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Obstructive sleep apnea (OSA) is a common disorder characterized by upper airway obstruction during sleep. To reduce the morbidity of OSA, sleep specialists have explored various methods of managing the condition, including manifold positive airway pressure (PAP) techniques and surgical procedures. Nasal obstruction can cause significant discomfort during sleep, and it is likely that improving nasal obstruction would enhance the quality of life and PAP compliance of OSA patients. Many reliable studies offer evidence to support this assumption. However, few comprehensive guidelines for managing OSA OSA through nasal surgery encompass all this evidence. In order to address this gap, the Korean Society of Otorhinolaryngology–Head and Neck Surgery and the Korean Society of Sleep and Breathing designated a guideline development group (GDG) to develop recommendations for nasal surgery in OSA patients. Several databases, including OVID Medline, Embase, the Cochrane Library, and KoreaMed, were searched to identify all relevant papers using a pre

The thyroid gland plays a critical role in the maintenance of whole-body metabolism. However, aging frequently impairs homeostatic maintenance by thyroid hormones due to increased prevalence of subclinical hypothyroidism associated with mitochondrial dysfunction, inflammation, and fibrosis. To understand the specific aging-related changes of endocrine function in thyroid epithelial cells, we performed single-cell RNA sequencing (RNA-seq) of 54 726 cells derived from pathologically normal thyroid tissues from 7 patients who underwent thyroidectomy. Thyroid endocrine epithelial cells were clustered into 5 distinct subpopulations, and a subset of cells was found to be particularly vulnerable with aging, showing functional deterioration associated with the expression of metallothionein (MT) and major histocompatibility complex class II genes. We further validated that increased expression of MT family genes are highly correlated with thyroid gland aging in bulk RNAseq datasets. This study provides evidence that aging induces specific transcriptomic changes across multiple cell populations in the human thyroid gland.

Radical new possibilities of improved treatment of cancer are on offer from an advanced medical technology already demonstrating its significance: next-generation sequencing (NGS). This refined testing provides unprecedentedly precise diagnoses and permits the use of focused and highly personalized treatments. However, across regions globally, many cancer patients will continue to be denied the benefits of NGS as long as some of the yawning gaps in its implementation remain unattended. The challenges at the regional and national levels are linked because putting the solutions into effect is highly dependent on cooperation between regional- and national-level cooperation, which could be hindered by shortfalls in interpretation or understanding. The aim of the paper was to define and explore the necessary conditions for NGS and make recommendations for effective implementation based on extensive exchanges with policy makers and stakeholders. As a result, the European Alliance for Personalised Medicine (EAPM) developed a maturity framework structured around demand-side and supply-side issues to enable interested stakeholders in different countries to self-evaluate according to a common matrix. A questionnaire was designed to identify the current status of NGS implementation, and it was submitted to different experts in different institutions globally. This revealed significant variability in the different aspects of NGS uptake. Within different regions globally, to ensure those conditions are right, this can be improved by linking efforts made at the national level, where patients have needs and where care is delivered, and at the global level, where major policy initiatives in the health field are underway or in preparation, many of which offer direct or indirect pathways for building those conditions. In addition, in a period when consensus is still incomplete and catching up is needed at a political level to ensure rational allocation of resources—even within individual countries—to enable the best ways to make the necessary provisions for NGS, a key recommendation is to examine where closer links between national and regional actions could complement, support, and mutually reinforce efforts to improve the situation for patients.

IntroductionDespite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. MethodsHere, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. ResultsDifferential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. DiscussionAberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression.

Purpose To evaluate pregnancy outcomes according to placental location in women with placenta previa and to evaluate the risk of adverse outcomes in women with anterior placenta previa. Methods This retrospective cohort study was conducted on cesarean deliveries due to placenta previa at three university hospitals between May 1999 and February 2020. Patients were categorized into anterior previa (209 women) and posterior previa (572 women) groups. We analyzed the demographic factors, obstetric outcomes, and neonatal outcomes of the two groups. Results High maternal parity was associated with a greater occurrence of anterior placenta previa. More pregnant women in the anterior group were hospitalized because of vaginal bleeding during pregnancy. A high percentage of patients in the anterior group had undergone a previous cesarean section. Blood transfusion is more common among patients with anterior placenta previa thanthose with posterior placenta previa;anterior placenta previa is more likely to accompany placenta accreta spectrum. In the anterior group, more cases were born with an abnormal fetal presentation. Conclusion Anterior previa is more common in higher parity and is more fatal than posterior previa because of increased maternal morbidity such as excessive blood loss, massive transfusion, and placental accreta. It is important to accurately determine the location of the placenta using ultrasound during antenatal care visits. A multidisciplinary approach becomes relevant in the case of anterior PP because of the risk of bleeding that necessitates blood transfusion.

Motivation Protein complex structure prediction is important for many applications in bioengineering. A widely used method for predicting the structure of protein complexes is computational docking. Although many tools for scoring protein–protein docking models have been developed, it is still a challenge to accurately identify near-native models for unknown protein complexes. A recently proposed model called the geometric vector perceptron–graph neural network (GVP-GNN), a subtype of equivariant graph neural networks, has demonstrated success in various 3D molecular structure modeling tasks. Results Herein, we present G-RANK, a GVP-GNN-based method for the scoring of protein-protein docking models. When evaluated on two different test datasets, G-RANK achieved a performance competitive with or better than the state-of-the-art scoring functions. We expect G-RANK to be a useful tool for various applications in biological engineering. Availability and implementation Source code is available at https://github.com/ha01994/grank. Contact kds@kaist.ac.kr Supplementary information Supplementary data are available at Bioinformatics Advances online.

Distinguishing how genetics impact cellular processes can improve our understanding of variable risk for diseases. Although single-cell omics have provided molecular characterization of cell types and states on diverse tissue samples, their genetic ancestry and effects on cellular molecular traits are largely understudied. Here, we developed Monopogen, a computational tool enabling researchers to detect single nucleotide variants (SNVs) from a variety of single cell transcriptomic and epigenomic sequencing data. It leverages linkage disequilibrium from external reference panels to identify germline SNVs from sparse sequencing data and uses Monovar to identify novel SNVs at cluster (or cell type) levels. Monopogen can identify 100K~3M germline SNVs from various single cell sequencing platforms (scRNA-seq, snRNA-seq, snATAC-seq etc), with genotyping accuracy higher than 95%, when compared against matched whole genome sequencing data. We applied Monopogen on human retina, normal breast and Asian immune diversity atlases, showing that that derived genotypes enable accurate global and local ancestry inference and identification of admixed samples from ancestrally diverse donors. In addition, we applied Monopogen on ~4M cells from 65 human heart left ventricle single cell samples and identified novel variants associated with cardiomyocyte metabolic levels and epigenomic programs. In summary, Monopogen provides a novel computational framework that brings together population genetics and single cell omics to uncover genetic determinants of cellular quantitative traits.

By matching domestic ODA projects for specific implementation in accordance with the 2020 Fire and Disaster Prevention Agency Facility Infrastructure Master Plan and 2030 Vision, a social safety net construction project in Vietnam, its business feasibility was analyzed. Vietnam is undergoing rapid change and urbanization. As a result, demand in the firefighting sector is expected to increase rapidly. Because there are no domestic manufacturers of firefighting vehicles in Vietnam, the demand is largely satisfied through imports; however, the firefighting vehicles and additional devices provided through this ODA project should greatly contribute to the promotion of domestic exports. To represent the environmental factors that can cause fires in 58 provinces, the selection of project areas to support firefighting vehicles is based on population, jurisdictional area, population density, age of firefighting vehicles, number of firefighting targets, and number of firefighting vehicles in the past four years; the trend of reinforcement of firefighting vehicles and regional characteristics is determined. Twelve provinces in Vietnam were selected in the same way as the selected areas to support firefighting vehicles. This ODA project is expected to provide an opportunity to improve the legal and institutional aspects of the firefighting and disaster prevention field in Vietnam by applying domestic advanced firefighting force deployment standards.

Malignant tumours arising from the sublingual glands are very rare, and the extent and frequency of local invasion or regional spread in malignant sublingual gland tumour (MSLT) has not been fully studied due to the disease rarity. To provide comprehensive features of local and regional spread of MSLT, we reviewed 20 surgical cases for detailed pathological analyses among 26 cases diagnosed as having primary MSLT. Adenoid cystic carcinoma (ACC) was the most common pathological subtype, followed by mucoepidermoid carcinoma. Disease-free and overall survivals at 5 years were 76.1 % and 77.7 %, respectively. High-grade malignant tumours and grade 2-3 ACC accounted for 41.7 % and 85.7 %. Clinical and pathological extraparenchymal extensions were found in 34.6 % and 80.0 %, respectively. Tumour invasion to the lingual nerve and submandibular gland/ductal system were also detected in 40.0 % and 28.6 %. The incidences of lingual nerve invasion in ACC and ACC ≥4 cm were 30.8 % and 42.9 %. Regional nodal involvement occurred in seven of 26 cases, and all metastatic lymph nodes were found in neck levels Ib and IIa. In summary, a significant portion of MSLT cases consisted of high-grade tumours and grade 2-3 ACC; therefore local invasion into adjacent structures should be cautiously evaluated in cases of MSLT.

To investigate whether women with a short cervical length (CL), but delivered at term in the first pregnancy might have increased risks of having short cervix and spontaneous preterm birth (sPTB) in the subsequent pregnancies.This is a retrospective cohort study including singleton gestations who were delivered between Jan 2011 and Dec 2018, who had had one childbirth experience and who had transvaginal sonographic CL assessment performed at mid-trimester (18 ~ 30 weeks) in both pregnancy. The women were divided into four group according to the history of preterm birth and a short cervix ( 25 mm before 30 weeks of gestation): (1) the Preterm-short cervix group, (2) the Preterm-no shortening group, (3) the Term-short cervix group, and (4) the Term-no shortening group. We compared the risk of having short cervix and sPTB during the second pregnancy of women. Secondary outcomes were threatened preterm labor, need for tocolytics, and cerclage placement.A total of 804 women met our inclusion criteria. The rate of having short cervix ( 25 mm before 28 weeks of gestation) during the second pregnancy in women in the Term-short cervix group (43.2%) was significantly higher than those in women in the Term-no shortening group (6.6%), and in the Preterm-no shortening group (8.8%) (all p 0.001 with Bonferroni correction), but not higher than those in women with the Preterm-short cervix group (30.8%, p 0.05 with Bonferroni correction). When compared with women in the Preterm-no shortening group, women in the Term-short cervix group were also at an increased risk of need for need of tocolytics (60.2% vs. 26.5%) and cerclage placement (15.9% vs. 6.1%, all p 0.001). Women in the Term-short cervix group had an increased risk of sPTB ( 37 weeks) during the second pregnancy, as compared to those in the Term-no shortening group (adjusted odds ratio 5.098, 95% CI 2.107-11.874).Women with a history of short cervix in their first pregnancy, but who delivered at term, were at increased risk of having a short cervix and sPTB in their second pregnancy, as compared to women with a history of term delivery without cervical shortening. Thus, short cervix of the previous pregnancy might be a predictive factors for preterm birth in the subsequent pregnancy.

Many surgeons have modified the technique to reduce bleeding from anastomosis line since Bentall and De Bono introduced aortic root replacement using a composite graft. We present a new composite, butterfly wing–shaped, valve graft fixated using hand-made double sewing cuff. The “wings of a butterfly” technique is a method of reinforcement suturing between an added sewing cuff and residual aortic wall at the proximal stump and helps to reduce bleeding after the modified Bentall's procedure.

Objectives The introduction of Personalised Medicine (PM) into healthcare systems could benefit from a clearer understanding of the distinct national and regional frameworks around the world. Recent engagement by international regulators on maximising the use of real-world evidence (RWE) has highlighted the scope for improving the exploitation of the treasure-trove of health data that is currently largely neglected in many countries. The European Alliance for Personalised Medicine (EAPM) led an international study aimed at identifying the current status of conditions. Methods A literature review examined how far such frameworks exist, with a view to identifying conducive factors – and crucial gaps. This extensive review of key factors across 22 countries and 5 regions revealed a wide variety of attitudes, approaches, provisions and conditions, and permitted the construction of a comprehensive overview of the current status of PM. Based on seven key pillars identified from the literature review and expert panels, the data was quantified, and on the basis of further analysis, an index was developed to allow comparison country by country and region by region. Results The results show that United States of America is leading according to overall outcome whereas Kenya scored the least in the overall outcome. Conclusions Still, common approaches exist that could help accelerate take-up of opportunities even in the less prosperous parts of the world.

Owing to rapid advancements in NGS (next generation sequencing), genomic alteration is now considered an essential predictive biomarkers that impact the treatment decision in many cases of cancer. Among the various predictive biomarkers, tumor mutation burden (TMB) was identified by NGS and was considered to be useful in predicting a clinical response in cancer cases treated by immunotherapy. In this study, we directly compared the lab-developed-test (LDT) results by target sequencing panel, K-MASTER panel v3.0 and whole-exome sequencing (WES) to evaluate the concordance of TMB. As an initial step, the reference materials (n = 3) with known TMB status were used as an exploratory test. To validate and evaluate TMB, we used one hundred samples that were acquired from surgically resected tissues of non-small cell lung cancer (NSCLC) patients. The TMB of each sample was tested by using both LDT and WES methods, which extracted the DNA from samples at the same time. In addition, we evaluated the impact of capture region, which might lead to different values of TMB; the evaluation of capture region was based on the size of NGS and target sequencing panels. In this pilot study, TMB was evaluated by LDT and WES by using duplicated reference samples; the results of TMB showed high concordance rate (R2 = 0.887). This was also reflected in clinical samples (n = 100), which showed R2 of 0.71. The difference between the coding sequence ratio (3.49%) and the ratio of mutations (4.8%) indicated that the LDT panel identified a relatively higher number of mutations. It was feasible to calculate TMB with LDT panel, which can be useful in clinical practice. Furthermore, a customized approach must be developed for calculating TMB, which differs according to cancer types and specific clinical settings. [BMB Reports 2021; 54(7): 386-391].

Background Although the World Health Organization and health authorities in most countries recommend that pregnant women receive inactivated influenza virus vaccines, coverage remains low. This study aimed to investigate (1) the proportion of pregnant women who received an influenza vaccination and influencing factors and (2) the proportion of obstetrics and gynecology (OBGYN) doctors who routinely recommend influenza vaccination to pregnant women and influencing factors. Methods Two separate, anonymized questionnaires were developed for physicians and pregnant and postpartum women and were distributed to multicenters and clinics in South Korea. The proportions of women who received influenza vaccination during pregnancy and OBGYN doctors who routinely recommend the influenza vaccine to pregnant women were analyzed. Independent influencing factors for both maternal influenza vaccination and OBGYN doctors’ routine recommendations to pregnant women were analyzed using log-binomial regression analysis. Results The proportion of self-reported influenza vaccination during pregnancy among 522 women was 63.2%. Pregnancy-related independent factors influencing maternal influenza vaccination were “(ever) received information about influenza vaccination during pregnancy” (OR 8.9, 95% CI 4.17–19.01), “received vaccine information about from OBGYN doctors” (OR 11.44, 95% CI 5.46–24.00), “information obtained from other sources” (OR 4.38, 95% CI 2.01–9.55), and “second/third trimester” (OR 2.41, 95% CI 1.21–4.82).. Among 372 OBGYN doctors, 76.9% routinely recommended vaccination for pregnant women. Independent factors effecting routine recommendation were “working at a private clinic or hospital” (OR 5.33, 95% CI 2.44–11.65), “awareness of KCDC guidelines” (OR 3.11, 95% CI 1.11–8.73), and “awareness of the 2019 national free influenza vaccination program for pregnant women” (OR 4.88, 95% CI 2.34–10.17). OBGYN doctors most commonly chose ‘guidelines proposed by the government or public health (108, 46%) and academic committees (59, 25%), as a factor which expect to affect the future recommendation Conclusion This study showed that providing information about maternal influenza vaccination, especially by OBGYN doctors, is crucial for increasing vaccination coverage in pregnant women. Closer cooperation between the government and OBGYN academic societies to educate OBGYN doctors might enhance routine recommendations.

Loss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differential pharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WT-p.G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQ-regulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2., Hearing loss: genetically tailored treatment strategy for congenital deafness People with a certain type of inherited hearing loss may stand to benefit from a personalized, genetically tailored treatment strategy. A research team from South Korea led by Byung Yoon Choi from Seoul National University College of Medicine identified three new mutations in KCNQ4, a gene that encodes a potassium channel protein found in the inner ear, that can cause congenital deafness. Strikingly, the authors identified the first hyperactive KCNQ4 variant. They inserted these gene variants into human cells in culture, and found that drugs known to affect the activity of this channel protein had different effects on different mutations. Impairments caused by two of the variants were prevented by drug treatment; the third variant proved resistant to the same therapeutic approach. The authors propose further validating the therapeutic responsiveness of different KCNQ4 variants in genetically engineered mice.

Highlights • H&N radiation treatment plan directives are typically not patient-specific. • Patient-specific directives may facilitate the best-achievable dose distribution. • Use of an AI-guided tool significantly improved achieved dose for nearly all OARs., Background and purpose Volumetric modulated arc therapy (VMAT) planning for head and neck cancer is a complex process. While the lowest achievable dose for each individual organ-at-risk (OAR) is unknown a priori, artificial intelligence (AI) holds promise as a tool to accurately estimate the expected dose distribution for OARs. We prospectively investigated the benefits of incorporating an AI-based decision support tool (DST) into the clinical workflow to improve OAR sparing. Materials and methods The DST dose prediction model was based on 276 institutional VMAT plans. Under an IRB-approved prospective trial, the physician first generated a custom OAR directive for 50 consecutive patients (physician directive, PD). The DST then estimated OAR doses (AI directive, AD). For each OAR, the treating physician used the lower directive to form a hybrid directive (HD). The final plan metrics were compared to each directive. A dose difference of 3 Gray (Gy) was considered clinically significant. Results Compared to the AD and PD, the HD reduced OAR dose objectives by more than 3 Gy in 22% to 75% of cases, depending on OAR. The resulting clinical plan typically met these lower constraints and achieved mean dose reductions between 4.3 and 16 Gy over the PD, and 5.6 to 9.1 Gy over the AD alone. Dose metrics achieved using the HD were significantly better than institutional historical plans for most OARs and NRG constraints for all OARs. Conclusions The DST facilitated a significantly improved treatment directive across all OARs for this generalized H&N patient cohort, with neither the AD nor PD alone sufficient to optimally direct planning.

Previous studies suggested that genetic, environmental factors and their interactions could affect body fat mass (BFM). However, studies describing these effects were performed at a single time point in a population. In this study, we investigated the interaction between genetic and environmental factors in affecting BFM and implicate the healthcare utilization of lifestyle modifications from a personalized and genomic perspective. We examined how nutritional intake or physical activity changes in the individuals affect BFM concerning the genetic composition. We conducted an observational study including 259 adult participants with single nucleotide polymorphism (SNP) genotyping and longitudinal lifestyle monitoring, including food consumption and physical activities, by following lifestyle modification guidance. The participants’ lifelog data on exercise and diet were collected through a wearable device for 3 months. Moreover, we measured anthropometric and serologic markers to monitor their potential changes through lifestyle modification. We examined the influence of genetic composition on body fat reduction induced by lifestyle changes using genetic risk scores (GRSs) of three phenotypes: GRS-carbohydrate (GRS-C), GRS-fat (GRS-F), and GRS-exercise (GRS-E). Our results showed that lifestyle modifications affected BFM more significantly in the high GRS class compared to the low GRS class, indicating the role of genetic factors affecting the efficiency of the lifestyle modification-induced BFM changes. Interestingly, the influence of exercise modification in the low GRS class with active lifestyle change was lower than that in the high GRS class with inactive lifestyle change (P = 0.022), suggesting the implication of genetic factors for efficient body fat control.

Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (γδ) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of their unique properties such as non-reliance on major histocompatibility complex expression, their ability to infiltrate human tumors and recognize tumor antigens, relative insensitivity to immune checkpoint molecules, and broad tumor cytotoxicity. Therefore, it is now critical to better characterize human γδ T-cell subsets and their mechanisms in RCCs, especially the stage of differentiation. In this study, we aimed to identify γδ T cells that might have adaptive responses against RCC progression. We characterized γδ T cells in peripheral blood and tumor-infiltrating lymphocytes (TILs) in freshly resected tumor specimens from 20 RCC patients. Furthermore, we performed a gene set enrichment analysis on RNA-sequencing data from The Cancer Genome Atlas (TCGA) derived from normal kidneys and RCC tumors to ascertain the association between γδ T-cell infiltration and anti-cancer immune activity. Notably, RCC-infiltrating CD3low Vγ9Vδ1 T cells with a terminally differentiated effector memory phenotype with up-regulated activation/exhaustion molecules were newly detected as predominant TILs, and the cytotoxic activity of these cells against RCC was confirmed in vitro. In an additional analysis of the TCGA RCC dataset, γδ T-cell enrichment scores correlated strongly with those for CTLs, Th1 cells, “exhausted” T cells, and M1 macrophages, suggesting active involvement of γδ T cells in anti-tumor rather than pro-tumor activity, and Vδ1 cells were more abundant than Vδ2 or Vδ3 cells in RCC tumor samples. Thus, we posit that Vγ9Vδ1 T cells may represent an excellent candidate for adoptive immunotherapy in RCC patients with a high risk of relapse after surgery.

Purpose We investigated the feasibility of using an anatomically localized, target-enriched liquid biopsy (TLB) in mouse models of lung cancer.Materials and Methods After irradiating xenograft mouse with human lung cancer cell lines, H1299 (NRAS proto-oncogene, GTPase [NRAS] Q61K) and HCC827 (epidermal growth factor receptor [EGFR] E746-750del), circulating (cell-free) tumor DNA (ctDNA) levels were monitored with quantitative polymerase chain reaction on human long interspersed nuclear element-1 and cell line-specific mutations. We checked dose-dependency at 6, 12, or 18 Gy to each tumor-bearing mouse leg using 6-MV photon beams. We also analyzed ctDNA of lung cancer patients by LiquidSCAN, a targeted deep sequencing to validated the clinical performances of TLB method.Results Irradiation could enhance the detection sensitivity of NRAS Q61K in the plasma sample of H1299-xenograft mouse to 4.5- fold. While cell-free DNA (cfDNA) level was not changed at 6 Gy, ctDNA level was increased upon irradiation. Using double-xenograft mouse with H1299 and HCC827, ctDNA polymerase chain reaction analysis with local irradiation in each region could specify mutation type matched to transplanted cell types, proposing an anatomically localized, TLB. Furthermore, when we performed targeted deep sequencing of cfDNA to monitor ctDNA level in 11 patients with lung cancer who underwent radiotherapy, the average ctDNA level was increased within a week after the start of radiotherapy.Conclusion TLB using irradiation could temporarily amplify ctDNA release in xenograft mouse and lung cancer patients, which enables us to develop theragnostic method for cancer patients with accurate ctDNA detection.

Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti–PD-1 antibodies. However, 50% of microsatellite instability–high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)–derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. Significance: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features. See related commentary by Fontana and Smyth, p. 2126. This article is highlighted in the In This Issue feature, p. 2113

Synthetic small diameter vascular grafts frequently fail owing to intimal hyperplasia, results from mismatched compliance between the vascular graft and native vessels. A vascular graft with a negative Poisson's ratio (NPR, materials expand transversely when pulled axially) was suggested to enhance compliance. We produced a three-layer tubular vascular scaffold with NRP properties. The luminal side consisted of nanosized electrospun fibers for endothelial cell (EC) growth. The middle layer was an NPR structure created using 3D printing, and the outer layer was a microsized electrospun fiber layer for vascular smooth muscle cell (VSMC) growth. The developed multi-layer tubular vascular scaffold contained NPR value. And the NPR vascular scaffold showed 1.7 time higher compliance than the PPR scaffold and 3.8 times higher than that of commercial polytetrafluoroethylene (PTFE) vascular graft. In addition, the ECs and VSMCs were well survived and proliferated on the scaffold during 10 days of culture. From the optimized co-culture condition of the VSMCs and ECs that VSMC phenotype changed was inhibited, we successfully generated a thin luminal layer, which consisted of ECs and the proper thickness of the VSMC layer under the ECs. This scaffold may have a potential to replace conventional artificial vascular graft by providing enhanced compliance and improved cell culture environment.

Ovarian cancer is the fifth leading cause of cancer, followed by front line is mostly platinum agents and PARP inhibitors, and very limited option in later lines. Therefore, there is a need for alternative therapeutic options. Nectin-2, which is overexpressed in ovarian cancer, is a known immune checkpoint that deregulates immune cell function. In this study, we generated a novel anti-nectin-2 antibody (chimeric 12G1, c12G1), and further characterized it using epitope mapping, enzyme-linked immunosorbent assay, surface plasmon resonance, fluorescence-activated cell sorting, and internalization assays. The c12G1 antibody specifically bound to the C2 domain of human nectin-2 with high affinity (KD = 2.90 × 10−10 M), but not to mouse nectin-2. We then generated an antibody-drug conjugate comprising the c12G1 antibody conjugated to DM1 and investigated its cytotoxic effects against cancer cells in vitro and in vivo. c12G1-DM1 induced cell cycle arrest at the mitotic phase in nectin-2-positive ovarian cancer cells, but not in nectin-2-negative cancer cells. c12G1-DM1 induced ~100-fold cytotoxicity in ovarian cancer cells, with an IC50 in the range of 0.1 nM~7.4 nM, compared to normal IgG-DM1. In addition, c12G1-DM1 showed ~91% tumor growth inhibition in mouse xenograft models transplanted with OV-90 cells. These results suggest that c12G1-DM1 could be used as a potential therapeutic agent against nectin-2-positive ovarian cancers.

Macrolide-resistant Mycoplasma pneumoniae (MRMP) has become prevalent in children. This study investigated the clinical and laboratory variables of MRMP and macrolide-sensitive M. pneumoniae (MSMP) and identified factors associated with prolonged hospital admission in children.A prospective multicenter study was conducted in 1063 children18 years old in July 2018-June 2020. The 454 had a positive M. pneumoniae polymerase chain reaction assay.Most subjects had MRMP (78.4%), and all mutated strains had the A2063G transition. We defined MRMP* (n = 285) as MRMP pneumonia requiring admission and MSMP* (n = 72) as MSMP pneumonia requiring admission. Patients with MRMP pneumonia were older, more likely to have segmental/lobar pneumonia, and had more febrile days than those with MSMP pneumonia. C-reactive protein (CRP), lactate dehydrogenase (LDH), and percentage neutrophils were more strongly associated with MRMP* than MSMP* groups. Percentage neutrophils, CRP, and alanine aminotransferase significantly changed between admission and follow-up measurements in patients with MRMP* (P 0.05). The duration of admission positively correlated with the number of febrile days after initiation of antibiotic medication and laboratory variables (white blood cell count, CRP, and aspartate aminotransferase [AST]) (P 0.05). Random forest analysis indicated that the number of febrile days after initiation of antibiotic medication, AST, and percentage neutrophils at admission was over five.This study indicated that children with M. pneumoniae pneumonia with a higher number of febrile days after initiation of antibiotic medication, AST, and percentage neutrophils at admission were more likely to have prolonged admission duration.

BackgroundPrevious studies primarily targeted the ability of polygenic risk scores (PRSs) to predict a specific disease, and only a few studies have investigated the association between genetic risk scores and cardiovascular (CV) mortality. We assessed PRSs for coronary artery disease (CAD) and type 2 diabetes (T2DM) as the predictive factors for CV mortality, independent of traditional risk factors, and further investigated the additive effect between lifestyle behavior and PRS on CV mortality.MethodsWe used genetic and phenotypic data from UK Biobank participants aged 40–69 years at baseline, collected with standardized procedures. Genome-wide PRSs were constructed using >6 million genetic variants. Cox proportional hazard models were used to analyze the relationship between PRS and CV mortality with stratification by age, sex, disease status, and lifestyle behavior.ResultsOf 377,909 UK Biobank participants having European ancestry, 3,210 (0.8%) died due to CV disease during a median follow-up of 8.9 years. CV mortality risk was significantly associated with CAD PRS [low vs. very high genetic risk groups, CAD PRS hazard ratio (HR) 2.61 (2.02–3.36)] and T2DM PRS [HR 2.08 (1.58–2.73)], respectively. These relationships remained significant even after an adjustment for a comprehensive range of demographic and clinical factors. In the very high genetic risk group, adherence to an unfavorable lifestyle was further associated with a substantially increased risk of CV mortality [favorable vs. unfavorable lifestyle with very high genetic risk for CAD PRS, HR 8.31 (5.12–13.49); T2DM PRS, HR 5.84 (3.39–10.04)]. Across all genetic risk groups, 32.1% of CV mortality was attributable to lifestyle behavior [population attributable fraction (PAF) 32.1% (95% CI 28.8–35.3%)] and 14.1% was attributable to smoking [PAF 14.1% (95% CI 12.4–15.7%)]. There was no evidence of significant interaction between PRSs and age, sex, or lifestyle behavior in predicting the risk of CV mortality.ConclusionPRSs for CAD or T2DM and lifestyle behaviors are the independent predictive factors for future CV mortality in the white, middle-aged population. PRS-based risk assessment could be useful to identify the individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CV mortality.

Creativity is heritable and exhibits familial aggregation with psychiatric disorders, but its genomic basis and genetic relationship with psychiatric disorders remain largely unknown. Here, we conducted a genome-wide association study (GWAS) using an expanded, machine learning-based definition of creativity in individuals of European ancestry from the UK Biobank (n= 241,736) and identified 25 creativity-associated loci. Extensive genetic overlap with psychiatric disorders, including schizophrenia, major depression, bipolar I disorder, attention deficit/hyperactivity disorder, and anorexia nervosa, was demonstrated by the genetic correlation, polygenic risk score, and MiXeR analyses. The condFDR and conjFDR analyses identified additional loci for creativity and psychiatric disorders, as well as shared genetic loci between creativity and psychiatric disorders. This GWAS showed significant correlations with GWASs using traditional definitions of creativity and GWASs adjusted for educational attainment. Our findings contribute to the understanding of the genetic architecture of creativity and reveal its polygenic relationships with psychiatric disorders.

Subjective well-being (SWB) has been explored in European ancestral populations; however, whether the SWB genetic architecture is shared across populations remains unclear. We conducted a cross-population genome-wide association study for SWB using samples from Korean (n = 110,919) and European (n = 563,176) ancestries. Five ancestry-specific loci and twelve cross-ancestry significant genomic loci were identified. One novel locus (rs12298541 near HMGA2) associated with SWB was also identified through the European meta-analysis. Significant cross-ancestry genetic correlation for SWB between samples was observed. Polygenic risk analysis in an independent Korean cohort (n = 22,455) demonstrated transferability between populations. Significant correlations between SWB and major depressive disorder, and significant enrichment of central nervous system-related polymorphisms heritability in both ancestry populations were found. Hence, large-scale cross-ancestry genome-wide association studies can advance our understanding of SWB genetic architecture and mental health.

Despite substantial advances in disease genetics, studies to date have largely focused on individuals of European descent, limiting further discoveries of novel functional genetic variants in other ethnic groups. To alleviate the paucity of East Asian population genome resource, we established Korean Variant Archive 2 (KOVA 2), composed of 1,896 whole genome sequences and 3,409 whole exome sequences from healthy individuals of Korean ethnicity. This is the largest genome database from the ethnic Korean population to date, surpassing the 1,909 Korean individuals deposited in gnomAD. The variants in KOVA 2 displayed all known genetic features of those from previous genome databases, and we compiled data from Korean-specific runs of homozygosity, positively selected intervals, and structural variants. In doing so, we found loci that are strongly selected in the Koreans relative to other East Asians, such as ADH1A/1B and UHRF1BP1. Our analysis of allele ages revealed a correlation of variant functionality and evolutionary age. The data can be browsed and downloaded from a public website (https://www.kobic.re.kr/kova/). We anticipate KOVA 2 will serve as a valuable resource for genetic studies on East Asian populations.

Background: Young-PEARL study showed median progression-free survival (PFS) of 20·1 months in the palbociclib plus endocrine therapy group versus 14·4 months in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], log-rank p=0·0235). We conducted exploratory biomarker analysis to predict the efficacy of the trial. Methods: This was a phase II trial that randomized 184 patients with HR+ MBC in premenopausal women to palbociclib plus exemestane with GNRH agonist (Arm A, n=79) versus capecitabine (Arm B, n=62). We performed targeted sequencing (CancerSCANTM) containing 375 cancer-related genes (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response in terms of PFS. Result: By research-based PAM50 subtyping, 73% of patients classified as Luminal (Luminal A and Luminal B), and showed better prognosis in all patients and Arm A (p Conclusions: The alteration of a few genes including Rb1 loss may be associated with resistance of palbociclib in HR-positive premenopausal population with MBC. Luminal type showed better prognosis, and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. ESR1 mutation was found in low population frequency because all patients didn’t received AI therapy. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy. Clinical trial information: NCT02592746. Citation Format: Kyunghee Park, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Woong-Yang Park, Seock-Ah Im, Yeon Hee Park. Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-19.

In this research, a novel Microbial reverse-electrodialysis electrolysis struvite-precipitation cell (MRESC) was developed for energy recovery through struvite (MgNH4PO4·6H2O) crystallization and hydrogen production concurrently in a single process without any electrical-grid energy consumption. This hybrid system can effectively transfer the salinity gradient energy to electrical energy as a driving force to produce hydrogen gas coupled with struvite recovery and organic wastewater degradation. A MRESC containing 10 pairs of RED cells, supplied solutions typical of high concentration (600 mM NaCl) and low concentration (12 mM NaCl) at 1.0 mL/min, was operated in the fed-batch mode. The rates of hydrogen production and struvite crystallization were determined to be 0.71 m3-H2/m3-Van/d and 7.62 g/m2/h, respectively. The gas produced was >92% H2. The Coulombic efficiency was close to or above 100% with a COD removal of 84 ± 6%, and an overall energy efficiency of 28%. The morphology and structure of the main component of accumulated crystal at the cathode were verified by a scanning electron microscope with energy dispersive spectroscopy (SEM-EDS) and X-ray diffraction. These results showed that the MRESC system could be used as an effective bioelectrochemical method for energy recovery in the form of pure hydrogen gas and struvite simultaneously.