Accelerating the discovery of novel magnetic materials using machine learning-guided adaptive feedback.

Magnetic materials are essential for energy generation and information devices, and they play an important role in advanced technologies and green energy economies. Currently, the most widely used magnets contain rare earth (RE) elements. An outstanding challenge of notable scientific interest is the discovery and synthesis of novel magnetic materials without RE elements that meet the performance and cost goals for advanced electromagnetic devices. Here, we report our discovery and synthesis of an RE-free magnetic compound, Fe3CoB2, through an efficient feedback framework by integrating machine learning (ML), an adaptive genetic algorithm, first-principles calculations, and experimental synthesis. Magnetic measurements show that Fe3CoB2 exhibits a high magnetic anisotropy (K1 = 1.2 MJ/m3) and saturation magnetic polarization (Js = 1.39 T), which is suitable for RE-free permanent-magnet applications. Our ML-guided approach presents a promising paradigm for efficient materials design and discovery and can also be applied to the search for other functional materials.

π-Extended Nonfullerene Acceptor for Compressed Molecular Packing in Organic Solar Cells To Achieve over 20% Efficiency.

Organic photovoltaics (OPVs) suffer from a trade-off between efficient charge transport and suppressed nonradiative recombination due to the aggregation-induced luminance quenching of organic semiconductors. To resolve this grand challenge, a π-extended nonfullerene acceptor (NFA) B6Cl with large voids among the honeycomb network is designed and introduced into photovoltaic systems. We find that the presence of a small amount of (i.e., 0.5 or 1 wt %) B6Cl can compress the molecular packing of the host acceptor L8-BO, leading to shortened π-π stacking distance from 3.59 to 3.50 Å (that will improve charge transport) together with ordered alkyl chain packing (that will inhibit nonradiative energy loss due to the suppressed C-C and C-H bonds vibrations), as validated by high-energy X-ray scattering measurements. This morphology transformation ultimately results in simultaneously improved JSC, FF, and VOC of OPVs. As a result, the maximum PCEs of PM6:L8-BO and D18:L8-BO are increased from 19.1 and 19.3% to 19.8 and 20.2%, respectively, which are among the highest values for single-junction OPVs. The university of B6Cl to increase the performance of OPVs is further evidenced in a range of polymer:NFA OPVs.

Loss of Gcn2 exacerbates gossypol induced oxidative stress, apoptosis and inflammation in zebrafish.

Gossypol, a naturally occurring compound found in cottonseed meal, shows promising therapeutic potential for human diseases. However, within the aquaculture industry, it is considered an antinutritional factor. The incorporation of cottonseed meal into fish feed introduces gossypol, which induces intracellular stresses and hinders overall health of farmed fish. The aim of this study is to determine the role of General control nonderepressible 2 (gcn2), a sensor for intracellular stresses in gossypol-induced stress responses in fish. In the present study, we established two gcn2 knockout zebrafish lines. A feeding trial was conducted to assess the growth-inhibitory effect of gossypol in both wild type and gcn2 knockout zebrafish. The results showed that in the absence of gcn2, zebrafish exhibited increased oxidative stress and apoptosis when exposed to gossypol, resulting in higher mortality rates. In feeding trial, dietary gossypol intensified liver inflammation in gcn2-/- zebrafish, diminishing their growth and feed conversion. Remarkably, administering the antioxidant N-acetylcysteine (NAC) was effective in reversing the gossypol induced oxidative stress and apoptosis, thereby increasing the gossypol tolerance of gcn2-/- zebrafish. Exposure to gossypol induces more severe mitochondrial stress in gcn2-/- zebrafish, thereby inducing metabolic disorders. These results reveal that gcn2 plays a protective role in reducing gossypol-induced oxidative stress and apoptosis, attenuating inflammation responses, and enhancing the survivability of zebrafish in gossypol-challenged conditions. Therefore, maintaining appropriate activation of Gcn2 may be beneficial for fish fed diets containing gossypol.

Exploring bacterial community assembly in vadose and saturated zone soil for tailored bioremediation of a long-term hydrocarbon-contaminated site.

Indigenous soil microbial communities play a pivotal role in the in situ bioremediation of contaminated sites. However, research on the distribution characteristics of microbial communities at various soil depths remains limited. In particular, there is little information on the assembly of microbial communities, especially those with degradation potential, in the vadose and saturated zones of hydrocarbon-contaminated sites. In this study, 18 soil samples were collected from the vadose zone and saturated zone at a long-term hydrocarbon-contaminated site. The diversity, composition, and driving factors of assembly of the soil bacterial community were determined by high-throughput sequencing analysis. Species richness and diversity were significantly higher in the vadose zone soils than in the saturated zone soils. Significant differences in abundance at both the phylum and genus levels were observed between the two zones. Soil bacterial community assembly was driven by the combination of pollution stress and nutrients in the vadose zone but by nutrient limitations in the saturated zone. The abundance of dechlorinating bacteria was greater in the saturated zone soils than in the vadose zone soils. Compared with contaminant concentrations, nutrient levels had a more pronounced impact on the abundance of dechlorinating bacteria. In addition, the interactions among dechlorinating bacterial populations were stronger in the saturated zone soils than in the vadose zone soils. These findings underscore the importance of comprehensively understanding indigenous microbial communities, especially those with degradation potential, across different soil layers to devise specific, effective in situ bioremediation strategies for contaminated sites.

Identification and characterization of differentially expressed circular RNAs in extraocular muscle of oculomotor nerve palsy.

BACKGROUND: Oculomotor nerve palsy (ONP) is a neuroparalytic disorder resulting in dysfunction of innervating extraocular muscles (EOMs), of which the pathological characteristics remain underexplored. METHODS: In this study, medial rectus muscle tissue samples from four ONP patients and four constant exotropia (CXT) patients were collected for RNA sequencing. Differentially expressed circular RNAs (circRNAs) were identified and included in functional enrichment analysis, followed by interaction analysis with microRNAs and mRNAs as well as RNA binding proteins. Furthermore, RT-qPCR was used to validate the expression level of the differentially expressed circRNAs. RESULTS: A total of 84 differentially expressed circRNAs were identified from 10,504 predicted circRNAs. Functional enrichment analysis indicated that the differentially expressed circRNAs significantly correlated with skeletal muscle contraction. In addition, interaction analyses showed that up-regulated circRNA_03628 was significantly interacted with RNA binding protein AGO2 and EIF4A3 as well as microRNA hsa-miR-188-5p and hsa-miR-4529-5p. The up-regulation of circRNA_03628 was validated by RT-qPCR, followed by further elaboration of the expression, location and clinical significance of circRNA_03628 in EOMs of ONP. CONCLUSIONS: Our study may shed light on the role of differentially expressed circRNAs, especially circRNA_03628, in the pathological changes of EOMs in ONP.

Risk Factors for Surgical Site Infections After Lower Extremity Open Revascularization.

BACKGROUND: Surgical site infection (SSI) is a serious complication of lower extremity open revascularization and is associated with increased morbidity, increased healthcare costs, and decreased postoperative quality of life. The objective of this study was to determine factors associated with an increased risk of developing postoperative SSI in patients undergoing lower extremity revascularization. Associations between SSI and postoperative complications were also identified. METHODS: Patients who underwent lower extremity open revascularization from 2014-2017 were identified using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). A multivariate logistic regression analysis was used to determine risk factors associated with SSIs within 30 days of the operation and postoperative complications. Odds ratios (ORs) were adjusted for demographics, preoperative comorbidities, procedure type, and intraoperative variables. RESULTS: Ten thousand nine hundred ten patients who underwent lower extremity open revascularization were identified, with a mean age of 67.24 years and of whom 7,318 (67%) were male. Of the 10,910 patients, 922 (8.45%) had an SSI within 30 days of the operation. Risk factors associated with developing SSI included body mass index 25-29.9 (OR, 1.34; 95% confidence interval [CI], 1.08-1.67), body mass index ≥ 30 (OR, 2.12; 95% CI, 1.71-2.62), history of severe chronic obstructive pulmonary disease (OR, 1.47; 95% CI, 1.18-1.84), preprocedural beta-blocker use (OR, 1.25; CI 95%, 1.05-1.49), procedure time > 214 minutes (OR, 1.44; 95% CI, 1.22-1.70), and creatinine > 1.2 (OR 1.03; 95% CI, 0.87-1.21). One factor associated with a decreased risk of developing SSI was male gender (OR, 0.71; 95% CI, 0.60-0.84). Patients who developed an SSI were more likely to have adverse outcomes such as myocardial infarction/stroke, major amputation, bleeding requiring transfusion or secondary procedure, or require a reintervention in the treated segment. CONCLUSIONS: There are various patient-related and operative factors that increase the likelihood of developing an SSI after lower extremity open revascularization. These findings indicate that addressing modifiable perioperative SSI risk factors may be beneficial in decreasing rates of SSI and improving postoperative outcomes.

Machine Learning-Guided Discovery of Ternary Compounds Containing La, P, and Group 14 Elements.

We integrate a deep machine learning (ML) method with first-principles calculations to efficiently search for the energetically favorable ternary compounds. Using La-Si-P as a prototype system, we demonstrate that ML-guided first-principles calculations can efficiently explore crystal structures and their relative energetic stabilities, thus greatly accelerate the pace of material discovery. A number of new La-Si-P ternary compounds with formation energies less than 30 meV/atom above the known ternary convex hull are discovered. Among them, the formation energies of La5SiP3 and La2SiP phases are only 2 and 10 meV/atom, respectively, above the convex hull. These two compounds are dynamically stable with no imaginary phonon modes. Moreover, by replacing Si with heavier-group 14 elements in the eight lowest-energy La-Si-P structures from our ML-guided predictions, a number of low-energy La-X-P phases (X = Ge, Sn, Pb) are predicted.

Racial disparities in minimally invasive esophagectomy and gastrectomy for upper GI malignancies.

BACKGROUND: Esophageal cancer and gastric cancer are two important causes of upper GI malignancies. Literature has shown that minimally invasive esophagectomies (MIE) and gastrectomies (MIG), have shorter length of stay and fewer complications. However, limited literature exists about the association between race and access to MIE and MIG. This study aims to identify the racial disparities in the different approaches to esophagectomy and gastrectomy. We further evaluate the relationship between the race and postoperative complications. METHODS: This IRB-approved retrospective study utilized data from the American College of Surgeons National Quality Improvement Program. All recorded cases of MIE, MIG, open gastrectomy, and esophagectomy between 2012 and 2019 were isolated. Propensity score matching and univariate analysis was performed to assess the independent effect of black self-identified race on access and outcomes. p < 0.05 was required to achieve statistical significance. RESULTS: 7891 cases of esophagectomy and 5,132 cases of gastrectomy cases were identified. Using Propensity and logistic regression, we identified that black self-reported race is an independent predictor of open approach to gastrectomy (OR 1.6871943, 95% CI 1.431464-1.989829, p < 0.001). Black self-reported race was not predictive of operative approach among esophagectomy patients (OR 0.7942576, 95% CI 0.5698645-1.124228, p = 0.183). In contrast, black self-reported is an independent predictor of postoperative complications among esophagectomy patients only. Esophagectomy patients of black self-reported race were more likely to experience any complication (OR 1.4373437, 95% CI 1.1129239-1.8557096, p = 0.00537), severe complications (OR 1.3818966, 95% CI 1.0653087-1.7888454, p = 0.0144), and death (OR 2.00779762, 95% CI 1.08034921-3.56117535, p = 0.0211) within 30 days of their surgeries. CONCLUSION: Our analysis revealed a significant racial disparity in access to MIG and a higher incidence of post-operative complications amongst esophagectomy patients. Minimally invasive techniques are underutilized in racial minorities. The findings herein warrant further investigation to eliminate barriers and disparities.

Pollution Characteristics and Health Risk Assessment of Phthalate Esters in PSW Recycling Sites: A Typical Case Study.

The concentrations of six priority phthalate esters (PAEs) in 700 soil samples and 110 sediment samples from an area in China containing plastic solid waste (PSW) recycling sites were determined. The total concentrations of the six PAEs in soil and sediment were not detected - 274 and not detected - 597 mg kg-1, respectively, and the mean concentrations in soil and sediment were 14.4 and 31.7 mg kg-1, respectively. The dominant PAEs were di(2-ethylhexyl) phthalate and di-n-butyl phthalate. PAEs were detected in soil collected from the surface to 0.5 m below ground level around the PSW recycling sites, and the concentrations were markedly higher in these areas than at other polluted sites. PSW recycling is an important source of PAEs to soil and sediment. The di(2-ethylhexyl)phthalate concentrations in soil were higher than the relevant concentrations that pose environmental risks for sensitive land uses and non-sensitive land uses (42 and 121 mg kg-1, respectively), indicating emissions of PAEs from PSW recycling sites may pose environmental risks. The results indicate that PAE pollution at PSW sites needs to be better controlled and managed.

How to Look for Compounds: Predictive Screening and in†situ Studies in Na-Zn-Bi System.

Here, the combination of theoretical computations followed by rapid experimental screening and in situ diffraction studies is demonstrated as a powerful strategy for novel compounds discovery. When applied for the previously "empty" Na-Zn-Bi system, such an approach led to four novel phases. The compositional space of this system was rapidly screened via the hydride route method and the theoretically predicted NaZnBi (PbClF type, P4/nmm) and Na11 Zn2 Bi5 (Na11 Cd2 Sb5 type, P 1 ‾ ) phases were successfully synthesized, while other computationally generated compounds on the list were rejected. In addition, single crystal X-ray diffraction studies of NaZnBi indicate minor deviations from the stoichiometric 1 : 1 : 1 molar ratio. As a result, two isostructural (PbClF type, P4/nmm) Zn-deficient phases with similar compositions, but distinctly different unit cell parameters were discovered. The vacancies on Zn sites and unit cell expansion were rationalized from bonding analysis using electronic structure calculations on stoichiometric "NaZnBi". In-situ synchrotron powder X-ray diffraction studies shed light on complex equilibria in the Na-Zn-Bi system at elevated temperatures. In particular, the high-temperature polymorph HT-Na3 Bi (BiF3 type, Fm 3 ‾ m) was obtained as a product of Na11 Zn2 Bi5 decomposition above 611 K. HT-Na3 Bi cannot be stabilized at room temperature by quenching, and this type of structure was earlier observed in the high-pressure polymorph HP-Na3 Bi above 0.5 GPa. The aforementioned approach of predictive synthesis can be extended to other multinary systems.

Pancreatic Carcinosarcoma Clinical Outcome Analysis of the National Cancer Institute Database.

BACKGROUND: Pancreatic carcinosarcomas (PCS) are rare aggressive biphasic malignancies with a poor prognosis. We aimed to improve the understanding of PCS by analyzing variables that influence the mortality of PCS patients. METHODS: The Surveillance, Epidemiology, and End Results database was queried for cases of PCS from 1973 to 2016. Cases were analyzed for patient demographics, tumor characteristics, and surgical intervention. Kaplan-Meier and Cox regression analyses were applied to investigate the overall survival (OS) and prognostic factors. RESULTS: Thirty-nine cases of PCS were identified along with the disease demographics and characteristics. The majority of patients had a regionally invasive or metastatic disease. There was a significant decrease in OS with the increase of the tumor extension. Conversely, surgery showed to improve OS in the crude analysis, including patients that underwent lymphadenectomy. In addition, the unadjusted Cox regression results showed decreased hazard ratios with a local disease versus distant metastasis and with cancer-directed surgery versus no surgery. Nevertheless, the adjusted Cox regression results revealed that metastatic disease was the only significant predictor of survival. CONCLUSIONS: This population-based study provides some insight to a very rare disease by analyzing 39 cases of PCS. Our finding suggests considering PCS as a nonsurgical disease and reserving surgery solely for patients with a localized disease in combination or after neoadjuvant therapy. Consequently, there is a need to further investigate novel therapies for this aggressive malignancy.

Association of Clostridioides difficile with adverse clinical outcomes in patients with acute diverticulitis: A nationwide study.

BACKGROUND AND AIM: Acute diverticulitis (AD) is a common gastrointestinal disease with a significant health care-associated burden. Patients hospitalized with AD have many risk factors for developing Clostridioides difficile infection (CDI). CDI is associated with poor outcomes in many diseases but has yet to be studied in AD. METHODS: We utilized data from the National Inpatient Sample from January 2012 to October 2015 for patients hospitalized with AD and CDI compared with AD alone. Primary outcomes, which were mortality, length of stay, and hospitalization cost, were compared. Secondary outcomes were complications of diverticulitis and need for surgical interventions. Risk factors for mortality in AD and risk factors associated with CDI in AD patients were analyzed. RESULTS: Among 767 850 hospitalizations for AD, 8755 also had CDI. A propensity score-matched cohort analysis demonstrated that CDI was associated with increased risk of inpatient mortality (odds ratio [OR] 2.78, 95% confidence interval [CI] 1.30, 5.95), prolonged duration of hospitalization by 4.27 days (P < 0.0001), total hospital cost by $33 271 (P < 0.0001), need for surgery (OR 1.45, 95% CI 1.22, 1.71), and complications of diverticulitis (OR 1.45, 95% CI 1.21, 1.74). Predictors of CDI among patients with AD included female gender (1.12 OR, 95% CI 1.01, 1.24), three or more comorbidities (1.81 OR, 95% CI 1.57, 2.09), and admissions to teaching hospitals (1.44 OR, 95% CI 1.22, 1.70). CONCLUSIONS: Clostridioides difficile infection in AD is associated with increased mortality, length of stay, and hospital cost. Preventative measures should be made for at-risk patients with AD to decrease infection rate and poor outcomes.

Expanding Access to Large-Scale Genomic Data While Promoting Privacy: A Game Theoretic Approach.

Emerging scientific endeavors are creating big data repositories of data from millions of individuals. Sharing data in a privacy-respecting manner could lead to important discoveries, but high-profile demonstrations show that links between de-identified genomic data and named persons can sometimes be reestablished. Such re-identification attacks have focused on worst-case scenarios and spurred the adoption of data-sharing practices that unnecessarily impede research. To mitigate concerns, organizations have traditionally relied upon legal deterrents, like data use agreements, and are considering suppressing or adding noise to genomic variants. In this report, we use a game theoretic lens to develop more effective, quantifiable protections for genomic data sharing. This is a fundamentally different approach because it accounts for adversarial behavior and capabilities and tailors protections to anticipated recipients with reasonable resources, not adversaries with unlimited means. We demonstrate this approach via a new public resource with genomic summary data from over 8,000 individuals-the Sequence and Phenotype Integration Exchange (SPHINX)-and show that risks can be balanced against utility more effectively than with traditional approaches. We further show the generalizability of this framework by applying it to other genomic data collection and sharing endeavors. Recognizing that such models are dependent on a variety of parameters, we perform extensive sensitivity analyses to show that our findings are robust to their fluctuations.

Differentially expressed circular RNAs in orbital adipose/connective tissue from patients with thyroid-associated ophthalmopathy.

Our study aimed to investigate the differentially expressed circRNAs and their potential roles in orbital adipose/connective tissue from patients with thyroid-associated ophthalmopathy (TAO). The orbital adipose/connective tissue samples from three TAO patients and three control individuals were collected for RNA sequencing after depletion of ribosomal RNA. Differentially expressed mRNAs and up-regulated circRNAs were used for co-expression analysis. Functional and pathway enrichment analysis were conducted for the up- and down-regulated mRNAs in the circRNA-mRNA co-expression network. Meanwhile, circRNA-miRNA interaction network was established by miRanda software. The expression levels of mRNAs and circRNAs in control and TAO samples were determined by qRT-PCR. Among all the 16,329 circRNAs predicted from RNA sequencing data, 163 circRNAs (95 down-regulated and 68 up-regulated) were differentially expressed in TAO samples. Besides, 607 differentially expressed mRNAs were identified. The co-expression analysis showed circRNA_14940 was correlated with CCND1 and TNXB, while circRNA_10135 was correlated with PTGFR, and circRNA_14936 was correlated with TNFRSF19. The up-regulated CCND1 participated in Wnt signaling pathway. The down-regulated TNXB was involved in the ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathway. PTGFR participated in neuroactive ligand-receptor interaction and calcium signaling pathway. TNFRSF19 was involved in cytokine-cytokine receptor interaction. In the interaction network, circRNA_14936 could interact with hsa-miR-10392-3p, and circRNA_12367 could interact with hsa-miR-1228-3p. Moreover, the expression changes of MMP2, TNXB, PTGFR, CCND1, and TNFRSF19, as well as circRNA_14936, circRNA_14940, and circRNA_12367 were validated by qRT-PCR. In conclusion, the differentially expressed circRNAs might participate in pathogenesis of TAO, and we speculated that circRNA_14940-CCND1-Wnt signaling pathway might be an important regulatory axis.

The stability of horizontal ocular alignment of triad exotropia after one-step triple surgery.

PURPOSE: A-pattern exotropia, superior oblique muscle overaction, and dissociated vertical deviation may coexist and are referred to as triad exotropia. The present study evaluated the postoperative stability of horizontal ocular alignment of triad exotropia and possible prognostic factors. METHODS: Medical records of patients with triad exotropia who had one-step triple surgery of superior oblique muscle weakening, superior rectus muscle recession, and lateral rectus muscle recession were reviewed. The horizontal alignment and postoperative drift of triad exotropia were analyzed and compared with constant exotropia. RESULTS: The triad exotropia showed a mean of 7.7△ (± 8.5△) eso-drift, while the constant exotropia was (3.5△ ± 3.4△) exo-drift. Multiple linear regression analysis showed that the degree of superior oblique muscle overaction after surgery (P = 0.011) was the only factor associated with horizontal drift. Patients with superior oblique muscle underaction showed larger eso-drift when compared to patients without superior oblique muscle underaction (- 18.0△ ± 11.1△ vs. - 5.1△ ± 5.7△; P = 0.024). The final success rates of the triad exotropia and constant exotropia groups were 53.3% and 69.2%, respectively, and the overcorrection rates were 26.7% and 2.6% (P = 0.035). CONCLUSIONS: An overall trend of eso-drift in primary position occurred in triad exotropia after triple surgery up to a follow-up of 25 months. Patients presenting superior oblique muscle underaction after surgery seemed to have large angles of eso-drift, which might be taken into account in surgical planning and follow-up.

mTCTScan: a comprehensive platform for annotation and prioritization of mutations affecting drug sensitivity in cancers.

Cancer therapies have experienced rapid progress in recent years, with a number of novel small-molecule kinase inhibitors and monoclonal antibodies now being widely used to treat various types of human cancers. During cancer treatments, mutations can have important effects on drug sensitivity. However, the relationship between tumor genomic profiles and the effectiveness of cancer drugs remains elusive. We introduce Mutation To Cancer Therapy Scan (mTCTScan) web server (http://jjwanglab.org/mTCTScan) that can systematically analyze mutations affecting cancer drug sensitivity based on individual genomic profiles. The platform was developed by leveraging the latest knowledge on mutation-cancer drug sensitivity associations and the results from large-scale chemical screening using human cancer cell lines. Using an evidence-based scoring scheme based on current integrative evidences, mTCTScan is able to prioritize mutations according to their associations with cancer drugs and preclinical compounds. It can also show related drugs/compounds with sensitivity classification by considering the context of the entire genomic profile. In addition, mTCTScan incorporates comprehensive filtering functions and cancer-related annotations to better interpret mutation effects and their association with cancer drugs. This platform will greatly benefit both researchers and clinicians for interrogating mechanisms of mutation-dependent drug response, which will have a significant impact on cancer precision medicine.

Association between MTHFR C677T polymorphism and thyroid cancer risk: a meta-analysis.

In the light of the relationship between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and thyroid cancer (TC) exist objection, a meta-analysis of the MTHFR C677T polymorphism with thyroid cancer risk was performed. All the available studies were identified through a search of the PubMed, Embase, Web of Science, and Chinese Biomedical Literature Database (CBM) up to March 2014. The association between the MTHFR C677T polymorphism and thyroid cancer risk was conducted by odds ratios (ORs) and 95 % confidence intervals (95 % CIs). A total of five independent studies with 2,554 cases and 2,671 controls were included in our meta-analysis. Significant association was found between MTHFR C677T polymorphism and thyroid cancer risk in recessive model in overall populations (TT vs. TC/CC: OR = 1.88, 95 % CI = 1.59-2.21, P = 0.00), but there was no association between MTHFR C677T polymorphism and thyroid cancer risk found in other four models in overall populations (T vs. C: OR = 1.25, 95 % CI = 0.96-1.62, P = 0.10; TT vs. CC: OR = 1.11, 95 % CI = 0.93-1.33, P = 0.26; TC vs. CC: OR = 1.23, 95 % CI = 0.84-1.82, P = 0.29; TT/TC vs. CC: OR = 1.28, 95 % CI = 0.89-1.84, P = 0.19). In the subgroup analysis base on the ethnicity, the results suggested that MTHFR C677T polymorphism was significantly associated with thyroid cancer risk both in Caucasian and Asian populations in recessive model: (Caucasians: TT vs. TC/CC: OR = 2.28, 95 % CI = 1.11-4.67, P = 0.025; Asians: TT vs. TC/CC: OR = 1.86, 95 % CI = 1.57-2.20, P = 0.00). In conclusions, our meta-analysis suggested that the MTHFR C677T polymorphism is associated with thyroid cancer both in Caucasians and Asians.

Exploring the therapeutic potential of tetrahydrobiopterin for heart failure with preserved ejection fraction: A path forward.

A large number of patients are affected by classical heart failure (HF) symptomatology with preserved ejection fraction (HFpEF) and multiorgan syndrome. Due to high morbidity and mortality rate, hospitalization and mortality remain serious socioeconomic problems, while the lack of effective pharmacological or device treatment means that HFpEF presents a major unmet medical need. Evidence from clinical and basic studies demonstrates that systemic inflammation, increased oxidative stress, and impaired mitochondrial function are the common pathological mechanisms in HFpEF. Tetrahydrobiopterin (BH4), beyond being an endogenous co-factor for catalyzing the conversion of some essential biomolecules, has the capacity to prevent systemic inflammation, enhance antioxidant resistance, and modulate mitochondrial energy production. Therefore, BH4 has emerged in the last decade as a promising agent to prevent or reverse the progression of disorders such as cardiovascular disease. In this review, we cover the clinical progress and limitations of using downstream targets of nitric oxide (NO) through NO donors, soluble guanylate cyclase activators, phosphodiesterase inhibitors, and sodium-glucose co-transporter 2 inhibitors in treating cardiovascular diseases, including HFpEF. We discuss the use of BH4 in association with HFpEF, providing new evidence for its potential use as a pharmacological option for treating HFpEF.

Anoikis-related CTNND1 is associated with immuno-suppressive tumor microenvironment and predicts unfavorable immunotherapeutic outcome in non-small cell lung cancer.

Background: Immunotherapy has greatly changed the treatment of advanced non-small cell lung cancer (NSCLC). Anoikis is a programmed cell death process associated with cancer. However, the correlation between anoikis-related genes and the tumor microenvironment (TME) features and immunotherapeutic outcome in NSCLC has not been fully explored. Methods: The bulk and single-cell transcriptome data of NSCLC were downloaded from TCGA and GEO databases. The distribution of anoikis-related genes on different cell types at the single-cell level was analyzed, and these genes specifically expressed by tumor cells and immunotherapy-related were further extracted. Next, the candidate gene CTNND1 was identified and its correlations with the TME features and immunotherapeutic outcome in NSCLC were explored in multiple public cohorts. Finally, an in-house cohort was used to determine the CTNND1 expression and immuno-correlation in NSCLC. Results: At single-cell atlas, we found that anoikis-related genes expressed specifically in tumor cells of NSCLC. By intersecting anoikis-related genes, immunotherapy-associated genes, and the genes expressed in tumor cells, we obtained a special biomarker CTNND1. In addition, cell-cell communication analysis revealed that CTNND1+ tumor cells communicated with immune subpopulations frequently. Moreover, we found that high expression of CTNND1 was related to immuno-suppressive status of NSCLC. The expression of CTNND1 and its immuno-correlation were also validated, and the results showed that CTNND1 was highly expressed in NSCLC tissues and tumors with high CTNND1 expression accompanied with low CD8+ T cells infiltration. Conclusions: Overall, our study reported that CTNND1 can be considered as a novel biomarker for the predication of immunotherapeutic responses and a potential target for NSCLC therapy.