Synthesis of Perdeuterated Alkyl Amines/Amides with Pt/C as Catalyst under Mild Conditions.

A convenient method for the synthesis of perdeuterated alkyl amides/amines is disclosed. Perdeuterated acetyl amides can be achieved by a hydrogen-deuterium (H/D) exchange protocol with Pt/C as a catalyst and D2O as a deuterium source under mild conditions. After removal or reduction of the acetyl group, this protocol can provide perdeuterated primary, secondary, and tertiary amines, which are difficult to achieve via other methods.

Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing.

BACKGROUND: Trio-based whole-exome sequencing (trio-WES) enables identification of pathogenic variants, including copy-number variants (CNVs), in children with unexplained neurodevelopmental delay (NDD) and neurodevelopmental comorbidities (NDCs), including autism spectrum disorder (ASD), epilepsy, and attention deficit hyperactivity disorder. Further phenotypic and genetic analysis on trio-WES-tested NDD-NDCs cases may help to identify key phenotypic factors related to higher diagnostic yield of using trio-WES and novel risk genes associated with NDCs in clinical settings. METHODS: In this study, we retrospectively performed phenotypic analysis on 163 trio-WES-tested NDD-NDCs children to determine the phenotypic differences between genetically diagnosed and non-genetically diagnosed groups. Additionally, we conducted genetic analysis of ASD genes with the help of Simons Foundation for Autism Research Institute (SFARI) Gene database to identify novel possible ASD-risk genes underlying genetic NDD conditions. RESULTS: Among these 163 patients, pathogenic variants were identified in 82 cases (82/163, 50.3%), including 20 cases with CNVs. By comparing phenotypic variables between genetically diagnosed group (82 cases) and non-genetically diagnosed group (81 cases) with multivariate binary logistic regression analysis, we revealed that NDD-NDCs cases presenting with severe-profound NDD [53/82 vs 17/81, adjusted-OR (95%CI): 4.865 (2.213 - 10.694), adjusted-P < 0.001] or having multiple NDCs [26/82 vs 8/81, adjusted-OR (95%CI): 3.731 (1.399 - 9.950), adjusted-P = 0.009] or accompanying ASD [64/82 vs 35/81, adjusted-OR (95%CI): 3.256 (1.479 - 7.168), adjusted-P = 0.003] and head circumference abnormality [33/82 vs 11/81, adjusted-OR (95%CI): 2.788 (1.148 - 6.774), adjusted-P = 0.024] were more likely to have a genetic diagnosis using trio-WES. Moreover, 37 genes with monogenetic variants were identified in 48 patients genetically diagnosed with NDD-ASD, and 15 dosage-sensitive genes were identified in 16 individuals with NDD-ASD carrying CNVs. Most of those genes had been proven to be ASD-related genes. However, some of them (9 genes) were not proven sufficiently to correlate with ASD. By literature review and constructing protein-protein interaction networks among these 9 candidate ASD-risk genes and 102 established ASD genes obtained from the SFARI Gene database, we identified CUL4B, KCNH1, and PLA2G6 as novel possible ASD-risk genes underlying genetic NDD conditions. CONCLUSIONS: Trio-WES testing is recommended for patients with unexplained NDD-NDCs that have severe-profound NDD or multiple NDCs, particularly those with accompanying ASD and head circumference abnormality, as these independent factors may increase the likelihood of genetic diagnosis using trio-WES. Moreover, NDD patients with pathogenic variants in CUL4B, KCNH1 and PLA2G6 should be aware of potential risks of developing ASD during their disease courses.

Identification of a novel phenotype of external ear deformity related to Coffin-Siris syndrome-9 and literature review.

De novo germline variants of the SRY-related HMG-box 11 gene (SOX11) have been reported to cause Coffin-Siris syndrome-9 (CSS-9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies to date have documented the external ear malformation caused by SOX11 deficiency. Here, we reported a Chinese male with unilateral microtia and bilateral sensorineural deafness who showed CSS-like manifestations, including dysmorphic facial features, impaired neurodevelopment, and fingers/toes malformations. Using trio-based whole-exome sequencing, a de novo missense variant in SOX11 (NM_003108.4: c.347A>G, p.Y116C) was identified and classified as pathogenic variant as per American College of Medical Genetics guidelines. Moreover, a systematic search of the literature yielded 12 publications that provided data of 55 SOX11 intragenic variants affecting various protein-coding regions of SOX11 protein. By quantitatively analyzing phenotypic spectrum information related to these 56 SOX11 variants (including our case), we found variants affecting different regions of SOX11 protein (high-mobility group [HMG] domain and non-HMG regions) appear to influence the phenotypic spectrum of organ malformations in CSS-9; variants altering the HMG domain were more likely to cause the widest range of organ anomalies. In summary, this is the first report of CSS with external ear malformation caused by pathogenic variant in SOX11, indicating that the SOX11 gene may be not only essential for the development of the inner ear but also critical for the morphogenesis of the external ear. In addition, thorough clinical examination is recommended for patients who carry pathogenic SOX11 variants that affect the HMG domain, as these variants may cause the widest range of organ anomalies underlying this condition.

Effects of ankle-foot orthoses on gait parameters in post-stroke patients with different Brunnstrom stages of the lower limb: a single-center crossover trial.

BACKGROUND: Ankle-foot orthoses (AFO) can improve gait posture and walking ability in post-stroke patients. However, the effect of AFO on gait parameters in post-stroke patients according to the Brunnstrom stage of stroke recovery of the lower limbs remains unclear. The study aimed to investigate whether stroke patients with different Brunnstrom stages benefit from wearing AFO. METHODS: Twenty-five post-stroke participants included 18 men (50 ± 13 years) and 7 women (60 ± 15 years). The patients were divided based on Brunnstrom stage III or IV of the lower limbs. All patients underwent the gait and timed up and go (TUG) test using a gait analysis system while walking barefoot or with an AFO. The spatiotemporal and asymmetric parameters were analyzed. RESULTS: All 25 patients completed the study. Significant differences were observed between barefoot and AFO use in TUG time (P < 0.001) but not walking velocity (P > 0.05). The main effect of the swing time ratio was significant in both groups (P < 0.05); however, the main effects of stride length, stance time, and gait asymmetry ratio were nonsignificant (P > 0.05). For barefoot versus AFO, the main effects of stride length (P < 0.05) and swing time (P < 0.01) ratios were significant, whereas those of stance time and gait asymmetry ratio were nonsignificant (P > 0.05). CONCLUSIONS: Post-stroke patients with lower Brunnstrom stages benefitted more from AFO, particularly in gait asymmetry.

Cervical lymph node metastasis prediction from papillary thyroid carcinoma US videos: a prospective multicenter study.

BACKGROUND: Prediction of lymph node metastasis (LNM) is critical for individualized management of papillary thyroid carcinoma (PTC) patients to avoid unnecessary overtreatment as well as undesired under-treatment. Artificial intelligence (AI) trained by thyroid ultrasound (US) may improve prediction performance. METHODS: From September 2017 to December 2018, patients with suspicious PTC from the first medical center of the Chinese PLA general hospital were retrospectively enrolled to pre-train the multi-scale, multi-frame, and dual-direction deep learning (MMD-DL) model. From January 2019 to July 2021, PTC patients from four different centers were prospectively enrolled to fine-tune and independently validate MMD-DL. Its diagnostic performance and auxiliary effect on radiologists were analyzed in terms of receiver operating characteristic (ROC) curves, areas under the ROC curve (AUC), accuracy, sensitivity, and specificity. RESULTS: In total, 488 PTC patients were enrolled in the pre-training cohort, and 218 PTC patients were included for model fine-tuning (n = 109), internal test (n = 39), and external validation (n = 70). Diagnostic performances of MMD-DL achieved AUCs of 0.85 (95% CI: 0.73, 0.97) and 0.81 (95% CI: 0.73, 0.89) in the test and validation cohorts, respectively, and US radiologists significantly improved their average diagnostic accuracy (57% vs. 60%, P = 0.001) and sensitivity (62% vs. 65%, P < 0.001) by using the AI model for assistance. CONCLUSIONS: The AI model using US videos can provide accurate and reproducible prediction of cervical lymph node metastasis in papillary thyroid carcinoma patients preoperatively, and it can be used as an effective assisting tool to improve diagnostic performance of US radiologists. TRIAL REGISTRATION: We registered on the Chinese Clinical Trial Registry website with the number ChiCTR1900025592.

Adipose transplantation improves metabolism and atherosclerosis but not perivascular adipose tissue abnormality or vascular dysfunction in lipodystrophic Seipin/Apoe null mice.

Adipose dysfunction in lipodystrophic SEIPIN deficiency is associated with multiple metabolic disorders and increased risks of developing cardiovascular diseases, such as atherosclerosis, cardiac hypertrophy, and heart failure. Recently, adipose transplantation has been found to correct adipose dysfunction and metabolic disorders in lipodystrophic Seipin knockout mice; however, whether adipose transplantation could improve lipodystrophy-associated cardiovascular consequences is still unclear. Here, we aimed to explore the effects of adipose transplantation on lipodystrophy-associated metabolic cardiovascular diseases in Seipin knockout mice crossed into atherosclerosis-prone apolipoprotein E (Apoe) knockout background. At 2 months of age, lipodystrophic Seipin/Apoe double knockout mice and nonlipodystrophic Apoe knockout controls were subjected to adipose transplantation or sham operation. Seven months later, mice were euthanized. Our data showed that although adipose transplantation had no significant impact on endogenous adipose atrophy or gene expression, it remarkably increased plasma leptin but not adiponectin concentration in Seipin/Apoe double knockout mice. This led to significantly reduced hyperlipidemia, hepatic steatosis, and insulin resistance in Seipin/Apoe double knockout mice. Consequently, atherosclerosis burden, intraplaque macrophage infiltration, and aortic inflammatory gene expression were all attenuated in Seipin/Apoe double knockout mice with adipose transplantation. However, adipocyte morphology, macrophage infiltration, or fibrosis of the perivascular adipose tissue was not altered in Seipin/Apoe double knockout mice with adipose transplantation, followed by no significant improvement of vasoconstriction or relaxation. In conclusion, we demonstrate that adipose transplantation could alleviate lipodystrophy-associated metabolic disorders and atherosclerosis but has an almost null impact on perivascular adipose abnormality or vascular dysfunction in lipodystrophic Seipin/Apoe double knockout mice.NEW & NOTEWORTHY Adipose transplantation (AT) reverses multiply metabolic derangements in lipodystrophy, but whether it could improve lipodystrophy-related cardiovascular consequences is unknown. Here, using Seipin/Apoe double knockout mice as a lipodystrophy disease model, we showed that AT partially restored adipose functionality, which translated into significantly reduced atherosclerosis. However, AT was incapable of reversing perivascular adipose abnormality or vascular dysfunction. The current study provides preliminary experimental evidence on the therapeutic potential of AT on lipodystrophy-related metabolic cardiovascular diseases.

64 picosecond time resolved time-correlated single photon counting imaging.

High-speed imaging of dynamic scenes is a challenging and important task in many applications. However, conventional imaging methods based on charge coupled devices or complementary metal oxide semiconductors have limitations in temporal resolution and photon sensitivity. To address this problem, we propose a novel high-speed imaging scheme that combines single-pixel imaging with single photon detection and time-correlated single photon counting. Our scheme can achieve high-speed imaging with 64 ps resolution by repeating the motion scenes and using binary outputs from single photon detectors. We demonstrate our scheme by reconstructing the switching process of a digital micro-mirror device and a liquid crystal spatial light modulator. Our scheme can be further improved to 1 ps resolution by using a more accurate time-correlated single photon counting system. Moreover, our scheme can adapt to different speed scenes by adjusting the temporal resolution and reducing the sampling time. Our high temporal resolution imaging scheme further expands the application areas of single-pixel imaging and provides solutions for scenes requiring single photon detection and higher temporal resolution, such as reproducible chemical reaction processes imaging, cellular or sub-cellular bio imaging, single-molecule imaging of rotary motors, high-speed equipment inspection, and other periodic high-speed scenes imaging.

TIRPnet: Risk prediction of traditional Chinese medicine ingredients based on a deep neural network.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has a history of over 3000 years of medical practice. Due to the complex ingredients and unclear pharmacological mechanism of TCM, it is very difficult to predict its risks. With the increase in the number and severity of spontaneous reports of adverse drug reactions (ADRs) of TCM, its safety has received widespread attention. AIM OF THE STUDY: In this study, we proposed a framework based on deep learning to predict the probability of adverse reactions caused by TCM ingredients and validated the model using real-world data. MATERIALS AND METHODS: The spontaneous reporting data from Jiangsu Province of China was selected as the research data, which included 72,561 ADR reports of TCMs. All the ingredients of these TCMs were collected from the medical website and correlated with the corresponding ADRs. Then, a risk prediction model was constructed based on a deep neural network (DNN), named TIRPnet. Based on one-hot encoded data, our model achieved the optimal performance by fine-tuning some hyperparameters. The ten most commonly used TCM ingredients and their ADRs were collected as the test set to evaluate their performance as objective criteria. RESULTS: TIRPnet was constructed as a 7-layer DNN. The experimental results showed that TIRPnet performs excellently in all indicators, with a sensitivity of 0.950, specificity of 0.995, accuracy of 0.994, precision of 0.708, and F1 of 0.811. CONCLUSIONS: The proposed TIRPnet owns the ability to predict the ADRs of a single TCM ingredient by learning a large number of TCM-related spontaneous reports, which can help doctors design safe prescriptions and provide technical support for the pharmacovigilance of TCM.

A Cu hollow fiber with coaxially grown Bi nanosheet arrays as an integrated gas-penetrable electrode enables high current density and durable formate electrosynthesis.

While high current density formate (HCOO-) electrosynthesis from CO2 reduction has been achieved in a flow cell assembly, the inevitable flooding and salt precipitation of traditional gas-diffusion electrodes (GDEs) severely limit the overall energy efficiency and stability. In this work, an integrated gas-penetrable electrode (GPE) for HCOO- electrosynthesis was developed by coaxially growing vertically aligned high density Bi nanosheet arrays on a porous Cu hollow fiber (Bi NSAs@Cu HF) via controllable galvanic replacement. The interior porous Cu HF serves as a robust gas-penetrable and conductive host for continuously delivering CO2 gas to surface-anchored Bi NSAs, resulting in numerous well-balanced triphase active interfaces for the electrocatalytic CO2 reduction reaction (CO2RR). The most active Bi NSAs@Cu HF GPE exhibits a high HCOO- faradaic efficiency (FEHCOO-) of over 80% in a wide potential window (330 mV) with a linearly increased partial current density (jHCOO-) up to -261.6 mA cm-2 at -1.11 V vs. the reversible hydrogen electrode (RHE). The Bi NSAs@Cu HF GPE also sustains a FEHCOO- of >80% at a high total current density of -300 mA cm-2, corresponding to a jHCOO- of >-240 mA cm-2, for more than 60 h. This work provides new perspectives on designing efficient and durable integrated GPEs for a sustainable CO2RR on a large scale.

Multi-needle blow-spinning technique for fabricating collagen nanofibrous nerve guidance conduit with scalable productivity and high performance.

Nerve guidance conduits (NGCs) have been widely accepted as a promising strategy for peripheral nerve regeneration. Fabricating ideal NGCs with good biocompatibility, biodegradability, permeability, appropriate mechanical properties (space maintenance, suturing performance, etc.), and oriented topographic cues is still current research focus. From the perspective of translation, the technique stability and scalability are also an important consideration for industrial production. Recently, blow-spinning technique shows great potentials in nanofibrous scaffolds fabrication, possessing high quality, high fiber production rates, low cost, ease of maintenance, and high reliability. In this study, we proposed for the first time the preparation of a novel NGC via blow-spinning technique to obtain optimized performances and high productivity. A new collagen nanofibrous neuro-tube with the bilayered design was developed, incorporating inner oriented and outer random topographical cues. The bilayer structure enhances the mechanical properties of the conduit in dry and wet, displaying good radial support and suturing performance. The porous nature of the blow-spun collagen membrane enables good nutrient delivery and metabolism. The in vitro and in vivo evaluations indicated the bilayer-structure conduit could promoted Schwann cells growth, neurotrophic factors secretion, and axonal regeneration and motor functional recovery in rat.

Mulberry (Morus alba L.) leaf water extract attenuates type 2 diabetes mellitus by regulating gut microbiota dysbiosis, lipopolysaccharide elevation and endocannabinoid system disorder.

ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry (Morus alba L.) leaf is a well-known herbal medicine and has been used to treat diabetes in China for thousands of years. Our previous studies have proven mulberry leaf water extract (MLWE) could improve type 2 diabetes mellitus (T2D). However, it is still unclear whether MLWE could mitigate T2D by regulating gut microbiota dysbiosis and thereof improve intestinal permeability and metabolic dysfunction through modulation of lipopolysaccharide (LPS) and endocannabinoid system (eCBs). AIM OF STUDY: This study aims to explore the potential mechanism of MLWE on the regulation of metabolic function disorder of T2D mice from the aspects of gut microbiota, LPS and eCBs. MATERIALS AND METHODS: Gut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. LPS, N-arachidonoylethanolamine (AEA) and 2-ararchidonylglycerol (2-AG) contents in blood were determined by kits or liquid phase chromatography coupled with triple quadrupole tandem mass spectrometry, respectively. The receptors, enzymes or tight junction protein related to eCBs or gut barrier were detected by RT-PCR or Western blot, respectively. RESULTS: MLWE reduced the serum levels of AEA, 2-AG and LPS, decreased the expressions of N-acylphophatidylethanolamine phospholipase D, diacylglycerol lipase-α and cyclooxygenase 2, and increased the expressions of fatty acid amide hydrolase (FAAH), N-acylethanolamine-hydrolyzing acid amidase (NAAA), alpha/beta hydrolases domain 6/12 in the liver and ileum and occludin, monoacylglycerol lipase and cannabinoid receptor 1 in the ileum of T2D mice. Furthermore, MLWE could change the abundances of the genera including Acetatifactor, Anaerovorax, Bilophila, Colidextribacter, Dubosiella, Gastranaerophilales, Lachnospiraceae_NK4A136_group, Oscillibacter and Rikenella related to LPS, AEA and/or 2-AG. Moreover, obvious improvement of MLWE treatment on serum AEA level, ileum occludin expression, and liver FAAH and NAAA expression could be observed in germ-free-mimic T2D mice. CONCLUSION: MLWE could ameliorate intestinal permeability, inflammation, and glucose and lipid metabolism imbalance of T2D by regulating gut microbiota, LPS and eCBs.

Efficacy and safety of leuprorelin 3-month depot (11.25 mg) for idiopathic central precocious puberty treatment of Chinese girls: a single-center retrospective study.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of 3-month leuprorelin acetate (3-month LA, 11.25 mg) for the treatment of idiopathic central precocious puberty (ICPP) in Chinese girls. METHODS: We conducted a single-center retrospective study in China on 28 girls with ICPP who received at least one year of 3-month LA treatment. Data from anthropometry, biochemistry, bone age (BA), and pelvic ultrasonography were assessed before and every 6 months during medication. RESULTS: At CPP diagnosis, the mean chronological age (CA) was 7.8±0.8 years, with bone age advancement (BA-CA) of 1.5±0.8 years. After treatment initiation, growth velocity decreased significantly from 8.5±1.6 cm/year to 5.8±1.1 cm/year at month 12 (p<0.001). GnRH-stimulated peak LH ≤3IU/L, the primary efficacy criterion, was observed in 27 out of 28 (96.4 %) children at month 3. Basal estradiol <20 pg/mL was achieved by all 28 girls (100 %) at month 6 and remained stable at month 12. Basal follicle-stimulating hormone (FSH) decreased from 4.1±3.5 to 1.7±0.9 (p<0.001), and basal LH was also significantly reduced from 3.3±6.5 to 0.7±0.8 (p=0.035) at month 12. The mean predicted adult height (PAH) at treatment initiation was 152.7±5.8 cm, it increased significantly to 157.5±5.5 cm (p=0.007) after one-year treatment. Pubertal development was slowed in most patients, and in some cases, it was even reversed. Only one patient (3.6 %) reported local intolerance. CONCLUSIONS: Three-month leuprorelin acetate is a safe and effective treatment for suppressing the pituitary-gonadal axis and restoring impaired adult height in Chinese girls.

Gram-level NH3 Electrosynthesis via NOx reduction on a Cu Activated Co Electrode.

Ambient electrochemical ammonia (NH3 ) synthesis is one promising alternative to the energy-intensive Haber-Bosch route. However, the industrial requirement for the electrochemical NH3 production with amperes current densities or gram-level NH3 yield remains a grand challenge. Herein, we report the high-rate NH3 production via NO2 - reduction using the Cu activated Co electrode in a bipolar membrane (BPM) assemble electrolyser, wherein BPM maintains the ion balance and the liquid level of electrolyte. Benefited from the abundant Co sites and optimal structure, the target modified Co foam electrode delivers a current density of 2.64 A cm-2 with the Faradaic efficiency of 96.45 % and the high NH3 yield rate of 279.44 mg h-1 cm-2 in H-type cell using alkaline electrolyte. Combined with in situ experiments and theoretical calculations, we found that Cu optimizes the adsorption behavior of NO2 - and facilitates the hydrogenation steps on Co sites toward a rapid NO2 - reduction process. Importantly, this activated Co electrode affords a large NH3 production up to 4.11 g h-1 in a homemade reactor, highlighting its large-scale practical feasibility.

Hypoxia-induced PLOD2 promotes clear cell renal cell carcinoma progression via modulating EGFR-dependent AKT pathway activation.

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that is both common and aggressive, with a rising incidence in recent decades. Hypoxia is a key factor that plays a vital role in the tumorigenesis and metastasis of malignancy. However, the precise mechanisms of hypoxia driving ccRCC progression were not totally uncovered. Our study found that hypoxia level was elevated in ccRCC and might be an independent risk factor of prognosis in ccRCC patients. We identified a key protein PLOD2 was induced under hypoxic conditions and strongly associated with poor prognosis in ccRCC patients. When PLOD2 was depleted, the proliferation and migration of ccRCC cells were reduced in vitro and in vivo, while overexpression of PLOD2 had the opposite effect. Mechanically, the study further revealed that PLOD2 was transcriptionally activated by HIF1A, which binds to a specific promoter region of the PLOD2 gene. PLOD2 was also shown to interact with EGFR, leading to the phosphorylation of the receptor. Furthermore, PLOD2 was responsible for binding to the extracellular domain of EGFR, which ultimately activated the AKT signaling pathway, thus promoting the malignant progression of ccRCC. Treatment with the PLOD2 inhibitor Minoxidil significantly suppressed ccRCC progression by inactivating the EGFR/AKT signaling axis. In summary, the findings of this study shed light on the molecular mechanisms behind PLOD2 expression in ccRCC and suggest that it may serve as a potential predictor and therapeutic target for the clinical prognosis and treatment of ccRCC.

Study on the effect of digital economy development on carbon emissions: evidence from 30 provinces in China.

Currently, China is moving towards the era of the digital economy, which is gradually becoming a new engine of high-quality development. In the "double carbon" strategy context, the digital economy is characterized by low carbon emissions and high permeability, making it essential for carbon emission reduction. There needs to be more empirical research on the digital economy and carbon emissions. Given this, this study empirically examines the impact of digital economy development on carbon emissions intensity and its mechanisms in a multidimensional way based on the panel data of 30 provincial-level administrative regions in China from 2011 to 2019, utilizing a fixed-effects model, a mediated-effects model, a spatial Durbin model, and other methods. The study results show that (1) the digital economy can significantly reduce carbon emissions intensity. (2) The digital economy can indirectly affect the intensity of carbon emissions through industrial structure, energy structure, and environmental regulation. (3) The development of the local digital economy has a positive spillover effect on the carbon emissions intensity of neighbouring places. However, the overall effect is negative. This paper reveals some new features of the digital economy and carbon emissions intensity, which provides a reference for advancing the country's construction and realizing China's "double carbon" goal.

Immunotherapy Combined with Chemotherapy in Relapse Metaplastic Breast Cancer.

Metaplastic breast cancer (MBC) is a rare disease, and there was rarely reported the treatment after recurrence and metastasis. Here, we report the treatment of an adult patient who suffered from MBC with lung, lymph nodes and left pleura metastasis after radical surgery. The next-generation sequencing result demonstrated that it had tumor mutational burden (TMB) of 12.0 Muts/Mb and microsatellite stability. The patient received sintilimab, an immune checkpoint inhibitor, plus chemotherapy and achieved partial response (PR). This is a report of a good outcome of metastatic MBC achieving 24 months of progression-free survival (PFS) and 39 months of overall survival (OS) with a combination therapy of immune checkpoint inhibitor and chemotherapy. Immuno-chemotherapy may have antitumor activity for relapse MBC. TMB may serve as a potential predictor associated with PD-1 inhibitors in MBC and help clinicians make an optimum treatment strategy.

A novel fluorescent dye selectively images and kills cancer stem cells by targeting mitochondria: Evidence from a cell line­based zebrafish xenograft model.

Numerous agents such as near-infrared dyes that are characterized by specialized cancer imaging and cytotoxicity effects have key roles in cancer diagnosis and therapy via molecularly targeting special biological tissues, organelles and processes. In the present study, a novel fluorescent compound was demonstrated to inhibit cancer cell proliferation in a zebrafish model with slight in vivo toxicity. Further studies demonstrated selective staining of cancer cells and even putative cancer stem cells via accumulation of the dye in the mitochondria of cancer cells, compared with normal cells. Moreover, this compound was also used to image cancer cells in vivo using a zebrafish model. The compound displayed no apparent toxicity to the host animal. Overall, the data indicated that this compound was worthy of further evaluation due to its low toxicity and selective cancer cell imaging and killing effects. It could be a useful tool in cancer research.

Association between ankle-brachial blood pressure index with all-cause and cardiovascular mortality in adults without arterial stiffness.

PURPOSE: To explore the relationship between ankle-brachial blood pressure index (ABPI) and all-cause or cardiovascular mortality in adults without arterial stiffness. METHODS: A total of 6784 participants without arterial stiffness were enrolled from National Health and Nutrition Examination Survey 1999-2004. The hazard ratio (HR) and 95% confidence interval (CI) of ABPI associating with the risk of all-cause and cardiovascular mortality was calculated by Cox proportional regression models adjusted for demographic and traditional risk factors. Dose-response relationship was explored with restricted cubic spines. RESULTS: After an average follow-up of 12.1 years, 1844 all-cause deaths and 299 cardiovascular deaths occurred. Compared with the lowest ABPI quartile, the second quartile was associated with the lowest risk of all-cause mortality (HR 0.89, 95%CI 0.79-0.98; p = 0.036) and cardiovascular mortality (HR 0.75, 95%CI 0.56-0.98; p = 0.048). Besides, dose-response analysis revealed that ABPI was nonlinearly correlated to all-cause mortality (p for nonlinearity < 0.001) and linearly correlated to cardiovascular mortality (p for nonlinearity = 0.459). CONCLUSIONS: The relationship between ABPI and all-cause and cardiovascular mortality followed a L-shape curve. A lower ABPI was independently associated with an increased risk of all-cause and cardiovascular mortality in adults without arterial stiffness.

The triglyceride glucose index was U-shape associated with all-cause mortality in population with cardiovascular diseases.

BACKGROUND: The triglyceride and glucose (TyG) index has been considered a simple surrogate marker of insulin resistance, related to a high risk of mortality. However, few studies have investigated the specific relationship between the TyG index and all-cause mortality among population with cardiovascular diseases. METHODS: 2,072 participants with cardiovascular diseases were enrolled from the National Health and Nutrition Examination Survey (NHANES) 1999-2014. The TyG index was calculated as log [fasting triglycerides (mg/dL) x fasting glucose (mg/dL)/2]. Outcomes were all-cause mortality and cardiovascular mortality. The baseline levels of TyG associated with the risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined quantile categories with Cox regression models. RESULTS: After a follow-up of 16.8 years, 791 all-cause deaths and 184 cardiovascular deaths occurred. Restricted cubic splines showed that the association between levels of TyG index and the risk of all-cause mortality was non-linear (p < 0.001) and the TyG index associated with the lowest risk of all-cause mortality ranges 8.83 to 9.06 in individuals with cardiovascular diseases. Compared with the reference quartile of 8.84 ~ 9.29, the multivariate-adjusted hazards ratios and 95% confidence intervals were 1.40 (1.13-1.74; p = 0.002) in the lowest quartile and 1.08 (0.88, 1.32; p = 0.475) in the highest quartile for all-cause mortality. However, TyG was not associated with cardiovascular mortality. CONCLUSIONS: TyG index was U-shape associated with the risk of all-cause mortality in participants with cardiovascular diseases and the level associated with the lowest risk ranged 8.83 to 9.06.

Genome-wide identification of PYL/PYR-PP2C (A)-SnRK2 genes in Eutrema and their co-expression analysis in response to ABA and abiotic stresses.

ABA signaling core components PYR/PYL, group A PP2C and SnRK2 play important roles in various environmental stress responses of plants. This study identified 14 PYR/PYL, 9 PP2C (A), and 10 SnRK2 genes from halophytic Eutrema. Phylogenetic analysis showed 4 EsPYR/PYL, 4 EsPP2C (A) and 3 EsSnRK2 subfamilies characterized, which was supported by their gene structures and protein motifs. Large-scale segmental duplication event was demonstrated to be a major contributor to expansion of the EsPYL-PP2C (A)-SnRK2 gene families. Synteny relationship analysis revealed more orthologous PYL-PP2C (A)-SnRK2 gene pairs located in collinear blocks between Eutrema and Brassica than that between Eutrema and Arabidopsis. RNA-seq and qRT-PCR revealed EsABI1, EsABI2 and EsHAL2 showed a significantly up-regulated expression in leaves and roots in response to ABA, NaCl or cold stress. Three markedly co-expression modules of ABA/R-brown, NaCl/L-lightsteelblue1 and Cold/R-lightgreen were uncovered to contain EsPYL-PP2C (A)-SnRK2 genes by WGCNA analysis. GO and KEGG analysis indicated that the genes of ABA/R-brown module containing EsHAB1, EsHAI2 and EsSnRK2.6 were enriched in proteasome pathway. Further, EsHAI2-OE transgenic Arabidopsis lines showed significantly enhanced seeds germination and seedlings growth. This work provides a new insight for elucidating potential molecular functions of PYL-PP2C (A)-SnRK2 responding to ABA and abiotic stresses.