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Neurodegenerative diseases (NDDs) present significant challenges due to limited treatment options, ethical concerns surrounding traditional animal models, and the time-consuming and costly process of using human-induced pluripotent stem cells (iPSCs). We addressed these issues by developing a 3D culture protocol for differentiating SH-SY5Y cells into glutamatergic neurons, enhancing physiological relevance with a 3D microarray culture plate. Our protocol optimized serum concentration and incorporated retinoic acid (RA) to improve differentiation. We analyzed the proportions of N-type and S-type cells, observing that RA in the maturation stage not only reduced cell proliferation but also enhanced the expression of MAP2 and VGLUT1, indicating effective neuronal differentiation. Our approach demonstrates the strong expression of glutamatergic neuron phenotypes in 3D SH-SY5Y neural spheroids, offering a promising tool for high-throughput NDD modeling and advancing drug discovery and therapeutic development. This method overcomes limitations associated with conventional 2D cultures and animal models, providing a more effective platform for NDD research., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Titrating tacrolimus concentration in liver transplantation recipients remains a challenge in the early post-transplant period. This multicenter retrospective cohort study aimed to develop and validate a machine-learning algorithm to predict tacrolimus concentration. Data from 443 patients undergoing liver transplantation between 2017 and 2020 at an academic hospital in South Korea were collected to train machine-learning models. Long short-term memory (LSTM) and gradient-boosted regression tree (GBRT) models were developed using time-series doses and concentrations of tacrolimus with covariates of age, sex, weight, height, liver enzymes, total bilirubin, international normalized ratio, albumin, serum creatinine, and hematocrit. We conducted performance comparisons with linear regression and populational pharmacokinetic models, followed by external validation using the eICU Collaborative Research Database collected in the United States between 2014 and 2015. In the external validation, the LSTM outperformed the GBRT, linear regression, and populational pharmacokinetic models with median performance error (8.8%, 25.3%, 13.9%, and - 11.4%, respectively; P < 0.001) and median absolute performance error (22.3%, 33.1%, 26.8%, and 23.4%, respectively; P < 0.001). Dosing based on the LSTM model's suggestions achieved therapeutic concentrations more frequently on the chi-square test (P < 0.001). Patients who received doses outside the suggested range were associated with longer ICU stays by an average of 2.5 days (P = 0.042). In conclusion, machine learning models showed excellent performance in predicting tacrolimus concentration in liver transplantation recipients and can be useful for concentration titration in these patients., (© 2024. The Author(s).)

This study aimed to create and validate a predictive model for renal function following live kidney donation, using pre-donation factors. Accurately predicting remaining renal function post live kidney donation is currently insufficient, necessitating an effective assessment tool. A multicenter retrospective study of 2318 live kidney donors from two independent centers (May 2007-December 2019) was conducted. The primary endpoint was the reduction in eGFR to below 60 mL/min/m 2 6 months post-donation. The primary endpoint was achieved in 14.4% of the training cohort and 25.8% of the validation cohort. Sex, age, BMI, hypertension, preoperative eGFR, and remnant kidney proportion (RKP) measured by computerized tomography (CT) volumetry were found significant in the univariable analysis. These variables informed a scoring system based on multivariable analysis: sex (male: 1, female: 0), age at operation (< 30: 0, 30-39: 1, 40-59: 2, ≥ 60: 3), preoperative eGFR (≥ 100: 0, 90-99: 2, 80-89: 4, < 80: 5), and RKP (≥ 52%: 0, < 52%: 1). The total score ranged from 0 to 10. The model showed good discrimination for the primary endpoint in both cohorts. The prediction model provides a useful tool for estimating post-donation renal dysfunction risk, factoring in the side of the donated kidney. It offers potential enhancement to pre-donation evaluations., (© 2024. The Author(s).)

BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3-4 and 4-5). In the iVL 4-5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3-4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients., (© 2024. The Author(s).)

The effect of diabetes distress on glycemic control and its association with diabetes complications is still poorly understood. We aimed to study the clinical features of patients with high diabetes distress, focusing on changes in glycemic control and risk of diabetic complications. From the Korean National Diabetes Program data, we investigated 1862 individuals with type 2 diabetes mellitus (T2DM) who completed diabetic complication studies and the Korean version of the Problem Areas in Diabetes Survey (PAID-K). A total score of PAID-K ≥ 40 was considered indicative of high distress. Individuals with high distress (n = 589) had significantly higher levels of glycated hemoglobin than those without distress (7.4% vs. 7.1%, p < 0.001). This trend persisted throughout the 3-year follow-up period. Higher PAID-K scores were associated with younger age, female gender, longer duration of diabetes, and higher carbohydrate intake (all p < 0.05). There was a significant association between high distress and diabetic neuropathy (adjusted odds ratio, 1.63; p = 0.002), but no significant association was found with other complications, including retinopathy, albuminuria, and carotid artery plaque. In conclusion, high diabetes distress was associated with uncontrolled hyperglycemia and higher odds of having diabetic neuropathy., (© 2024. The Author(s).)

Protocol biopsy is a reliable method for assessing allografts status after kidney transplantation (KT). However, due to the risk of complications, it is necessary to establish indications and selectively perform protocol biopsies by classifying the high-risk group for early subclinical rejection (SCR). Therefore, the purpose of this study is to analyze the incidence and risk factors of early SCR (within 2 weeks) and develop a prediction model using machine learning. Patients who underwent KT at Samsung Medical Center from January 2005 to December 2020 were investigated. The incidence of SCR was investigated and risk factors were analyzed. For the development of prediction model, machine learning methods (random forest, elastic net, extreme gradient boosting [XGB]) and logistic regression were used and the performance between the models was evaluated. The cohorts of 987 patients were reviewed and analyzed. The incidence of SCR was 14.6%. Borderline cellular rejection (BCR) was the most common type of rejection, accounting for 61.8% of cases. In the analysis of risk factors, recipient age (OR 0.98, p = 0.03), donor BMI (OR 1.07, p = 0.02), ABO incompatibility (OR 0.15, p < 0.001), HLA II mismatch (two [OR 6.44, p < 0.001]), and ATG induction (OR 0.41, p < 0.001) were associated with SCR in the multivariate analysis. The logistic regression prediction model (average AUC = 0.717) and the elastic net model (average AUC = 0.712) demonstrated good performance. HLA II mismatch and induction type were consistently identified as important variables in all models. The odds ratio analysis of the logistic prediction model revealed that HLA II mismatch (OR 6.77) was a risk factor for SCR, while ATG induction (OR 0.37) was a favorable factor. Early SCR was associated with HLA II mismatches and induction agent and prediction model using machine learning demonstrates the potential to predict SCR., (© 2023. The Author(s).)

In honeycomb multilayers with staggered AB-sublattice potentials, we predict gapless edge states localized to either of the odd and the even layers for the AA[Formula: see text] stacking order in which the sublattice-pseudospin polarizations of adjacent layers are antiparallel. Gaps in the projected layer-pseudospin spectrum suppress interlayer hopping between odd and even layers. The layer-valley Chern number corresponding to the edge states was obtained by decomposing the occupied state into two layer-pseudospin sectors by using a projected layer-pseudospin operator. For the AB[Formula: see text] stacking, the sublattice-pseudospin polarizations of adjacent layers are antiparallel, but the layer-pseudospin spectrum gap closes at the interface of the topologically different states, leading to gapped edge states. For the AA and AB stackings where the sublattice-pseudospin polarizations of the adjacent layers are parallel, the gapless edge states corresponding to quantum valley Hall states are evenly distributed across the layers., (© 2023. Springer Nature Limited.)

Greater graft-failure-risk of female-to-male liver transplantation (LT) is thought to be due to acute decrease in hepatic-estrogen-signaling. Our previous research found evidence that female hepatic-estrogen-signaling decreases after 40 years or with macrosteatosis. Thus, we hypothesized that inferiority of female-to-male LT changes according to donor-age and macrosteatosis. We stratified 780 recipients of grafts from living-donors into four subgroups by donor-age and macrosteatosis and compared graft-failure-risk between female-to-male LT and other LTs within each subgroup using Cox model. In recipients with ≤ 40 years non-macrosteatotic donors, graft-failure-risk was significantly greater in female-to-male LT than others (HR 2.03 [1.18-3.49], P = 0.011). Within the subgroup of recipients without hepatocellular carcinoma, the inferiority of female-to-male LT became greater (HR 4.75 [2.02-11.21], P < 0.001). Despite good graft quality, 1y-graft-failure-probability was 37.9% (23.1%-57.9%) in female-to-male LT within this subgroup while such exceptionally high probability was not shown in any other subgroups even with worse graft quality. When donor was > 40 years or macrosteatotic, graft-failure-risk was not significantly different between female-to-male LT and others (P > 0.60). These results were in agreement with the estrogen receptor immunohistochemistry evaluation of donor liver. In conclusion, we found that the inferiority of female-to-male LT was only found when donor was ≤ 40 years and non-macrosteatotic. Abrogation of the inferiority when donor was > 40 years or macrosteatotic suggests the presence of dominant contributors for post-transplant graft-failure other than graft quality/quantity and supports the role of hepatic-estrogen-signaling mismatch on graft-failure after female-to-male LT., (© 2023. Springer Nature Limited.)

Ulmus macrocarpa Hance bark (UmHb) has been used as a traditional herbal medicine in East Asia for bone concern diseases for a long time. To find a suitable solvent, we, in this study, compared the efficacy of UmHb water extract and ethanol extract which can inhibit osteoclast differentiation. Compared with two ethanol extracts (70% and 100% respectively), hydrothermal extracts of UmHb more effectively inhibited receptor activators of nuclear factor κB ligand-induced osteoclast differentiation in murine bone marrow-derived macrophages. We identified for the first time that (2R,3R)-epicatechin-7-O-β-D-apiofuranoside (E7A) is a specific active compound in UmHb hydrothermal extracts through using LC/MS, HPLC, and NMR techniques. In addition, we confirmed through TRAP assay, pit assay, and PCR assay that E7A is a key compound in inhibiting osteoclast differentiation. The optimized condition to obtain E7A-rich UmHb extract was 100 mL/g, 90 °C, pH 5, and 97 min. At this condition, the content of E7A was 26.05 ± 0.96 mg/g extract. Based on TRAP assay, pit assay, PCR, and western blot, the optimized extract of E7A-rich UmHb demonstrated a greater inhibition of osteoclast differentiation compared to unoptimized. These results suggest that E7A would be a good candidate for the prevention and treatment of osteoporosis-related diseases., (© 2023. The Author(s).)

Coronavirus disease 2019 (COVID-19) is a recent pandemic that caused serious global emergency. To identify new and effective therapeutics, we employed a drug repurposing approach. The poly (ADP ribose) polymerase inhibitors were used for this purpose and were repurposed against the main protease (Mpro) target of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). The results from these studies were used to design compounds using the 'Grow Scaffold' modules available on Discovery Studio v2018. The three designed compounds, olaparib 1826 and olaparib 1885, and rucaparib 184 demonstrated better CDOCKER docking scores for Mpro than their parent compounds. Moreover, the compounds adhered to Lipinski's rule of five and demonstrated a synthetic accessibility score of 3.55, 3.63, and 4.30 for olaparib 1826, olaparib 1885, and rucaparib 184, respectively. The short-range Coulombic and Lennard-Jones potentials also support the potential binding of the modified compounds to Mpro. Therefore, we propose these three compounds as novel SARS-CoV-2 inhibitors., (© 2023. The Author(s).)

Supraglottic airway (SGA) may have advantages over endotracheal tube (ETT) regarding laryngospasm, coughing, sore throat, and hemodynamic changes; however, studies on the use of SGA in laparoscopic donor nephrectomy (LDN) are lacking. Here, we aimed to confirm the safety and feasibility of second-generation SGA in LDN and compare them with those of ETT. Enrolled adult donors (aged > 18 years) who underwent LDN between August 2018 and November 2021 were divided into two groups-ETT vs. SGA. Airway pressure, lung compliance, desaturation, and hypercapnia were recorded during surgery. After propensity score matching for baseline characteristics and surgical duration, 82 and 152 donors were included in the ETT and SGA groups, respectively, and their outcomes were compared. The peak airway pressure was lower in the SGA group than in the ETT group 5 min after pneumoperitoneum. Dynamic lung compliance was higher in the SGA group than in the ETT group during surgery. There were no cases of intraoperative desaturation, hypercapnia, or postoperative aspiration pneumonitis. The use of second-generation SGA, a safe alternative to ETT for LDN, resulted in reduced airway resistance and increased lung compliance, which suggests its benefits for airway management in kidney donors., (© 2023. The Author(s).)

Fibroblast growth factor 21 (FGF21) has pharmaceutical potential against obesity-related metabolic disorders, including non-alcoholic fatty liver disease. Since thermal stability is a desirable factor for therapeutic proteins, we investigated the thermal behavior of human FGF21. FGF21 remained soluble after heating; thus, we examined its temperature-induced structural changes using circular dichroism (CD). FGF21 showed inter-convertible temperature-specific CD spectra. The CD spectrum at 100 °C returned to that at 20 °C when the heated FGF21 solution was cooled. Through loop swapping, the connecting loop between β10 and β12 in FGF21 was revealed to be associated with the unique thermal behavior of FGF21. According to surface plasmon resonance (SPR) experiments, in vitro cell-based assays, and model high-fat diet (HFD)-induced obesity studies, heated FGF21 maintained biological activities that were comparable to those of non-heated and commercial FGF21s. Based on sequence comparison and structural analysis, five point-mutations were introduced into FGF21. Compared with the wild type, the heated FGF21 variant displayed improved therapeutic potential in terms of body weight loss, the levels of hepatic triglycerides and lipids, and the degree of vacuolization of liver in HFD-fed mice., (© 2023. The Author(s).)

Dendritic cell (DC)-based immunotherapies have been shown to be a potential treatment option for various cancers; however, the exact strategies in ovarian cancer remain unknown. Here, we report the effectiveness of mouse CD8α+ DCs derived from bone marrow hematopoietic stem cells (BM-HSCs), equivalent to human CD141+ DCs, which have proven to be a highly superior subset. Mono-DCs from monocytes and stem-DCs from HSCs were characterized by CD11c+ CD80+ CD86+ and CD8α+ Clec9a+ expression, respectively. Despite a lower dose compared with Mono-DCs, mice treated with pulsed Stem-DCs showed a reduced amount of ascitic fluid and lower body weights compared with those of vehicle-treated mice. These mice treated with pulsed stem-DCs appeared to have fewer tumor implants, which were usually confined in the epithelium of tumor-invaded organs. All mice treated with DCs showed longer survival than the vehicle group, especially in the medium/high dose pulsed Stem-DC treatment groups. Moreover, the stem-DC-treated group demonstrated a low proportion of myeloid-derived suppressor cells and regulatory T cells, high interleukin-12 and interferon-γ levels, and accumulation of several tumor-infiltrating lymphocytes. Together, these results indicate that mouse CD8α+ DCs derived from BM-HSCs decrease tumor progression and enhance antitumor immune responses against murine ovarian cancer, suggesting that better DC vaccines can be used as an effective immunotherapy in EOC treatment. Further studies are necessary to develop potent DC vaccines using human CD141+ DCs., (© 2023. The Author(s).)

Transfer learning using a pre-trained model with the ImageNet database is frequently used when obtaining large datasets in the medical imaging field is challenging. We tried to estimate the value of deep learning for facial US images by assessing the classification performance for facial US images through transfer learning using current representative deep learning models and analyzing the classification criteria. For this clinical study, we recruited 86 individuals from whom we acquired ultrasound images of nine facial regions. To classify these facial regions, 15 deep learning models were trained using augmented or non-augmented datasets and their performance was evaluated. The F-measure scores average of all models was about 93% regardless of augmentation in the dataset, and the best performing model was the classic model VGGs. The models regarded the contours of skin and bones, rather than muscles and blood vessels, as distinct features for distinguishing regions in the facial US images. The results of this study can be used as reference data for future deep learning research on facial US images and content development., (© 2022. The Author(s).)

Although serum uric acid level and systemic inflammation have been highlighted as risk factors for type 2 diabetes mellitus (T2DM), little is known about these associations in the Korean population. Thus, we examined the individual and combined associations of serum uric acid and systemic inflammation (evaluated using high-sensitivity C-reactive protein [hs-CRP] measurement) with the future risk of T2DM. A total of 4152 Korean adults aged 45-76 years without T2DM, cancer, or gout at baseline in 2007-2008 from the Korean Genome and Epidemiology Study were followed up until 2016. Cox proportional hazard models were used to estimate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2DM according to sex-specific tertiles of serum uric acid and hs-CRP levels after adjustment for confounders. During the mean follow-up of 7.3 years, 548 participants developed T2DM. High serum uric acid and hs-CRP levels were independently associated with an increased incidence of T2DM. The multivariable-adjusted HRs (95% CIs) for the incidence of T2DM in the highest tertiles of serum uric acid and hs-CRP were 1.54 (1.24-1.93) and 1.90 (1.48-2.43), respectively. High levels of serum uric acid and hs-CRP in combination were associated with an increased incidence of T2DM (HR: 4.69; 95% CI: 2.81-7.84) compared to low levels of serum uric acid and hs-CRP. These findings suggest that the combination of high serum uric acid and hs-CRP levels was significantly associated with an elevated incidence of T2DM; however, their synergistic effects were not observed in middle-aged and elderly Korean adults., (© 2022. The Author(s).)

We aimed to compare the short- and long-term outcomes of simultaneous laparoscopic, hybrid, and open resection for colorectal cancer and synchronous liver metastases. We retrospectively analyzed the data of 647 patients with simultaneous resection of colorectal cancer and liver metastases between January 2006 and December 2018 at three tertiary referral hospitals. Patient's baseline characteristics, perioperative outcomes, pathological examination results, liver-specific recurrence rate and survivals were compared between the propensity score-matched groups. Forty-two and 81 patients were selected for the laparoscopic vs. hybrid groups, and 48 and 136 patients for laparoscopic vs. open groups, respectively. The laparoscopic group had fewer wound complications (2.1 vs. 13.2%; p = 0.028) than the open group, and a shorter postoperative hospital stay than the hybrid and open groups (8 vs. 11 days, p < 0.001 for both). The 5-year liver-specific recurrence rates were 38.7% and 46.0% in the laparoscopic and hybrid groups, respectively (p = 0.270), and 34.0% and 37.0% in the laparoscopic and open groups, respectively (p = 0.391). Simultaneous laparoscopic resection for colorectal cancer and liver metastases can be performed safely with significantly enhanced postoperative recovery and comparable long-term outcomes compared to hybrid and open resection., (© 2022. The Author(s).)

Roles for the non-coding small RNA RyhB in quorum-sensing and iron-dependent gene modulation in the human pathogen V. vulnificus were assessed in this study. Both the quorum sensing master regulator SmcR and the Fur-iron complex were observed to bind to the region upstream of the non-coding small RNA RyhB gene to repress expression, which suggests that RyhB is associated with both quorum-sensing and iron-dependent signaling in this pathogen. We found that expression of LuxS, which is responsible for the biosynthesis of autoinducer-2 (AI-2), was higher in wild type than in a ryhB-deletion isotype. RyhB binds directly to the 5'-UTR (untranslated region) of the luxS transcript to form a heteroduplex, which not only stabilizes luxS mRNA but also disrupts the secondary structure that normally obscures the translational start codon and thereby allows translation of LuxS to begin. The binding of RyhB to luxS mRNA requires the chaperone protein Hfq, which stabilizes RyhB. These results demonstrate that the small RNA RyhB is a key element associated with feedback control of AI-2 production, and that it inhibits quorum-sensing signaling in an iron-dependent manner. This study, taken together with previous studies, shows that iron availability and cell density signals are funneled to SmcR and RyhB, and that these regulators coordinate cognate signal pathways that result in the proper balance of protein expression in response to environmental conditions., (© 2022. The Author(s).)

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy., (© 2021. The Author(s).)

We investigated the clinical relevance of urinary cytokines/chemokines reflecting intrarenal immunologic micromilieu as prognostic markers and the optimal measurement timing after living donor kidney transplantation (LDKT). This prospective cohort study included 77 LDKT patients who were followed for ≥ 5 years. Patients were divided into control (n = 42) or acute rejection (AR, n = 35) group. Early AR was defined as AR occurring within 3 months. Serum and urine cytokines/chemokines were measured serially as follows: intraoperative, 8/24/72 h, 1 week, 3 months, and 1 year after LDKT. Intrarenal total leukocytes, T cells, and B cells were analyzed with immunohistochemistry followed by tissueFAXS. Urinary MCP-1 and fractalkine were also analyzed in a validation cohort. Urinary MCP-1 after one week was higher in the AR group. Urinary MCP-1, fractalkine, TNF-α, RANTES, and IL-6 after one week were significantly higher in the early AR group. Intrarenal total leukocytes and T cells were elevated in the AR group compared with the control group. Urinary fractalkine, MCP-1, and IL-10 showed positive correlation with intrarenal leukocyte infiltration. Post-KT 1 week urinary MCP-1 showed predictive value in the validation cohort. One-week post-KT urinary MCP-1 may be used as a noninvasive diagnostic marker for predicting AR after LDKT., (© 2021. The Author(s).)

For pheochromocytoma and sympathetic paraganglioma (PPGL), surgery can be used as a curative treatment; however, the life-threatening risk of perioperative hemodynamic instability (HI) presents challenges. This study aimed to analyze the incidence and predictive factors of perioperative HI. The electronic medical records of 114 consecutive patients who underwent surgery for PPGLs at our institution were retrospectively reviewed. HI was defined as one or more episodes of systolic blood pressure > 200 mmHg or mean blood pressure < 60 mmHg during surgery. The factors predictive of perioperative HI were determined using both univariate and multivariate analyses. Intraoperative HI occurred in 79 (69.3%) patients. In multivariate analysis, α-adrenergic receptor blocker duration (days) (odds ratio, 1.015; 95% confidence interval, 1.001-1.029) was a predictor for intraoperative HI. Postoperative hypotension occurred in 36 (31.6%) patients. Higher urine epinephrine levels, and greater preoperative highest heart rate (HR) were predictive factors for postoperative hypotension in PPGL patients. Caution should be taken in perioperative management for PPGL, especially with long duration of α-adrenergic receptor blocker use, higher urine epinephrine levels, and greater preoperative highest HR., (© 2021. The Author(s).)

The relationship between AMY1 single nucleotide polymorphisms (SNPs), dietary carbohydrates, and the risk of type 2 diabetes is unclear. We aimed to evaluate this association using an ongoing large-scale prospective study, namely the Korean Genome and Epidemiology Study. We selected six genetic variants of the AMY1 gene: rs10881197, rs4244372, rs6696797, rs1566154, rs1930212, and rs1999478. Baseline dietary data were obtained using a semi-quantitative food frequency questionnaire. Type 2 diabetes was defined according to the criteria of the World Health Organization and American Diabetes Association. During an average follow-up period of 12 years (651,780 person-years), 1082 out of 4552 (23.8%) patients had type 2 diabetes. Three AMY1 SNPs were significantly associated with diabetes incidence among patients with carbohydrate intake > 65% of total energy: rs6696797, rs4244372, and rs10881197. In multivariable Cox models, Korean women with the rs6696797 AG or AA genotype had 28% higher incidence of type 2 diabetes (hazard ratio 1.28, 95% confidence interval 1.06-1.55) than Korean women with the rs6696797 GG genotype. We did not observe significant associations between AMY1 SNPs, dietary carbohydrates, and diabetes incidence in Korean men. We conclude that AMY1 genetic variants and dietary carbohydrate intake influence the incidence of type 2 diabetes in Korean women only. Korean women who are minor carriers of the AMY1 rs6696797, rs4244372, and rs10881197 genotypes may benefit from a low-carbohydrate diet to prevent the future risk of type 2 diabetes., (© 2021. The Author(s).)

Irreversible electroporation (IRE) is a local non-thermal ablative technique currently used to treat solid tumors. Here, we investigated the clinical potency and safety of IRE with an endoscope in the upper gastrointestinal tract. Pigs were electroporated with recently designed endoscopic IRE catheters in the esophagus, stomach, and duodenum. Two successive strategies were introduced to optimize the electrical energy for the digestive tract. First, each organ was electroporated and the energy upscaled to confirm the upper limit energy inducing improper tissue results, including bleeding and perforation. Excluding the unacceptable energy from the first step, consecutive electroporations were performed with stepwise reductions in energy to identify the energy that damaged each layer. Inceptive research into inappropriate electrical intensity contributed to extensive hemorrhage and bowel perforation for each tissue above a certain energy threshold. However, experiments performed below the precluded energy accompanying hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays showed that damaged mucosal area and depth significantly decreased with decreased energy. Relevant histopathology showed infiltration of inflammatory cells with pyknotic nuclei at the electroporated lesion. This investigation demonstrated the possibility of endoscopic IRE in mucosal dysplasia or early malignant tumors of the hollow viscus., (© 2021. The Author(s).)

Many groups are working to improve the results of clinical allogeneic islet transplantation in a primate model. However, few studies have focused on the optimal islet dose for achieving normal glycemia without exogenous insulin after transplantation in primate models or on the relationship between rejection and islet amyloid polypeptide (IAPP) expression. We evaluated the dose (10,000, 20,000, and > 25,000 islet equivalents (IEQ)/kg) needed to achieve normal glycemia without exogenous insulin after transplantation using eleven cynomolgus monkeys, and we analyzed the characteristics exhibited in the islets after transplantation. 10,000 IEQ/kg (N = 2) failed to control blood glucose level, despite injection with the highest dose of exogenous insulin, and 20,000 IEQ/kg group (N = 5) achieved unstable control, with a high insulin requirement. However, 25,000 IEQ/kg (N = 4) achieved normal glycemia without exogenous insulin and maintained it for more than 60 days. Immunohistochemistry results from staining islets found in liver biopsies indicated that as the number of transplanted islets decreased, the amount of IAPP accumulation within the islets increased, which accelerated CD3 + T cell infiltration. In conclusion, the optimal transplantation dose for achieving a normal glycemia without exogenous insulin in our cynomolgus monkey model was > 25,000 IEQ/kg, and the accumulation of IAPP early after transplantation, which depends on the transplanted islet dose, can be considered one factor in rejection.

The use of kidneys from donation after brain death (DBD) donors with acute kidney injury (AKI) is a strategy to expand the donor pool. The aim of this study was to evaluate how kidney transplantation (KT) from a donor with AKI affects long-term graft survival in various situations. All patients who underwent KT from DBD donors between June 2003 and April 2016 were retrospectively reviewed. The KDIGO (Kidney Disease: Improving Global Outcomes) criteria were used to classify donor AKI. The cohort included 376 donors (no AKI group, n = 117 [31.1%]; AKI group n = 259 [68.9%]). Death-censored graft survival was similar according to the presence of AKI, AKI severity, and the AKI trend (p = 0.929, p = 0.077, and p = 0.658, respectively). Patients whose donors had AKI who received using low dose (1.5 mg/kg for three days) rabbit anti-thymocyte globulin (r-ATG) as the induction agent had significantly superior death-censored graft survival compared with patients in that group who received basiliximab (p = 0.039). AKI in DBD donors did not affect long-term death-censored graft survival. Low-dose r-ATG may be considered as an induction immunosuppression in recipients receiving kidneys with AKI because it showed better graft survival than basiliximab.

The primary purpose was to examine the relationship between the muscle architectural characteristics of short and long-distance cyclist-including muscle thickness, fascicle angle, and fascicle length-of the anterior thigh and posterior leg and its impact in 20-s cycling power. The secondary purpose was to clarify the muscle variables that predict the cycling power by using ultrasonography to measure the muscle architectural characteristics. Twenty-four varsity cyclists participated in this study, of whom 12 were short-distance cyclists and 12 were long-distance cyclists. B-mode ultrasonography was used to measure muscle architecture parameters. A cycle ergometer was used to measure the cycling power. The rectus femoris, vastus medialis, and medial head of gastrocnemius were significantly thicker in short-distance cyclists than in long-distance cyclists at every site (p < 0.05). Our analysis revealed that the rectus femoris fascicle length at the 30% level of the thigh was a significant independent predictor of the 20-s cycling power in short-distance cyclists, while the rectus femoris fascicle angle at the 50% level was that of the 20-s cycling power in long-distance cyclists. These findings highlight the significance of rectus femoris muscle architecture to cycling power.

Sepsis is caused by organ dysfunction initiated by an unrestrained host immune response to infection. The emergence of antibiotic-resistant bacteria has rapidly increased in the last decades and has stimulated a firm research platform to combat infections caused by antibiotic-resistant bacteria that cannot be eradicated with conventional antibiotics. Strategies like epigenetic regulators such as lysine demethylase (Kdm) has received attention as a new target. Thus, we sought to investigate the epigenetic mechanisms in sepsis pathophysiology with the aim of discovering new concepts for treatment. A transcriptome analysis of dendritic cells during their inflammatory state identified Kdm as a critical molecule in sepsis regulation. Next, 8-hydroxyquinoline-5-carboxylic acid (IOX1) ability to control endotoxemia induced by Lipopolysaccharide and bacterial sepsis was demonstrated. IOX1 has been shown to regulate endotoxemia and sepsis caused by Escherichia coli and carbapenem-resistant Acinetobacter baumannii and has also contributed to the suppression of multidrug-resistant bacterial growth through the inhibition of DNA Gyrase. These findings show that IOX1 could be a component agent against bacterial sepsis by functioning as a broad-spectrum antibiotic with dual effects.

Diabetic nephropathy (DN) is a major complication of diabetes mellitus. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that has been involved in the progression of several kidney injuries. However, the roles of NQO1 in DN are still unclear. We investigated the effects of NQO1 deficiency in streptozotocin (STZ)-induced DN mice. NQO1 was upregulated in the glomerulus and podocytes under hyperglycemic conditions. NQO1 knockout (NKO) mice showed more severe changes in blood glucose and body weight than WT mice after STZ treatment. Furthermore, STZ-mediated pathological parameters including glomerular injury, blood urea nitrogen levels, and foot process width were more severe in NKO mice than WT mice. Importantly, urine albumin-to-creatinine ratio (ACR) was higher in healthy, non-treated NKO mice than WT mice. ACR response to STZ or LPS was dramatically increased in the urine of NKO mice compared to vehicle controls, while it maintained a normal range following treatment of WT mice. More importantly, we found that NQO1 can stimulate actin polymerization in an in vitro biochemical assay without directly the accumulation on F-actin. In summary, NQO1 has an important role against the development of DN pathogenesis and is a novel contributor in actin reorganization via stimulating actin polymerization.

We have investigated the effects of hydrogen adsorption on the [Formula: see text] topological insulator by using the density functional theory calculations. We found that hydrogen adsorption on the surface leads to surface reconstruction to reduce the band bending effect. Contrasting to a previous report that hydrogen adsorption transforms the single Dirac cone at the Brillouin zone center into three Dirac cones at the zone boundary, the Dirac cones at the zone center corresponding to the topological surface states were confirmed to be robust against the hydrogen adsorption and surface reconstruction. Hydrogen adsorption induces a Rashba-like spin-splitting of the topological surface state, and can introduce Rashba-like quantum well states within the bulk gap, which can be attributed to a semiconductor-like band bending at an interface.

PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA-mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G 0 /G 1 phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA-mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA-mutant cells. Alpelisib partially reversed epithelial-mesenchymal transition markers in PIK3CA-mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA-mutant GC cells.

Our density functional theory calculations show that tiny-gap semiconductor SiGe monolayer is a quantum valley Hall insulator with a spontaneous electric polarization and, under a small biaxial strain, undergoes a topological phase transition between the states with opposite valley Chern numbers. The topological phase transition entails abrupt inversion of the in-plane electric polarization corresponding to inversion of the sublattice pseudospin polarization, while the out-of-plane electric polarization shows a linear response to the biaxial strain as well as to the perpendicular electric field regardless of the phase transition. Thus, the quantum valley Hall state entails in-plane ferroelectricity corresponding to a sublattice pseudospin ferromagnetism.

Threatened miscarriage is a common gynaecological emergency, with up to 25% of women eventually progressing to spontaneous miscarriage. The uncertainty of pregnancy outcomes results in significant anxiety. However, there is currently no acceptable framework for triaging patients presenting with threatened miscarriage. We aim to evaluate the efficacy and safety of a novel clinical protocol using a single serum progesterone level to prognosticate and guide management of patients with threatened miscarriage. 1087 women presenting with threatened miscarriage were enrolled in the study. The primary outcome was spontaneous miscarriage by 16 weeks' gestation. Among the 77.9% (847/1087) of study participants with serum progesterone ≥ 35 nmol/L who were not treated with oral dydrogesterone, the miscarriage rate was 9.6% (81/847). This did not differ significantly from the 8.5% (31/364) miscarriage rate observed in our prior studies; p = 0.566. Among women with serum progesterone < 35 nmol/L who were treated with dydrogesterone, the miscarriage rate was 70.8% (170/240). Our novel clinical triage protocol using a single serum progesterone level allowed both effective risk stratification and a reduction in progestogen use with no significant adverse pregnancy outcomes. This protocol, based on a single serum progesterone cutoff, can be readily adapted for use in other healthcare institutions.

The mitochondrial calcium uniporter (MCU) plays essential roles in mitochondrial calcium homeostasis and regulates cellular functions, such as energy synthesis, cell growth, and development. Thus, MCU activity is tightly controlled by its regulators as well as post-translational modification, including phosphorylation by protein kinases such as proline-rich tyrosine kinase 2 (Pyk2) and AMP-activated protein kinase (AMPK). In our in vitro kinase assay, the MCU N-terminal domain (NTD) was phosphorylated by protein kinase C isoforms (PKC βII , PKC δ , and PKC ε ) localized in the mitochondrial matrix. In addition, we found the conserved S92 was phosphorylated by the PKC isoforms. To reveal the structural effect of MCU S92 phosphorylation (S92p), we determined crystal structures of the MCU NTD of S92E and D119A mutants and analysed the molecular dynamics simulation of WT and S92p. We observed conformational changes of the conserved loop2-loop4 (L2-L4 loops) in MCU NTD S92E , NTD D119A , and NTD S92p due to the breakage of the S92-D119 hydrogen bond. The results suggest that the phosphorylation of S92 induces conformational changes as well as enhancements of the negative charges at the L2-L4 loops, which may affect the dimerization of two MCU-EMRE tetramers.

Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in tumor microenvironments. These cells strongly support tumor progression and are considered to be potent therapeutic targets. Therefore, drugs targeting CAFs have been developed, but most of them have failed in clinical trials. The discovery of additional drugs to inactivate or eliminate CAFs is thus essential. In this study, we developed a high-throughput screening system to find anti-CAF drugs using reporter cells that express Twist1 promoter-GFP. This screening system uses the activity of the Twist1 promoter as an indicator of CAF activation because Twist1 is known to be a central player in CAF activation. Using this screening system, we found that dihydrorotenone (DHR), an inhibitor of electron transfer chain complex 1 in mitochondria, can effectively deactivate CAFs. DHR-treated CAFs exhibited reduced expression of CAF-enriched markers, decreased capability of collagen gel contraction, and impaired ability to engage in tumor-promoting activities, such as facilitating the proliferation and colonization of cancer cells. Furthermore, conditioned media from DHR-treated CAFs attenuated tumor progression in mice grafted with MNK28 cells. In conclusion, DHR can be considered as a candidate drug targeting CAFs.

We have investigated the valley Chern number and gapless edge states in wide-gap semiconductor SiC and BN monolayers by using the density functional theory calculations. We found that while SiC monolayer has a non-quantized valley Chern number due to a partial mixing of the Berry curvature peaks pertaining to the opposite valleys, there exist topologically protected gapless edge states within the bulk gap, leading to a quantum valley Hall effect. Doping of the opposite charge carriers causes a backscattering-free valley current flowing on the opposite edge, which can be used for experimental confirmation and application at room temperature. BN monolayer, on the other hand, was found to have gapped edge states due to the too large staggered AB-sublattice potentials.

The most obvious method to observe transplanted islets in the liver is direct biopsy, but the distribution and location of the best biopsy site in the recipient's liver are poorly understood. Islets transplanted into the whole liver of five diabetic cynomolgus monkeys that underwent insulin-independent survival for an extended period of time after allo-islet transplantation were analyzed for characteristics and distribution tendency. The liver was divided into segments (S1-S8), and immunohistochemistry analysis was performed to estimate the diameter, beta cell area, and islet location. Islets were more distributed in S2 depending on tissue size; however, the number of islets per tissue size was high in S1 and S8. Statistical analysis revealed that the characteristics of islets in S1 and S8 were relatively similar to other segments despite various transplanted islet dosages and survival times. In conclusion, S1, which exhibited high islet density and reflected the overall characteristics of transplanted islets, can be considered to be a reasonable candidate for a liver biopsy site in this monkey model. The findings obtained from the five monkey livers with similar anatomical features to human liver can be used as a reference for monitoring transplanted islets after clinical islet transplantation.

LeuO plays the role of a master regulator in the cyclic-L-phenylalanine-L-proline (cFP)-dependent signaling pathway in Vibrio vulnificus. cFP, as shown through isothermal titration calorimetry analysis, binds specifically to the periplasmic domain of ToxR. Binding of cFP triggers a change in the cytoplasmic domain of ToxR, which then activates transcription of leuO encoding a LysR-type regulator. LeuO binds to the region upstream of its own coding sequence, inhibiting its own transcription and maintaining a controlled level of expression. A five-bp deletion in this region abolished expression of LeuO, but a ten-bp deletion did not, suggesting that a DNA bending mechanism is involved in the regulation. Furthermore, binding of RNA polymerase was significantly lower both in the deletion of the ToxR binding site and in the five-bp deletion, but not in the ten-bp deletion, as shown in pull-down assays using an antibody against RNA polymerase subunit α. In summary, multiple factors are involved in control of the expression of LeuO, a master regulator that orchestrates downstream regulators to modulate factors required for survival and pathogenicity of the pathogen.

Our density functional theory calculations show that while AB-stacked bilayer silicene has a non-quantized spin-valley Chern number, there exist backscattering-free gapless edge states within the bulk gap, leading to a quantum spin-valley Hall effect. Using a tight-binding model for a honeycomb bilayer, we found that the interlayer potential difference and the staggered AB-sublattice potential lead to abrupt and gradual change of the valley Chern number from a quantized value to zero, respectively, while maintaining backscattering-free gapless edge states if the valley Chern number is not too close to zero. Under an inversion symmetry-breaking potential in the form of the staggered AB-sublattice potential, such as an antiferromagnetic order and a hexagonal diatomic sheet, a finite but non-quantized (spin-)valley Chern number can correspond to a quantum (spin-)valley Hall insulator.

Non-alcoholic fatty liver disease (NAFLD) is excessive fat build-up in the liver without alcohol consumption and includes hepatic inflammation and damage. Excessive influx of fatty acids to liver from circulation is thought to be a pathogenic cause for the development of NAFLD. Thus, inhibition of fatty acid intake into hepatocyte would be a maneuver for protection from high fat diet (HFD)-induced NAFLD. This study was initiated to determine whether sodium fluorocitrate (SFC) as a fatty acid uptake inhibitor could prevent palmitate-induced lipotoxicity in hepatocytes and protect the mice from HFD-induced NAFLD. SFC significantly inhibited the cellular uptake of palmitate in HepG2 hepatocytes, and thus prevented palmitate-induced fat accumulation and death in these cells. Single treatment with SFC reduced fasting-induced hepatic steatosis in C57BL/6J mice. Concurrent treatment with SFC for 15 weeks in HFD-fed C57BL/6J mice prevented HFD-induced fat accumulation and stress/inflammatory signal activation in the liver. SFC restored HFD-induced increased levels of serum alanine aminotransferase and aspartate aminotransferases as hepatic injury markers in these mice. SFC treatment also improved HFD-induced hepatic insulin resistance, and thus ameliorated HFD-induced hyperglycemia. In conclusion, inhibition of fatty acid mobilization into liver through SFC treatment can be a strategy to protect from HFD-induced NAFLD.

Enoyl-acyl carrier protein reductase (ENR) catalyzes the last reduction step in the bacterial type II fatty acid biosynthesis cycle. ENRs include FabI, FabL, FabL2, FabK, and FabV. Previously, we reported a unique triclosan (TCL) resistant ENR homolog that was predominant in obligate intracellular pathogenic bacteria and Apicomplexa. Herein, we report the biochemical and structural basis of TCL resistance in this novel ENR. The purified protein revealed NADH-dependent ENR activity and shared similarity to prototypic FabI. Thus, this metagenome-derived ENR was designated FabI2. Unlike other prototypic bacterial ENRs with the YX 6 K type catalytic domain, FabI2 possessed a unique YX 7 K type catalytic domain. Computational modeling followed by site-directed mutagenesis revealed that mild resistance (20 µg/ml of minimum inhibitory concentration) of FabI2 to TCL was confined to the relatively less bulky side chain of A128. Substitution of A128 in FabI2 with bulky valine (V128) elevated TCL resistance. Phylogenetic analysis further suggested that the novel FabI2 and prototypical FabI evolved from a common short-chain dehydrogenase reductase family. To our best knowledge, FabI2 is the only known ENR shared by intracellular pathogenic prokaryotes, intracellular pathogenic lower eukaryotes, and a few higher eukaryotes. This suggests that the ENRs of prokaryotes and eukaryotes diverged from a common ancestral ENR of FabI2.

The risk of lung cancer is higher in idiopathic pulmonary fibrosis (IPF) because both conditions share common risk factors. However, no standard treatment modality for LC in IPF exists due to rare incidence, poor prognosis, and acute exacerbation (AE) of IPF during treatment. We aimed to determine the efficacy of LC treatments and the prognosis in LC patients with IPF according to the LC stage and GAP (gender [G], age [A], and two physiology variables [P]) stage. From 2003 to 2016, 160 retrospectively enrolled patients were classified according to the LC clinical stage and GAP stage. The average (±standard deviation) patient age was 70.1 ± 8.2 years; the cohort predominantly comprised men (94.4%). In GAP stage I, surgery was significantly associated with better survival outcomes in LC. In contrast, no treatment modality yielded significant clinical improvement in GAP stage II/III. The incidences of AE in IPF and its mortality during treatment were 13.8% and 6.3%, respectively. AE occurred commonly in advanced GAP stage. Active treatment should be considered in GAP stage I. The performance status and LC stage should be considered when deciding about the necessity of surgery for patients in advanced GAP stage.

The impact on infant caregiver as a reservoir of pathogens has not been exploited with perspective to powdered infant formula (PIF). Here we reveal novel route of pathogen transfer through hand-spoon-PIF unexpectedly occurred by even typical practices of caregivers, handling of PIF and storage of feeding-spoon in PIF container. Hand-spoon-PIF contamination route was simulated to analyze the transfer and subsequent survival of pathogens. Major pathogens associated with infantile fatal diseases (Cronobacter sakazakii, Salmonella enterica, Staphylococcus aureus) were readily transmitted to PIF from skin (3-6 log CFU/hand) via spoons following long-term survival of transferred pathogens (3 weeks; use-by date of PIF) as the excessive level of infectious dose, highlighting direct onset of diseases. Low bacterial load on skin (ca. 1 log CFU/hand) could prevent cross-contamination of PIF, however, at least 72 h survival of transferred pathogen on spoons demonstrated the probability on re-contamination of PIF. To our knowledge, this is the first study to investigate the cross-contamination of utensils in contact with powdered-foods. Bacterial load on hands is the key determinant of pathogen transfer and the extent of risk are species-dependent. These evidential results redefine risk of caregivers' practices and facilitate incorporation of cross-contamination into risk-assessment as underestimated route of infection.

Soy isoflavones, particularly genistein, have been shown to exhibit anti-obesity effects. When compared with the isoflavones genistin, daidzin, coumestrol, genistein, daidzein, 6-o-dihydroxyisoflavone, equol, 3'-o-dihydroxyisoflavone, and 8-o-dihydroxyisoflavone, a remarkably higher inhibitory effect on lipid accumulation was observed for orobol treatment during adipogenesis in 3T3-L1 cells. To identify the cellular target of orobol, its pharmacological effect on 395 human kinases was analyzed. Of the 395 kinases, orobol showed the lowest half maximal inhibitory concentration (IC 50 ) for Casein Kinase 1 epsilon (CK1ε), and bound to this target in an ATP-competitive manner. A computer modeling study revealed that orobol may potentially dock with the ATP-binding site of CK1ε via several hydrogen bonds and van der Waals interactions. The phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, a substrate of CK1ε, was inhibited by orobol in isobutylmethylxanthine, dexamethasone and insulin (MDI)-induced 3T3-L1 cells. It was also found that orobol attenuates high fat diet-induced weight gain and lipid accumulation without affecting food intake in C57BL/6J mice. These findings underline orobol's potential for development as a novel agent for the prevention and treatment of obesity.

The purpose of this study was to evaluate the prognostic impact of major histocompatibility complex (MHC) class I expression and programmed death-ligand 1 (PD-L1) expression in patients with head and neck squamous cell carcinoma (HNSCC). A total of 158 patients with HNSCC were evaluated retrospectively. The expression of MHC class I and PD-L1 was analyzed in tumor specimens using immunohistochemistry. The association between MHC class I/PD-L1 expression and clinical outcome was evaluated by Kaplan-Meier and Cox regression analyses. Among 158 patients, 103 (65.2%) showed positive PD-L1 expression, and 20 (12.7%) showed no detectable expression of MHC class I. The frequency of PD-L1 positive expression with concomitant MHC class I loss was 7.0%. In the PD-L1-positive group, MHC class I loss was associated with a significantly worse survival compared with MHC class I positivity (median overall survival 39.3 months vs. not reached; P = 0.005), whereas MHC class I status provided no prognostic impact in the PD-L1 negative group. Neither PD-L1 nor MHC class I alone showed a significant difference in overall survival. The loss of MHC class I expression in PD-L1-positive HNSCC was associated with a poor clinical outcome. This suggested that MHC class I expression status might be useful for the prognosis of tumor progression in HNSCC when combined with PD-L1 expression status. External validation with enough numbers of participants in such subgroup should be needed for validation.

Napier grass is an important tropical forage-grass and of growing potential as an energy crop. One-hundred-five Napier grass accessions, encompassing two independent collections, were subjected to genotyping by sequencing which generated a set of high-density genome-wide markers together with short sequence reads. The reads, averaging 54 nucleotides, were mapped to the pearl millet genome and the closest genes and annotation information were used to select candidate genes linked to key forage traits. 980 highly polymorphic SNP markers, distributed across the genome, were used to assess population structure and diversity with seven-subgroups identified. A few representative accessions were selected with the objective of distributing subsets of a manageable size for further evaluation. Genome-wide linkage disequilibrium (LD) analyses revealed a fast LD-decay, on average 2.54 kbp, in the combined population with a slower LD-decay in the ILRI collection compared with the EMBRAPA collection, the significance of which is discussed. This initiative generated high-density markers with a good distribution across the genome. The diversity analysis revealed the existence of a substantial amount of variation in the ILRI collection and identified some unique materials from the EMBRAPA collection, demonstrating the potential of the overall population for further genetic and marker-trait-association studies.

While 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) has been investigated in extremity sarcomas, there is no evidence on its usefulness in retroperitoneal sarcoma. This study was designed to evaluate the usefulness of 18 F-FDG PET/CT in predicting aggressiveness of retroperitoneal liposarcoma. Patients experienced surgery for retroperitoneal liposarcoma from November 2007 to February 2018 and underwent preoperative 18 F-FDG PET/CT were included. Preoperative maximum standardized uptake value (SUV max ) was calculated. To evaluate the predictability of SUV max for Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 3, receiver operating characteristics (ROC) curve analysis was performed. To analyze whether SUV max can be a risk factor for prognosis, multivariable Cox regression was performed including potential risk factors regarding operation and histopathology. A total of 133 patients were included. ROC curve showed area under the curve of 0.877 (P < 0.001), with a cut-off point of 4.5 SUV max showing 85.7% sensitivity and 78.3% specificity. Cox analyses showed that SUV max  > 4.5 was a significant factor for recurrence-free survival (HR = 2.148, CI 1.301-3.546, P = 0.003) and overall survival (HR = 5.052, CI 1.854-13.766, P = 0.002). SUV max is highly predictive of FNCLCC grade 3 and SUV max  > 4.5 can be used as a prognostic factor before obtaining the histopathology.

A large optical nonlinearity has been observed for the photo-responsive liquid crystals under the condition that the nematic phase is close to the isotropic condition. The direct observation of the photo-response of a liquid crystal by the time-resolved transient grating phase imaging technique revealed that the optical nonlinearity was caused by the transiently generated phase formed inside the photo-induced isotropic region. A shock-like flow was observed for the formation of the transiently generated phase. Based on the theoretical calculation, we propose that a flow generated at the disordered/ordered interface induced the reorientation of the liquid crystal molecules, thereby generating a larger polarization and ultimately causing the optical nonlinearity.

Various treatment methods for tracheal defects have been attempted, such as artificial implants, allografts, autogenous grafts, and tissue engineering; however, no perfect method has been established. We attempted to create an effective artificial trachea via a tissue engineering method using 3D bio-printing. A multi-layered scaffold was fabricated using a 3D printer. Polycaprolactone (PCL) and hydrogel were used with nasal epithelial and auricular cartilage cells in the printing process. An artificial trachea was transplanted into 15 rabbits and a PCL scaffold without the addition of cells was transplanted into 6 rabbits (controls). All animals were followed up with radiography, CT, and endoscopy at 3, 6, and 12 months. In the control group, 3 out of 6 rabbits died from respiratory symptoms. Surviving rabbits in control group had narrowed tracheas due to the formation of granulation tissue and absence of epithelium regeneration. In the experimental group, 13 of 15 animals survived, and the histologic examination confirmed the regeneration of epithelial cells. Neonatal cartilage was also confirmed at 6 and 12 months. Our artificial trachea was effective in the regeneration of respiratory epithelium, but not in cartilage regeneration. Additional studies are needed to promote cartilage regeneration and improve implant stability.

Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to treat metabolic diseases; however, most of them exhibit side effects such as body weight gain and oedema. Therefore, we developed a novel PPARα/γ dual agonist that modulates glucose and lipid metabolism without adverse effects. We synthesised novel compounds composed of coumarine and chalcone, determined their crystal structures, and then examined their binding affinity toward PPARα/γ. We investigated the expression of PPARα and PPARγ target genes by chemicals in HepG2, differentiated 3T3-L1, and C2C12 cells. We examined the effect of chemicals on glucose and lipid metabolism in db/db mice. Only MD001 functions as a PPARα/γ dual agonist in vitro. MD001 increased the transcriptional activity of PPARα and PPARγ, resulting in enhanced expression of genes related to β-oxidation and fatty acid and glucose uptake. MD001 significantly improved blood metabolic parameters, including triglycerides, free fatty acids, and glucose, in db/db mice. In addition, MD001 ameliorated hepatic steatosis by stimulating β-oxidation in vitro and in vivo. Our results demonstrated the beneficial effects of the novel compound MD001 on glucose and lipid metabolism as a PPARα/γ dual agonist. Consequently, MD001 may show potential as a novel drug candidate for the treatment of metabolic disorders.

This study aimed to clarify intersection patterns and points among the superficial temporal artery (STA), superficial temporal vein (STV), and auriculotemporal nerve (ATN) based on surface anatomical landmarks to provide useful anatomical information for surgical decompression treatments of migraine headaches in Asians. Thirty-eight hemifaces were dissected. The positional patterns among the ATN, STA, and STV were divided into three morphological types. In type I, the ATN ran toward the temporal region and superficially intersected the STA and STV (n = 32, 84.2%). In type II, the ATN ran toward the temporal region and deeply intersected the STA and STV (n = 4, 10.5%). In type III, the ATN ran toward the temporal region and deeply intersected the STV alone (n = 2, 5.3%). The intersection points of types II and III were 10.3 ± 5.6 mm (mean ± SD) and 10.4 ± 6.1 mm anterior and 42.1 ± 21.6 mm and 41.4 ± 18.7 mm superior to the tragus, respectively. The ATN superficially intersected the STA and STV in all the Korean cadaver, while the ATN deeply intersected the STA and STV in 15% of the Thai cadavers. The pattern of the ATN deeply intersecting the STA and STV was less common in present Asian populations than in previously-reported Caucasian populations, implying that migraine headaches (resulting from the STA and STV compressing the ATN) are less common in Asians.