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This single-centre study aimed to determine the clinicopathological characteristics and prognosis for patients with co-existing FL and DLBCL components (FL/DLBCL).We retrospectively analysed the clinical characteristics and prognosis of patients diagnosed with FL/DLBCL (n = 56) and with pure FL (n = 260) or de novo DLBCL (n = 812) (controls) between January 2013 and December 2021.The median age of patients with FL/DLBCL was 52 years. The amount of the DLBCL component ranged from 5 to 95%. Among the 56 FL/DLBCL cases analysed, 67.9% were of germinal centre B-cell (GCB) origin, 26.8% non-GCB origin, and 5.3% were unclassified. The clinical features of patients with FL/DLBCL were intermediate, falling between those of FL and DLBCL. Propensity-score matching was performed for patients with similar baseline characteristics who were receiving the rituximab plus cyclophosphamide, doxorubicin or epirubicin, vindesine, and prednisone (R-CHOP) regimen. Patients with FL/DLBCL showed inferior outcomes compared to those with FL, with a lower complete remission (CR) rate, progression-free survival (PFS), and overall survival (OS). Bone marrow involvement and B symptoms were identified as independent adverse prognostic factors for PFS among patients with FL/DLBCL. Patients with FL/DLBCL presented a lower CR rate and PFS but similar OS to those with DLBCL when receiving the R-CHOP regimen.Patients with FL/DLBCL showed inferior treatment response and survival than those with pure FL and had a lower CR rate and PFS, but similar OS to those with DLBCL in the rituximab era.

Auxin is a critical phytohormone that is involved in the regulation of most plant growth and developmental responses. In particular, epigenetic mechanisms, like histone modifications and DNA methylation, were reported to affect auxin biosynthesis and transport. However, the involvement of other epigenetic factors, such as histone variant H2A.Z, in the auxin-related developmental regulation remains unclear. We report that the histone variant H2A.Z knockdown mutant in Arabidopsis Col-0 ecotype, h2a.z-kd, has more lateral roots and weak gravitational responses related to auxin-regulated growth performances. Further study revealed that auxin promotes the eviction of H2A.Z from the auxin-responsive genes SMALL AUXIN-UP RNAs (SAURs) to activate their transcriptions. We found that IAA promotes the transcription of H2A.Z genes through HOMEOBOX PROTEIN 22/25 (AtHB22/25) transcription factors which work as downstream targets of ARF7/19 in auxin signaling. Double mutant of hb22 hb25 showed similar lateral root and gravitropism phenotypes to h2a.z-kd. Our results shed light on a reciprocal regulation hub through INOSITOL AUXOTROPHY 80-mediated H2A.Z eviction and ARF7/19-HB22/25-mediated H2A.Z transcription to modulate the activation of SAURs and plant growth in Arabidopsis.

RNF214 is an understudied ubiquitin ligase without any knowledge of its biological functions or specific protein substrates. Using an APEX2-mediated proximity labeling method coupled with the mass spectrometry technique, we identified the TEAD transcription factors in the Hippo pathway as interactors of RNF214. We showed that RNF214 induces non-proteolytic ubiquitylation at a conserved single lysine residue of TEADs, enhances the interactions between TEADs and the transcription coactivators of the Hippo pathway including YAP and TAZ, and then promotes transactivation of the downstream genes of the Hippo signaling. Moreover, we proved that YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, we found that RNF214 is overexpressed in hepatocellular carcinoma (HCC). Clinical and statistical analysis indicated that high expression levels of RNF214 are associated with low differentiation status and poor prognosis of HCC. Consistently, we showcased that RNF214 promotes proliferation, migration and invasion of HCC cells and HCC tumorigenesis in mouse models via the Hippo pathway. Collectively, our data revealed that RNF214 is a critical component in the Hippo pathway by forming a new signaling axis of RNF214-TEAD-YAP, thereby upregulating the transcriptional activities of the YAP/TAZ-TEAD complex. More importantly, our results suggest that RNF214 serves as an oncogene of HCC and could be a potential drug target of HCC therapy.

To establish and validate a nomogram for predicting lymph node metastasis (LNM) of papillary thyroid carcinoma (PTC) in the cervical central region. This retrospective study included 287 PTC patients with 309 nodules treated from December 2018 to May 2020 at our hospital. The cohort was divided randomly into a training set and a testing set according to a 7:3 ratio. The training set contained 216 nodules, and the testing set contained 93 nodules. The nomogram was developed using the training set, and the data of the testing set were used to validate the performance of nomogram. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. The study showed multifocality, thyroid lesion size, and American College of Radiology Thyroid Imaging, Reporting and Data System (TI-RADS) score were significantly independently associated with LNM in the cervical central region. In the testing set, the calibration curve showed that the nomogram had good discrimination with a C-index of 0.775 (95% confidence interval, 0.680-0.869) and adequate calibration (P = 0.808). By decision curve analysis and clinical impact curve analysis, the nomogram was shown to have a satisfactory net benefit between thresholds of 0.40 and 0.75. The nomogram can be used for predicting LNM of PTC in the cervical central region and may provide valuable guidance for planning the surgical treatment of PTC patients.

Inflammation causes tissue damage and promotes ventricular remodeling after myocardial infarction (MI), and the infiltration and polarization of macrophages play an important role in regulating inflammation post-MI. Here, we investigated the anti-inflammatory function of curcumin after MI and studied its relationship with macrophage polarization. In vivo, curcumin not only attenuated ventricular remodeling 3 months after MI but also suppressed inflammation during the first 7 days post-MI. Importantly, the results of qPCR and immunochemistry showed that curcumin decreased M1 (iNOS, CCL2, and CD86) but increased M2 macrophage (Arg1, CD163, and CD206) marker expression in the myocardium of MI mice during the first 7 days post-MI. And flow cytometry analysis indicated that curcumin suppressed M1 (CD45+Gr-1-CD11b+iNOS+ cells) but enhanced M2 macrophage (CD45+Gr-1-CD11b+Arg+ cells) expansion in the myocardium of MI mice during the first 7 days post-MI. In vitro, curcumin decreased LPS/IFNγ-elevated M1 macrophage marker (iNOS and CD86) expression and the proportion of M1 macrophages (iNOS+F4/80+ cells) but increased LPS/IFNγ-suppressed M2 macrophage marker (Arg1 and CD206) expression and the proportion of M2 macrophages (Arg1+F4/80+ cells). In addition, curcumin modulates M1/M2 macrophage polarization partly via AMPK. In conclusion, curcumin suppressed the MI-induced inflammation by modulating macrophage polarization partly via the AMPK pathway.

Killer cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch has been shown to be protective for acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia. Mesenchymal stem cells (MSC) have been considered as one of the most promising prophylaxis for severe GVHD. However, there are no prospective or retrospective studies determining whether they can work synergistically on GVHD. To investigate the potential influence of KIR matching and MSCs, and their synergism on aGVHD and cGVHD after allo-HSCT in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Data from 104 patients with AML and 50 patients with ALL treated with allo-HSCT in the transplantation unit were retrospectively analyzed. KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software to generate KIR data. Cox proportional hazards models were used in multivariate analyses. KIR receptor-ligand matching was associated with an increased risk of grade II-IV aGVHD compared to KIR receptor-ligand mismatching (p < 0.001) in AML patients, but KIR ligand-mismatching had no significant effect on aGVHD or cGVHD in ALL patients. In contrast, MSCs reduced the incidence of grade II-IV aGVHD in both AML and ALL patients (AML: p = 0.006; ALL: p = 0.008) regardless of KIR mismatching. The combination of KIR receptor-ligand mismatch and MSC transplantation significantly suppressed grade II-IV aGVHD occurrence in AML patients (p = 0.039). In the KIR mismatch group, the incidence of aGVHD was 2.8% in patients receiving MSC compared to 14.6% in those who did not (p = 0.047). KIR receptor-ligand mismatch, MSC transplantation and their combined use significantly reduced the risk of aGVHD after allo-HSCT. These data provide a clinically applicable strategy to reduce aGVHD, thus improving allo-HSCT outcome.

Background Diffuse large B‐cell lymphoma (DLBCL) patients refractory to rituximab‐based immunochemotherapy have a dismal prognosis. However, the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries. To validate the definition and outcomes of refractory DLBCL in China, we conducted a multicenter, retrospective cohort study. Methods The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL (REAL‐TREND) study was performed using real‐world data from 8 centers in China. DLBCL patients with curative intent were included in the REAL‐TREND dataset. Overall survival (OS) was estimated using the Kaplan‐Meier method and compared by the log‐rank test. Due to heterogeneity in response rates among different centers, the response rates of refractory patients were pooled using random‐effect models. Multivariate survival analysis was performed using the Cox regression model. Results A total of 2778 DLBCL patients diagnosed between January, 2010 and December, 2015 were enrolled to this study. After validating previous definitions, the SCHOLAR‐1 study was most suitable to define refractory DLBCL. The estimated 5‐year cumulative incidence of refractory patients was 20% (95% confidence Interval [CI] = 18%‐22%). After the determination of refractory disease, overall response rate and complete remission rate were 30% (95% CI = 22%‐38%) and 9% (95% CI = 4%‐15%), respectively. Patients with either no response to immunochemotherapy or relapse within 12 months after stem‐cell transplantation had inferior survival with a median OS of 5.9 months (95% CI = 5.5‐7.1 months) and 2‐year OS rate of 16% (95% CI = 12%‐20%). International prognostic index score 4‐5 (hazard ratio [HR] = 2.22; 95% CI = 1.47‐3.35), central nervous system relapse (HR = 1.43; 95% CI = 1.04‐1.97), and best response status (HR = 2.68; 95% CI = 1.42‐5.03 for partial remission. HR = 5.97, 95% CI = 3.21‐11.11 for stable disease/progressive disease) were independent unfavorable prognostic factors. Conclusions This is the first large‐scale Asian cohort study focusing on outcomes of refractory DLBCL. The definition of the SCHOLAR‐1 study identifies patients with homogenously inferior survival, thus is appropriate to select refractory DLBCL. Due to poor clinical outcomes in the rituximab era, patients with refractory DLBCL may be potential candidates for novel treatment modalities.

Most acute lymphoblastic leukemia (ALL) patients are treated with chemotherapy as primary care. Although treatment response is usually positive, resistance and relapse often occur through unclear mechanisms. Here, we presented clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL. By analyzing our patient specimens and an existing database, a strong correlation between the abundance of nucleolin and disease relapse/poor survival was observed. Altering the NCL expression resulted in changes in drug sensitivity in cell lines. High levels of nucleolin could up-regulate components of the ATP-binding cassette transporters via the activation of the ERK pathway, which resulted in a decrease in drug accumulation inside the cells. NCL protein was mainly distributed in the cytoplasm and membrane in ALL cells compared with cell nuclei of normal cells. Moreover, targeting NCL with AS1411, a nucleolin-binding oligonucleotide aptamer, drastically increased sensitivity to chemotherapeutic drugs in cells/patients derived xenograft mice and extended survival of the diseased mice. Our results indicated that NCL could be a prognostic marker and provided initial preclinical evidence that inhibiting nucleolin expression could enhance drug sensitivity during ALL chemotherapy.

The prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to that in children. Hence, ALL remains challenging to cure in the adult population. Aberrant genetic alterations have been observed in ALL, although the patterns of differential gene alterations in adult and pediatric ALL have not been comprehensively determined on a genome-wide scale. We investigated the biologic differences in genomic profiles between adults (n = 64) and children (n = 54) with ALL and relationship between genomic heterogeneity and prognosis. The 2 populations showed similar common mutation types but an increased prevalence of genetic alterations in adult ALL. The median numbers of gene mutations were 17 (range: 1–53) and 4.5 (range: 1–19) per sample in adult and pediatric ALL, respectively (p

This study aimed to assess the efficacy and safety of hypomethylating agent (HMA)-based regimens in the treatment of older adult patients with acute myeloid leukaemia (AML), unfit for standard induction chemotherapy. Treatment outcomes and prognostic factors of 140 older adult patients with AML who were unfit for intensive chemotherapy and were treated with HMA-based therapies were retrospectively analysed. The median age of the group was 70 years, and poor-risk cytogenetics and secondary/treatment-related AML (s/t-AML) accounted for 45.6% and 34.3% of these patients, respectively. The overall response rate was 48.6%, and 40.1% for patients who achieved complete remission (CR) or CR with incomplete blood count recovery. The median overall survival (OS) was 10.4 months, and the 1-, 2-, and 5-year OS rates were 42.6%, 19.9%, and 4.9%, respectively. Early mortality accounted for 4.3% of all cases, and infection occurred in 87.1% of all patients during induction therapy. Patients who received HMA and low-dose chemotherapy presented with significantly superior response and long-term survival rates compared to those who received HMA alone. They also showed comparable outcomes to those treated with the azacitidine plus venetoclax protocol. Low-dose chemotherapy in combination with decitabine or azacitidine showed a similar response rate and prognosis. Age ≥ 75years and a white blood cell (WBC) count ≥ 10 × 109 cells/L were identified as independent adverse prognostic factors for OS, while poor-risk cytogenetics, percentage of bone marrow blasts, and s/tAML had no significant impact on OS when patients were treated with HMA-based regimens. In conclusion, HMA combined with low-dose chemotherapy was effective and safe in older adults with AML who were unfit for intensive chemotherapy, and no difference was observed between decitabine and azacitidine.

Various traditional Chinese medicines from the genus Ilex (Aquifoliaceae) have been reported to have excellent hypolipidaemic effects. Although triterpenoids have been found to be the main active components, the underlying mechanisms have not been clarified.This study aimed to investigate the lipid-lowering effect, structure-activity relationship and action mechanism of triterpenoids from the genus Ilex.FFA was used to induce HepG2 cells to establish a classical lipid-lowering activity screening model for the activities of 31 triterpenoids, and the contents of intracellular lipids, TC, and TG were measured. Furthermore, the structure-activity relationship was discussed. Mechanistically, UPLC-Q/TOF-MS-based metabolomics and lipidomics studies were performed, and metabolic pathways were analysed to investigate the lipid-lowering mechanism. Moreover, western blotting was performed to analyse the expression of key proteins of lipid metabolism and predict the targets of action.Thirteen triterpenoids significantly reduced intracellular lipid accumulation and decreased the levels of TG and TC. Among them, rotundic acid (RA) showed stronger lipid-lowering activity than the simvastatin-positive group, and structure-activity relationship analysis indicated that the hydroxyl groups at C-3 and C-19, hydroxymethyl groups at C-23, and carboxyl groups at C-28 may be the key groups for biological activity. Twenty-two metabolites in the metabolomics study and 19 metabolites in the lipidomics study were identified. The identified biomarkers were primarily glycerophosphocholine, LysoPCs, PCs, TAGs, LysoPEs, LysoPIs and sphingolipids, which are involved in glycerophospholipid and sphingolipid metabolism. Moreover, western blotting analysis showed that the expression of SREBP-1 and HMGCR decreased, while AMPK and ACC phosphorylation and the expression of CPT1A and CYP7A1 increased in the RA-treated group.The results suggested that triterpenoids from the genus Ilex showed significant lipid-lowering effects and that RA may be a novel hypolipidaemic drug candidate. Moreover, the underlying mechanism indicated that RA showed a lipid-lowering effect by regulating glycerophospholipid and sphingolipid metabolism and activating the AMPK pathway.

Air pollution is a common problem for many countries around the world in the process of industrialization as well as a challenge to sustainable development. This paper has selected Chengdu-Chongqing region of China as the research object, which suffers from severe air pollution and has been actively involved in air pollution control in recent years to achieve sustainable development. Based on the historical data of 16 cities in this region from January 2015 to November 2019 on six major air pollutants, this paper has first conducted evaluation on the monthly air quality of these cities within the research period by using Principal Component Analysis and the Technique for Order Preference by Similarity to an Ideal Solution. Based on that, this paper has adopted the Long Short-Term Memory neural network model in deep learning to forecast the monthly air quality of various cities from December 2019 to November 2020. The aims of this paper are to enrich existing literature on air pollution control, and provide a novel scientific tool for design and formulation of air pollution control policies by innovatively integrating commonly used evaluation models and deep learning forecast methods. According to the research results, in terms of historical evaluation, the air quality of cities in the Chengdu-Chongqing region was generally moving in the same trend in the research period, with distinct characteristics of cyclicity and convergence. Year- on-year speaking, the effectiveness of air pollution control in various cities has shown a visible improvement trend. For example, Ya&rsquo, an&rsquo, s lowest air quality evaluation score has improved from 0.3494 in 2015 to 0.4504 in 2019, Zigong&rsquo, s lowest air quality score has also risen from 0.4160 in 2015 to 0.6429 in 2019. Based on the above historical evaluation and deep learning forecast results, this paper has proposed relevant policy recommendations for air pollution control in the Chengdu-Chongqing region.

IntroductionHeart failure with preserved ejection fraction (HFpEF) affects more than half of the patients with heart failure. HFpEF and sarcopenia can interact with each other and contribute to reduced physiological function and increased mortality in elderly patients. Resistance training (RT) or resistance exercise rehabilitation (RER) may have benefits for elderly HFpEF patients with sarcopenia. Whey protein supplementation (WPS) may increase the effects of exercise on strength and muscle mass, in addition to promoting heart function and quality of life (QoL). However, studies are needed to evaluate effects of RER and WPS in patients with HFpEF with sarcopenia.Methods and analysisThis is a prospective, randomised, controlled clinical trial in which patients with HFpEF with sarcopenia will be randomly allocated to three groups, control, RT and RT+WP. Participants in all groups will receive basic intervention including standard medicine treatment, home-based aerobic exercise and basic nutritional intervention. The RT group will undergo resistance exercise programmes, and the RT+WP group will receive daily WPS apart from resistance exercise. The study variables will be evaluated at baseline and 12 weeks. Primary outcome measure is the change of 6 min walking distance. Secondary outcomes include parameters of muscle status, cardiac function, nutritional status, QoL and major adverse cardiovascular events. The primary efficacy analysis will follow the intention-to-treat principle.Ethics and disseminationThis study was approved by Ethics Committee of China-Japan Friendship Hospital for Clinical Research (No. 2022-KY-003). The results of this study will be disseminated via peer-reviewed publications and presentations at conferences.Trial registration numberChiCTR2200061069.

The Ubiquitin-fold modifier 1 (Ufm1) is a ubiquitin-like protein that can also be conjugated to protein substrates and subsequently alter their fates. Both UFMylation and de-UFMylation are mediated by Ufm1-specific proteases (UFSPs). In humans, it is widely believed that UFSP2 is the only active Ufm1 protease involved in Ufm1 maturation and de-UFMylation, whereas UFSP1 is thought to be inactive. Here, Liang et al. provide strong evidence showing that human UFSP1 is also an active Ufm1 protease. These results solve an age-old mystery in the human Ufm1 conjugation system and could have a greater impact not only on Ufm1 biology but also on the translation of genes employing nontraditional start codons.

In semiconductor manufacturing systems, those defects on wafer maps tend to cluster and then these spatial patterns provide important process information for helping operators in finding out root-causes of abnormal processes. Deep learning has achieved many successes in image and visual analysis. This study concentrates on developing a hybrid deep learning model to learn effective discriminative features from wafer maps through a deep network structure. This paper proposes a novel feature learning method, stacked convolutional sparse denoising auto-encoder (SCSDAE) for wafer map pattern recognition (WMPR) in semiconductor manufacturing processes, in which the features will be extracted from images directly. Different from the regular stacked denoising auto-encoder (SDAE) and convolutional neural network (CNN), SCSDAE integrates CNN and SDAE to learn effective features and accumulate the robustness layer by layer, which adopts SDAE as the feature extractor and stacks well-designed fully connected SDAE in a convolutional way to obtain much robust feature representations. The effectiveness of the proposed method has been demonstrated by experimental results from a simulation dataset and real-world wafer map dataset (WM-811K). This study provides the guidance to applications of hybrid deep learning in semiconductor manufacturing processes to improve product quality and yields.

Online consumer reviews are becoming one of the key drivers of hospitality firm performance. Although research has investigated different aspects of online reviews such as their volume and length, issues regarding the effectiveness of review response demand for further investigation. Drawing on theories of expectancy value and communication, we develop and test a framework of consumer expectations regarding company responses. Results from two experiments show that consumer preferences for responses to their online reviews depend on the factors of valence (positive vs. negative), explanation type (explained action vs. explained reaction), and response channel (private vs. public). Perceived usefulness is found to be the underlying mechanism that explains these effects. The study’s theoretical contributions and managerial implications are discussed.

Recognition of various defect patterns exhibited in discrete manufacturing processes can significantly reduce the diagnostic processes, and increase manufacturing process stability and quality. Thus the effective recognizers are in great demand to improve the performance of process pattern recognition (PPR). Deep learning has been widely applied in image and visual analysis with great successes. However, the application of deep learning in feature learning for process control is still few. This paper presents an effective and reliable deep learning method known as stacked denoising autoencoder (SDAE) for PPR in manufacturing processes. This paper will concentrate on developing an SDAE model to learn effective features from the process signals and then implementing an effective PPR through a deep network architecture. Feature visualization is also performed to explicitly present the feature representation of the proposed SDAE model. The effectiveness of the proposed PPR method is verified through a big simulation dataset and Tennessee Eastman process. The result shows that the proposed method obtains good feature learning and PPR performance.

Eating abnormalities are one of the core symptoms of frontotemporal dementia (FTD), especially for behavioral variant FTD (bvFTD), and semantic variant primary progressive aphasia (svPPA). A group of FTD patients (43 bvFTD, 29 svPPA) underwent single-photon emission CT (SPECT) to measure the region cerebral blood flow (rCBF). The Cambridge Behavioral Inventory (CBI) was used to measure the eating abnormalities. A whole-brain voxel-based correlation between eating abnormalities and rCBF was investigated. In bvFTD, the sweet preference was correlated with decreased rCBF in the bilateral gyrus rectus and temporal pole, and eating the same food was correlated with the left ventral anterior cingulate cortex. In svPPA, decreased rCBF in the left inferior temporal gyrus was correlated with eating the same food. These findings showed that either different symptoms in the same subtype or the same symptom in different subtypes of FTD may be correlated with different regions, indicating different neural mechanisms behind them.

This paper proposes a new two-dimensional manifold learning algorithm called two-dimensional joint local/nonlocal discriminant analysis (2DJLNDA) for 2D image feature extraction, which directly extracts projective vectors from 2D image matrices rather than image vectors. Different from other typical 2D methods, e.g., two-dimensional principal component analysis (2DPCA), two-dimensional linear discriminative analysis (2DLDA), two-dimensional locality-preserving projection (2DLPP), 2DJLNDA preserves not only local/nonlocal intrinsic structure but also local/nonlocal penalization structure of the image data in the high-dimensional space, which can be powerful in extracting intrinsic information of the image data in the low-dimensional space. The experimental results on the ORL, Yale, AR and UMIST face datasets indicate that 2DJLNDA is capable of extracting effective image features and outperforms 2DPCA, 2DLDA and 2DLPP. The 2D image features extracted by 2DJLNDA further improve the performance of deep neural networks (DNNs), e.g., stacked denoising autoencoder, and convolutional neural network (CNN) significantly. These studying results illustrate that the feature face images will provide more discriminant features than the original face images for DNNs. Therefore, 2DJLNDA-based 2D feature image extraction can be used as an effective preprocessing of DNNs (e.g., CNN) for face recognition.