70-positive depositions increased proportionally with ablation protocols in the porcine liver and CBD (all P < .05). Ablation length and depth linearly increased with ablation protocols from 8.74 ± 0.25 to 31.25 ± 0.67 mm and 1.61 ± 0.09 to 11.94 ± 0.44 mm, respectively. CONCLUSIONS: The SES-RFA system with polarity-switching between electrodes provided an even circumferential area of ablation and enhanced ablation depth between the electrodes. This novel endobiliary RFA system is a promising modality for local ablation in patients with unresectable MBO.

Sirolimus-coated Eustachian tube balloon dilatation for treating Eustachian tube dysfunction in a rat model.

Eustachian tube balloon dilatation (ETBD) has shown promising results in the treatment of ET dysfunction (ETD); however, recurrent symptoms after ETBD frequently occur in patients with refractory ETD. The excessive pressure of balloon catheter during ETBD may induce the tissue hyperplasia and fibrotic changes around the injured mucosa. Sirolimus (SRL), an antiproliferative agent, inhibits tissue proliferation. An SRL-coated balloon catheter was fabricated using an ultrasonic spray coating technique with a coating solution composed of SRL, purified shellac, and vitamin E. This study aimed to investigate effectiveness of ETBD with a SRL-coated balloon catheter to prevent tissue proliferation in the rat ET after ETBD. In 21 Sprague-Dawley rats, the left ET was randomly divided into the control (drug-free ETBD; n = 9) and the SRL (n = 9) groups. All rats were sacrificed for histological examination immediately after and at 1 and 4 weeks after ETBD. Three rats were used to represent the normal ET. The SRL-coated ETBD significantly suppressed tissue proliferation caused by mechanical injuries compared with the control group. ETBD with SRL-coated balloon catheter was effective and safe to maintain ET luminal patency without tissue proliferation at the site of mechanical injuries for 4 weeks in a rat ET model.

Antifungal Activity-Guided Analysis of Actinostemma lobatum Extracts through Serial Sub-fractions.

Plants are treasure trove of novel compounds that have potential for antifungal chemicals and drugs. In our previous study, we had screened plant extracts obtained from more than eight hundred plant materials collected in Korea, and found that butanol fraction of the Actinostemma lobatum were most potent in suppressing growth of diverse fungal pathogens of plants. Here in this study, we describe further analysis of the butanol fraction, and summarize the results of subsequent antifungal activity test for the sub-fractions against a selected set of plant pathogenic fungi. This line of analyses allowed us to identify the sub-fractions that could account for a significant proportion of observed antifungal activity of initial butanol fraction from A. lobatum. Further analysis of these sub-fractions and determination of structure would provide the shortlist for novel compounds that can be a lead to new agrochemicals.

Effects of bipolar irreversible electroporation with different pulse durations in a prostate cancer mouse model.

Irreversible electroporation (IRE) is a non-thermal ablation technique for local tumor treatment known to be influenced by pulse duration and voltage settings, affecting its efficacy. This study aims to investigate the effects of bipolar IRE with different pulse durations in a prostate cancer mouse model. The therapeutic effectiveness was assessed with in vitro cell experiments, in vivo tumor volume changes with magnetic resonance imaging, and gross and histological analysis in a mouse model. The tumor volume continuously decreased over time in all IRE-treated groups. The tumor volume changes, necroptosis (%), necrosis (%), the degree of TUNEL-positive cell expression, and ROS1-positive cell (%) in the long pulse duration-treated groups (300 µs) were significantly increased compared to the short pulse duration-treated groups (100 µs) (all p < 0.001). The bipolar IRE with a relatively long pulse duration at the same voltage significantly increased IRE-induced cell death in a prostate cancer mouse model.

Effects of L-Type Voltage-Gated Calcium Channel (LTCC) Inhibition on Hippocampal Neuronal Death after Pilocarpine-Induced Seizure.

Epilepsy, marked by abnormal and excessive brain neuronal activity, is linked to the activation of L-type voltage-gated calcium channels (LTCCs) in neuronal membranes. LTCCs facilitate the entry of calcium (Ca2+) and other metal ions, such as zinc (Zn2+) and magnesium (Mg2+), into the cytosol. This Ca2+ influx at the presynaptic terminal triggers the release of Zn2+ and glutamate to the postsynaptic terminal. Zn2+ is then transported to the postsynaptic neuron via LTCCs. The resulting Zn2+ accumulation in neurons significantly increases the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, contributing to reactive oxygen species (ROS) generation and neuronal death. Amlodipine (AML), typically used for hypertension and coronary artery disease, works by inhibiting LTCCs. We explored whether AML could mitigate Zn2+ translocation and accumulation in neurons, potentially offering protection against seizure-induced hippocampal neuronal death. We tested this by establishing a rat epilepsy model with pilocarpine and administering AML (10 mg/kg, orally, daily for 7 days) post-epilepsy onset. We assessed cognitive function through behavioral tests and conducted histological analyses for Zn2+ accumulation, oxidative stress, and neuronal death. Our findings show that AML's LTCC inhibition decreased excessive Zn2+ accumulation, reactive oxygen species (ROS) production, and hippocampal neuronal death following seizures. These results suggest amlodipine's potential as a therapeutic agent in seizure management and mitigating seizures' detrimental effects.

A phosphodiesterase 4 (PDE4) inhibitor, amlexanox, reduces neuroinflammation and neuronal death after pilocarpine-induced seizure.

Epilepsy, a complex neurological disorder, is characterized by recurrent seizures caused by aberrant electrical activity in the brain. Central to this study is the role of lysosomal dysfunction in epilepsy, which can lead to the accumulation of toxic substrates and impaired autophagy in neurons. Our focus is on phosphodiesterase-4 (PDE4), an enzyme that plays a crucial role in regulating intracellular cyclic adenosine monophosphate (cAMP) levels by converting it into adenosine monophosphate (AMP). In pathological states, including epilepsy, increased PDE4 activity contributes to a decrease in cAMP levels, which may exacerbate neuroinflammatory responses. We hypothesized that amlexanox, an anti-inflammatory drug and non-selective PDE4 inhibitor, could offer neuroprotection by addressing lysosomal dysfunction and mitigating neuroinflammation, ultimately preventing neuronal death in epileptic conditions. Our research utilized a pilocarpine-induced epilepsy animal model to investigate amlexanox's potential benefits. Administered intraperitoneally at a dose of 100 â€‹mg/kg daily following the onset of a seizure, we monitored its effects on lysosomal function, inflammation, neuronal death, and cognitive performance in the brain. Tissue samples from various brain regions were collected at predetermined intervals for a comprehensive analysis. The study's results were significant. Amlexanox effectively improved lysosomal function, which we attribute to the modulation of zinc's influx into the lysosomes, subsequently enhancing autophagic processes and decreasing the release of inflammatory factors. Notably, this led to the attenuation of neuronal death in the hippocampal region. Additionally, cognitive function, assessed through the modified neurological severity score (mNSS) and the Barnes maze test, showed substantial improvements after treatment with amlexanox. These promising outcomes indicate that amlexanox has potential as a therapeutic agent in the treatment of epilepsy and related brain disorders. Its ability to combat lysosomal dysfunction and neuroinflammation positions it as a potential neuroprotective intervention. While these findings are encouraging, further research and clinical trials are essential to fully explore and validate the therapeutic efficacy of amlexanox in epilepsy management.

Age-stratified analysis of temporomandibular joint osteoarthritis using cone-beam computed tomography.

Purpose: This study aimed to evaluate age-stratified radiographic features in temporomandibular joint osteoarthritis using cone-beam computed tomography. Materials and Methods: In total, 210 joints from 183 patients (144 females, 39 males, ranging from 12 to 88 years old with a mean age of 44.75±19.97 years) diagnosed with temporomandibular joint osteoarthritis were stratified by age. Mandibular condyle position and bony changes (flattening, erosion, osteophytes, subchondral sclerosis, and subchondral pseudocysts in both the condyle and articular eminence, thickening of the glenoid fossa, joint space narrowing, and joint loose bodies) were evaluated through cone-beam computed tomography. After adjusting for sex, the association between age groups and radiographic findings was analyzed using both a multiple regression model and a multinomial logistic regression model (α=0.05). Results: The prevalence of joint space narrowing and protruded condyle position in the glenoid fossa significantly increased with age (P<0.05). The risks of bony changes, including osteophytes and subchondral pseudocysts in the condyle; flattening, erosion, osteophyte, and subchondral sclerosis in the articular eminence; joint loose bodies; and thickening of the glenoid fossa, also significantly rose with increasing age (P<0.05). The number of radiographic findings increased with age; in particular, the increase was more pronounced in the temporal bone than in the mandibular condyle (P<0.05). Conclusion: Increasing age was associated with a higher frequency and greater diversity of bony changes in the temporal bone, as well as a protruded condyle position in the glenoid fossa, resulting in noticeable joint space narrowing in temporomandibular joint osteoarthritis.

Three-Day Monitoring of Adhesive Single-Lead Electrocardiogram Patch for Premature Ventricular Complex: Prospective Study for Diagnosis Validation and Evaluation of Burden Fluctuation.

BACKGROUND: Wearable electrocardiogram (ECG) monitoring devices are used worldwide. However, data on the diagnostic yield of an adhesive single-lead ECG patch (SEP) to detect premature ventricular complex (PVC) and the optimal duration of wearing an SEP for PVC burden assessment are limited. OBJECTIVE: We aimed to validate the diagnostic yield of an SEP (mobiCARE MC-100, Seers Technology) for PVC detection and evaluate the PVC burden variation recorded by the SEP over a 3-day monitoring period. METHODS: This is a prospective study of patients with documented PVC on a 12-lead ECG. Patients underwent simultaneous ECG monitoring with the 24-hour Holter monitor and SEP on the first day. On the subsequent second and third days, ECG monitoring was continued using only SEP, and a 3-day extended monitoring was completed. The diagnostic yield of SEP for PVC detection was evaluated by comparison with the results obtained on the first day of Holter monitoring. The PVC burden monitored by SEP for 3 days was used to assess the daily and 6-hour PVC burden variations. The number of patients additionally identified to reach PVC thresholds of 10%, 15%, and 20% during the 3-day extended monitoring by SEP and the clinical factors associated with the higher PVC burden variations were explored. RESULTS: The recruited data of 134 monitored patients (mean age, 54.6 years; males, 45/134, 33.6%) were analyzed. The median daily PVC burden of these patients was 2.4% (IQR 0.2%-10.9%), as measured by the Holter monitor, and 3.3% (IQR 0.3%-11.7%), as measured in the 3-day monitoring by SEP. The daily PVC burden detected on the first day of SEP was in agreement with that of the Holter monitor: the mean difference was -0.07%, with 95% limits of agreement of -1.44% to 1.30%. A higher PVC burden on the first day was correlated with a higher daily (R2=0.34) and 6-hour burden variation (R2=0.48). Three-day monitoring by SEP identified 29% (12/42), 18% (10/56), and 7% (4/60) more patients reaching 10%, 15%, and 20% of daily PVC burden, respectively. Younger age was additionally associated with the identification of clinically significant PVC burden during the extended monitoring period (P=.02). CONCLUSIONS: We found that the mobiCARE MC-100 SEP accurately detects PVC with comparable diagnostic yield to the 24-hour Holter monitor. Performing 3-day PVC monitoring with SEP, especially among younger patients, may offer a pragmatic alternative for identifying more individuals exceeding the clinically significant PVC burden threshold.

TonEBP/NFAT5 expression is associated with cisplatin resistance and migration in macrophage-induced A549 cells.

BACKGROUND: Macrophages promote angiogenesis, metastasis, and drug resistance in several cancers. Similarly, TonEBP/NFAT5 induces metastasis in renal carcinoma and colon cancer cells. However, the role of this transcription factor and that of macrophages in lung cancer cells remains unclear. Therefore, this study investigated the effects of macrophages and TonEBP/NFAT5 expression on cisplatin resistance and migration in A549 lung adenocarcinoma cells. RESULTS: A549 cells were cultured alone or indirectly co-cultured with THP-1-derived macrophages using a transwell culture chamber. Cisplatin-induced cell death was markedly decreased and migration increased in co-cultured A549 cells. Macrophage-conditioned media (CM) showed a similar effect on drug resistance and migration. Cisplatin-induced apoptosis, DNA fragmentation, and cleaved apoptotic proteins PARP and caspase-3 were markedly reduced in macrophage CM-induced A549 cells. Here, ERK, p38, JNK, and NF-κB activities were increased by macrophage CM. Furthermore, the proteins involved in cisplatin resistance and cancer cell migration were identified using specific inhibitors of each protein. ERK and NF-κB inhibition considerably reduced cisplatin resistance. The increase in macrophage CM-induced migration was partially reduced by treatment with ERK, JNK, and NF-κB inhibitors. TonEBP/NFAT5 expression was increased by macrophages, resulting in increased cisplatin resistance, cell migration, and invasion. Moreover, RNAi-mediated knockdown of TonEBP/NFAT5 reduced cisplatin resistance, migration, and invasion in macrophage CM-induced A549 cells. CONCLUSIONS: These findings demonstrate that paracrine factors secreted from macrophages can change A549 cells, resulting in the induction of drug resistance against cisplatin and migration. In addition, the TonEBP/NFAT5 ratio, increased by macrophages, is an important regulator of the malignant transformation of cells.

Nobiletin enhances mitochondrial function by regulating SIRT1/PGC-1α signaling in porcine oocytes during in vitro maturation.

Nobiletin is a natural flavonoid found in citrus fruits with beneficial effects, including anti-inflammatory, anti-cancer and anti-oxidation effects. The aim of this study was to investigate whether nobiletin improves mitochondrial function in porcine oocytes and examine the underlying mechanism. Oocytes enclosed by cumulus cells were cultured in TCM-199 for 44 h with 0.1% dimethyl sulfoxide (control), or supplemented with 5, 10, 25, and 50 µM of nobiletin (Nob5, Nob10, Nob25, and Nob50, respectively). Oocyte maturation rate was significantly enhanced in Nob10 (70.26 ± 0.45%) compared to the other groups (control: 60.12 ± 0.47%; Nob5: 59.44 ± 1.63%; Nob25: 63.15 ± 1.38%; Nob50: 46.57 ± 1.19%). The addition of nobiletin reduced the levels of reactive oxygen species and increased glutathione levels. Moreover, Nob10 promoted mitochondrial biogenesis by upregulating the protein levels of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α). This resulted in an increase in the number of active mitochondria, mitochondrial DNA copy number, mitochondrial membrane potential, and ATP production, thereby enhancing mitochondrial function. The protein level of p53 decreased, followed by the phosphorylation of B-cell lymphoma 2, suggesting a reduction in mitochondria-mediated apoptosis in the Nob10 group. Additionally, the release of cytochrome c from the mitochondria was significantly diminished along with a decrease in the protein expression of caspase 3. Thus, nobiletin has a great potential to promote the in vitro maturation of porcine oocytes by suppressing oxidative stress and promoting mitochondrial function through the upregulation of the SIRT1/PGC-1α signaling pathway.

Interruption of p38MAPK-MSK1-CREB-MITF-M pathway to prevent hyperpigmentation in the skin.

Background: Melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH), is exclusively present in melanocytes where α-MSH/MC1R stimulate melanin pigmentation through microphthalmia-associated transcription factor M (MITF-M). Toll-like receptor 4 (TLR4), a receptor of endotoxin lipopolysaccharide (LPS), is distributed in immune and other cell types including melanocytes where LPS/TLR4 activate transcriptional activity of nuclear factor (NF)-κB to express cytokines in innate immunity. LPS/TLR4 also up-regulate MITF-M-target melanogenic genes in melanocytes. Here, we propose a molecular target of antimelanogenic activity through elucidating inhibitory mechanism on α-MSH-induced melanogenic programs by benzimidazole-2-butanol (BI2B), an inhibitor of LPS/TLR4-activated transcriptional activity of NF-κB. Methods: Ultraviolet B (UV-B)-irradiated skins of HRM-2 hairless mice and α-MSH-activated melanocyte cultures were employed to examine melanogenic programs. Results: Topical treatment with BI2B ameliorated UV-B-irradiated skin hyperpigmentation in mice. BI2B suppressed the protein or mRNA levels of melanogenic markers, such as tyrosinase (TYR), MITF-M and proopiomelanocortin (POMC), in UV-B-exposed and pigmented skin tissues. Moreover, BI2B inhibited melanin pigmentation in UV-B-irradiated co-cultures of keratinocyte and melanocyte cells and that in α-MSH-activated melanocyte cultures. Mechanistically, BI2B inhibited the activation of cAMP response element-binding protein (CREB) in α-MSH-induced melanogenic programs and suppressed the expression of MITF-M at the promoter level. As a molecular target, BI2B primarily inhibited mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)-catalyzed kinase activity on p38MAPK. Subsequently, BI2B interrupted downstream pathway of p38MAPK-mitogen and stress-activated protein kinase-1 (MSK1)-CREB-MITF-M, and suppressed MITF-M-target melanogenic genes, encoding enzymes TYR, TYR-related protein-1 (TRP-1) and dopachrome tautomerase (DCT) in melanin biosynthesis, and encoding proteins PMEL17 and Rab27A in the transfer of pigmented melanosomes to the overlaying keratinocytes in the skin. Conclusion: Targeting the MKK3-p38MAPK-MSK1-CREB-MITF-M pathway was suggested as a rationale to inhibit UV-B- or α-MSH-induced facultative melanogenesis and as a strategy to prevent acquired pigmentary disorders in the skin.

Comparison of Novel Telemonitoring System Using the Single-lead Electrocardiogram Patch With Conventional Telemetry System.

BACKGROUND AND OBJECTIVES: Although a single-lead electrocardiogram (ECG) patch may provide advantages for detecting arrhythmias in outpatient settings owing to user convenience, its comparative effectiveness for real-time telemonitoring in inpatient settings remains unclear. We aimed to compare a novel telemonitoring system using a single-lead ECG patch with a conventional telemonitoring system in an inpatient setting. METHODS: This was a single-center, prospective cohort study. Patients admitted to the cardiology unit for arrhythmia treatment who required a wireless ECG telemonitoring system were enrolled. A single-lead ECG patch and conventional telemetry were applied simultaneously in hospitalized patients for over 24 hours for real-time telemonitoring. The basic ECG parameters, arrhythmia episodes, and signal loss or noise were compared between the 2 systems. RESULTS: Eighty participants (mean age 62±10 years, 76.3% male) were enrolled. The three most common indications for ECG telemonitoring were atrial fibrillation (66.3%), sick sinus syndrome (12.5%), and atrioventricular block (10.0%). The intra-class correlation coefficients for detecting the number of total beats, atrial and ventricular premature complexes, maximal, average, and minimal heart rates, and pauses were all over 0.9 with p values for reliability <0.001. Compared to a conventional system, a novel system demonstrated significantly lower signal noise (median 0.3% [0.1-1.6%] vs. 2.4% [1.4-3.7%], p<0.001) and fewer episodes of signal loss (median 22 [2-53] vs. 64 [22-112] episodes, p=0.002). CONCLUSIONS: The novel telemonitoring system using a single-lead ECG patch offers performance comparable to that of a conventional system while significantly reducing signal loss and noise. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0008176.

Localized Photodynamic Therapy Using a Chlorin e6-Embedded Silicone-Covered Self-Expandable Metallic Stent as a Palliative Treatment for Malignant Esophageal Strictures.

Localized photodynamic therapy (PDT) uses a polymeric-photosensitizer (PS)-embedded, covered self-expandable metallic stent (SEMS). PDT is minimally invasive and a noteworthy potential alternative for treating esophageal strictures, where surgery is not a viable option. However, preclinical evidence is insufficient, and optimized irradiation energy dose ranges for localized PDT are unclear. Herein, we validated the irradiation energy doses of the SEMS (embedded in a PS using chlorin e6 [Ce6] and covered in silicone) and PDT-induced tissue changes in a rat esophagus. Cytotoxicity and phototoxicity in the Ce6-embedded SEMS piece with laser irradiation were significantly higher than that of the silicone-covered SEMS with or without laser and the Ce6-embedded silicone-covered SEMS without laser groups (all p < 0.001). Moreover, surface morphology, atomic changes, and homogeneous coverage of the Ce6-embedded silicone-covered membrane were confirmed. The ablation range of the porcine liver was proportionally increased with the irradiation dose (all p < 0.001). The ablation region was identified at different irradiation energy doses of 50, 100, 200, and 400 J/cm2. The in vivo study in the rat esophagus comprised a control group and 100, 200, and 400 J/cm2 energy-dose groups. Finally, histology and immunohistochemistry (TUNEL and Ki67) confirmed that the optimized Ce6-embedded silicone-covered SEMS with selected irradiation energy doses (200 and 400 J/cm2) effectively damaged the esophageal tissue without ductal perforation. The polymeric PS-embedded silicone-covered SEMS can be easily placed via a minimally invasive approach and represents a promising new approach for the palliative treatment of malignant esophageal strictures.

Targeting phosphorylation circuits on CREB and CRTCs as the strategy to prevent acquired skin hyperpigmentation.

Background: The cAMP response element-binding protein (CREB) and CREB-regulated transcription coactivators (CRTCs) cooperate in the transcriptional activation of microphthalmia-associated transcription factor subtype M (MITF-M) that is a master regulator in the biogenesis, pigmentation and transfer of melanosomes at epidermal melanocytes. Here, we propose the targeting of phosphorylation circuits on CREB and CRTCs in the expression of MITF-M as the rationale to prevent skin hyperpigmentation by elucidating the inhibitory activity and mechanism of yakuchinone A (Yaku A) on facultative melanogenesis. Methods: We employed human epidermal melanocyte cell, mouse skin, and mouse melanoma cell, and applied Western blotting, reverse transcription-polymerase chain reaction, immunoprecipitation and confocal microscopy to conduct this study. Results: This study suggested that α-melanocyte stimulating hormone (α-MSH)-induced melanogenic programs could switch on the axis of protein kinase A-salt inducible kinases (PKA-SIKs) rather than that of PKA-AMP activated protein kinase (PKA-AMPK) during the dephosphorylation of CRTCs in the expression of MITF-M. SIK inhibitors rather than AMPK inhibitors stimulated melanin production in melanocyte cultures in the absence of extracellular melanogenic stimuli, wherein SIK inhibitors increased the dephosphorylation of CRTCs but bypassed the phosphorylation of CREB for the expression of MITF-M. Treatment with Yaku A prevented ultraviolet B (UV-B)-irradiated skin hyperpigmentation in mice and inhibited melanin production in α-MSH- or SIK inhibitor-activated melanocyte cultures. Mechanistically, Yaku A suppressed the expression of MITF-M via dually targeting the i) cAMP-dependent dissociation of PKA holoenzyme at the upstream from PKA-catalyzed phosphorylation of CREB coupled with PKA-SIKs axis-mediated dephosphorylation of CRTCs in α-MSH-induced melanogenic programs, and ii) nuclear import of CRTCs after SIK inhibitor-induced dephosphorylation of CRTCs. Conclusions: Taken together, the targeting phosphorylation circuits on CREB and CRTCs in the expression of MITF-M could be a suitable strategy to prevent pigmentary disorders in the skin.

Enhancer of zeste homolog 2 (EZH2)-dependent sirtuin-3 determines sensitivity to glucose starvation in radioresistant head and neck cancer cells.

Sirtuin 3 (SIRT3) regulates mitochondrial function as a mitochondrial deacetylase during oxidative stress. However, the specific regulatory mechanism and function of SIRT3 in radioresistant cancer cells are unclear. In this study, we aim to investigate how SIRT3 determines the susceptibility to glucose deprivation and its regulation in p53-based radioresistant head and neck cancer cells. We observed mitochondrial function using two established isogenic radioresistant subclones (HN3R-A [p53 null] and HN3R-B [p53 R282W]) with intratumoral p53 heterogeneity. Cell counting analysis was performed to evaluate cell proliferation and cell death. The correlation between the regulation of SIRT3 and enhancer of zeste homolog 2 (EZH2) was confirmed by immunoblotting and chromatin immunoprecipitation assay. p53-deficient radioresistant cells (HN3R-A) expression reduced SIRT3 levels and increased sensitivity to glucose deprivation due to mitochondrial dysfunction compared to other cells. In these cells, activation of SIRT3 significantly prevented glucose deprivation-induced cell death, whereas the loss of SIRT3 increased the susceptibility to glucose deficiency. We discovered that radiation-induced EZH2 directly binds to the SIRT3 promoter and represses the expression. Conversely, inhibiting EZH2 increased the expression of SIRT3 through epigenetic changes. Our findings indicate that p53-deficient radioresistant cells with enhanced EZH2 exhibit increased sensitivity to glucose deprivation due to SIRT3 suppression. The regulation of SIRT3 by EZH2 plays a critical role in determining the cell response to glucose deficiency in radioresistant cancer cells. Therefore, EZH2-dependent SIRT3 could be used as a predictive biomarker to select treatment options for patients with radiation-resistance.