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In order to explore the adsorption characteristics of phosphorus from molecules with different molecular structures and varying number of phosphate groups on metal-modified biochar, walnut shell biochar was modified with LaCl

Postherpetic neuralgia (PHN) is a painful condition that persists for 1 month or more after herpes zoster rash has healed. Radiofrequency thermocoagulation (RF-TC) provides analgesia by destroying the dorsal root ganglion and blocking the pain upload pathway; nonetheless, the concomitant neurological-related side effects and recurrence remain a concern.In this study, 228 patients with PHN in the thoracic segment treated with RF-TC of the dorsal root ganglion of the spinal nerve were included, and were followed up regularly after surgery. The numerical rating scale (NRS) scores, time to recurrence, and intraoperative and postoperative adverse events were recorded and analyzed. The Kaplan-Meier method was used to plot survival curves and calculate the cumulative effective rate and recurrence rate. Cox regression analyses were performed to identify factors associated with postoperative recurrence. Predictive models were built to assess the value of applications.The NRS scores decreased in all postoperative periods compared with preoperative ones. At 10-year-follow-up, recurrence was observed in 34.6% (79/228) of patients that underwent PHN. The main postoperative complications were numbness and reduced abdominal muscle strength, which gradually decreased with time, while the abdominal muscle strength gradually recovered. No other adverse events occurred. Interval-censored multivariable Cox regression analysis demonstrated that disease course, complications, pain grade, and type of RF electrode were associated with a significantly higher risk of relapse. The main intraoperative adverse effect was a transient increase in pain during RF-TC.CT-guided RF-TC of the dorsal root ganglion of the spinal nerve for PHN is a relatively safe and effective surgical option. Disease course, type of RF electrode, complications, and pain grade are risk factors for postoperative recurrence and can assist in clinical decision-making before the RF-CT procedure.

Understanding the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is an urgent problem in clinical trials. Increasing pieces of evidence have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating mitochondria-related gene expression. Mitochondria have been acknowledged as the key triggers of cardiac I/R injury. However, the potential impact of miR-130a on mitochondria remains unclear in myocardial IRI. Exploring the regulatory mechanism of miR-130a on mitochondria may provide a new target for IRI therapy. In the present study, we found that miR-130a significantly increased in acute myocardial infarction (AMI) patients and myocardial I/R rats. MiR-130a could downregulate the viability of cardiomyocytes and the knockdown of miR-130a could protect the viability of cardiomyocytes under hypoxia-reoxygenation (HR). Over-expression of miR-130a resulted in mitochondrial dysfunction. It was evidenced by decreases in mitochondrial ATP production, mitochondrial membrane potential (MMP), and an increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect against mitochondrial damage, show elevation of mitochondrial ATP production rate and MMP, and reduce ROS production. We further explored the effect of miR-130a on the mitochondrial quality control (QMC) system by determining mitochondrial-protein-specific proteases and analyzed mitochondrial morphology by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targeted mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a targeted GJA1, and GJA1 rescued IRI by enhancing ATP production rate and oxidative phosphorylation, meanwhile protecting cell viability, MMP, and activating mitophagy. In addition, the knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while the knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI.

A set of myelodysplasia-related (MDS-R) gene mutations are incorporated into the 2022 European LeukemiaNet risk classification as adverse genetic factors for acute myeloid leukemia (AML) based on their poor prognostic impact on older patients. The impact of these mutations on younger patients (age de novo non-M3 AML, we identified MDS-R mutations in 32.7% of the total cohort, 44.9% of older patients and 23.4% of younger patients. The patients with MDS-R mutations had a significantly lower complete remission rate in both younger and older age groups. With a median follow-up of 9.2 years, the MDS-R group experienced shorter overall survival (P = 0.034 for older and 0.035 for younger patients) and event-free survival (P = 0.004 for older and 0.042 for younger patients). Furthermore, patients with MDS-R mutations more frequently harbored measurable residual disease that was detectable using next generation sequencing at morphological CR than those without MDS-R mutations. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) might ameliorate the negative impact of MDS-R mutations. In summary, AML patients with MDS-R mutations have significantly poorer outcomes regardless of age. More intensive treatment, such as allo-HSCT and/or novel therapies, is warranted for AML patients with MDS-R mutations.

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in the cellular response to various stresses and has been confirmed to maintain the homeostasis of the internal environment. However, the potential effects of SESN2 in regulating dendritic cells (DCs) pyroptosis in the context of sepsis and the related mechanisms are poorly characterized. In this study, we found that SESN2 was capable of decreasing gasdermin D (GSDMD)-dependent pyroptosis of splenic DCs by inhibiting endoplasmic reticulum (ER) stress (ERS)-related nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated ASC pyroptosome formation and caspase-1 (CASP-1) activation. Furthermore, SESN2 deficiency induced NLRP3/ASC/CASP-1-dependent pyroptosis and the production of proinflammatory cytokines by exacerbating the PERK–ATF4–CHOP signaling pathway, resulting in an increase in the mortality of septic mice, which was reversed by inhibiting ERS. These findings suggest that SESN2 appears to be essential for inhibiting NLRP3 inflammasome hyperactivation, reducing CASP-1-dependent pyroptosis, and improving sepsis outcomes through stabilization of the ER. The present study might have important implications for exploration of novel potential therapeutic targets for the treatment of sepsis complications. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-021-03970-z.

To investigate lattice distortion evolutions of CrCoNi medium-entropy alloy (MEA), CrFeCoNi, and CrMnFeCoNi high-entropy alloys (HEAs) with temperature increasing from 300 to 1323 K, we conduct in situ synchrotron-radiation-based X-ray diffraction experiments. Electron backscattering diffraction, energy-dispersive X-ray spectroscopy and X-ray absorption near edge fine structure spectra (XANES) are further carried out to uncover variations of microstructure, morphology and oxidation resistance. Generally, the lattice will expand continuously with temperature increasing, however, the expansion rate is affected by grain growth and oxidation. The oxidation resistance of CrCoNi MEA is slightly higher than CrFeCoNi HEA, and much higher than CrMnFeCoNi HEA. The XANES spectra demonstrate higher oxidation resistance of Ni, Co, and Fe than Cr and Mn. Formation of local short-range order structures around Ni and Co is observed, but no such features are observed around Fe and Mn. The present findings are significant on deepening the understandings of correlations between atomic structure and mechanical properties in advanced HEAs.

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR

Background As a meaningful subtype of ischemic stroke in Asians, Branch atheromatous disease (BAD)-related stroke is associated with high early neurological deterioration (END) and disability, but is understudied and without recommended therapy. The mechanism of END still remains unclear. Branch atheromatous disease-related stroke study (BAD-study) therefore aims to investigate demographic, clinical and radiological features, and prognosis of BAD-related stroke in Chinese patients. Methods/design BAD-study is a nationwide, multicenter, consecutive, prospective, observational cohort study enrolling patients aged 18–80 years with BAD-related stroke within 72 h after symptom onset. Initial clinical data, laboratory tests, and imaging data are collected via structured case report form, and follow-ups will be performed at 7 days, 30 days, 90 days, 6 months and 12 months after enrollment. The primary outcome is the score on modified Rankin Scale at 90-day follow-up with single-blinded assessment. Secondary outcomes include END within 7 days, and National institute of health stroke scale score, Barthel index, cerebrovascular events, major bleeding complications, and all-cause mortality during 90-day follow-up. Characteristics of penetrating and parent artery will be assessed by high-resolution magnetic resonance imaging combined with other imaging techniques. Discussion BAD-study can provide demographic, clinical, radiological, and prognostic characteristics of BAD-related stroke, and thereby potentially figure out the vascular mechanism of early neurological deterioration and optimize therapy strategy with the aid of advanced imaging technique. Baseline data and evidence will also be generated for randomized controlled trials on BAD-related stroke in the future.

Extending the benefits of tumor molecular profiling for all cancer patients requires a comprehensive analysis of tumor genomes across distinct patient populations worldwide. In this study, we perform deep next-generation DNA sequencing (NGS) from tumor tissues and matched blood specimens from over 10,000 patients in China by using a 450-gene comprehensive assay, developed and implemented under international clinical regulations. We perform a comprehensive comparison of somatically altered genes, the distribution of tumor mutational burden (TMB), gene fusion patterns, and the spectrum of various somatic alterations between Chinese and American patient populations. Here, we show 64% of cancers from Chinese patients in this study have clinically actionable genomic alterations, which may affect clinical decisions related to targeted therapy or immunotherapy. These findings describe the similarities and differences between tumors from Chinese and American patients, providing valuable information for personalized medicine.

Retinal pigment epithelium (RPE) degeneration plays an important role in a group of retinal disorders such as retinal degeneration (RD) and age-related macular degeneration (AMD). The mechanism of RPE cell death is not yet fully elucidated. Ferroptosis, a novel regulated cell death pathway, participates in cancer and several neurodegenerative diseases. Glutathione peroxidase 4 (GPx-4) and ferroptosis suppressor protein 1 (FSP1) have been proposed to be two main regulators of ferroptosis in these diseases; yet, their roles in RPE degeneration remain elusive. Here, we report that both FSP1-CoQ10-NADH and GSH-GPx-4 pathways inhibit retinal ferroptosis in sodium iodate (SIO)-induced retinal degeneration pathologies in human primary RPE cells (HRPEpiC), ARPE-19 cell line, and mice. GSH-GPx-4 signaling was compromised after a toxic injury caused by SIO, which was aggravated by silencing GPx-4, and ferroptosis inhibitors robustly protected RPE cells from the challenge. Interestingly, while inhibition of FSP1 caused RPE cell death, which was aggravated by SIO exposure, overexpression of FSP1 effectively protected RPE cells from SIO-induced injury, accompanied by a significant down-regulation of CoQ10/NADH and lipid peroxidation. Most importantly, in vivo results showed that Ferrostatin-1 not only remarkably alleviated SIO-induced RPE cell loss, photoreceptor death, and retinal dysfunction but also significantly ameliorated the compromised GSH-GPx-4 and FSP1-CoQ10-NADH signaling in RPE cells isolated from SIO-induced RPE degeneration. These data describe a distinct role for ferroptosis in controlling RPE cell death in vitro and in vivo and may provide a new avenue for identifying treatment targets for RPE degeneration.

Background This study intends to establish a combined prediction model that integrates the clinical symptoms,the lung lesion volume, and the radiomics features of patients with COVID-19, resulting in a new model to predict the severity of COVID-19. Methods The clinical data of 386 patients with COVID-19 at several hospitals, as well as images of certain patients during their hospitalization, were collected retrospectively to create a database of patients with COVID-19 pneumonia. The contour of lungs and lesion locations may be retrieved from CT scans using a CT-image-based quantitative discrimination and trend analysis method for COVID-19 and the Mask R-CNN deep neural network model to create 3D data of lung lesions. The quantitative COVID-19 factors were then determined, on which the diagnosis of the development of the patients' symptoms could be established. Then, using an artificial neural network, a prediction model of the severity of COVID-19 was constructed by combining characteristic imaging features on CT slices with clinical factors. ANN neural network was used for training, and tenfold cross-validation was used to verify the prediction model. The diagnostic performance of this model is verified by the receiver operating characteristic (ROC) curve. Results CT radiomics features extraction and analysis based on a deep neural network can detect COVID-19 patients with an 86% sensitivity and an 85% specificity. According to the ROC curve, the constructed severity prediction model indicates that the AUC of patients with severe COVID-19 is 0.761, with sensitivity and specificity of 79.1% and 73.1%, respectively. Conclusions The combined prediction model for severe COVID-19 pneumonia, which is based on deep learning and integrates clinical aspects, pulmonary lesion volume, and radiomics features of patients, has a remarkable differential ability for predicting the course of disease in COVID-19 patients. This may assist in the early prevention of severe COVID-19 symptoms.

Previous studies have indicated that long non-coding RNAs (lncRNAs) were closely related to diabetes. In this study, we aimed to explore the possible role and mechanism of lncRNA MEG3 in the occurrence and development of type 2 diabetes mellitus (T2DM) and its vascular complications. A case–control study involving 115 subjects was conducted, including 53 T2DM patients (37 patients with vascular complication and 16 patients without vascular complications) and 62 healthy subjects. We performed real-time polymerase chain reaction (RT-PCR) analysis of the lncRNA MEG3 and miR-146a levels in peripheral blood mononuclear cells (PBMCs) in the 115 samples. We found that the expression of lncRNA MEG3 was upregulated in the T2DM patients with vascular complication (DC group) compared with T2DM patients without vascular complication (D group) (P

PF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta®). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and safety of PF-06881894 vs pegfilgrastim reference products (US- and EU-Neulasta®) in healthy volunteers. A phase 1, open-label, randomized, crossover study was conducted to assess the pharmacologic equivalence and safety of a single 6-mg dose of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU. The primary PD endpoints were area under the effect-versus-time curve for absolute neutrophil count (ANC) from dose administration to 288 h postdose, and maximum observed ANC value among subjects confirmed negative for anti-pegfilgrastim antibodies. Primary PK variables included area under the serum pegfilgrastim-versus-time curve from the time of dose administration to time infinity and maximum observed serum pegfilgrastim concentration. A second phase 1, open-label, randomized (1:1), parallel-group, non-inferiority study was conducted to assess the immunogenicity and safety of multiple 6-mg doses of PF-06881894 versus pegfilgrastim-US. The primary endpoint for the immunogenicity study was the proportion of subjects with both negative baseline and confirmed positive postdose anti-pegfilgrastim antibodies at any time during the study. Across the single- and multiple-dose studies (N = 153 and N = 420 treated subjects, respectively), demographics for age (18–65 years), male gender (n = 264/573), and white race (n = 423/573) were similar. Three-way PD/PK equivalence of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU was demonstrated with the primary PD endpoints and primary PK variables being completely contained within the predefined 90% confidence interval acceptance limits (80–125%). The non-inferiority of PF-06881894 versus pegfilgrastim-US in terms of immunogenicity was established according to the prespecified non-inferiority margin (≤10%). Overall, there were no clinically meaningful differences in safety profiles among or between study groups. Single-dose PF-06881894 demonstrated PD/PK equivalence and comparable safety with US- and EU-pegfilgrastim reference products. Multiple-dose PF-06881894 demonstrated immunogenicity non-inferiority to pegfilgrastim-US with comparable safety. Both studies contributed to the totality of evidence supporting biosimilarity. ClinicalTrials.gov identifiers: NCT02629289 (C1221001); NCT03273842 (C1221005).

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma often with extranodal involvement at diagnosis, and yet how this feature correlates with survival awaits elucidation. To address this issue, a correlative analysis between clinical features of 127 MCL patients and their overall survival (OS) was conducted. In this cohort, the median age at MCL diagnosis was 62 years and 81% were males. Eighty-four percent of patients were Ann Arbor stage 4, and 15% were blastoid variants. In patients with gastrointestinal MCL, approximately 40% had gastric involvement. In treatment, CHOP-based induction chemotherapy was given to 61.1% of patients. One-third of patients undertook autologous stem cell transplant (SCT), and 4.7% had allogeneic SCT. The median OS was 82 months and well-stratified in MIPI risk groups. In the multivariate analysis for OS, blastoid variants and gastric involvement were both independent risk factors whereas auto-SCT had a protective effect. Overall, this study corroborated with the current understandings and international therapeutic standards for MCL. Auto-SCT associated with a better OS while allo-SCT remained an option for blastoid variants and those who failed Auto-SCT. Interestingly, patients with gastric involvement tended to have worse survival, a finding that spawns more studies to investigate the mechanism.

In order to make full use of the driver’s long-term driving experience in the process of perception, interaction and vehicle control of road traffic information, a driving behavior rule extraction algorithm based on artificial neural network interface (ANNI) and its integration is proposed. Firstly, based on the cognitive learning theory, the cognitive driving behavior model is established, and then the cognitive driving behavior is described and analyzed. Next, based on ANNI, the model and the rule extraction algorithm (ANNI-REA) are designed to explain not only the driving behavior but also the non-sequence. Rules have high fidelity and safety during driving without discretizing continuous input variables. The experimental results on the UCI standard data set and on the self-built driving behavior data set, show that the method is about 0.4% more accurate and about 10% less complex than the common C4.5-REA, Neuro-Rule and REFNE. Further, simulation experiments verify the correctness of the extracted driving rules and the effectiveness of the extraction based on cognitive driving behavior rules. In general, the several driving rules extracted fully reflect the execution mechanism of sequential activity of driving comprehensive cognition, which is of great significance for the traffic of mixed traffic flow under the network of vehicles and future research on unmanned driving.

Background Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease, and few cases combine with Crohn’s disease. We present the first SLE patient concurrent with Crohn’s disease and rectovaginal fistula. She was successfully treated with vedolizumab and surgical intervention. Besides, she also had a rare opportunistic infection, cryptococcal pneumonia, in previous adalimumab treatment course. Case A 57 year-old female had SLE in disease remission for 27 years. She suffered from progressive rectal ulcers with anal pain and bloody stool, and Crohn’s disease was diagnosed. She received adalimumab, but the lesion still progressed to a rectovaginal fistula. Besides, she suffered from an episode of cryptococcal pneumonia under adalimumab treatment course. Therefore, we changed the biologics to vedolizumab, and arrange a transverse colostomy for stool diversion. She had clinical remission without active inflammation, but the fistula still persisted. Then, she received a restorative proctectomy with colo-anal anastomosis and vaginal repair. Follow-up endoscopy showed no more rectal ulcers or fistula tracts, and contrast enema also noted no residual rectovaginal fistula. Conclusion When a SLE patient had unusual rectal ulcers, Crohn’s disease should be considered. Biologics combined with surgical intervention is an optimal solution for Crohn’s disease with rectovaginal fistula. Although cryptococcal pneumonia is a rare opportunistic infection in the biological treatment, we should always keep it in mind.

Three comparative clinical studies assessed the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and safety of PF-06881893 (filgrastim-aafi; Nivestym™), a filgrastim biosimilar, versus US-licensed reference product (filgrastim; US-Neupogen®) in healthy volunteers (HVs). Two separate open-label, crossover-design PK/PD studies were conducted: a single-dose study (n = 24) and a multiple-dose study (n = 60). In each study, HVs were randomized to Nivestym followed by US-Neupogen, or vice versa. Study drug (5 μg/kg) was administered subcutaneously as a single injection or as five consecutive daily injections. Primary PK and PD endpoints were area under the filgrastim serum concentration–time curve, maximum observed concentration, area under the effect curve (AUEC) for absolute neutrophil count (ANC), maximum observed ANC, AUEC for cluster of differentiation (CD)-34+ count, and maximum observed CD34+ count. In an open-label, parallel-design, non-inferiority, comparative immunogenicity study, HVs were randomized (n = 128/treatment) to Nivestym or US-Neupogen. The primary endpoint was the proportion of subjects with a negative baseline antidrug antibody (ADA) test result and one or more confirmed post-dose positive ADA result. Overall demographics were as follows: female (n = 162/340); White (n = 274/340), Black (n = 58/340), and other (n = 8/340); age (18–65 years); and weight (50.8–96.5 kg). All primary PK and PD endpoints met the pre-specified criteria for PK and PD equivalence. The primary endpoint in the comparative immunogenicity study met pre-specified criteria for non-inferiority. Nivestym demonstrated PK and PD equivalence in single and multiple subcutaneous-dose settings and non-inferiority for immunogenicity to US-Neupogen, with a comparable safety profile, supporting the demonstration of biosimilarity. ClinicalTrials.gov C1121002 (NCT02766647); C1121003 (NCT02766634); C1121012 (NCT02923791).

Hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). We conducted this study to investigate the incidence and risk factors of hepatic VOD for patients receiving HSCT in Taiwan. We retrospectively analyzed the data from a nationwide registry for patients receiving HSCT, which was collected by the Taiwan Society of Blood and Marrow Transplantation. The data collection period was from 2009 to 2014. A total 2345 patients were reviewed and 39 patients among them were diagnosed as having hepatic VOD. The cumulative incidence of hepatic VOD in the whole cohort of 2345 patients was 1.66%. In multivariate analysis, disease diagnosis of myelodysplastic syndrome, chronic HCV infection, condition regimens of bulsulfan intravenously administered, and antithymocyte immunoglobulin were independent factors to predict higher risk of hepatic VOD. The overall mortality rate for patients with hepatic VOD was 79%. Patients with hepatic VOD had significant worse survival outcomes when compared with those without hepatic VOD (P = 0.00063). In conclusion, although the incidence is low, hepatic VOD remains a serious complication after HSCT in Taiwan. The findings of this study could be the basis for developing prophylactic or early treatment strategies for hepatic VOD.

In view of the supercavitation effect, a novel device named the rotational supercavitating evaporator (RSCE) has been designed for the desalination. In order to improve the blade shape of the rotational cavitator in the RSCE for the performance optimization, the blade shapes of different sizes are designed by utilizing the improved calculation method for the blade shape and the validated empirical formulae based on previous two-dimensional numerical simulations, from which the optimized blade shape with the wedge angle of 45° and the design speed of 5 000 r/min is selected. The estimation method for the desalination performance parameters is developed to validate the feasibility of the utilization of the results obtained by the two-dimensional numerical simulations in the design of the three-dimensional blade shape. Three-dimensional numerical simulations are then conducted for the supercavitating flows around the rotational cavitator with the optimized blade shape at different rotational speeds to obtain the morphological characteristics of the rotational natural supercavitation. The results show that the profile of the supercavity tail is concaved toward the inside of the supercavity due to the re-entrant jet. The empirical formulae for estimating the supercavity size with consideration of the rotation are obtained by fitting the data, with the exponents different from those obtained by the previous two-dimensional numerical simulations. The influences of the rotation on the morphological characteristics are analyzed from the perspectives of the tip and hub vortices and the interaction between the supercavity tail and the blade. Further numerical simulation of the supercavitating flow around the rotational cavitator made up by the blades with exit edge of uniform thickness illustrate that the morphological characteristics are also affected by the blade shape.