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Background: Diabetic bone healing remains a great challenge due to its pathological features including biochemical disturbance, excessive inflammation, and reduced blood vessel formation. In previous studies, small intestine submucosa (SIS) has been demonstrated for its immunomodulatory and angiogenic properties, which are necessary to diabetic bone healing. However, the noticeable drawbacks of SIS such as fast degradation rate, slow gelling time, and weak mechanical property seriously impede the 3D printing of SIS for bone repair. Method: In this study, we developed a novel kind of 3D-printed scaffold composed of alginate, nano-hydroxyapatite, and SIS. The morphological characterization, biocompatibility, and in vitro biological effects of the scaffolds were evaluated, and an established diabetic rat model was used for testing the in vivo biological effect of the scaffold after implantation. Results: The in vitro and in vivo results show that the addition of SIS can tune the immunomodulatory properties and angiogenic and osteogenic performances of 3D-printed scaffold, where the macrophages polarization of M2 phenotype, migration and tube formation of HUVECs, as well as osteogenic expression of ALP, are all improved, which bode well with the functional requirements for treating diabetic bone nonunion. Furthermore, the incorporation of alginate substantially improves the printability of composites with tunable degradation properties, thereby broadening the application prospect of SIS-based materials in the field of tissue engineering. Conclusion: The fabricated 3D-printed Alg/HA/SIS scaffold provides desirable immunomodulatory effect, as well as good osteogenic and angiogenic performances in vitro and in vivo, which properties are well-suited with the requirement for treating diabetic bone defects. Translational potential of this article: The incorporation of SIS and alginate acid not only provides good printability of the newly fabricated 3D-printed Alg/HA/SIS scaffold, but also improves its immunoregulatory and angiogenic properties, which suits well with the requirement for treating diabetic bone disease and opens up new horizons for the development of implants associating diabetic bone healings.

Abstract Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration. Despite extensive studies on mineralized parenchymal tissue rebuilding, regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet. Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage. But to date, the absence of promising therapeutic biomaterials/scaffolds remains. The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds. To address these issues, in this study, we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds. Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses. A feasible scaffold, polylactic acid electrospinning membrane (PLA), was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center, meanwhile supporting proper osteointegration with defect bony edges. Especially, transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered. This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing, offering clinicians potential choices for regenerating such complicated injuries.

Abstract Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin’s function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.

Abstract Background Abnormal placental development is a significant factor contributing to perinatal morbidity and mortality, affecting approximately 5–7% of pregnant women. Trophoblast syncytialization plays a pivotal role in the establishment and maturation of the placenta, and its dysregulation is closely associated with several pregnancy-related disorders, including preeclampsia and intrauterine growth restriction. However, the underlying mechanisms and genetic determinants of syncytialization are largely unknown. Methods We conducted a systematic drug screen using an epigenetic compound library to systematically investigate the epigenetic mechanism essential for syncytialization, and identified mixed lineage leukemia 1 (MLL1), a histone 3 lysine 4 methyltransferase, as a crucial regulator of trophoblast syncytialization. BeWo cells were utilized to investigate the role of MLL1 during trophoblast syncytialization. RNA sequencing and CUT&Tag were further performed to search for potential target genes and the molecular pathways involved. Human placenta tissue was used to investigate the role of MLL1 in TEA domain transcription factor 4 (TEAD4) expression and the upstream signaling during syncytialization. A mouse model was used to examine whether inhibition of MLL1-mediated H3K4me3 regulated placental TEAD4 expression and fetoplacental growth. Results Genetic knockdown of MLL1 or pharmacological inhibition of the MLL1 methyltransferase complex (by MI-3454) markedly enhanced syncytialization, while overexpression of MLL1 inhibited forskolin (FSK)-induced syncytiotrophoblast formation. In human placental villous tissue, MLL1 was predominantly localized in the nuclei of cytotrophoblasts. Moreover, a notable upregulation in MLL1 expression was observed in the villus tissue of patients with preeclampsia compared with that in the control group. Based on RNA sequencing and CUT&Tag analyses, depletion of MLL1 inhibited the Hippo signaling pathway by suppressing TEAD4 expression by modulating H3K4me3 levels on the TEAD4 promoter region. TEAD4 overexpression significantly reversed the FSK-induced or MLL1 silencing-mediated trophoblast syncytialization. Additionally, decreased hypoxia-inducible factor 1A (HIF1A) enrichment at the MLL1 promoter was observed during syncytialization. Under hypoxic conditions, HIF1A could bind to and upregulate MLL1, leading to the activation of the MLL1/TEAD4 axis. In vivo studies demonstrated that the administration of MI-3454 significantly enhanced fetal vessel development and increased the thickness of the syncytial layer, thereby supporting fetoplacental growth. Conclusions These results revealed a novel epigenetic mechanism underlying the progression of syncytialization with MLL1, and suggest potential avenues for identifying new therapeutic targets for pregnancy-related disorders.

Summary: Lysine crotonylation has attracted widespread attention in recent years. However, little is known about bacterial crotonylation, particularly crotonyltransferase and decrotonylase, and its effects on antibiotic resistance. Our study demonstrates the ubiquitous presence of crotonylation in E. coli, which promotes bacterial resistance to polymyxin. We identify the crotonyltransferase YjgM and its regulatory pathways in E. coli with a focus on crotonylation. Further studies show that YjgM upregulates the crotonylation of the substrate protein PmrA, thereby boosting PmrA’s affinity for binding to the promoter of eptA, which, in turn, promotes EptA expression and confers polymyxin resistance in E. coli. Additionally, we discover that PmrA’s crucial crotonylation site and functional site is Lys 164. These significant discoveries highlight the role of crotonylation in bacterial drug resistance and offer a fresh perspective on creating antibacterial compounds.

Microwave remote sensing offers a powerful tool for monitoring the growth of short, dense vegetation such as soybeans. As the plants mature, changes in their biomass and 3-D structure impact the electromagnetic (EM) backscatter signal. This backscatter information holds valuable insights into crop health and yield, prompting the need for a comprehensive understanding of how structural and biophysical properties of soybeans as well as soil characteristics contribute to the overall backscatter signature. In this study, a full-wave model is developed for simulating L-band backscatter from soybean fields. Leveraging the ANSYS high-frequency structure simulator (HFSS) framework, the model solves for the scattering of EM waves from realistic 3-D structural models of soybean, explicitly incorporating the interplant scattering effects. The model estimates of backscatter match well with the field observations from the SMAPVEX16-MicroWEX and SMAPVEX12, with average differences of 1–2 dB for co-pol and less than 4 dB for cross-pol. Furthermore, the model effectively replicates the temporal dynamics of crop backscatter throughout the growing season. The HFSS analysis revealed that the stems, pods, and soil are the primary contributors to HH-pol backscatter, while the branches contribute to VV-pol, and leaves impact the cross-pol signatures. In addition, a sensitivity study with a 3-D bare soil surface resulted in an average variation of 8 dB in co- and cross-pol, even when the root-mean-square height and correlation length were held constant. These capabilities underscore the model's potential to provide insights into the underlying dynamics of the backscatter for growing vegetation.

In this paper, we investigate distributed online optimization over multi-agent networks, where a group of agents aim to cooperatively seek the minimum value of a time-varying global loss function that can be expressed as the sum of the local loss functions privately owned by a single agent on the network at each iteration. In addition, all agents do not know the future loss function, and information about the loss function is disclosed only after the agent has made a decision. We are interested in scenarios where the communication topology of a multi-agent network is a sequence of time-varying unbalanced graphs and the loss function of each agent is a class of non-strongly convex functions. We generalize the distributed online Newton step algorithm to a more general multi-agent network by introducing a consensual-based auxiliary estimation to rescale the contribution of each agent in optimization. Our algorithm only uses row stochastic matrices and does not require the agent to know the out-degree of its in-neighbors. The convergence of regret bound over time-varying unbalanced networks is rigorously proved. Simulation results also verify the effectiveness of the proposed algorithm, and show its advantage in convergence speed compared with the first-order algorithms.

[INLINE:1] Activated G-protein-coupled receptor 39 (GPR39) has been shown to attenuate inflammation by interacting with sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). However, whether GPR39 attenuates neuropathic pain remains unclear. In this study, we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats. Intrathecal injection of TC-G 1008, a specific agonist of GPR39, significantly alleviated mechanical allodynia in the rats with spared nerve injury, improved spinal cord mitochondrial biogenesis, and alleviated neuroinflammation. These changes were abolished by GPR39 small interfering RNA (siRNA), Ex-527 (SIRT1 inhibitor), and PGC-1α siRNA. Taken together, these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1α pathway in rats with spared nerve injury.

BackgroundSerum albumin plays a pivotal role in regulating plasma oncotic pressure and modulating fluid distribution among various body compartments. Previous research examining the association between maternal serum albumin levels and fetal growth yielded limited and inconclusive findings. Therefore, the specific influence of serum albumin on fetal growth remains poorly understood and warrants further investigation.MethodsA retrospective study involved 39200 women who had a singleton live birth at a tertiary-care academic medical center during the period from January 2017 to December 2020. Women were categorized into four groups according to the quartile of albumin concentration during early pregnancy: Q1 group, ≤41.0 g/L; Q2 group, 41.1-42.6 g/L; Q3 group, 42.7-44.3 g/L and Q4 group, >44.3 g/L. The main outcome measures were mid-term estimated fetal weight, birthweight and gestational age. Multivariate linear and logistic regression analysis were performed to detect the independent effect of maternal serum albumin level on fetal growth after adjusting for important confounding variables.ResultsIn the crude analysis, a significant inverse correlation was found between early pregnancy maternal serum albumin levels and fetal growth status, including mid-term ultrasound measurements, mid-term estimated fetal weight, birthweight, and gestational age. After adjustment for a number of confounding factors, mid-term estimated fetal weight, birthweight, and birth height decreased significantly with increasing albumin levels. Compared to the Q2 group, the Q4 group had higher rates of preterm birth (aOR, 1.16; 95% CI, 1.01–1.34), small-for-gestational-age (aOR, 1.27; 95% CI, 1.11–1.45) and low birthweight (aOR, 1.41; 95% CI, 1.18–1.69), and lower rate of large-for-gestational-age (aOR, 0.85; 95% CI, 0.78–0.94). Moreover, to achieve the optimal neonatal outcome, women with higher early pregnancy albumin levels required a greater reduction in albumin levels in later pregnancy stages.ConclusionsA higher maternal serum albumin level during early pregnancy was associated with poor fetal growth, with the detrimental effects becoming apparent as early as the mid-gestation period. These findings provided vital information for clinicians to predict fetal growth status and identify cases with a high risk of adverse neonatal outcomes early on.

Abstract Cancer-associated adipocytes (CAAs), one of the primary stromal components, exhibit intimate crosstalk and release multiple cell factors mediating local and systemic biological effects. However, the role of CAAs in the regulation of systemic immune responses and their potential value in the clinical treatment of triple-negative breast cancer (TNBC) are not well described. Transcriptome sequencing was performed on CAA and normal adipocyte (NA) tissues isolated from surgically resected samples from TNBC patients and healthy controls. Cytokines, including C-X-C motif chemokine ligand 8 (CXCL8, also known as IL-8), secreted from NAs and CAAs were compared by transcriptome sequencing and enzyme-linked immunosorbent assay (ELISA). Proliferation, migration and invasion assays were employed to analyze the role of CAAs and CAA-derived CXCL8 (macrophage inflammatory protein-2 (MIP2) as a functional surrogate in mice). TNBC syngraft models were established to evaluate the curative effect of targeting CXCL8 in combination with anti-PD-1 therapies. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), polymerase chain reaction (PCR) array, flow cytometry, immunohistochemistry (IHC), and immunofluorescence (IF) were applied to analyze immune cell infiltration and epithelial–mesenchymal transition (EMT) markers. Specifically, we demonstrated that CAAs and CAA-derived CXCL8 played important roles in tumor growth, EMT, metastasis and tumor immunity suppression. CAA-derived CXCL8 remodeled the tumor immune microenvironment not only by suppressing CD4+ T and CD8+ T immune cell infiltration but also by upregulating CD274 expression in TNBC. The combination of targeting the CXCL8 pathway and blocking the PD-1 pathway synergistically increased the tumor immune response and inhibited tumor progression. Thus, our results highlight the molecular mechanisms and translational significance of CAAs in tumor progression and immune ecosystem regulatory effects and provide a better understanding of the potential clinical benefit of targeting CAA-derived CXCL8 in antitumor immunity and as a new therapeutic moiety in TNBC.

The HVDC transmission system has played an important role in modern power system. In traditional HVDC transmission line protection, the differential protection is invulnerable to high fault resistance, but its time delay is too long due to the distributed capacitance current. In order to solve this problem, a novel pilot differential protection is proposed in this paper. The compensating voltage on the setting point on the line can be calculated by using the voltage and current at two terminals of the line, separately. The difference value of the compensating voltages calculated by the voltage and current at rectifier side terminal and the inverter side terminal are defined as the differential voltage in this paper. When external fault occurs, the compensating voltage on the setting point calculated by the rectifier side terminal and inverter side terminal should be almost the same, so the differential voltage should be relatively small. However, when internal fault occurs, the compensating voltage on the setting point calculated by the two terminals are different, so the differential voltage should be relatively large. The analysis proves that the differential voltage can be used to identify the fault. A ±800 kV UHVDC system is modeled for simulation in PSCAD/EMTDC, and the correctness and effectiveness of the proposed protection method is verified.

Background: Early life stress (ELS) is a major risk factor for depression in adolescents. The nucleus accumbens (NAc) is a key center of the reward system, and spine remodeling in the NAc contributes to the development of depression. The Si-Ni-San formula (SNS) is a fundamental prescription for treating depression in traditional Chinese medicine. However, little is known about the effects of SNS on behavioral abnormalities and spine plasticity in the NAc induced by ELS.Purpose: This study aimed to investigate the therapeutic effect and the modulatory mechanism of SNS on abnormal behaviors and spine plasticity in the NAc caused by ELS.Methods: We utilized a model of ELS that involved maternal separation with early weaning to explore the protective effects of SNS on adolescent depression. Depressive-like behaviors were evaluated by the sucrose preference test, the tail suspension test, and the forced swimming test; anxiety-like behaviors were monitored by the open field test and the elevated plus maze. A laser scanning confocal microscope was used to analyze dendritic spine remodeling in the NAc. The activity of Rac1 was detected by pull-down and Western blot tests. Viral-mediated gene transfer of Rac1 was used to investigate its role in ELS-induced depression-like behaviors in adolescence.Results: ELS induced depression-like behaviors but not anxiety-like behaviors in adolescent mice, accompanied by an increase in stubby spine density, a decrease in mushroom spine density, and decreased Rac1 activity in the NAc. Overexpression of constitutively active Rac1 in the NAc reversed depression-related behaviors, leading to a decrease in stubby spine density and an increase in mushroom spine density. Moreover, SNS attenuated depression-like behavior in adolescent mice and counteracted the spine abnormalities in the NAc induced by ELS. Additionally, SNS increased NAc Rac1 activity, and the inhibition of Rac1 activity weakened the antidepressant effect of SNS.Conclusion: These results suggest that SNS may exert its antidepressant effects by modulating Rac1 activity and associated spine plasticity in the NAc.

Abstract Background Novel antibody‒drug conjugates (ADC) have shown great efficacy in HER2-low advanced breast cancer. However, the clinical features of HER2-low disease still need to be clarified. The current study aims to evaluate the distribution and dynamic change in HER2 expression in patients with disease recurrence and the clinical outcome of those patients. Methods Patients with pathologically diagnosed relapsed breast cancer between 2009 and 2018 were included. Samples were considered HER2-zero when the immunohistochemistry (IHC) score was 0, HER2-low when the IHC score was 1 + or 2 + with negative fluorescence in situ hybridization (FISH) results, and HER2-positive when the IHC score was 3 + or the FISH results were positive. Breast cancer-specific survival (BCSS) was compared among the three HER2 groups. Changes in HER2 status were also evaluated. Results A total of 247 patients were included. Among recurrent tumors, 53 (21.5%) were HER2-zero, 127 (51.4%) were HER2-low, and 67 (27.1%) were HER2-positive. The HER2-low subtype represented 68.1% of the HR-positive breast cancer group and 31.3% of the HR-negative group (P

Metabolic reprogramming plays vital roles in tumorigenesis. Here, Chen et al. reveal that mitochondria-encoded mcPGK1 drives the mitochondrial translocation of PGK1, promoting liver tumorigenesis and TIC self-renewal by switching energy production from OXPHOS to glycolysis.

The authors make the following corrections to the published paper [...]

The Qinling Mountains in East Asia serve as the geographical boundary between the north and south of China and are also indicative of climatic differences, resulting in rich ecological and species diversity. However, few studies have focused on the responses of plants to geological and climatic changes in the Qinling Mountains and adjacent regions. Therefore, we investigated the evolutionary origins and phylogenetic relationships of three Pedicularis species in there to provide molecular evidence for the origin and evolution of plant species. Ecological niche modeling was used to predict the geographic distributions of three Pedicularis species during the last interglacial period, the last glacial maximum period, and current and future periods, respectively. Furthermore, the distribution patterns of climate fluctuations and the niche dynamics framework were used to assess the equivalence or difference of niches among three Pedicularis species. The results revealed that the divergence of three Pedicularis species took place in the Miocene and Holocene periods, which was significantly associated with the large-scale uplifts of the Qinling Mountains and adjacent regions. In addition, the geographic distributions of three Pedicularis species have undergone a northward migration from the past to the future. The most important environmental variables affecting the geographic distributions of species were the mean diurnal range and annual mean temperature range. The niche divergence analysis suggested that the three Pedicularis species have similar ecological niches. Among them, P. giraldiana showed the highest niche breadth, covering nearly all of the climatic niche spaces of P. dissecta and P. bicolor. In summary, this study provides novel insights into the divergence and origins of three Pedicularis species and their responses to climate and geological changes in the Qinling Mountains and adjacent regions. The findings have also provided new perspectives for the conservation and management of Pedicularis species.

BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.MethodsIn this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.ResultsWe found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.ConclusionsHence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.

Abstract Introduction Tumor immune microenvironment (TIME) plays a vital role in breast cancer development, treatment resistance, and prognosis. This study evaluates the association of TIME profiling and 21-gene recurrence score (RS) in early Luminal breast cancer patients. Methods ER+ /HER2-, pN0 breast cancer patients with available RS results who received surgery between January 2009 and December 2013 were enrolled. TIME markers, including stromal tumor infiltrating lymphocytes (TILs), CD3, CD4, CD8, and tumor PD-L1 expression, were comprehensively analyzed. Association of TIME markers with RS, as well as their correlation with breast cancer-specific survival (BCSS) were tested. Results Overall, 385 patients were included, of whom 341 (88.6%) had TILs ≤10%. TIME markers were positively but moderately correlated with each other (Spearman r 0.28–0.53, all P

Abstract No fully validated risk-stratification strategies have been established in China where colonoscopies resources are limited. We aimed to develop and validate a fecal immunochemical test (FIT)-based risk-stratification model for colorectal neoplasia (CN); 10,164 individuals were recruited from 175 centers nationwide and were randomly allocated to the derivation (n = 6776) or validation cohort (n = 3388). Multivariate logistic analyses were performed to develop the National Colorectal Polyp Care (NCPC) score, which formed the risk-stratification model along with FIT. The NCPC score was developed from eight independent predicting factors and divided into three levels: low risk (LR 0–14), intermediate risk (IR 15–17), and high risk (HR 18–28). Individuals with IR or HR of NCPC score or FIT+ were classified as increased-risk individuals in the risk-stratification model and were recommended for colonoscopy. The IR/HR of NCPC score showed a higher prevalence of CNs (21.8%/32.8% vs. 11.0%, P

Genetic mutations of insulin receptor (IR) cause severe insulin resistance syndromes with no current treatment or cure. Here, the authors present that insulin-independent IR activation mechanism by peptide agonist which activate non-functional IR mutants that cause the insulin resistance syndromes.

Fast and accurate analysis of orientations and deformation states from Kikuchi patterns is vital to understand the crystalline materials’ micro- and macro-mechanical behavior. Here, a pattern reconstruction-aided Siamese network is developed to extract the crystal orientations and deformation states from Kikuchi patterns. We demonstrate the pattern reconstruction technique is essential for accurate predictions at large-area EBSD scans since the remapping operation enables the Siamese network to consider changes in experimental setup parameters dynamically. Moreover, the reconstruction technique serves as a data augmentation method that expands 342,225 raw patterns to 5,475,600 reconstructed patterns. The resulting Siamese network achieves unprecedented accuracy and robustness over a wide range of experimental setup parameters including pattern center, camera elevation and exposure time. Compared to the cross-correlation based high-resolution EBSD (HR-EBSD) analysis, it shows improved robustness against large rotations and achieves accurate measurements even if the rotation angle is as large as 25°. Further investigation also indicates the Siamese network trained on pure aluminum can be generalized at copper, nickel and 316 stainless steel without retraining, suggesting broad and desirable applicability.

Recent studies have demonstrated that the combination of Cyclin-Dependent Kinase 4/6 Inhibitor (CDK4/6i) and endocrine therapy (ET) is more effective than ET alone and significantly improves progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor-2 negative (HER2-) breast cancer (BC). Palbociclib is the first CDK4/6i approved for use, and its clinical advantages have been shown. However, 30% of patients will continue to develop secondary drug resistance. Therefore, exploring the parameters that can predict the efficacy of Palbociclib and developing a clinical prediction model is essential for evaluating the prognosis of patients.

Background: Recent studies have found that senescence-associated genes play a significant role in cancer biological processes. We aimed to analyze the characteristics and role of senescence-associated genes in triple-negative breast cancer (TNBC).Methods: We systematically screened senescence-associated secretory phenotype (SASP) genes based on the gene expression information in the TCGA database. According to the expression levels of senescence-associated genes, TNBC was classified into two subtypes, namely, TNBCSASP1 and TNBCSASP2, using an unsupervised cluster algorithm. We then performed gene expression, enrichment pathway, immune infiltration, mutational profile characterization, drug sensitivity and prognostic value analyses for the two subtypes. The reliability and prognostic predictive utility of this classification model were validated. The most prognostically relevant gene, FAM3B, was comprehensively identified and validated by tissue microarray in TNBC.Results: TNBC was classified into two senescence-associated subtypes, TNBCSASP1 and TNBCSASP2, based on the set of senescence-associated secretory phenotype genes, among which the TNBCSASP1 subtype had a poor prognosis. The TNBCSASP1 subtype was immunosuppressed, with suppressed immune-related signaling pathways and low immune cell infiltration. The effect of the mutation on the TP53 and TGF-β pathways could be related to the poor prognosis of the TNBCSASP1 subtype. Drug sensitivity analysis showed that AMG.706, CCT007093, and CHIR.99021 were potential targeted drugs for the TNBCSASP1 subtype. Finally, FAM3B was a key biomarker affecting the prognosis of patients with triple-negative breast cancer. Compared to normal breast tissue, the expression of FAM3B was reduced in triple-negative breast cancer. Survival analysis showed that overall survival was significantly shorter in triple-negative breast cancer patients with high FAM3B expression.Conclusion: A senescence-associated signature with different modification patterns has critical potential for providing a better understanding of TNBC biological processes, and FAM3B might serve as an applicable target for TNBC therapy.

Single segment substitution line (SSSL) libraries are an ideal platform for breeding by design. To develop SSSLs-Xihui18 covering the whole genome, a novel rice chromosome segment substitution line (CSSL), Z783, carrying two substitution segments (average length of 6.55 Mb) on Chr.4 and Chr.9 was identified, which was a gap in the library previously. Z783 was developed from the progeny of recipient “Xihui18” (an indica restorer line) and donor “Huhan3” (a japonica cultivar) by advanced backcross combined molecular marker-assisted selection (MAS). It displayed multiple panicles and less spikelets and wide grains. Then, a F2 population derived from Xihui18/Z783 was used to map quantitative trait loci (QTLs) for yield-related traits by the mixed linear model method. Nine QTLs were detected (p < 0.05). Furthermore, three SSSLs were constructed by MAS, and all 9 QTLs could be validated, and 15 novel QTLs could be detected by these SSSLs by a one-way ANOVA analysis. The genetic analysis showed that qSSP4 for less spikelets and qGW9 for wide grain all displayed dominant gene action in their SSSLs. Finally, qSSP4 and qGW9 were fine-mapped to intervals of 2.75 Mb and 1.84 Mb, on Chromosomes 4 and 9, respectively. The results lay a solid foundation for their map cloning and molecular breeding by design.

This short review provides an in-depth analysis of the achievements and further developments of the catalytic hydrogenation of carbon dioxide (CO2) to methanol from those that are worth learning about based on the transformation of syngas into methanol. We begin by exploring the environmental and energy-related implications of utilizing CO2 as a feedstock for methanol production by emphasizing its potential to mitigate greenhouse gas emissions and facilitate renewable energy integration. Then, different catalytic formulations focusing on precious metals, copper-based catalysts, and metal oxides are summarized, and insights into their advantages and limitations in the aspects of catalytic activity, selectivity, and stability are discussed. Precious metal catalysts, such as platinum and iridium, exhibit high activity but are cost-prohibitive, while copper-based catalysts present a promising and cost-effective alternative. Metal oxides are considered for their unique properties in CO2 activation. Mechanistic insights into reaction pathways are explored, with a particular emphasis on copper-based catalysts. Moreover, the complex steps involved in CO2 hydrogenation to methanol are discussed to shed light on the key intermediates and active sites responsible for catalysis, which is crucial for catalyst design and optimization. Finally, we stress the importance of ongoing research and development efforts to enhance catalyst efficiency, mechanistic comprehension, and process optimization. This review serves as a valuable resource for researchers, engineers, and policymakers working toward a more sustainable and carbon-neutral energy future. By harnessing CO2 as a carbon feedstock for methanol synthesis, we have the potential to address environmental concerns and advance the utilization of renewable energy sources, further contributing to the transition to a cleaner and more sustainable energy landscape.

Background and aimThe purpose of this study was to investigate and validate the efficacy of a nomogram model in predicting early objective response rate (ORR) in u-HCC patients receiving a combination of TACE, Lenvatinib, and anti-PD-1 antibody treatment after 3 months (triple therapy).MethodThis study included 169 u-HCC cases from five different hospitals. As training cohorts (n = 102), cases from two major centers were used, and external validation cohorts (n = 67) were drawn from the other three centers. The clinical data and contrast-enhanced MRI characteristics of patients were included in this retrospective study. For evaluating MRI treatment responses, the modified revaluation criteria in solid tumors (mRECIST) were used. Univariate and multivariate logistic regression analyses were used to select relevant variables and develop a nomogram model. Our as-constructed nomogram was highly consistent and clinically useful, as confirmed by the calibration curve and decision curve analysis (DCA); an independent external cohort also calibrated the nomogram.ResultsThe ORR was 60.9% and the risk of early ORR was independently predicted by AFP, portal vein tumor thrombus (PVTT), tumor number, and size in both the training (C-index = 0.853) and test (C-index = 0.800) cohorts. The calibration curve revealed that the nomogram-predicted values were consistent with the actual response rates in both cohorts. Furthermore, DCA indicated that our developed nomogram performed well in clinical settings.ConclusionThe nomogram model accurately predicts early ORR achieved by triple therapy in u-HCC patients, which aids in individual decision-making and modifying additional therapies for u-HCC cases.

Abstract In this paper, we use the new version of Gedanken experiment to investigate the weak cosmic censorship conjecture(WCCC) for RN-AdS black holes surrounded by quintessence. The process of matter fields falling into the black hole can be regarded as a dynamic process. Since the perturbation of matter fields doesn’t affect the spacetime geometry, we propose the stability condition and assume the process of matter fields falling into the black hole satisfies the null energy condition. Based on the stability condition and the null energy condition, the first-order and second-order perturbation inequalities are derived. As a result, we show that the WCCC for RN-AdS black holes surrounded by quintessence cannot be violated under the second-order approximation of matter fields perturbation.

Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, but the underlying mechanisms are unclear. Here, we utilized an ELS model of maternal separation with early weaning to explore the protective role of EPA in adolescent depression. We found that that ELS induced depression-like behavior rather than anxiety-like behavior in adolescent mice. RNA-sequencing results showed that ELS changed the transcription pattern in the liver, including 863 upregulated genes and 971 downregulated genes, especially those related to the biosynthesis of unsaturated fatty acids metabolism in the liver. Moreover, ELS decreased the expression of the rate-limiting enzymes, fatty acid desaturases 1/2 (FADS1/2), involved in the biosynthesis of EPA in the liver. Additionally, ELS reduced the levels of EPA in the liver, serum, and hippocampus, and EPA administration improved depression-like behavior-induced by ELS. Our results provide transcriptomic evidence that ELS increases the risk of adolescent depression by reducing the synthesis of unsaturated fatty acids in the liver, especially EPA, and suggest that supplementation with EPA should be investigated as a potential treatment for adolescent depression.

Identification of sudden cardiac death (SCD) with a structurally normal heart remains an important challenge in forensic pathology. Long QT syndrome (LQTS) is known as an inherited or acquired channelopathy, which is characterized with prolonged QT interval, and is likely to cause SCD in young adults. In this circumstance, no specific pathological change in the heart can be found anatomically or histologically in the LQTS victims. Thus, postmortem LQTS diagnosis is mainly based on clinical manifestations and genetic testing. Here, we reported a 26-year-old woman who was found dead at home with a history of unexplained syncope. Her clinical records and an electrocardiograph (ECG) obtained 3 months before her death showed a QTc interval of 539 ms which implicates the diagnosis of LQTS. Although the autopsy and pathological examination findings lacked specificity, we noticed enhanced lipofuscin accumulation in cardiomyocytes, which might be related to LQTS. After excluding potential diseases and injuries, we made the postmortem diagnosis as LQTS according to ECG, clinical history, and forensic postmortem findings. In conclusion, we provided clinical and pathological features of an SCD case due to LQTS, which might enrich the understanding of forensic postmortem SCD diagnosis with nonstructural cardiac diseases.

Primary breast osteosarcoma is a rare subtype of breast malignancy with limited clinical evidence, inadequate biological understanding, and unmet treatment consensus. Here, we report an unusual case of primary breast osteosarcoma developing in the same quadrant of the breast 2 years after initial dissection and radiation of invasive ductal carcinoma. Thorough evaluations of imaging and pathology were conducted while genomic alterations of both primary and secondary tumors, as well as peripheral blood samples, were explored through the next-generation sequencing technique. A comprehensive review of the current literature was also performed on this rare malignancy.

PurposeIn our study, we aim to analyze the impact of clinicopathological factors on the recommendation of extended endocrine therapy (EET) in patients with ER+ breast cancer and to retrospectively validate the value of CTS5 in EET decision making.Patients and methodsThe retrospective analysis was performed in patients with ER+ breast cancer who have finished 4.5–5 years of adjuvant endocrine therapy and undergone MDT discussion from October 2017 to November 2019. Multivariate logistic regression was used to identify the independent factors for treatment recommendation. CTS5 was calculated for retrospective validation of the EET decision making.ResultsTwo hundred thirty-five patients were received; 4.5–5 years of adjuvant endocrine therapy were included in the study. Multivariate analysis suggested that age (OR 0.460, 95% CI 0.219–0.965, p = 0.04), pN (OR 39.350, 95% CI 9.831–157.341, P < 0.001), and receipt of chemotherapy (OR 3.478, 95% CI 1.336–9.055, p = 0.011) were independent predictors for the recommendation of EET. In the previously selective estrogen receptor modulator (SERM)–treated subgroup, pN and receipt of chemotherapy were independent predictors for the recommendation of EET. In the previously AI-treated subgroup, age, pN, and receipt of chemotherapy were independent predictors. Adverse events did not affect the recommendation in patients previously treated with adjuvant endocrine treatment nor in the previously SERM or AI-treated subgroups. CTS5 (OR 21.887, 95% CI 2.846–168.309, p = 0.003) remained an independent predictor for the recommendation of EET.ConclusionsOur study indicated that age, lymph nodal status, and receipt of chemotherapy were independent predictors for the recommendation of EET. The application of the CTS5 on EET decision making might be valuable among ER+ breast cancer patients.

This study is designed to determine the H2S origin in the Ordovician Ma5 Member of Daniudi gas field and study the corrosion behavior of N80, P110 and N80S tubing and casings in medium-sulfur content HE16, micro-sulfur HE3 and low-sulfur HE1 gas wells. Therefore, method of weight loss of coupon on site were used to determine the corrosion rate. Similarly, SEM, XRD and EDS analyses were employed to know the corrosion products while establishing the relationship with H2S formation conditions. Results of this study show that, as the production time increases, there was initial increase in the volume of H2S before it finally decreases. Among the different sulfur gas wells, the corrosion rate of the HE16 is the largest, followed by the low-sulfur HE3 and the micro-sulfur HE1 (smallest). Within a gas well there exist a proportional relationship where higher partial pressure of H2S leads to higher corrosion rate. Generally, there is a trend of initial increase followed by decrease in the corrosion temperature of the gas wells in order of decreasing sulfur content (HE16, HE3 and HE1 well). Thus, the average corrosion temperature changing-rate of N80, P110, N80S pipe in the medium sulfur content well area, low sulfur content and micro-sulfur wells are 15.13%, 31.01% and 49.45% respectively. Although, the wells have some coupon corrosion products in common, there is still some basic differences in the composition of the HE1 wells (FeCO 3 and CaCO 3), HE3 wells (FeCO 3, FeS and CaCO 3) and HE16 wells (FeCO 3, FeS0.9, FeS and CaCO 3). These corrosion products are clearly stratified in the HE16 and HE3 wells, while no stratification occur in the HE1 wells. The densely structured FeCO 3 is well-distributed within just as the loose and poorly-converted sulfides are distributed on the surface. Both uniform and local corrosion exist simultaneously in the study area. The galvanic corrosion between the product substrate as well as the pitting caused by the inorganic salt result in local corrosion. In the micro-sulfur gas well, only uniform corrosion occur to form FeCO 3 as the corrosion product. For future development of the M5 member of Daniudi gas field, N80 tubing and casing is recommended for the micro-sulfur gas well, P110 or N80S material tubing and casing for the low sulfur gas well and N80S oil jacket for the sulfur gas well. It is good to note that special attention should be paid to the influence of temperature changes on the corrosion rate of the tubing and casing in the low-sulfur and medium-sulfur well zones.

Ganoderma lucidum (GL) is a well-known medicinal mushroom that has been extensively cultivated. Our previous study has shown that abundant Trichoderma colonies grow on the casing soil surface, posing cultivation obstacles for GL. However, an understanding of species-level characteristics of Trichoderma strains and their adverse effects on GL growth is limited. This study aimed to investigate the diversity and potential effects of Trichoderma from GL-cultivated soils. Over 700 Trichoderma isolates were collected from two trails in Longquan Country, southeast China. Eight Trichoderma species, including T. atrioviride, T. guizhouense, T. hamatum, T. harzianum, T. koningiopsis, T. pleuroticola, T. sp. irale, and T. virens, were identified based on the combination alignment of tef-1α and rpb2 sequences. The number of Trichoderma colonies increased dramatically during GL cultivation, with an increase of 9.2-fold in the Lanju trail. T. virens accounted for the most colonies (33.33 and 32.50% in Lanju and Chengbei, respectively) at the end of GL cultivation. The Trichoderma species growth varied but was satisfactory under different temperature or pH conditions. Moreover, Trichoderma species showed different adverse effects on GL growth. The non-volatile metabolites from T. virens and volatile metabolites from T. atroviride displayed the strongest antagonistic activity. Furthermore, the volatile 6-pentyl-2H-pyran-2-one (6-PP) showed a significant inhibitory effect on GL growth with an 8.79 μl mL−1 headspace of 50% effective concentration. The different Trichoderma spp. produced different amounts of 6-PP. The most efficient 6-PP producer was T. atroviride. To the best of our knowledge, this study is the first to demonstrate the abundance of competitive Trichoderma species associated with GL cultivation. Our results would contribute to.

The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.

This study aimed to establish a bidirectional fermentation system using Tremella fuciformis and Acanthopanax trifoliatus to promote the transformation and utilization of the synthesized antioxidant metabolites from fermentation supernatant. The effect of fermentation conditions on the total phenolic content was investigated using response surface methodology in terms of three factors, including temperature (22–28°C), pH (6–8), and inoculum size (2–8%, v/v). The optimized fermentation parameters were: 28°C, pH 8, and an inoculum size of 2%, which led to a maximum total phenolic content of 314.79 ± 6.89 μg/mL in the fermentation supernatant after 24 h culture. The content of total flavonoids and polysaccharides reached 78.65 ± 0.82 μg/mL and 9358.08 ± 122.96 μg/mL, respectively. In addition, ABTS+, DPPH⋅, and ⋅OH clearance rates reached 95.09, 88.85, and 85.36% at 24 h under optimized conditions, respectively. The content of total phenolics, flavonoids and polysaccharides in the optimized fermentation supernatant of T. fuciformis–Acanthopanax trifoliatus increased by 0.88 ± 0.04, 0.09 ± 0.02, and 33.84 ± 1.85 times that of aqueous extracts from A. trifoliatus, respectively. Simultaneously, 0.30 ± 0.00, 0.26 ± 0.01, and 1.19 ± 0.12 times increase of antioxidant activity against ABTS+, DPPH⋅, and ⋅OH clearance rates were observed, respectively. Additionally, the metabolite composition changes caused by fermentation were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) based on untargeted metabolomics and the phytochemical profile of fermentation supernatant differentiated significantly based on unsupervised principal component analysis (PCA) during fermentation from 24 to 96 h. Furthermore, a significant increase in antioxidant phenolic and flavonoid compounds, such as ellagic acid, vanillin, luteolin, kaempferol, myricetin, isorhamnetin, and (+)-gallocatechin, was observed after fermentation. Thus, these results indicated that the fermentation broth of T. fuciformis and A. trifoliatus had significant antioxidant activity, and may have potential application for health products such as functional beverages, cosmetics, and pharmaceutical raw materials.

Objective: To establish a new classification of biliary tumor thrombus (BTT). Methods: Overall survival of patients with BTT was first used to determine whether it correlated with current hepatocellular carcinoma staging systems. Univariate and multivariate analyses were used to determine factors affecting the overall survival (OS) to form the basis of our new classification for BTT. Results: All 6 international staging systems showed overlapping survival curves. Univariate followed by multivariate analyses showed that total bilirubin and intrahepatic/extrahepatic BTT were significant risk factors of OS. Based on these data, a new BTT classification was defined as: Type I: intrahepatic BTT; and Type II: extrahepatic BTT involving a common bile duct or common hepatic duct. Type I was further subdivided into type Ia: BTT involving a second-order intrahepatic duct or above, and type Ib: BTT involving a first-order intrahepatic duct. Type II was further subdivided into type IIa and type IIb using a cut-off total bilirubin (TB) > 300 μmol/L. The numbers (percentages) of patients with types I and II BTT were 69 (34.2%) and 133 (65.8%), respectively. The median OS of type I patients was significantly higher than that of type II patients (37.5 months vs. 23.2 months; P = 0.002). Using subgroup analyses, OS outcomes were significantly different between the subgroups of type IIb and type IIa, although there was no significant difference between the type Ia and type Ib subgroups (P = 0.07). Conclusions: A new BTT classification was established to predict prognoses of HCC patients with BTT who underwent liver resection.

Breast cancer is a kind of malignant tumor that seriously endangers women's life and health. Once diagnosed, most patients will receive a combination of treatments to achieve a cure. However, breast cancer is a heterogeneous disease. Even with the same clinical stage and pathological features, its response to treatment and postoperative recurrence risk may still be completely different. With the advent of genomic assay, some patients with early-stage breast cancer who originally needed treatment can still achieve long-term disease-free survival without adjuvant chemotherapy, so as to achieve personalized and accurate treatment mode to a certain extent. In this paper, we reviewed the 5 most widely used and studied genomic panel technologies in breast cancer, namely Oncotype DX , MammaPrint , RecurIndex , PAM50, and EndoPredict , according to accessibility and availability. Based on the results of the completed or ongoing clinical studies, we summarized the origin, applicable population, and clinical efficacy of each detection method, and discussed the potential development prospect of detection technology in the future.

In order to rapidly screen microalgae species as feedstocks for antioxidants, extracts were obtained from 16 microalgae strains (under 11 genera, 7 classes) using two methods: a one-step extraction with ethanol/water and a three-step fractionating procedure using hexane, ethylacetate, and water successively. Measuring the total phenol content (TPC), total carotenoid content (TCC), and antioxidant activity of the extracts, indicating TPC and TCC, played an important role in determining the antioxidant activity of the microalgae. A weighted scoring system was used to evaluate the antioxidant activity, and the scores of microalgal samples from two extraction methods were calculated using the same system. Among the investigated microalgae, Euglena gracilis SCSIO-46781 had the highest antioxidant score, contributing to high TPC and TCC, followed by Arthrospira platensis SCSIO-44012, Nannochloropsis sp. SCSIO-45224, Phaeodactylum tricornutum SCSIO-45120, and Nannochloropsis sp. SCSIO-45006, respectively. Additionally, the above-mentioned five strains are currently being applied in commercial production, indicating this system could be effective not only for screening microalgal antioxidants, but also for screening microalgal species/strains with strong adaptation to environmental stress, which is a critical trait for their commercial cultivation.

Abstract Background Trastuzumab has changed the prognosis of HER2+ breast cancer. We aimed to investigate the prognosis of ER+/HER2+ patients treated with trastuzumab, thus to guide escalation endocrine treatment in ER+ breast cancer. Methods ER-positive early breast cancer patients operated at Ruijin Hospital between Jan. 2009 and Dec. 2017 were retrospectively included. Eligible patients were grouped as HER2-negative (HER2-neg) or HER2-positive with trastuzumab treatment (HER2-pos-T). Kaplan-Meier analysis and Cox proportional hazards model were used to compare the disease-free survival (DFS) and overall survival (OS) between these two groups. Results A total of 3761 patients were enrolled: 3313 in the HER2-neg group and 448 in the HER2-pos-T group. Patients in the HER2-pos-T group were associated with pre/peri-menopause, higher histological grade, LVI, higher Ki-67 level, lower ER and PR levels (all P

Objective To investigate the Young's modulus value of infraspinatus tendons using shear wave elastography (SWE) technique in normal adults, and to analyze the influence of gender, postures, exercise, and dominant side on Young's modulus of infraspinatus tendons. Methods This is a prospective cross‐sectional study. From January 2019 to July 2020, 14 healthy subjects were identified, including seven males and seven females aged between 24 to 34, with a mean age of 27.67 ± 3.08 years. The Young's modulus of their infraspinatus tendons was measured by two operators using SWE in neutral and maximum external rotation positions of both sides before exercise and the dominant side after exercise. The Young's modulus values in different sexes, different postures, before vs after exercise, and dominant vs non‐dominant side were statistically analyzed. Results All 14 subjects completed the data collection process. The mean Young's modulus values of infraspinatus tendon for dominant sides in neutral position were 33.04 ± 3.01 kPa for males and 28.76 ± 3.09 kPa for females. And for non‐dominant sides in the neutral position, the values were 33.02 ± 2.38 kPa for males and 28.86 ± 2.47 kPa for females. In the maximum external rotation position, the values for dominant sides were 50.19 ± 4.86 kPa for males and 42.79 ± 4.44 kPa for females, and for non‐dominant sides were 50.95 ± 3.24 kPa for males and 42.42 ± 3.66 kPa for females. After exercise, the mean Young's modulus values of infraspinatus tendon for dominant sides in neutral position were 54.56 ± 3.76 kPa for males and 46.66 ± 5.99 kPa for females. And for the maximum external rotation position, the values were 59.13 ± 3.78 kPa for males and 54.49 ± 5.67 kPa for females. The Young's modulus of infraspinatus tendon in the neutral and maximum external rotation positions showed statistically significant differences in males and females, as well as before and after exercise (P 0.05). Intergroup reliability between both operators was excellent (ICC > 0.85). Conclusion There are gender‐related differences and post‐exercise increase in Young's modulus, yet such a difference cannot be witnessed between the dominant and non‐dominant sides.

Abstract Background The 21-gene recurrence score (RS) can predict chemotherapy benefit in estrogen receptor-positive, human epidermal growth factor receptor-2-negative (ER+/HER2-) early breast cancer patients. Age would influence the interaction between RS and chemotherapy effect. The current study aimed to determine RS thresholds which were predictive of chemotherapy benefit in young and old women, respectively. Methods Patients diagnosed with pN0–1, ER+/HER2- breast cancer between 2009 and 2016 were retrospectively reviewed. Propensity score matching was performed according to chemotherapy usage. After stratifying patients with different cutoffs of age, the RS threshold indicating chemotherapy benefit in each age strata were determined by cox proportional hazard models. Results A total of 1227 patients were included. The median age was 58 years and the median RS was 24. After matching, the RS thresholds suggesting chemotherapy benefit varied with age. For patients ≤55 years, chemotherapy benefit was observed in those having RS > 25 (P = 0.03), with 4-year invasive disease-free survival (IDFS) of 97.0 and 89.3% in patients receiving chemotherapy or not. While patients derived no benefit from chemotherapy if they had RS ≤25 (P = 0.66, 4-year IDFS: 95.3% vs. 94.6%). For patients > 55 years, adjuvant chemotherapy was associated with better prognosis in those with RS > 36 (P = 0.014, 4-year IDFS: 94.7% vs. 76.2%), but not in those having RS ≤36 (P = 0.13, 4-year IDFS: 92.3% vs. 95.8%). Conclusions Old patients need higher RS thresholds to demonstrate the chemotherapy benefit. Further efforts are warranted to investigate the association between age and predictive RS thresholds.

PurposeThis study aimed to evaluate the rates of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 heterogeneity in multifocal or multicentric breast cancer (MMBC) and its association with treatment pattern and disease outcomes.MethodsMMBC patients with ER, PR, HER2, and Ki67 results for each tumor focus were retrospectively analyzed using Kappa test and categorized into the homogeneous group (Homo group) and the heterogeneous group (Hetero group). Chi-square tests were performed to compare the clinical features and treatment options between the groups. Disease-free survival (DFS) and overall survival (OS) rates were estimated from Kaplan–Meier curves and compared between two groups.ResultsA total of 387 patients were included, and 93 (24.0%) were classified into the Hetero group. Adjuvant endocrine therapy was more frequently assigned for patients in the Hetero group than in the Homo group (84.9% vs. 71.7%, p = 0.046). There was no difference in terms of adjuvant anti-HER2 therapy (28.3% vs. 19.6%, p = 0.196) and chemotherapy (69.9% vs. 69.8%, p = 0.987) usage between the two groups. At a median follow-up of 36 months, DFS rates were 81.2% for the Hetero group and 96.5% for the Homo group (p = 0.041; adjusted HR, 2.95; 95% CI, 1.04–8.37). The estimated 3-year OS rates for the groups were 95.8% and 99.5%, respectively (p = 0.059; adjusted HR, 5.36; 95% CI, 0.97–29.69).ConclusionHeterogeneity of ER, PR, HER2, or Ki67 was present in 24.0% patients with MMBC. Biomarkers heterogeneity influenced adjuvant endocrine therapy usage and was associated with worse disease outcomes, indicating further clinical evaluation.

Abstract Background Tribenuron methyl (TBM) is an herbicide that inhibits sulfonylurea acetolactate synthase (ALS) and is one of the most widely used broad-leaved herbicides for crop production. However, soil residues or drifting of the herbicide spray might affect the germination and growth of rapeseed, Brassica napus, so it is imperative to understand the response mechanism of rape to TBM during germination. The aim of this study was to use transcriptome analysis to reveal the gene responses in herbicide-tolerant rapeseed to TBM stress during seed germination. Results 2414, 2286, and 1068 differentially expressed genes (DEGs) were identified in TBM-treated resistant vs sensitive lines, treated vs. control sensitive lines, treated vs. control resistant lines, respectively. GO analysis showed that most DEGs were annotated to the oxidation-reduction pathways and catalytic activity. KEGG enrichment was mainly involved in plant-pathogen interactions, α-linolenic acid metabolism, glucosinolate biosynthesis, and phenylpropanoid biosynthesis. Based on GO and KEGG enrichment, a total of 137 target genes were identified, including genes involved in biotransferase activity, response to antioxidant stress and lipid metabolism. Biotransferase genes, CYP450, ABC and GST, detoxify herbicide molecules through physical or biochemical processes. Antioxidant genes, RBOH, WRKY, CDPK, MAPK, CAT, and POD regulate plant tolerance by transmitting ROS signals and triggering antioxidant enzyme expression. Lipid-related genes and hormone-related genes were also found, such as LOX3, ADH1, JAZ6, BIN2 and ERF, and they also played an important role in herbicide resistance. Conclusions This study provides insights for selecting TBM-tolerant rapeseed germplasm and exploring the molecular mechanism of TBM tolerance during germination.

Abstract Background Although postoperative delirium is a frequent complication of surgery, little is known about risk factors for delirium occurring in the post-anaesthesia care unit (PACU). The aim of this study was to determine pre- and intraoperative risk factors for the development of recovery room delirium (RRD) in patients undergoing elective non-cardiovascular surgery. Methods RRD was diagnosed according to the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). We collected perioperative data in 228 patients undergoing elective non-cardiovascular surgery under general anaesthesia and performed univariate and multivariate logistic regression to identify risk factors related to RRD. PACU and postoperative events were recorded to assess the outcome of RRD. Results Fifty-seven patients (25%) developed RRD. On multivariate analysis, maintenance of anaesthesia with inhalation anaesthetic agents (OR = 6.294, 95% CI 1.4–28.8, corrected p = 0.03), malignant primary disease (OR = 3.464, 95% CI = 1.396–8.592, corrected p = 0.018), American Society of Anaesthesiologists Physical Status (ASA-PS) III–V (OR = 3.389, 95% CI = 1.401–8.201, corrected p = 0.018), elevated serum total or direct bilirubin (OR = 2.535, 95% CI = 1.006–6.388, corrected p = 0.049), and invasive surgery (OR = 2.431, 95% CI = 1.103–5.357, corrected p = 0.035) were identified as independent risk factors for RRD. RRD was associated with higher healthcare costs (31,428 yuan [17,872–43,674] versus 16,555 yuan [12,618–27,788], corrected p = 0.002), a longer median hospital stay (17 days [12–23.5] versus 11 days [9–17], corrected p = 0.002), and a longer postoperative stay (11 days [7–15] versus 7 days [5–10], corrected p = 0.002]). Conclusions Identifying patients at high odds for RRD preoperatively would enable the formation of more timely postoperative delirium management programmes.

Abstract Background The 21-gene recurrence score (RS) testing can predict the prognosis for luminal breast cancer patients. Meanwhile, patients > 50 years with RS > 25 have improved survival with adjuvant chemotherapy. The current study aimed to develop a nomogram with routine parameters to predict RS. Methods We included patients diagnosed with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative who underwent the 21-gene RS testing and aged > 50 years. The primary outcome was high-risk RS (> 25). Univariate and multivariate analyses were performed to identify significant predictors. A predictive nomogram based on logistic model was developed and evaluated with receiver operating characteristic (ROC) curves. The nomogram was internally validated for discrimination and calibration with bootstrapping method, and externally validated in another cohort. We then assessed the nomogram in different subgroups of patients and compared it with several published models. Results A total of 1100 patients were included. Five clinicopathological parameters were used as predictors of a high-risk RS, including tumor grade, histologic subtype, ER expression, PR expression, and Ki-67 index. The area under the curve (AUC) was 0.798 (95% CI 0.772–0.825) and optimism adjusted AUC was 0.794 (95% CI 0.781–0.822). External validation demonstrated an AUC value of 0.746 (95% CI 0.685–0.807), which had no significant difference with the training cohort (P = 0.124). Calibration plots indicated that the nomogram-predicted results were well fitted to the actual outcomes in both internal and external validation. The nomogram had better discriminate ability in patients who had tumors > 2 cm (AUC = 0.847, 95% CI 0.804–0.890). When compared with four other existing models, similar AUC was observed between our nomogram and the model constructed by discriminate Lee et al. Conclusions We developed a user-friendly nomogram to predict the high-risk RS in luminal breast cancer patients who were older than 50 years of age, which could guide treatment decision making for those who have no access to the 21-gene RS testing.

In order to accurately predict the production performance of coalbed methane (CBM) wells and to formulate a reasonable production system, this paper established a coal reservoir permeability model considering the influence of pulverized coal blockage. Then, on the basis of this model, the flow velocity sensitivity (FVS) experimental data of 15 groups of coal samples taken from the Baode Block, Qinshui Basin, Liulin Block, Hancheng Block, and the Huanglong Coalfield were fitted to determine the permeability models for different coal samples. On this basis, this newly established permeability model was incorporated into a previously developed CBM well performance analysis software, and production history matching was carried out on two CBM wells. Finally, the effects of the parameters of pulverized coal blockage on the permeability of coal reservoirs and the production performance of CBM wells were studied by taking the fitting parameters of CBM Well W1 as the reference. And the following research results are obtained. First, this new model considering the influence of pulverized coal blockage can quantitatively describe the variation of coal reservoir permeability with fluid velocity. In addition, this model can be incorporated into a CBM numerical simulation software or a CBM well performance analysis software to apply it in a wide range. Second, the coal reservoir permeability is less affected by pulverized coal blockage in the Baode Block, but this effect shall not be ignored in the Qinshui Basin and the Huanglong Coalfield. Third, the greater the theoretical maximum permeability damage degree (Dmax) and the permeability damage degree index (n) are, the lower the relative flow velocity (v0.5) corresponding to the critical flow velocity of pulverized coal blockage is and the more obvious the effect of pulverized coal blockage on coal reservoir permeability is. Fourth, in order to reduce the adverse effect of pulverized coal blockage on coal reservoir permeability, it is suggested to reduce the production pressure difference appropriately in the process of production, especially in the initial stage of gas production, so as to avoid severe damage to coal reservoir permeability.