Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

Accelerating open modification spectral library searching on tensor core in high-dimensional space.

MOTIVATION: Driven by technological advances, the throughput and cost of mass spectrometry (MS) proteomics experiments have improved by orders of magnitude in recent decades. Spectral library searching is a common approach to annotating experimental mass spectra by matching them against large libraries of reference spectra corresponding to known peptides. An important disadvantage, however, is that only peptides included in the spectral library can be found, whereas novel peptides, such as those with unexpected post-translational modifications (PTMs), will remain unknown. Open modification searching (OMS) is an increasingly popular approach to annotate modified peptides based on partial matches against their unmodified counterparts. Unfortunately, this leads to very large search spaces and excessive runtimes, which is especially problematic considering the continuously increasing sizes of MS proteomics datasets. RESULTS: We propose an OMS algorithm, called HOMS-TC, that fully exploits parallelism in the entire pipeline of spectral library searching. We designed a new highly parallel encoding method based on the principle of hyperdimensional computing to encode mass spectral data to hypervectors while minimizing information loss. This process can be easily parallelized since each dimension is calculated independently. HOMS-TC processes two stages of existing cascade search in parallel and selects the most similar spectra while considering PTMs. We accelerate HOMS-TC on NVIDIA's tensor core units, which is emerging and readily available in the recent graphics processing unit (GPU). Our evaluation shows that HOMS-TC is 31× faster on average than alternative search engines and provides comparable accuracy to competing search tools. AVAILABILITY AND IMPLEMENTATION: HOMS-TC is freely available under the Apache 2.0 license as an open-source software project at https://github.com/tycheyoung/homs-tc.

IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates.

During endoplasmic reticulum (ER) stress, homeostatic signaling through the unfolded protein response (UPR) augments ER protein-folding capacity. If homeostasis is not restored, the UPR triggers apoptosis. We found that the ER transmembrane kinase/endoribonuclease (RNase) IRE1alpha is a key component of this apoptotic switch. ER stress induces IRE1alpha kinase autophosphorylation, activating the RNase to splice XBP1 mRNA and produce the homeostatic transcription factor XBP1s. Under ER stress--or forced autophosphorylation--IRE1alpha's RNase also causes endonucleolytic decay of many ER-localized mRNAs, including those encoding chaperones, as early events culminating in apoptosis. Using chemical genetics, we show that kinase inhibitors bypass autophosphorylation to activate the RNase by an alternate mode that enforces XBP1 splicing and averts mRNA decay and apoptosis. Alternate RNase activation by kinase-inhibited IRE1alpha can be reconstituted in vitro. We propose that divergent cell fates during ER stress hinge on a balance between IRE1alpha RNase outputs that can be tilted with kinase inhibitors to favor survival.

A multiprotein supercomplex controlling oncogenic signalling in lymphoma.

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCß to promote the assembly of the CARD11-BCL10-MALT1 adaptor complex, which recruits and activates IκB kinase4-6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR-Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.

Metagenomic next-generation sequencing reveals co-infection with Legionella pneumophila and Fusobacterium necrophorum in a patient with severe pneumonia: a case report.

BACKGROUND: Legionella pneumonia is one of the most severe types of atypical pneumonia, impairing multiple organ systems, posing a threat to life. Diagnosing Legionella pneumonia is challenging due to difficulties in culturing the bacteria and limitations in immunoassay sensitivity and specificity. CASE PRESENTATION: This paper reports a rare case of sepsis caused by combined infection with Legionella pneumophila and Fusobacterium necrophorum, leading to respiratory failure, acute kidney injury, acute liver injury, myocardial damage, and electrolyte disorders. In addition, we systematically reviewed literature on patients with combined Legionella infections, analyzing their clinical features, laboratory results and diagnosis. CONCLUSIONS: For pathogens that require prolonged incubation periods and are less sensitive to conventional culturing methods, metagenomic next-generation sequencing (mNGS) can be a powerful supplement to pathogen screening and plays a significant role in the auxiliary diagnosis of complex infectious diseases.

Biomechanical evaluation of different oblique lumbar interbody fusion constructs: a finite element analysis.

BACKGROUND: Finite element analysis (FEA) was performed to investigate the biomechanical differences between different adjunct fixation methods for oblique lumbar interbody fusion (OLIF) and to further analyze its effect on adjacent segmental degeneration. METHODS: We built a single-segment (Si-segment) finite element model (FEM) for L4-5 and a double-segment (Do-segment) FEM for L3-5. Each complete FEM was supplemented and modified, and both developed two surgical models of OLIF with assisted internal fixation. They were OLIF with posterior bilateral percutaneous pedicle screw (TINA system) fixation (OLIF + BPS) and OLIF with lateral plate system (OLIF + LPS). The range of motion (ROM) and displacement of the vertebral body, cage stress, adjacent segment disc stress, and spinal ligament tension were recorded for the four models during flexion/extension, right/left bending, and right/left rotation by applying follower load. RESULTS: For the BPS and LPS systems in the six postures of flexion, extension, right/left bending, and right/left rotation, the ROM of L4 in the Si-segment FEM were 0.32°/1.83°, 0.33°/1.34°, 0.23°/0.47°, 0.24°/0.45°, 0.33°/0.79°, and 0.34°/0.62°; the ROM of L4 in the Do-segment FEM were 0.39°/2.00°, 0.37°/1.38°, 0.23°/0.47°, 0.21°/0.44°, 0.33°/0.57°, and 0.31°/0.62°, and the ROM of L3 in the Do-segment FEM were 6.03°/7.31°, 2.52°/3.50°, 4.21°/4.38°, 4.21°/4.42°, 2.09°/2.32°, and 2.07°/2.43°. BPS system had less vertebral displacement, less cage maximum stress, and less spinal ligament tension in Si/Do-segment FEM relative to the LPS system. BPS system had a smaller upper adjacent vertebral ROM, greater intervertebral disc stress in terms of left and right bending as well as left and right rotation compared to the LPS system in the L3-4 of the Do-segment FEM. There was little biomechanical difference between the same fixation system in the Si/Do-segment FEM. CONCLUSIONS: Our finite element analysis showed that compared to OLIF + LPS, OLIF + BPS (TINA) is more effective in reducing interbody stress and spinal ligament tension, and it better maintains the stability of the target segment and provides a better fusion environment to resist cage subsidence. However, OLIF + BPS (TINA) may be more likely to cause adjacent segment degeneration than OLIF + LPS.

HyperSpec: Ultrafast Mass Spectra Clustering in Hyperdimensional Space.

As current shotgun proteomics experiments can produce gigabytes of mass spectrometry data per hour, processing these massive data volumes has become progressively more challenging. Spectral clustering is an effective approach to speed up downstream data processing by merging highly similar spectra to minimize data redundancy. However, because state-of-the-art spectral clustering tools fail to achieve optimal runtimes, this simply moves the processing bottleneck. In this work, we present a fast spectral clustering tool, HyperSpec, based on hyperdimensional computing (HDC). HDC shows promising clustering capability while only requiring lightweight binary operations with high parallelism that can be optimized using low-level hardware architectures, making it possible to run HyperSpec on graphics processing units to achieve extremely efficient spectral clustering performance. Additionally, HyperSpec includes optimized data preprocessing modules to reduce the spectrum preprocessing time, which is a critical bottleneck during spectral clustering. Based on experiments using various mass spectrometry data sets, HyperSpec produces results with comparable clustering quality as state-of-the-art spectral clustering tools while achieving speedups by orders of magnitude, shortening the clustering runtime of over 21 million spectra from 4 h to only 24 min.

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis.

OBJECTIVES: Innate immunity significantly contributes to systemic sclerosis (SSc) pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc. METHODS: The expression of TLR8 was analyzed based on a public dataset and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model. RESULTS: TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1ß, COL I, COL III, and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB, and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo. CONCLUSION: TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis.

Effects of storage duration of suspended red blood cells before intraoperative infusion on coagulation indexes, routine blood examination and immune function in patients with gastrointestinal tumors.

Objective: To investigate the effect of storage duration of suspended red blood cells (SRBC) before intraoperative infusion on coagulation indexes, routine blood examination and immune function in patients with gastrointestinal (GI) tumors. Methods: We divided clinical data of one hundred patients with GI tumors who underwent surgical treatment in our hospital into two different groups according to the storage duration of SRBC use for intraoperative infusion. The short-term group (n=50) had patients with SRBC storage durations shorter than two weeks, and the long-term group (n=50) had patients with storage durations longer than two weeks. We compared the coagulation, immune function, routine blood profile, electrolyte levels and adverse reactions assessment results between the two groups. Results: Compared with before transfusions, the levels of fibrinogen (FIB) and activated partial prothrombin time (APTT) after blood transfusions were higher than those before transfusion (P<0.05). The levels of hemoglobin (Hb) and hematocrit (HCT) in the two groups after blood transfusions were also higher than those before transfusion (P<0.05). However, the levels of CD4+ decreased and those of CD8+ increased in both groups after the blood transfusions. In addition, the levels of CD4+ and CD4+/CD8+ in the short-term group were higher than those of the long-term group (P<0.05) while the CD8+ levels were lower than that of the long-term group (P<0.05). After the blood transfusions, the potassium ion (K+) levels in the two groups increased, and those in the long-term group were higher than in the short-term group (P<0.05). The sodium ion (Na+) levels in the two groups increased after the transfusions, and the short-term group had higher levels than the long-term group (P<0.05). Finally, the incidence of adverse reactions in the short-term group (4.00%) was lower than that in the long-term group (18.00%) (P<0.05). Conclusion: Intraoperative infusion of SRBC with storage duration longer than two weeks increases the risk of perioperative adverse transfusion reactions, which implies that the storage duration of SRBC should be strictly controlled in clinical practice to reduce the risk of blood transfusion.

Effects of tetracycline antibiotics in chicken manure on soil microbes and antibiotic resistance genes (ARGs).

China is the world's largest livestock and poultry breeding country, but also the largest use of veterinary antibiotics. When a large amount of chicken manure is applied to the soil, it will cause the number of antibiotic residues and resistant bacteria to increase, which will bring about the pollution of antibiotic resistance genes (ARGs) in the soil, and then increase the risk of environmental pollution and human health. Field experiments were conducted to study the changes of soil tetracycline antibiotic residues, resistant bacteria and resistance genes treated with different types and dosage of chicken manure (no chicken manure, (CK), low fresh chicken manure treatment (300 kg·667 m-2), high fresh chicken manure treatment (600 kg·667 m-2), low decomposed chicken manure treatment (300 kg·667 m-2) and high decomposed chicken manure treatment (600 kg·667 m-2)). After one-year application of chicken manure, content of soil organic matter increased by 1.0%-3.2% compared with the control. The activity of soil catalase significantly increased by 84.3-91.5%, 81.9-102.9% in fresh and decomposed chicken manure treatments compared with the control, respectively. The amount of soil resistant bacteria under the same treatment was in the order of Anti-OTC > Anti-TC > Anti-CTC. After one-year application of chicken manure, the total tetracycline amount in the soil was increased by 168.5-217.9% compared with the control. The amount of antibiotic residue in soil treated with fresh chicken manure was 3.0-9.1% higher than that treated with decomposed chicken manure. The abundance of ARGs in the soil was in the order of that treated with high fresh chicken manure > low fresh chicken manure > high decomposed chicken manure > low decomposed chicken manure. The risk of tetracycline antibiotics to soil ecological environment may be greatly reduced after chicken manure decomposed.

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS: We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).

mTOR regulates GPVI-mediated platelet activation.

BACKGROUND: Due to mTOR (mammalian/mechanistic target of rapamycin) gene-loss mice die during embryonic development, the role of mTOR in platelets has not been evaluated using gene knockout technology. METHODS: A mouse model with megakaryocyte/platelet-specific deletion of mTOR was established, and be used to evaluate the role of mTOR in platelet activation and thrombus formation. RESULTS: mTOR-/- platelets were deficient in thrombus formation when grown on low-concentration collagen-coated surfaces; however, no deficiency in thrombus formation was observed when mTOR-/- platelets were perfused on higher concentration collagen-coated surfaces. In FeCl3-induced mouse mesenteric arteriole thrombosis models, wild-type (WT) and mTOR-/- mice displayed significantly different responses to low-extent injury with respect to the ratio of occluded mice, especially within the first 40 min. Additionally, mTOR-/- platelets displayed reduced aggregation and dense granule secretion (ATP release) in response to low doses of the glycoprotein VI (GPVI) agonist collagen related peptide (CRP) and the protease-activated receptor-4 (PAR4) agonist GYPGKF-NH2; these deficiencies were overcame by stimulation with higher concentration agonists, suggesting dose dependence of the response. At low doses of GPVI or PAR agonist, the activation of αIIbß3 in mTOR-/- platelets was reduced. Moreover, stimulation of mTOR-/- platelets with low-dose CRP attenuated the phosphorylation of S6K1, S6 and Akt Ser473, and increased the phosphorylation of PKCδ Thr505 and PKCε Ser729. Using isoform-specific inhibitors of PKCs (δ, ɛ, and α/ß), we established that PKCδ/ɛ, and especially PKCδ but not PKCα/ß or PKCθ, may be involved in low-dose GPVI-mediated/mTOR-dependent signaling. CONCLUSION: These observations indicate that mTOR plays an important role in GPVI-dependent platelet activation and thrombus formation.

Puerarin plays a protective role in chondrocytes by activating Beclin1-dependent autophagy.

Puerarin can protect chondrocytes, whereby ameliorating osteoarthritis. Puerarin also promotes autophagy. Autophagy maintains chondrocyte homeostasis. The role of autophagy in puerarin-protected chondrocytes is unknown. Puerarin promoted chondrocyte autophagy. Puerarin-protected chondrocytes were reversed by autophagy inhibitors and Beclin1 inhibitor. 3-MA or Beclin1 inhibitor in vivo reversed puerarin-ameliorated cartilage damage of osteoarthritis mice. Thus, puerarin can protect chondrocytes through Beclin1-dependent autophagy activation.

Increased Neck Tilt/T1 slope ratio may play an important role in patients with cervical kyphosis.

BACKGROUND: In previous studies, we demonstrated that the T1 slope (T1s) is associated with clinical outcomes, but the results were not specific for individuals. A recent study suggested that an increased pelvic tilt (PT)/sacral slope (SS) ratio may play an important role in the degeneration of lumbar scoliosis and pathogenesis of lumbar spondylolisthesis. Therefore, we aimed to explore the role of neck tilt (NT)/T1s in patients with cervical kyphosis. METHODS: In total, the data of 36 kyphosis patients who underwent anterior cervical hybrid decompression and fusion (ACHDF) for multilevel (3 levels) cervical spondylotic myelopathy were retrospectively analyzed. The radiographic measurements included the T1s, NT, C2-7 Cobb angle, and C2-7 sagittal vertical axis (SVA). The visual analog scale (VAS) and neck disability index (NDI) scores were used to determine the clinical prognosis. Pearson's correlation coefficient was calculated to assess the relationships among preoperative imaging examination parameters. RESULTS: The mean C2-7 Cobb angle was - 5.93 ± 3.00° before surgery, 9.67 ± 6.61° after surgery, and 7.91 ± 8.73° at the follow-up. The preoperative NT/T1s ratio was positively correlated with the ΔC2-7 Cobb angle (r = 0.358, p < 0.05) and negatively correlated with the preoperative C2-7 Cobb angle (r = -0.515, p < 0.01) and preoperative C2-7 SVA (r = -0.461, p < 0.01). The linear regression model indicated a positive correlation between the preoperative NT/T1s ratio and the ΔC2-7 Cobb angle (R2 = 0.122). CONCLUSIONS: The preoperative NT/T1s ratio may be positively correlated with changes in postoperative cervical spine curvature (Cobb angle). The NT/T1s ratio may be worthy of increased attention among sagittal parameters.

Distribution of cadmium in subcellular fraction and expression difference of its transport genes among three cultivars of pepper.

Cadmium (Cd) tolerance mechanisms in plant are mainly divided into two categories: evasion mechanism and tolerance mechanism. However, due to the complexity of the mechanism of Cd absorption and accumulation in crops, there are still disputes and controversies about Cd toxicity to plants and the mechanism of Cd tolerance in plants. The Cd absorption and accumulation mechanism in edible parts of pepper remains unknown. The present study characterized three pepper cultivars with different cadmium tolerance under cadmium stress. One high-Cd-accumulation type (X55), a medium-Cd-accumulation type (Daguo 99) and a low-Cd-accumulation type (Luojiao 318) were selected to study distribution characteristics of Cd in subcellular fractions of the three pepper varieties as well as expression difference of key Cd accumulation and tolerance genes under different cadmium levels. The results showed that under Cd stress, X55 and Daguo 99 mainly migrated Cd from root to stems and leaves, while Luojiao318 migrated it to the fruit. The Cd concentration in the subcellular fractions of pepper roots, stems, leaves and fruits was as follow: cell wall (F1) > organelle (F2) > cell soluble fraction (F3). The roots, stems and leaf cells of X55 have strong Cd compartmentalization capacity. The fruit cells of Daguo 99 have strong Cd compartmentalization capacity, while the roots of Luojiao318 have strong ability to inhibit Cd absorption. Under Cd stress, HMA1, HMA2 and NRAMP1-6 were up-regulated in roots, stems and fruits of the three varieties. FTP1-2 and FTP1-3 genes were significantly up-regulated in different materials, except the roots of Daguo 99. Under Cd treatment, PCS gene expression of pepper showed an order of that of X55 > Luojiao 318 >Daguo 99. The present study revealed that the cell wall of pepper played an important role in Cd separation and resistance. The difference in Cd accumulation ability of the pepper varieties may be related to differences in main expression sites and expression levels of HMA, NRAMP, FTP and PCS genes.

Correlation and the concentrations of Pb, Cd, Hg and As in vegetables and soils of Chongqing, China.

This paper studies the concentration of Pb, Cd, Hg and As in vegetable and soil of 13 main vegetable base, Chongqing, China, as well as the correlation between them. Results show that the concentrations of heavy metals in different vegetables from 13 main vegetable bases of Chongqing are also significantly different. The order of Pb concentration is root vegetable (the average value is 0.203 mg/kg) > leaf vegetable (the average value is 0.065 mg/kg) > solanaceous vegetable (the average value is 0.004 mg/kg); the order of Cd concentration is leaf vegetable (the average value is 0.090 mg/kg) > solanaceous vegetable (the average value is 0.061 mg/kg) > root vegetable (the average value is 0.049 mg/kg); the order of Hg concentration is leaf vegetable (the average value is 0.004 mg/kg) > root vegetable (the average value is 0.003 mg/kg) > solanaceous vegetable (the average value is 0.001 mg/kg); the order of As concentration is root vegetable (the average value is 0.116 mg/kg) > solanaceous vegetable (the average value is 0.057 mg/kg) > leaf vegetable (the average value is 0.026 mg/kg). Significant positive correlation was found between the Cd concentration in vegetables and the Cd concentration in soil, and the linear equation was y = 0.065 + 0.012x. There was no significant correlation between the concentrations of Pb, Hg and As in vegetables and Pb, Hg and As in soil.

A long noncoding RNA protects the heart from pathological hypertrophy.

The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized--but not naked--DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA-chromatin interaction.

Intraoperative injection of absorbable gelatin sponge (AGS) mixed with cement followed by spinal decompression to treat elderly with vertebral hemangiomas.

BACKGROUND: Elderly patients with vertebral hemangiomas are rare and might require surgery. Thus, the choice of surgery for these lesions remains controversial because of the rarity of these lesions. This study aimed to analyze the clinical efficacy of the intraoperative injection of absorbable gelatin sponge mixed with cement followed by spinal decompression to treat the elderly with typical vertebral hemangiomas. The risk factors for hemangioma recurrence were investigated through a literature review. METHODS: We retrospectively analyzed 13 patients with typical aggressive hemangiomas between January 2009 and January 2016. Of these patients, 7 were treated with spinal decompression combined with intraoperative vertebroplasty (Group A), and 6 patients were treated with decompression with intraoperative vertebroplasty and absorbable gelatin sponge (Group B). The general data and perioperative data of the patients were compared. Patients were followed up for at least 3 years, and postoperative complications and recurrence rates were recorded and compared. RESULTS: All patients had typical aggressive hemangiomas. The average age of all patients was 64.4 ± 3.3 years. The preoperative data did not differ significantly between the two groups (P > 0.05). The blood loss of groups A and B was 707.1 ± 109.7 ml and 416.7 ± 103.3 ml, respectively (P = 0.003) (P = 0.003), and the average surgery durations were 222 ± 47.8 min and 162 ± 30.2 min, respectively (P = 0.022). The average follow-up duration was 62 ± 19 months, and no cases of recurrence were found at the final follow-up assessment. CONCLUSIONS: Multimodal treatment significantly alleviated the clinical symptoms of elderly patients with typical aggressive vertebral hemangiomas. Intraoperative absorbable gelatin sponge injection is a safe and effective way to reduce blood loss and surgery duration.

Neural differentiation of bone marrow mesenchymal stem cells with human brain-derived neurotrophic factor gene-modified in functionalized self-assembling peptide hydrogel in vitro.

OBJECTIVE: To investigate the biocompatibility and differentiation of human brain-derived neurotrophic factor (hBDNF) gene-modified bone marrow mesenchymal stem cells (hBDNF-rMSCs) in a functionalized self-assembling peptide hydrogel. METHODS: hBDNF was engineered in rMSCs using adenovirus vector and the enhanced green fluorescence protein (eGFP) was used as a reporter gene. Mesenchymal stem cell-specific surface markers (CD90, CD29, and CD45) were used for identifying rat-derived MSCs. Fluorescence microscope was used to detect the transfection of rMSCs. hBDNF-rMSCs and control cells (eGFP-rMSCs) were seeded in a functional self-assembling peptide hydrogel (RADA16-PRG hydrogel) and a control hydrogel (RADA16 hydrogel). Cells were divided into three groups (hBDNF-rMSCs + RADA16 hydrogel, hBDNF-rMSCs + RADA16-PRG hydrogel, and eGFP-rMSCs + RADA16-PRG hydrogel) and a control group (eGFP-rMSCs + RADA16 hydrogel). Cell growth, cell proliferation, expression of hBDNF-mRNA, the level of hBDNF, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) protein were analyzed for each group. RESULTS: rMSCs were positive for CD90 and CD29 and negative for CD45, green fluorescence was strongly visible at 72 hours after transfection. Compared with control group, the expression of hBDNF-mRNA and levels of hBDNF protein in both hBDNF group were significantly increased (P < 0.01), the cell growth, cell proliferation, and levels of NSE and GFAP protein were significantly increased in three groups ( P < 0.01). Cell growth, cell proliferation, expression of hBDNF-mRNA, and levels of hBDNF, NSE, and GFAP protein in hBDNF-rMSCs + RADA16-PRG hydrogel group were significantly higher than that of hBDNF-rMSCs + RADA16 hydrogel group ( P < 0.01). CONCLUSION: Bone marrow MSCs can be induced into neural cells by the human brain-derived neurotrophic factor gene in a RADA16-PRG functionalized self-assembling peptide hydrogel.

Analysis of sagittal alignment parameters following anterior cervical hybrid decompression and fusion of multilevel cervical Spondylotic myelopathy.

BACKGROUND: To investigate the relationships between sagittal parameters and health-related quality of life (HRQOL) scores following anterior cervical hybrid decompression and fusion (ACHDF) of multilevel cervical spondylotic myelopathy (CSM) and to study the impact of the T1 slope (T1 s). METHODS: In total, 42 patients with complete radiographic measurements following ACHDF in the Spine Surgery Department of the First Affiliated Hospital of Fujian Medical University from August 2014 to January 2017 were retrospectively analysed. Radiographic measurements included C2-7 lordosis, T1 s, C2-7 sagittal vertical axis (SVA), cervical tilting and cranial tilting. The neck disability index (NDI) was used to evaluate the HRQOL. Spearman's correlation coefficients were calculated between pairs of cervical sagittal parameters and NDI scores. RESULTS: Preoperative NDI scores were correlated with preoperative T1 s (r = 0.413); follow-up NDI scores were correlated with follow-up T1 s (r = 0.534). The regression analysis indicated that a preoperative T1 s value of 42.36° corresponded to a preoperative NDI score of 25 (r2 = 0.171, P < 0.001). A follow-up T1 s value of 48.61° corresponded to a follow-up NDI score of 25 (r2 = 0.421, P < 0.01). The differences in C2-7 SVA and cranial tilting before and after the operation were statistically significant (P < 0.05). CONCLUSION: This study showed that the sagittal balance of the cervical vertebrae changed significantly after ACHDF, showing a forward trend. The sagittal parameters after ACHDF were related to clinical prognosis. An excessive T1 s can be considered a risk factor. The T1 s could provide a reference value to determine the correction of the sagittal balance of the cervical spine.