Environmental drivers of increased ecosystem respiration in a warming tundra.

Arctic and alpine tundra ecosystems are large reservoirs of organic carbon1,2. Climate warming may stimulate ecosystem respiration and release carbon into the atmosphere3,4. The magnitude and persistency of this stimulation and the environmental mechanisms that drive its variation remain uncertain5-7. This hampers the accuracy of global land carbon-climate feedback projections7,8. Here we synthesize 136 datasets from 56 open-top chamber in situ warming experiments located at 28 arctic and alpine tundra sites which have been running for less than 1 year up to 25 years. We show that a mean rise of 1.4 °C [confidence interval (CI) 0.9-2.0 °C] in air and 0.4 °C [CI 0.2-0.7 °C] in soil temperature results in an increase in growing season ecosystem respiration by 30% [CI 22-38%] (n = 136). Our findings indicate that the stimulation of ecosystem respiration was due to increases in both plant-related and microbial respiration (n = 9) and continued for at least 25 years (n = 136). The magnitude of the warming effects on respiration was driven by variation in warming-induced changes in local soil conditions, that is, changes in total nitrogen concentration and pH and by context-dependent spatial variation in these conditions, in particular total nitrogen concentration and the carbon:nitrogen ratio. Tundra sites with stronger nitrogen limitations and sites in which warming had stimulated plant and microbial nutrient turnover seemed particularly sensitive in their respiration response to warming. The results highlight the importance of local soil conditions and warming-induced changes therein for future climatic impacts on respiration.

Economic impact of managing invasive mold disease with isavuconazole compared with liposomal amphotericin B followed by posaconazole in Spain.

BACKGROUND: Invasive fungal infections (IFI) are associated with significant morbidity and mortality. The objective of this work was to compare the costs per adult patient, associated with intravenous isavuconazole (ISAV) followed by oral ISAV versus the regimen of liposomal amphotericin B followed by posaconazole (L-AMB→POSA) in the treatment of IFI. The comparison was conducted from the perspective of the Spanish National Health System (SNS). METHODS: As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration, hospitalization, laboratory tests and adverse events costs were evaluated from SNS perspective. Deterministic and probabilistic sensitivity analyzes were performed. RESULTS: Total costs per-patient were €24,715.54 with ISAV versus €29,753.53 with L-AMB→POSA, resulting in cost-savings per patient treated with ISAV of €5,037.99 (-16.9%). Treatment costs of IFI remained lower for ISAV than for L-AMB→POSA across all sensitivity analyses (-7,968.89€ to -326.59€), being treatment duration the most influential parameter. CONCLUSION: According to the present model, the treatment of IFIs with ISAV would generate savings for the SNS compared to L-AMB→POSA. These savings are attributed to the shorter duration of IV treatment, reduced use of healthcare resources and lower costs associated with managing adverse effects when ISAV was employed.

Detection of novel drug-adverse drug reaction signals in rheumatoid arthritis and ankylosing spondylitis: analysis of Korean real-world biologics registry data.

This study aimed to detect signals of adverse drug reactions (ADRs) associated with biological disease-modifying antirheumatic drugs (DMARDs) and targeted therapies in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients. Utilizing the KOrean College of Rheumatology BIOlogics & Targeted Therapy Registry (KOBIO) data, we calculated relative risks, excluded previously reported drug-ADR pairs, and externally validated remaining pairs using US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and single centre's electronic health records (EHR) data. Analyzing data from 2279 RA and 1940 AS patients, we identified 35 significant drug-ADR pairs in RA and 26 in AS, previously unreported in drug labels. Among the novel drug-ADR pairs from KOBIO, 15 were also significant in the FAERS data. Additionally, 2 significant drug-laboratory abnormality pairs were found in RA using CDM MetaLAB analysis. Our findings contribute to the identification of 14 novel drug-ADR signals, expanding our understanding of potential adverse effects related to biological DMARDs and targeted therapies in RA and AS. These results emphasize the importance of ongoing pharmacovigilance for patient safety and optimal therapeutic interventions.

Recommendations on the use of azole antifungals in hematology-oncology patients.

The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

EZH2 mutations at diagnosis in follicular lymphoma: a promising biomarker to guide frontline treatment.

EZH2 is mutated in nearly 25% of follicular lymphoma (FL) cases. Little is known about how EZH2 affects patients' response to therapy. In this context, the aim of this study was to retrospectively analyze the frequency of mutations in EZH2 at diagnosis in tissue and ctDNA in patients with FL and to assess the patients' outcomes after receiving immunochemotherapy, depending on the EZH2 mutation status. Among the 154 patients included in the study, 27% had mutated EZH2 (46% with high-grade and 26% with low-grade FL). Of the mutated tissue samples, the mutation in ctDNA was identified in 44% of cases. EZH2 mutation in ctDNA was not identified in any patient unmutated in the tissue.Unmutated patients who received R-CHOP had significantly more relapses than patients who received R-Bendamustine (16/49 vs. 2/23, p = 0.040). Furthermore, our results show that patients with mutated EZH2 treated with R-CHOP vs. those treated with R-Bendamustine present a lower incidence of relapse (10% vs. 42% p = 0.09 at 4 years), a higher PFS (92% vs. 40% p = 0.039 at 4 years), and higher OS (100% vs. 78% p = 0.039 at 4 years). Based on these data, RCHOP could be a more suitable regimen for mutated patients, and R-bendamustine for unmutated patients. These findings could mean the first-time identification of a useful biomarker to guide upfront therapy in FL.

Multi-qubit entanglement and algorithms on a neutral-atom quantum computer.

Gate-model quantum computers promise to solve currently intractable computational problems if they can be operated at scale with long coherence times and high-fidelity logic. Neutral-atom hyperfine qubits provide inherent scalability owing to their identical characteristics, long coherence times and ability to be trapped in dense, multidimensional arrays1. Combined with the strong entangling interactions provided by Rydberg states2-4, all the necessary characteristics for quantum computation are available. Here we demonstrate several quantum algorithms on a programmable gate-model neutral-atom quantum computer in an architecture based on individual addressing of single atoms with tightly focused optical beams scanned across a two-dimensional array of qubits. Preparation of entangled Greenberger-Horne-Zeilinger (GHZ) states5 with up to six qubits, quantum phase estimation for a chemistry problem6 and the quantum approximate optimization algorithm (QAOA)7 for the maximum cut (MaxCut) graph problem are demonstrated. These results highlight the emergent capability of neutral-atom qubit arrays for universal, programmable quantum computation, as well as preparation of non-classical states of use for quantum-enhanced sensing.

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy.

BACKGROUND: Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. PATIENTS AND METHODS: This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. RESULTS: Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. CONCLUSION: We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.

Molecular profiling of Asian patients with advanced melanoma receiving check-point inhibitor treatment.

OBJECTIVE: Melanoma is major medical challenge and being able to monitor treatment response is critical. This study aimed to use molecular profiling of Asian patients with advanced melanoma who were receiving treatment with check-point inhibitors (CPIs) to identify novel biomarkers of tumor response. METHODS: Next-generation sequencing (NGS) was performed using tumor specimens collected from 178 Asian patients with metastatic melanoma receiving CPIs. The NGS data and clinical-pathological factors were analyzed for potential genetic biomarkers of tumor response to CPI treatment. RESULTS: The most common melanoma subtype was acral melanoma (40%), followed by cutaneous melanoma (32%), mucosal melanoma (26%), and others (2%). For calculation of treatment efficacy, 164 of the patients could be evaluated. The overall response rate was 45.7%, of which 41 cases exhibited complete responses (25.0%) and 34 showed partial responses (20.7%). There were no significant differences in tumor responses based on melanoma subtype (P = 0.295). Genetically, NRAS mutations, TP53 mutations, and NF2 deletions were significantly associated with resistance to CPIs (P < 0.05). In contrast, MYC and RPS6KB1 amplifications were associated with responsiveness to CPIs (P < 0.05). Median progression-free survival (PFS) for patients treated with CPIs was 5.9 months (95% CI, 3.8-8.05 months). Univariate analysis identified TP53 and BRAF mutations, NF2 deletions, and BIRC2 amplifications as poor prognostic factors for PFS (P < 0.05). CONCLUSIONS: This study determined the integrated genomic profiles of Asian patients with metastatic melanoma receiving CPIs and identified candidate biomarkers that reflected treatment outcomes.

Radiomics Study of Thyroid Ultrasound for Predicting BRAF Mutation in Papillary Thyroid Carcinoma: Preliminary Results.

BACKGROUND AND PURPOSE: It is not known how radiomics using ultrasound images contribute to the detection of BRAF mutation. This study aimed to evaluate whether a radiomics study of gray-scale ultrasound can predict the presence or absence of B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation in papillary thyroid cancer. MATERIALS AND METHODS: The study retrospectively included 96 thyroid nodules that were surgically confirmed papillary thyroid cancers between January 2012 and June 2013. BRAF mutation was positive in 48 nodules and negative in 48 nodules. For analysis, ROIs from the nodules were demarcated manually on both longitudinal and transverse sonographic images. We extracted a total of 86 radiomics features derived from histogram parameters, gray-level co-occurrence matrix, intensity size zone matrix, and shape features. These features were used to build 3 different classifier models, including logistic regression, support vector machine, and random forest using 5-fold cross-validation. The performance including accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve, of the different models was evaluated. RESULTS: The incidence of high-suspicion nodules diagnosed on ultrasound was higher in the BRAF mutation-positive group than in the mutation-negative group (P = .004). The radiomics approach demonstrated that all classification models showed moderate performance for predicting the presence of BRAF mutation in papillary thyroid cancers with an area under the curve value of 0.651, accuracy of 64.3%, sensitivity of 66.8%, and specificity of 61.8%, on average, for the 3 models. CONCLUSIONS: Radiomics study using thyroid sonography is limited in predicting the BRAF mutation status of papillary thyroid carcinoma. Further studies will be needed to validate our results using various diagnostic methods.

Subclinical thyroid dysfunction, bone mineral density, and osteoporosis in a middle-aged Korean population.

Thyroid dysfunction is associated with the loss of bone density (osteoporosis). However, the connection between subclinical thyroid dysfunction and osteoporosis remains controversial. This study found no apparent association between subclinical hypothyroidism or subclinical hyperthyroidism and bone mineral density (BMD) in the lumbar spine and femur. INTRODUCTION: The present study examined the relationship between subclinical thyroid dysfunction and BMD in healthy middle-aged adults. METHODS: A total of 25,510 healthy Koreans with normal free thyroxine levels were enrolled from January 2011 to December 2016, and 91% of subjects visited only once. The average age of the 15,761 women was 45, and the average age of the 9749 men was 48. Levels of thyroid-stimulating hormone (TSH) and BMD were recorded in all subjects. BMD was measured using dual-energy X-ray absorptiometry. RESULTS: No apparent association was found between subclinical thyroid dysfunction and BMD in the lumbar spine, femur-neck, and proximal femur sites compared with a euthyroid group. Age, body mass index (BMI), and postmenopausal status affected BMD in women, and only BMI affected BMD in men. Subclinical hypothyroidism was independently associated with a lower risk of osteoporosis (odds ratio 0.657, 95% confidence interval 0.464-0.930) in 4710 postmenopausal women. CONCLUSIONS: No apparent association was found between subclinical hypothyroidism or subclinical hyperthyroidism defined on single TSH measurement and BMD at the lumbar spine and femur in a large cohort of middle-aged men and women. Subclinical hypothyroidism was independently associated with a lower risk of osteoporosis in postmenopausal women.

Rydberg-Mediated Entanglement in a Two-Dimensional Neutral Atom Qubit Array.

We demonstrate high fidelity two-qubit Rydberg blockade and entanglement on a pair of sites in a large two-dimensional qubit array. The qubit array is defined by a grid of blue detuned lines of light with 121 sites for trapping atomic qubits. Improved experimental methods have increased the observed Bell state fidelity to F_{Bell}=0.86(2). Accounting for errors in state preparation and measurement we infer a fidelity of F_{Bell}^{-SPAM}=0.88. Accounting for errors in single qubit operations we infer that a Bell state created with the Rydberg mediated C_{Z} gate has a fidelity of F_{Bell}^{C_{Z}}=0.89. Comparison with a detailed error model based on quantum process matrices indicates that finite atom temperature and laser noise are the dominant error sources contributing to the observed gate infidelity.

Diagnostic Accuracy and Scope of Intraoperative Transoral Ultrasound and Transoral Ultrasound-Guided Fine-Needle Aspiration of Retropharyngeal Masses.

The use of transoral sonography-guided fine-needle aspiration for intraoperative localization of retropharyngeal masses has been described by Fornage et al. The purpose of this study was to assess the accuracy of this technique. We reviewed the images and medical records of 26 patients with a retropharyngeal lesion suspicious for a metastatic lymph node of Rouviere identified on CT and/or PET/CT. There were 14 patients with a history of thyroid cancer, 7 with mucosal squamous cell carcinoma, 1 with renal cell carcinoma, 1 with parotid acinic cell cancer, 1 with metastatic colon adenocarcinoma, and 2 with no history of cancer. Intraoperative transoral sonography was performed using a commercially available endovaginal transducer. A transoral sonography-guided fine-needle aspiration was performed with a 25-cm-long 20-ga Chiba needle through a needle guide attached to the transducer shaft. Cytopathologic results were categorized as malignant, benign, or nondiagnostic. Transoral sonography and transoral sonography-guided fine-needle aspiration were performed in all patients. A diagnostic specimen was obtained in 25 of 26 (96%) patients with a 100% overall accuracy. Twelve patients underwent subsequent transoral resection of the retropharyngeal mass. In each patient, surgical pathology confirmed the fine-needle aspiration biopsy result. In 4 patients, transoral sonography-guided injection of methylene blue was used to facilitate intraoperative localization of the metastatic retropharyngeal mass. Transoral sonography and transoral sonography-guided fine-needle aspiration of suspicious masses in the retropharyngeal space are highly accurate procedures for identification and cytologic evaluation of benign and metastatic lymph nodes of Rouviere and for presurgical localization.

Correction: ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.

Since publication of the original article, the authors have noticed that there were errors in the labelling of Figures 6D and 6E. The correct figure and its legend are reproduced here. The authors wish to apologise for any inconvenience caused.

Factors associated with HIV/AIDS-related stigma and discrimination by medical professionals in Korea: A survey of infectious disease specialists in Korea.

OBJECTIVES: This study sought to identify factors associated with this discrimination by medical professionals in Korea. SUBJECTS AND METHODS: This study was a cross-sectional survey. We conducted web-based surveys against infectious disease specialists and infectious disease nurse. We evaluated the frequency of human immunodeficiency virus (HIV)/AIDS-related discrimination by medical professionals by health service type on the 5-point scale. We identified the association between several factors and HIV/AIDS-related stigma and discrimination by medical professionals on the 5-point scale. RESULTS: A total of 81 experts, 57 infectious disease specialists (approximately 27% of all infectious disease specialists in Korea) and 24 infectious disease nurse practitioners, participated in this study. The frequency of stigma and discrimination increased significantly when invasive treatment included both outpatient and inpatient services (both P < 0.05). Medical professional's preconceptions, fear of infection, and lack of knowledge have an association with HIV/AIDS-related stigma and discrimination by medical professionals. CONCLUSION: HIV/AIDS-related stigma and discrimination by medical professionals in Korea might be associated with factors related to the fear of medical professionals.

Updating genome annotation for the microbial cell factory Aspergillus niger using gene co-expression networks.

A significant challenge in our understanding of biological systems is the high number of genes with unknown function in many genomes. The fungal genus Aspergillus contains important pathogens of humans, model organisms, and microbial cell factories. Aspergillus niger is used to produce organic acids, proteins, and is a promising source of new bioactive secondary metabolites. Out of the 14,165 open reading frames predicted in the A. niger genome only 2% have been experimentally verified and over 6,000 are hypothetical. Here, we show that gene co-expression network analysis can be used to overcome this limitation. A meta-analysis of 155 transcriptomics experiments generated co-expression networks for 9,579 genes (∼65%) of the A. niger genome. By populating this dataset with over 1,200 gene functional experiments from the genus Aspergillus and performing gene ontology enrichment, we could infer biological processes for 9,263 of A. niger genes, including 2,970 hypothetical genes. Experimental validation of selected co-expression sub-networks uncovered four transcription factors involved in secondary metabolite synthesis, which were used to activate production of multiple natural products. This study constitutes a significant step towards systems-level understanding of A. niger, and the datasets can be used to fuel discoveries of model systems, fungal pathogens, and biotechnology.

Histogram analysis of greyscale sonograms to differentiate between the subtypes of follicular variant of papillary thyroid cancer.

AIM: To evaluate the diagnostic value of histogram analysis using ultrasound (US) to differentiate between the subtypes of follicular variant of papillary thyroid carcinoma (FVPTC). MATERIALS AND METHODS: The present study included 151 patients with surgically confirmed FVPTC diagnosed between January 2014 and May 2016. Their preoperative US features were reviewed retrospectively. Histogram parameters (mean, maximum, minimum, range, root mean square, skewness, kurtosis, energy, entropy, and correlation) were obtained for each nodule. RESULTS: The 152 nodules in 151 patients comprised 48 non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs; 31.6%), 60 invasive encapsulated FVPTCs (EFVPTCs; 39.5%), and 44 infiltrative FVPTCs (28.9%). The US features differed significantly between the subtypes of FVPTC. Discrimination was achieved between NIFTPs and infiltrative FVPTC, and between invasive EFVPTC and infiltrative FVPTC using histogram parameters; however, the parameters were not significantly different between NIFTP and invasive EFVPTC. CONCLUSION: It is feasible to use greyscale histogram analysis to differentiate between NIFTP and infiltrative FVPTC, but not between NIFTP and invasive EFVPTC. Histograms can be used as a supplementary tool to differentiate the subtypes of FVPTC.

iNKT cells prevent obesity-induced hepatic steatosis in mice in a C-C chemokine receptor 7-dependent manner.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are characterized by an increase in hepatic triglyceride content with infiltration of immune cells, which can cause steatohepatitis and hepatic insulin resistance. C-C chemokine receptor 7 (CCR7) is primarily expressed in immune cells, and CCR7 deficiency leads to the development of multi-organ autoimmunity, chronic renal disease and autoimmune diabetes. Here, we investigated the effect of CCR7 on hepatic steatosis in a mouse model and its underlying mechanism. Our results demonstrated that body and liver weights were higher in the CCR7-/- mice than in the wild-type (WT) mice when they were fed a high-fat diet. Further, glucose tolerance and insulin sensitivity were markedly diminished in CCR7-/- mice. The number of invariant natural killer T (iNKT) cells was reduced in the livers of the CCR7-/- mice. Moreover, liver inflammation was detected in obese CCR7-/- mice, which was ameliorated by the adoptive transfer of hepatic mononuclear cells from WT mice, but not through the transfer of hepatic mononuclear cells from CD1d-/- or interleukin-10-deficient (IL-10-/-) mice. Overall, these results suggest that CCR7+ mononuclear cells in the liver could regulate obesity-induced hepatic steatosis via induction of IL-10-expressing iNKT cells.

ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.

This corrects the article DOI: 10.1038/oncsis.2017.87.

ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.

Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2), epithelial cell-specific regulators of alternative splicing, are downregulated during the epithelial-mesenchymal transition (EMT). These factors have roles in tumor progression and metastasis in some cancers; however, their expression and function in ovarian cancer (OC) remain unclear. We found that ESRP1 and ESRP2 mRNAs were expressed at higher levels in OC cells than in immortalized ovarian surface epithelial (IOSE) cells, and confirmed their overexpression in OC tissues at the protein level. The Cancer Genome Atlas (TCGA) data analysis revealed frequent gene amplification of ESRP1 in OC tissues; however, we detected no significant correlation between ESRP1 gene copy number and gene expression in OC cells. Importantly, expression of ESRP1 and ESRP2 was inversely correlated with DNA methylation in OC cells, and ESRP2 overexpression in OC tissues was significantly associated with DNA hypomethylation. Notably, survival analysis using TCGA data from 541 OC tissues revealed that high ESRP1 expression was significantly associated with shorter 5-year survival of patients. Ectopic ESRP1 expression in mesenchymal OC cells promoted cell proliferation but suppressed cell migration. Furthermore, we found that ESRP1 drives a switch from mesenchymal to epithelial phenotype characterized by reduced cell migration in association with induction of epithelial cell-specific variant of CD44 and ENAH. Taken together, our findings suggest that an epigenetic mechanism is involved in ESRP1 overexpression, and that ESRP1 has a role in OC progression.