Explore the vast range of titles available.

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing. Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.

The characteristics of the upper-level circulation and thermodynamical properties for the period when two distinct cold surges broke out over East Asia during the 2005/06 winter are investigated. From early December 2005 to early January 2006, exceptionally cold weather lasted for approximately one month due to two successive cold surges that took place on 2 December 2005 and 2 January 2006, respectively. This study reveals that both involve the upper-tropospheric circulation, which induces the amplification and expansion of the surface Siberian high toward East Asia, but arose from different causes： the former is caused by the upper-level blocking originated from the North Pacific and the latter is caused by the upper-level wave train across the Eurasian Continent. In particular, it is suggested that the lower-tropospheric anomalous wind caused by upper-level circulation anomalies and a steep meridional temperature gradient amplified by phase-locked annual cycle combined to induce very strong cold advection in East Asia, which resulted in exceptionally cold weather that lasted for several weeks. The present results emphasize that the characteristics of the upper-tropospheric circulation can be considered as important precursors to cold surge occurrences in East Asia.

Possible impact of Arctic warming on the mid-latitudes has sparked interest. Analyses of observations and climate model simulations reveal two distinct patterns of Arctic warming that affect East Asia and North America, respectively. Arctic warming has sparked a growing interest because of its possible impacts on mid-latitude climate 1 , 2 , 3 , 4 , 5 . A number of unusually harsh cold winters have occurred in many parts of East Asia and North America in the past few years 2 , 6 , 7 , and observational and modelling studies have suggested that atmospheric variability linked to Arctic warming might have played a central role 1 , 3 , 4 , 8 , 9 , 10 , 11 . Here we identify two distinct influences of Arctic warming which may lead to cold winters over East Asia or North America, based on observational analyses and extensive climate model results. We find that severe winters across East Asia are associated with anomalous warmth in the Barents–Kara Sea region, whereas severe winters over North America are related to anomalous warmth in the East Siberian–Chukchi Sea region. Each regional warming over the Arctic Ocean is accompanied by the local development of an anomalous anticyclone and the downstream development of a mid-latitude trough. The resulting northerly flow of cold air provides favourable conditions for severe winters in East Asia or North America. These links between Arctic and mid-latitude weather are also robustly found in idealized climate model experiments and CMIP5 multi-model simulations. We suggest that our results may help improve seasonal prediction of winter weather and extreme events in these regions.

The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3–4N0) or III (ypTanyN1–2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m2 and leucovorin 20 mg/m2 on days 1–5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911. Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4–50·6). 3-year disease-free survival was 71·6% (95% CI 64·6–78·6) in the FOLFOX group and 62·9% (55·4–70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434–0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]). Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).

Several stomach diseases are attributed to the dysregulation of physiological function of gastric mucosal barrier by pathogens. Gastric organoids are a promising tool to develop treatment strategies for gastric infections. However, their functional features of in vivo gastric mucosal barrier and host–microbe interactions are limited due to the lack of physiological stimuli. Herein, a human stomach micro‐physiological system (hsMPS) with physiologically relevant gastric mucosal defense system is described based on the combination of organoid and MPS technology. A fluid flow enhanced epithelial‐mesenchymal interaction in the hsMPS enables functional maturation of gastric epithelial cells, which allows for the recreation of mesh‐like mucus layer containing high level of mucus protective peptides and well‐developed epithelial junctional complexes. Furthermore, gastroprotection mechanisms against Helicobacter pylori (H. pylori)  are successfully demonstrated in this system. Therefore, hsMPS represents a new in vitro tool for research where gastric mucosal defense mechanism is pivotal for developing therapeutic strategies.

The present study examines the impacts of snow initialization on surface air temperature by a number of ensemble seasonal predictability experiments using the NCAR Community Atmosphere Model version 3 (CAM3) AGCM with and without snow initialization. The study attempts to isolate snow signals on surface air temperature. In this preliminary study, any effects of variations in sea ice extent are ignored and do not explicitly identify possible impacts on atmospheric circulation. The Canadian Meteorological Center (CMC) daily snow depth analysis was used in defining initial snow states, where anomaly rescaling was applied in order to account for the systematic bias of the CAM3 snow depth with respect to the CMC analysis. Two suites of sea sonal (3 months long) ensemble hindcasts starting at each month in the colder part of the year (September–April) with and without the snow initialization were performed for 12 recent years (1999–2010), and the predictability skill of surface air temperature was estimated. Results show that considerable potential predictability increases up to 2 months ahead can be attained using snow initialization. Relatively large increases are found over East Asia, western Russia, and western Canada in the later part of this period. It is suggested that the predictability increases are sensitive to the strength of snow–albedo feedback determined by given local climate conditions; large gains tend to exist over the regions of strong snow–albedo feedback. Implications of these results for seasonal predictability over the extratropical Northern Hemisphere and future direction for this research are discussed.

Silicon dioxide nanoparticles (SiO NPs) are one of the most commonly used non-metal oxide nanomaterials because of their biocompatibility, biodegradability, and surface functionalization. However, the potential toxicological effects of SiO NPs have not been comprehensively investigated, and the available toxicological data are inconsistent. In particular, the toxicological effects of SiO NPs on reproductive and developmental functions are limited, and little information is available regarding their potential effects on fertility and early embryonic development. In this study, we investigated the potential reproductive and developmental toxicity of SiO NPs in mice, in accordance with the fertility and early embryonic development study design of International Council for Harmonization (ICH) S5 (R3) guideline. SiO NPs were administered once daily via oral gavage at doses of 0, 60, 250, and 1000 mg/kg during the pre-mating, mating, and early gestation periods. Endpoints related to fertility and early embryonic development were evaluated, including female fertility, tubal transport, implantation, early embryonic development, and functional aspects of male fertility. Additionally, the general health of the parental animals was also investigated. Oral administration of SiO NPs did not induce any SiO NPs-related adverse effects on female fertility indices, tubal transport, implantation outcomes, early embryonic development, and male fertility function. Additionally, no SiO NPs-related adverse effects were observed in clinical signs, body weight, food consumption, clinical pathology, macroscopic observations, and organ weights at any dose level. The results demonstrated that oral exposure to SiO NPs at dose levels up to 1000 mg/kg did not induce any significant adverse effects on fertility, early embryonic development, or general systemic health. These findings contribute to the human health risk assessment of SiO NPs, and further toxicological studies should address different physicochemical properties and additional exposure routes to resolve remaining uncertainties.

A low body mass index (BMI) is associated with increased mortality and low health-related quality of life in patients with COPD. The Asia-Pacific classification of BMI has a lower cutoff for overweight and obese categories compared to the World Health Organization (WHO) classification. The present study assessed patients with COPD among different BMI categories according to two BMI classification systems: WHO and Asia-Pacific. Patients with COPD aged 40 years or older from the Korean COPD Subtype Study cohort were selected for evaluation. We enrolled 1,462 patients. Medical history including age, sex, St George's Respiratory Questionnaire (SGRQ-C), the modified Medical Research Council (mMRC) dyspnea scale, and post-bronchodilator forced expiratory volume in 1 second (FEV ) were evaluated. Patients were categorized into different BMI groups according to the two BMI classification systems. FEV and the diffusing capacity of the lung for carbon monoxide (DLCO) percentage revealed an inverse \"U\"-shaped pattern as the BMI groups changed from underweight to obese when WHO cutoffs were applied. When Asia-Pacific cutoffs were applied, FEV and DLCO (%) exhibited a linearly ascending relationship as the BMI increased, and the percentage of patients in the overweight and obese groups linearly decreased with increasing severity of the Global Initiative for Chronic Obstructive Lung Disease criteria. From the underweight to the overweight groups, SGRQ-C and mMRC had a decreasing relationship in both the WHO and Asia-Pacific classifications. The prevalence of comorbidities in the different BMI groups showed similar trends in both BMI classifications systems. The present study demonstrated that patients with COPD who have a high BMI have better pulmonary function and health-related quality of life and reduced dyspnea symptoms. Furthermore, the Asia-Pacific BMI classification more appropriately reflects the correlation of obesity and disease manifestation in Asian COPD patients than the WHO classification.

Minimally invasive robotic surgery using fluorescence-guided images with a video laparoscope has been widely used because of its advantages of small incision, fast recovery time, and efficiency. However, the penetration depth limitation of fluorescence is a disadvantage caused by the absorption and scattering in tissues and blood cells. If this limitation can be overcome by additional imaging modalities, the surgical procedure can be quite efficient and precise. High-energy annihilation-gamma photons have a stronger penetration capability than visible and fluorescence photons. To characterize and validate a multimodal annihilation-gamma/near-infrared (NIR)/visible laparoscopic imaging system, an internal detector composed of an annihilation-gamma detector and an optical system was assembled inside a surgical stainless pipe with an outer diameter of 15.8 mm and an external detector with a dimension of 100  ×  100  mm2 placed at the opposite side of the internal detector. Integrated images of 511-keV gamma rays, NIR fluorescence, and visible light were obtained simultaneously. The 511-keV gamma image could be clearly seen with the acquisition of 5 s, while NIR and visible images could be presented in real time. This multimodal system has the potential for improving the surgery time and the quality of patient care.

Dexamethasone (Dex) has long been used as a potent immunosuppressive agent in the treatment of inflammatory and autoimmune diseases, despite serious side effects. In the present study, Dex and model antigen ovalbumin (OVA) were encapsulated with poly(lactic-co-glycolic acid) to deliver Dex and OVA preferentially to phagocytic cells, reducing systemic side effects of Dex. The OVA-specific immune tolerance-inducing activity of the nanoparticles (NPs) was examined. Polymeric NPs containing OVA and Dex (NP[OVA+Dex]) were prepared by the water-in-oil-in-water double emulsion solvent evaporation method. The effects of NP[OVA+Dex] on the maturation and function of immature dendritic cells (DCs) were examined in vitro. Furthermore, the OVA-specific immune tolerizing effects of NP[OVA+Dex] were confirmed in mice that were intravenously injected or orally fed with the NPs. Immature DCs treated in vitro with NP[OVA+Dex] did not mature into immunogenic DCs but instead were converted into tolerogenic DCs. Furthermore, profoundly suppressed generation of OVA-specific cytotoxic T cells and production of OVA-specific IgG were observed in mice injected with NP[OVA+Dex], whereas regulatory T cells were concomitantly increased. Feeding of mice with NP[OVA+Dex] also induced OVA-specific immune tolerance. The present study demonstrates that oral feeding as well as intravenous injection of poly(lactic-co-glycolic acid) NPs encapsulating both antigen and Dex is a useful means of inducing antigen-specific immune tolerance, which is crucial for the treatment of autoimmune diseases.