IDH2 regulates macrophage polarization and tumorigenesis by modulating mitochondrial metabolism in macrophages.

BACKGROUND: Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown. METHODS: In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified. RESULTS: IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial-mesenchymal transition. CONCLUSIONS: Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.

Mitofusin 1 and 2 overexpression reduces AßO-mediated ER stress and apoptosis in N2a APPswe cells.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and amyloid beta oligomers (AßO), which are pathological markers of AD, are known to be highly toxic. AßO increase mitochondrial dysfunction, which is accompanied by a decrease in mitochondrial fusion. Although mitofusin (Mfn) 1 and Mfn2 are mitochondrial fusion proteins, Mfn2 is known to regulate endoplasmic reticulum (ER) function, as it is located in the ER. Several studies have shown that AßO exacerbates ER stress, however, the exact mechanism requires further elucidation. In this study, we used mouse neuroblastoma cells stably overexpressing the amyloid precursor protein (APP) with the Swedish mutation (N2a APPswe cells) to investigate the role of Mfn in ER stress. Our results revealed that  amyloid beta (Aß) caused cellular toxicity in N2a APPswe cells, upregulated ER stress-related proteins, and promoted ER expansion. The AßO-mediated ER stress was reduced when Mfn1 and Mfn2 were overexpressed. Moreover, Mfn1 and Mfn2 overexpressed resulted in reduced apoptosis of N2a APPswe cells. In conclusion, our results indicate that both Mfn1 and Mfn2 reduce ER stress and apoptosis. Our data provide a foundation for future studies on the roles of Mfn1 and Mfn2 in the molecular mechanisms underlying AßO-mediated ER stress and the pathogenesis of AD.

Amount Estimation Method for Food Intake Based on Color and Depth Images through Deep Learning.

In this paper, we propose an amount estimation method for food intake based on both color and depth images. Two pairs of color and depth images are captured pre- and post-meals. The pre- and post-meal color images are employed to detect food types and food existence regions using Mask R-CNN. The post-meal color image is spatially transformed to match the food region locations between the pre- and post-meal color images. The same transformation is also performed on the post-meal depth image. The pixel values of the post-meal depth image are compensated to reflect 3D position changes caused by the image transformation. In both the pre- and post-meal depth images, a space volume for each food region is calculated by dividing the space between the food surfaces and the camera into multiple tetrahedra. The food intake amounts are estimated as the difference in space volumes calculated from the pre- and post-meal depth images. From the simulation results, we verify that the proposed method estimates the food intake amount with an error of up to 2.2%.

Mitochondrial peroxiredoxin 5 overexpression suppresses insulin-induced adipogenesis by downregulating the phosphorylation of p38.

Obesity is caused by the accumulation of excess lipids due to an energy imbalance. Differentiation of pre-adipocytes induces abnormal lipid accumulation, and reactive oxygen species (ROS) generated in this process promote the differentiation of pre-adipocytes through mitogen-activated protein kinase (MAPK) signaling. Peroxiredoxin (Prx) is a potent antioxidant enzyme, and peroxiredoxin 5 (Prx5), which is mainly expressed in cytosol and mitochondria, inhibits adipogenesis by regulating ROS levels. Based on previous findings, the present study was performed to investigate whether cytosolic Prx5 (CytPrx5) or mitochondrial Prx5 (MtPrx5) has a greater effect on the inhibition of adipogenesis. In this study, MtPrx5 decreased insulin-mediated ROS levels to reduce adipogenic gene expression and lipid accumulation more effectively than CytPrx5. In addition, we found that p38 MAPK mainly participates in adipogenesis. Furthermore, we verified that MtPrx5 overexpression suppressed the phosphorylation of p38 during adipogenesis. Thus, we suggest that MtPrx5 inhibits insulin-induced adipogenesis more effectively than CytPrx5.

PCNB exposure during early embryogenic development induces developmental delay and teratogenicity by altering the gene expression in Xenopus laevis.

Pentachloronitrobenzene (PCNB) is an organochlorine fungicide commonly used to treat seeds against seedling infections and controlling snow mold on golf courses. PCNB has been demonstrated to be toxic to living organisms, including fish and several terrestrial organisms. However, only phenotypical deformities have been studied, and the effects of PCNB on early embryogenesis, where primary organogenesis occurs, have not been completely studied. In the current study, the developmental toxicity and teratogenicity of PCNB is evaluated by using frog embryo teratogenesis assay Xenopus (FETAX). Our results confirmed the teratogenic potential of PCNB revealing the teratogenic index of 1.29 during early embryogenesis. Morphological studies revealed tiny head, bent axis, reduced inter ocular distance, hyperpigmentation, and reduced total body lengths. Whole mount in situ hybridization and reverse transcriptase polymerase chain reaction were used to identify PCNB teratogenic effects at the gene level. The gene expression analyses revealed that PCNB was embryotoxic to the liver and heart of developing embryos. Additionally, to determine the most sensitive developmental stages to PCNB, embryos were exposed to the compound at various developmental stages, demonstrating that the most sensitive developmental stage to PCNB is primary organogenesis. Taken together, we infer that PCNB's teratogenic potential affects not just the phenotype of developing embryos but also the associated genes and involving the oxidative stress as a possible mechanism of toxicity, posing a hazard to normal embryonic growth. However, the mechanisms of teratogenesis require additional extensive investigation to be defined completely.

A Sensing-Based Visualization Method for Representing Pressure Distribution in a Multi-Zone Building by Floor.

Airflow in a multi-zone building can be a major cause of pollutant transfer, excessive energy consumption, and occupants discomfort. The key to monitoring airflows and mitigating related problems is to obtain a comprehensive understanding of pressure relationships within the buildings. This study proposes a visualization method for representing pressure distribution within a multi-zone building by using a novel pressure-sensing system. The system consists of a Master device and a couple of Slave devices that are connected with each other by a wireless sensor network. A 4-story office building and a 49-story residential building were installed with the system to detect pressure variations. The spatial and numerical mapping relationships of each zone were further determined through grid-forming and coordinate-establishing processes for the building floor plan. Lastly, 2D and 3D visualized pressure mappings of each floor were generated, illustrating the pressure difference and spatial relationship between adjacent zones. It is expected that the pressure mappings derived from this study will allow building operators to intuitively perceive the pressure variations and the spatial layouts of the zones. These mappings also make it possible for operators to diagnose the differences in pressure conditions between adjacent zones and plan a control scheme for the HVAC system more efficiently.

Enhancement of target specificity of CRISPR-Cas12a by using a chimeric DNA-RNA guide.

The CRISPR-Cas9 system is widely used for target-specific genome engineering. CRISPR-Cas12a (Cpf1) is one of the CRISPR effectors that controls target genes by recognizing thymine-rich protospacer adjacent motif (PAM) sequences. Cas12a has a higher sensitivity to mismatches in the guide RNA than does Cas9; therefore, off-target sequence recognition and cleavage are lower. However, it tolerates mismatches in regions distant from the PAM sequence (TTTN or TTN) in the protospacer, and off-target cleavage issues may become more problematic when Cas12a activity is improved for therapeutic purposes. Therefore, we investigated off-target cleavage by Cas12a and modified the Cas12a (cr)RNA to address the off-target cleavage issue. We developed a CRISPR-Cas12a that can induce mutations in target DNA sequences in a highly specific and effective manner by partially substituting the (cr)RNA with DNA to change the energy potential of base pairing to the target DNA. A model to explain how chimeric (cr)RNA guided CRISPR-Cas12a and SpCas9 nickase effectively work in the intracellular genome is suggested. Chimeric guide-based CRISPR- Cas12a genome editing with reduced off-target cleavage, and the resultant, increased safety has potential for therapeutic applications in incurable diseases caused by genetic mutations.

Intra Prediction Method for Depth Video Coding by Block Clustering through Deep Learning.

In this paper, we propose an intra-picture prediction method for depth video by a block clustering through a neural network. The proposed method solves a problem that the block that has two or more clusters drops the prediction performance of the intra prediction for depth video. The proposed neural network consists of both a spatial feature prediction network and a clustering network. The spatial feature prediction network utilizes spatial features in vertical and horizontal directions. The network contains a 1D CNN layer and a fully connected layer. The 1D CNN layer extracts the spatial features for a vertical direction and a horizontal direction from a top block and a left block of the reference pixels, respectively. 1D CNN is designed to handle time-series data, but it can also be applied to find the spatial features by regarding a pixel order in a certain direction as a timestamp. The fully connected layer predicts the spatial features of the block to be coded through the extracted features. The clustering network finds clusters from the spatial features which are the outputs of the spatial feature prediction network. The network consists of 4 CNN layers. The first 3 CNN layers combine two spatial features in the vertical and horizontal directions. The last layer outputs the probabilities that pixels belong to the clusters. The pixels of the block are predicted by the representative values of the clusters that are the average of the reference pixels belonging to the clusters. For the intra prediction for various block sizes, the block is scaled to the size of the network input. The prediction result through the proposed network is scaled back to the original size. In network training, the mean square error is used as a loss function between the original block and the predicted block. A penalty for output values far from both ends is introduced to the loss function for clear network clustering. In the simulation results, the bit rate is saved by up to 12.45% under the same distortion condition compared with the latest video coding standard.

Major modifications to minimize thoracic esophago-gastric leak and eradicate esophageal stricture after Ivor Lewis esophagectomy.

BACKGROUND: The Ivor Lewis esophagectomy (ILE) remains the procedure of choice for localized middle or lower esophageal carcinoma. Nevertheless, anastomotic leak remains a common complication with rates from 3% to 25% and a stricture rate as high as 40%. The frequency of these complications suggests that the procedure itself may have inherent limitations including the use of potentially ischemic tissue for the esophagogastric anastomosis. We introduce a modified technique that reduces operative steps, preserves blood supply, and uses a modified esophagogastric anastomosis. METHODS: All consecutive patients undergoing ILE with the described modified technique were identified. An esophagram was performed on postoperative day six or seven. To ensure that all cases were identified, anastomotic leaks were defined as any radiographic evidence of contrast extravasation. RESULTS: A total of 110 patients underwent the modified esophagectomy with 2 anastomotic leaks (1.82%) and zero strictures. There was 1 late death but no early deaths (<30 or 90 days) or early re-admissions (<30 days). The average number of risk factors was 2.12, and 98 patients (90%) had at least 1 risk factor in their medical history. CONCLUSIONS: The modifications proposed simplify procedural steps, limit unnecessary dissection and introduce a technique that ends the practice of connecting ischemic tissue. We believe this technique contributes to surgical durability and reduces the rate of postoperative leak and eliminates stricture.

Amyloid-beta oligomers induce Parkin-mediated mitophagy by reducing Miro1.

Alzheimer's disease (AD) is a neurodegenerative disease associated with the accumulation of amyloid-beta oligomers (AßO). Recent studies have demonstrated that mitochondria-specific autophagy (mitophagy) contributes to mitochondrial quality control by selectively eliminating the dysfunctional mitochondria. Mitochondria motility, which is regulated by Miro1, is also associated with neuronal cell functions. However, the role played by Miro1 in the mitophagy mechanism, especially relative to AßO and neurodegenerative disorders, remains unknown. In this study, AßO induced mitochondrial dysfunction, enhanced Parkin-mediated mitophagy, and reduced mitochondrial quantities in hippocampal neuronal cells (HT-22 cells). We demonstrated that AßO-induced mitochondrial fragmentation could be rescued to the elongated mitochondrial form and that mitophagy could be mitigated by the stable overexpression of Miro1 or by pretreatment with N-acetylcysteine (NAC)-a reactive oxygen species (ROS) scavenger-as assessed by immunocytochemistry. Moreover, using time-lapse imaging, under live cell-conditions, we verified that mitochondrial motility was rescued by the Miro1 overexpression. Finally, in hippocampus from amyloid precursor protein (APP)/presenilin 1 (PS1)/Tau triple-transgenic mice, we noted that the co-localization between mitochondria and LC3B puncta was increased. Taken together, these results indicated that up-regulated ROS, induced by AßO, increased the degree of mitophagy and decreased the Miro1 expression levels. In contrast, the Miro1 overexpression ameliorated AßO-mediated mitophagy and increased the mitochondrial motility. In AD model mice, AßO induced mitophagy in the hippocampus. Thus, our results would improve our understanding of the role of mitophagy in AD toward facilitating the development of novel therapeutic agents for the treatment of AßO-mediated diseases.

Dieckol Ameliorates Aß Production via PI3K/Akt/GSK-3ß Regulated APP Processing in SweAPP N2a Cell.

The proteolytic processing of amyloid precursor protein (APP) by ß-secretase (BACE1) and γ-secretase releases amyloid-ß peptide (Aß), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer's disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aß accumulation. In addition, dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), ß-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPß, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3ß at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3ß. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3ß activation and Aß expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on Aß production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3ß, resulting in the reduction in Aß levels.

Peroxiredoxin 1 Controls Ovulation and Ovulated Cumulus-Oocyte Complex Activity through TLR4-Derived ERK1/2 Signaling in Mice.

Peroxiredoxins (PRDXs) are expressed in the ovary and during ovulation. PRDX1 activity related to the immuno-like response during ovulation is unknown. We investigated the roles of Prdx1 on TLR4 and ERK1/2 signaling from the ovulated cumulus-oocyte complex (COC) using Prdx1-knockout (K/O) and wild-type (WT) mice. Ovulated COCs were collected 12 and 16 h after pregnant mare serum gonadotropin/hCG injection. PRDX1 protein expression and COC secretion factors (Il-6, Tnfaip6, and Ptgs2) increased 16 h after ovulated COCs of the WT mice were obtained. We treated the ovulated COCs in mice with LPS (0.5 µg/mL) or hyaluronidase (Hya) (10 units/mL) to induce TLR4 activity. Intracellular reactive oxygen species (ROS), cumulus cell apoptosis, PRDX1, TLR4/P38/ERK1/2 protein expression, and COC secretion factors' mRNA levels increased in LPS- and Hya-treated COCs. The ERK inhibitor (U0126) and Prdx1 siRNA affected TLR4/ERK1/2 expression. The number and cumulus expansion of ovulated COCs by ROS were impaired in Prdx1 K/O mice but not in WT ones. Prdx1 gene deletion induced TLR4/P38/ERK1/2 expression and cumulus expansion genes. These results show the controlling roles of PRDX1 for TLR4/P38/ERK1/2 signaling activity in ovulated mice and the interlink of COCs with ovulation.

Evaluation of leaching characteristic and kinetic study of lithium from lithium aluminum silicate glass-ceramics by NaOH.

The behavior and mechanism of Li leaching from lithium aluminum silicate glass-ceramics which can be used as a secondary source of Li using aqueous NaOH solution was investigated. The Li leaching efficiency is increased with increasing concentration of NaOH, specific surface area, and reaction temperature. When leached under optimum conditions, 2 mol/L NaOH, 53 µm particle undersize, 1:10 solid/liquid ratio, 250 r/min stirring speed, 100°C reaction temperature, 12 hr, the Li leaching efficiency was approximately 70%. However, when the leaching experiment was performed for 48 hr, the concentration of Li+ ions contained in the leach liquor decreased from 1160 to 236 mg/L. To investigate the origin of this phenomenon, the obtained leach residue was analyzed by X-ray diffraction, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. These analyses show that zeolite was formed around the lithium aluminum silicate glass-ceramics, which affected the leaching of by adsorbing Li+ ions. In addition, using the shrinking-core model and the Arrhenius equation, the leaching reaction with NaOH was found to depends on the chemical reaction of the two reactants, with a higher than 41.84 kJ/mol of the activation energy.

Poziotinib suppresses ovarian cancer stem cell growth via inhibition of HER4-mediated STAT5 pathway.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with an overall 5-year survival rate of only 30%. EOC is associated with drug resistance, frequent recurrence, and poor prognosis. A major contributor toward drug resistance might be cancer stem cells (CSCs), which may remain after chemotherapy. Here, we aimed to find therapeutic agents that target ovarian CSCs. We performed a high-throughput screening using the Clinical Compound Library with a sphere culture of A2780 EOCs. Poziotinib, a pan-human epidermal growth factor receptor (HER) inhibitor, decreased sphere formation, viability, and proliferation, and induced G1 cell cycle arrest and apoptosis in ovarian CSCs. In addition, poziotinib suppressed stemness and disrupted downstream signaling of Wnt/ß-catenin, Notch, and Hedgehog pathways, which contribute to many characteristics of CSCs. Interestingly, HER4 was overexpressed in ovarian CSCs and Poziotinib reduced the phosphorylation of STAT5, AKT, and ERK, which are regulated by HER4. Our results suggest that HER4 may be a promising therapeutic target for ovarian CSCs, and that poziotinib may be an effective therapeutic option for the prevention of ovarian cancer recurrence.

Peroxiredoxin 4 inhibits insulin-induced adipogenesis through regulation of ER stress in 3T3-L1 cells.

Obesity was originally considered a disease endemic to developed countries but has since emerged as a global health problem. Obesity is characterized by abnormal or excessive lipid accumulation (World Health Organization, WHO) resulting from pre-adipocyte differentiation (adipogenesis). The endoplasmic reticulum (ER) produces proteins and cholesterol and shuttles these compounds to their target sites. Many studies have implicated ER stress, indicative of ER dysfunction, in adipogenesis. Reactive oxygen species (ROS) are also known to be involved in pre-adipocyte differentiation. Prx4 specific to the ER lumen exhibits ROS scavenging activity, and we thereby focused on ER-specific Prx4 in tracking changes in adipocyte differentiation and lipid accumulation. Overexpression of Prx4 reduced ER stress and suppressed lipid accumulation by regulating adipogenic gene expression during adipogenesis. Our results demonstrate that Prx4 inhibits ER stress, lowers ROS levels, and attenuates pre-adipocyte differentiation. These findings suggested enhancing the activity of Prx4 may be helpful in the treatment of obesity; the data also support the development of new therapeutic approaches to obesity and obesity-related metabolic disorders.

Peroxiredoxin 2 deficiency reduces white adipogenesis due to the excessive ROS generation.

Reactive oxygen species (ROS) act as signaling molecules to regulate various cell functions. Numerous studies have demonstrated ROS to be essential for the differentiation of adipocytes. Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant enzymes in mammalian cells. Prx2 is present in the cytoplasm and cell membranes and demonstrates ROS scavenging activity. We focused on Prx2 involvement in regulating adipogenesis and lipid accumulation and demonstrated that Prx2 expression was upregulated during adipocyte differentiation. In addition, the silencing of Prx2 (shPrx2) inhibited adipogenesis by modulating adipogenic gene expression, and cell death was enhanced via increased ROS production in shPrx2-3T3-L1 cells. These results demonstrate that shPrx2 triggers adipocyte cell death and weakens adipocyte function via ROS production. Taken together, our data suggest the participation of Prx2 in adipocyte function and differentiation. Our results also imply that the downregulation of Prx2 activity could help prevent obesity. Overall, findings support the development of ROS-based therapeutic solutions for the treatment of obesity and obesity-related metabolic disorders.

Optimal Lead Position in Patch-Type Monitoring Sensors for Reconstructing 12-Lead ECG Signals with Universal Transformation Coefficient.

The aim of this study was to reconstruct a 12-lead electrocardiograph (ECG) with a universal transformation coefficient and find the appropriate electrode position and shape for designing a patch-type ECG sensor. A 35-channel ECG monitoring system was developed, and 14 subjects were recruited for the experiment. A feedforward neural network with one hidden layer was applied to train the transformation coefficient. Three electrode shapes (5 cm × 5 cm square, 10 cm × 10 cm square, and right-angled triangle) were considered for the patch-type ECG sensor. The mean correlation coefficient (CC) and minimum CC methods were applied to evaluate the reconstruction performance. The average CCs between the standard 12-lead ECG and reconstructed 12-lead ECG were 0.860, 0.893, and 0.893 for a 5 cm × 5 cm square, 10 cm × 10 cm square, and right-angled triangle shape. The right-angled triangle showed the highest performance among the considered shapes. The results also suggested that the bottom of the central area of the chest was the most suitable position for attaching the patch-type ECG sensor.

Beat-to-Beat Continuous Blood Pressure Estimation Using Bidirectional Long Short-Term Memory Network.

Continuous blood pressure (BP) monitoring is important for patients with hypertension. However, BP measurement with a cuff may be cumbersome for the patient. To overcome this limitation, various studies have suggested cuffless BP estimation models using deep learning algorithms. A generalized model should be considered to decrease the training time, and the model reproducibility should be taken into account in multi-day scenarios. In this study, a BP estimation model with a bidirectional long short-term memory network is proposed. The features are extracted from the electrocardiogram, photoplethysmogram, and ballistocardiogram. The leave-one-subject-out (LOSO) method is incorporated to generalize the model and fine-tuning is applied. The model was evaluated using one-day and multi-day tests. The proposed model achieved a mean absolute error (MAE) of 2.56 and 2.05 mmHg for the systolic and diastolic BP (SBP and DBP), respectively, in the one-day test. Moreover, the results demonstrated that the LOSO method with fine-tuning was more compatible in the multi-day test. The MAE values of the model were 5.82 and 5.24 mmHg for the SBP and DBP, respectively.

End-to-End Deep Learning Architecture for Continuous Blood Pressure Estimation Using Attention Mechanism.

Blood pressure (BP) is a vital sign that provides fundamental health information regarding patients. Continuous BP monitoring is important for patients with hypertension. Various studies have proposed cuff-less BP monitoring methods using pulse transit time. We propose an end-to-end deep learning architecture using only raw signals without the process of extracting features to improve the BP estimation performance using the attention mechanism. The proposed model consisted of a convolutional neural network, a bidirectional gated recurrent unit, and an attention mechanism. The model was trained by a calibration-based method, using the data of each subject. The performance of the model was compared to the model that used each combination of the three signals, and the model with the attention mechanism showed better performance than other state-of-the-art methods, including conventional linear regression method using pulse transit time (PTT). A total of 15 subjects were recruited, and electrocardiogram, ballistocardiogram, and photoplethysmogram levels were measured. The 95% confidence interval of the reference BP was [86.34, 143.74] and [51.28, 88.74] for systolic BP (SBP) and diastolic BP (DBP), respectively. The R 2 values were 0.52 and 0.49, and the mean-absolute-error values were 4.06 ± 4.04 and 3.33 ± 3.42 for SBP and DBP, respectively. In addition, the results complied with global standards. The results show the applicability of the proposed model as an analytical metric for BP estimation.

Combined Poziotinib with Manidipine Treatment Suppresses Ovarian Cancer Stem-Cell Proliferation and Stemness.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women worldwide, with an overall 5 year survival rate below 30%. The low survival rate is associated with the persistence of cancer stem cells (CSCs) after chemotherapy. Therefore, CSC-targeting strategies are required for successful EOC treatment. Pan-human epidermal growth factor receptor 4 (HER4) and L-type calcium channels are highly expressed in ovarian CSCs, and treatment with the pan-HER inhibitor poziotinib or calcium channel blockers (CCBs) selectively inhibits the growth of ovarian CSCs via distinct molecular mechanisms. In this study, we tested the hypothesis that combination treatment with poziotinib and CCBs can synergistically inhibit the growth of ovarian CSCs. Combined treatment with poziotinib and manidipine (an L-type CCB) synergistically suppressed ovarian CSC sphere formation and viability compared with either drug alone. Moreover, combination treatment synergistically reduced the expression of stemness markers, including CD133, KLF4, and NANOG, and stemness-related signaling molecules, such as phospho-STAT5, phospho-AKT, phospho-ERK, and Wnt/ß-catenin. Moreover, poziotinib with manidipine dramatically induced apoptosis in ovarian CSCs. Our results suggest that the combinatorial use of poziotinib with a CCB can effectively inhibit ovarian CSC survival and function.