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Abstract Objectives This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non‐small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD‐L1). Materials and Methods Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB‐high (TMB‐H) was defined as ≥10 mutations/Mb. PD‐L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. Results EGFR‐sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD‐L1+/TMB‐H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD‐L1+/TMB‐H proportions than wild‐type genotypes. Histone‐lysine N‐methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD‐L1 expression, as well as higher PD‐L1+/TMB‐H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD‐L1+/TMB‐H proportions than wild‐type patients. The median progression‐free survival (PFS) was 5.47 months (95% CI 2.5–NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6–4.27) in wild‐type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co‐mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24–0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26–0.81, p = 0.007). Conclusion We found that tumors with different alterations in actionable target genes had variable expression of PD‐L1 and TMB in NSCLC. TP53/KMT2C co‐mutation might serve as a predictive biomarker for ICI responses in NSCLC. Implications for Practice Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non‐small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next‐generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD‐L1 expression. Our study demonstrated that KMT2C/TP53 co‐mutation might be an accurate, cost‐effective, and reliable biomarker to predict responses to PD‐1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.

Abstract. Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a rare but increasingly recognized subtype of CAA. CAA-RI consists of two subtypes: inflammatory cerebral amyloid angiopathy and amyloid β (Aβ)-related angiitis. Acute or subacute onset of cognitive decline or behavioral changes is the most common symptom of CAA-RI. Rapid progressive dementia, headache, seizures, or focal neurological deficits, with patchy or confluent hyperintensity on T2 or fluid-attenuated inversion recovery sequences and evidence of strictly lobar microbleeds or cortical superficial siderosis on susceptibility-weighted imaging imply CAA-RI. The gold standard for diagnosis is autopsy or brain biopsy. However, biopsy is invasive; consequently, most clinically diagnosed cases have been based on clinical and radiological data. Other diagnostic indexes include the apolipoprotein E ε4 allele, Aβ and anti-Aβ antibodies in cerebral spinal fluid and amyloid positron emission tomography. Many diseases with similar clinical manifestations should be carefully ruled out. Immunosuppressive therapy is effective both during initial presentation and in relapses. The use of glucocorticoids and immunosuppressants improves prognosis. This article reviews the pathology and pathogenesis, clinical and imaging manifestations, diagnostic criteria, treatment, and prognosis of CAA-RI, and highlights unsolved problems in the existing research.

Background: Hepatocellular carcinoma (HCC) remains an aggressive malignancy with a poor prognosis and a leading cause of cancer-related mortality globally. Cumulative evidence suggests critical roles for endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in chronic liver diseases. However, the role of ER stress in HCC pathogenesis, aggressiveness and therapy response remains unclear and understudied. Objectives: Against this background, the present study evaluated the therapeutic efficacy and feasibility of notopterol (NOT), a furanocoumarin and principal component of Notopterygium incisum, in the modulation of ER stress and cancer stemness, and the subsequent effect on liver oncogenicity. Methods: An array of biomolecular methods including Western blot, drug cytotoxicity, cell motility, immunofluorescence, colony and tumorsphere formation, flow-cytometric mitochondrial function, GSH/GSSG ratio, and tumor xenograft ex vivo assays were used in the study. Results: Herein, we demonstrated that NOT significantly suppresses the viability, migration, and invasion capacity of the human HCC HepJ5 and Mahlavu cell lines by disrupting ATF4 expression, inhibiting JAK2 activation, and downregulating the GPX1 and SOD1 expression in vitro. NOT also markedly suppressed the expression of vimentin (VIM), snail, b-catenin, and N-cadherin in the HCC cells, dose-dependently. Treatment with NOT significantly attenuated cancer stem cells (CSCs)-like phenotypes, namely colony and tumorsphere formation, with the concomitant downregulation of stemness markers OCT4, SOX2, CD133, and upregulated PARP-1 cleavage, dose-dependently. We also demonstrated that NOT anticancer activity was strongly associated with increased cellular reactive oxidative stress (ROS) but, conversely, reduced mitochondrial membrane potential and function in the HepJ5 and Mahlavu cells in vitro. Our tumor xenograft studies showed that compared with sorafenib, NOT elicited greater tumor growth suppression without adverse changes in mice body weights. Compared with the untreated control and sorafenib-treated mice, NOT-treated mice exhibited markedly greater apoptosis ex vivo, and this was associated with the co-suppression of stemness and drug-resistance markers OCT4, SOX2, ALDH1, and the upregulation of endoplasmic reticulum stress and oxidative stress factors PERK and CHOP. Conclusions: In summary, we demonstrated for the first time that NOT exhibits strong anticancer activity via the suppression of cancer stemness, enhanced endoplasmic reticulum stress and increased oxidative stress thus projecting NOT as a potentially effective therapeutic agent against HCC.

With the world’s energy reserves under strain and the requirements of national carbon emission regulations, the fuel efficiency and environmental friendliness of automobiles are becoming increasingly important. Due to the combination of long cruising range and energy efficiency, hybrid electric vehicles (HEVs) have been adopted as a reliable option for improving fuel economy and reducing emissions. In order to fully exploit the advantages of hybrid electric vehicles, energy management and torque distribution have become the focus of control strategies for HEVs, while also ensuring battery life and meeting requirements for fuel consumption, emissions and driving performance. Therefore, a great deal of research has been carried out on energy management strategies and many approaches have been offered in the literature. This review provides a comprehensive assessment of the literature, highlighting its contributions and making a complete reference for scholars interested in hybrid vehicle development, control, and optimization.

Permanent magnet synchronous motors (PMSMs) are commonly used in the automation industry. With the speedy development of digital system processors, predictive control as a modern control scheme has been applied to improve the dynamic performance and work efficiency of PMSMs. This paper provides an overview of the research status of PMSM-based predictive control strategies. The deficiencies of the three most popular predictive schemes, deadbeat predictive control, finite-control-set model predictive control, and continuous-control-set model predictive control, and existing improvement strategies such as delay compensation schemes, robust control schemes, and multi-vector control schemes, are summarized. Finally, current technological trends are discussed, emphasizing future research directions for predictive control in PMSM drive systems.

A high-pressure (HP) GaN nucleation layer (NL) was inserted between AlGaN buffer and an unintentionally doped (UID) GaN layer of an AlGaN/GaN HEMT on Si. The XRD and TEM showed that when the V/III ratio was optimized during the HP-GaN NL growth, the edge dislocation density in the HP-GaN NL layer could be reduced significantly. Experimental results exhibited a lower off-state leakage current, higher maximum ID and Gm (corresponding to 22.5% and 21.7% improvement, respectively), and lower on-state resistance. These results demonstrate that the electrical properties of the AlGaN/GaN HEMT can be improved through the insertion of a HP-GaN NL.

Shear localization is one of the most important failure mechanisms subjected to high-strain-rate deformation and has significant effects on the process, plastic deformation, and catastrophic failure of a material. Shear localization was observed in serrated chips produced during the high-speed cutting of the CoCrFeMnNi high-entropy alloy. Electron backscatter diffraction was performed to systematically investigate microstructural evolution during shear banding. The elongation and subdivision of the narrow grains were observed in the areas adjacent to the shear band. The microstructure inside the shear band was found to be composed of equiaxed ultrafine grains. The results reveal that grain subdivision and dynamic recrystallization might have significant roles in the microstructural evolution of shear bands. These results offer key insights into our understanding of shear localization and high-speed machining behavior for high entropy alloys.

Abstract Background Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL. Methods This phase 2 study with Simon’s two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Results In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5–43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29–339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43–106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94–438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab. Conclusions In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.

Abstract Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to anoxia. However, in vitro studies are often performed under oxygen levels that are far higher than those found in vivo. A number of devices are available to alter the oxygen environment in cell culture, including designs from our laboratory. However, in our devices and most other designs, changing the media in order to feed or dose cells remains a disruptive factor in maintaining a consistent hypoxic environment. This report presents a novel 96-well plate design that recirculates the local oxygen environment to shield cells during media changes and facilitates toxicity studies of cells cultured under varying oxygen levels. The principle behind the design is presented and the response of human pancreatic cancer PANC-1 cells treated with tirapazamine and doxorubicin under eight different static or cycling oxygen levels was measured. As expected, tirapazamine is progressively more toxic as oxygen levels decrease but retains some toxicity as oxygen is cycled between hypoxic and normoxic levels. Doxorubicin sensitivity is largely unaffected by changing oxygen levels. This technology is ideal for assessing the effects of oxygen as a variable in toxicity screens.

Deep brain stimulation of the bilateral subthalamic nucleus (STN) is a therapeutic option for patients with Parkinson’s disease (PD) in whom medical therapies have been ineffective. This retrospective cohort study analyzed the motor function of 27 patients with advanced PD, from the First Affiliated Hospital of Guangzhou Medical University, China, who received deep brain stimulation of the bilateral subthalamic nucleus and evaluated its therapeutic effects. The 10-year follow-up data of patients was analyzed in Qingyuan People’s Hospital, Sixth Affiliated Hospital of Guangzhou Medical University, China. The follow-up data were divided into two categories based on patients during levodopa treatment (on-medication) and without levodopa treatment (off-medication). Compared with baseline, the motor function of on-medication PD patients improved after deep brain stimulation of the bilateral subthalamic nucleus. Even 2 years later, the motor function of off-medication PD patients had improved. On-medication PD patients exhibited better therapeutic effects over the 5 years than off-medication PD patients. On-medication patients’ akinesia, speech, postural stability, gait, and cognitive function worsened only after 5 years. These results suggest that the motor function of patients with advanced PD benefitted from treatment with deep brain stimulation of the bilateral subthalamic nucleus over a period up to 5 years. The overall therapeutic effects were more pronounced when levodopa treatment was combined with deep brain stimulation of the bilateral subthalamic nucleus. This study was approved by Institutional Review Board of Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, China (approval No. QPH-IRB-A0140) on January 11, 2018.

Background: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs). Methods: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses. Results: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P

Abstract The development of resistance to anticancer drugs is believed to cause chemotherapy failure in pancreatic cancer (PC). The efflux of anticancer drugs mediated by ATP-binding cassette (ABC) transporters is a widely accepted mechanism for chemoresistance, but for ABCA subfamily members, which are characterized by their ability to transport lipids and cholesterol, its role in chemoresistance remains unknown. Here we found that the expression of ABCA8, a member of ABCA subfamily transporters, was significantly increased in human PC cells after gemcitabine (GEM) treatment, as well as in established GEM-resistant (Gem-R) PC cells. Importantly, ABCA8 knockdown reversed the chemoresistance phenotype of Gem-R cells, whereas ABCA8 overexpression significantly decreased the sensitivity of human PC cells to GEM, both in vitro and in vivo, demonstrating an important role of ABCA8 in regulating chemosensitivity. Moreover, our results showed that treatment with taurocholic acid (TCA), an endogenous substrate of ABCA8, also induced GEM insensitivity in PC cells. We further demonstrated that ABCA8 mediates the efflux of TCA out of PC cells, and that extracellular TCA activates extracellular signal-regulated kinase (ERK) signaling via the sphingosine 1-phosphate receptor 2 (S1PR2), which is responsible for ABCA8-induced GEM ineffectiveness. Together, these findings reveal a novel TCA-related mechanism of ABCA subfamily transporter-mediated chemoresistance that goes beyond the role of a drug pump and suggest ABCA8 or the TCA-S1RP2-ERK pathway as potential targets for improving the effectiveness of and overcoming the resistance to chemotherapy in PC.

Abstract. Background. Homozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 (HTRA1) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. This study was aimed to analyze the genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD. Methods. We presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1-related autosomal dominant CSVD included in PUBMED by the end of March 1, 2020. CARASIL probands with genetic diagnosis reported to date were also reviewed. The genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL. Results. Forty-four HTRA1-related autosomal dominant CSVD probands and 22 CARASIL probands were included. Compared with typical CARASIL, HTRA1-related autosomal dominant probands has a higher proportion of vascular risk factors (P

Background and Objective: Clinical studies have suggested that low tri-iodothyronine (T3) syndrome negatively affects the clinical outcomes of patients with acute heart failure (AHF). The aim of this prospective cohort study was to evaluate the effect of low T3 syndrome in terms of prognosis and risk-predictive potential in AHF. Methods: A prospective observational cohort study was conducted from April 2012 to August 2016 in Nanjing, China. All clinical baseline characteristics were retrieved from electronic medical records. Low T3 syndrome was defined by a low free T3 level (

The primary objective is to find out the epidemiology, characteristics, preparedness, and survival of elderly patients initiated on dialysis from a tertiary center in Sabah. All newly confirmed patients aged 65 and above who were initiated on renal replacement therapy (RRT) from January 1, 2014, to December 31, 2017, were included. There were two groups of patients: Group 1 – optimally prepared for RRT; Group 2 – suboptimally prepared for RRT. Survival outcome was recorded at the 3rd-, 6th-, and 12th-month interval. Diabetes mellitus accounted for majority of the primary cause of end-stage renal disease, 67.3%. The median duration of follow-up was 550 days (interquartile range = 787). There were 81 patients (30.5%) in Group 1. 182 patients (69.2%) in Group 2 were considered as suboptimally prepared for RRT. The survival of this elderly group was 85.6% at 3 months, 74.5% at six months, and 65% at 1 year. Group 2 patients had much poorer survival outcome compared to Group 1 (56% vs. 85.2% at one year, P

This paper is concerned with the electromagnetic theory of characteristic modes for general homogeneous material bodies using surface integral equations (SIEs), which are computationally more efficient than using volume integral equations (VIEs). However, the generalized eigenvalue equations (GEEs) based on SIEs are prone to generate spurious or extra modes, unlike their counterparts based on VIEs. In this work, several variant SIE-based GEEs are proposed to eliminate the spurious/extra modes and improve the numerical performances. These variant GEEs share a common point that the reactive power operator related to the material domain should be removed from the left-hand sides of GEEs by explicitly enforcing the boundary condition, because it seems sensitive to incur unwanted modes. These variant GEEs are diverse in choosing the active power operator related to the material domain on the right-hand sides to suit different medium parameters, which even can be dropped directly for lossless cases. Numerical results show that these variant GEEs do not generate spurious/extra resonant modes in observed frequency range, and at least one of the variants would have acceptable numerical accuracy.

Fungal polyketides (PKs) are one of the largest families of structurally diverse bioactive natural products biosynthesized by multidomain megasynthases, in which thioesterase (TE) domains act as nonequivalent decision gates determining both the shape and the yield of the polyketide intermediate. The endophytic fungus Preussia isomera XL-1326 was discovered to have an excellent capacity for secreting diverse bioactive PKs, i.e., the hot enantiomers (±)-preuisolactone A with antibacterial activity, the single-spiro minimoidione B with α-glucosidase inhibition activity, and the uncommon heptaketide setosol with antifungal activity, which drive us to illustrate how the unique PKs are biosynthesized. In this study, we first reported the genome sequence information of P. isomera. Based on genome mining, we discovered nine transcriptionally active genes encoding polyketide synthases (PKSs), Preu1–Preu9, of which those of Preu3, Preu4, and Preu6 were cloned and functionally characterized due to possessing complete sets of synthetic and release domains. Through heterologous expression in Saccharomyces cerevisiae, Preu3 and Preu6 could release high yields of orsellinic acid (OA) derivatives [3-methylorsellinic acid (3-MOA) and lecanoric acid, respectively]. Correspondingly, we found that Preu3 and Preu6 were clustered into OA derivative synthase groups by phylogenetic analysis. Next, with TE domain swapping, we constructed a novel “non-native” PKS, Preu6-TEPreu3, which shared a very low identity with OA synthase, OrsA, from Aspergillus nidulans but could produce a large amount of OA. In addition, with the use of Preu6-TEPreu3, we synthesized methyl 3-methylorsellinate (synthetic oak moss of great economic value) from 3-MOA as the substrate, and interestingly, 3-MOA exhibited remarkable antibacterial activities, while methyl 3-methylorsellinate displayed broad-spectrum antifungal activity. Taken together, we identified two novel PKSs to biosynthesize 3-MOA and lecanoric acid, respectively, with information on such kinds of PKSs rarely reported, and constructed one novel “non-native” PKS to largely biosynthesize OA. This work is our first step to explore the biosynthesis of the PKs in P. isomera, and it also provides a new platform for high-level environment-friendly production of OA derivatives and the development of new antimicrobial agents.

Sepsis represents a life-threatening organ dysfunction due to an aberrant host response. Of note is that majority of patients have experienced a severe immune depression during and after sepsis, which is significantly correlated with the occurrence of nosocomial infection and higher risk of in-hospital death. Nevertheless, the clinical sign of sepsis-induced immune paralysis remains highly indetectable and ambiguous. Given that, specific yet robust biomarkers for monitoring the immune functional status of septic patients are of prominent significance in clinical practice. In turn, the stratification of a subgroup of septic patients with an immunosuppressive state will greatly contribute to the implementation of personalized adjuvant immunotherapy. In this review, we comprehensively summarize the mechanism of sepsis-associated immunosuppression at the cellular level and highlight the recent advances in immune monitoring approaches targeting the functional status of both innate and adaptive immune responses.

IntroductionThe etiology and risk factor profile of ischemic stroke in young adults are different from those in older patients. However, current etiological classifications are more applicable for the older adults, posing a challenge to the diagnosis of young patients with ischemic stroke. In this study, we applied a modified risk factor categorization previously used in the International Pediatric Stroke Study (IPSS) to describe the risk factor profiles of Chinese young patients with ischemic stroke and explore the sex and age differences in the distribution of risk factors.MethodsThis is a single-center retrospective study. Patients aged 18–50 years with a first-ever ischemic stroke admitted to the Peking Union Medical College Hospital between 2013 and 2020 were consecutively included. The risk factors of patients were collected and divided into 10 categories according to the modified IPSS criteria and the sex and age differences were explored.ResultsA total of 538 patients were enrolled in this study. The median age was 39 years and 62.6% were men. At least one IPSS risk factor category was identified in the 93.3% of all patients. The most common IPSS subtype was atherosclerosis-related risk factors (61.7%), followed by prothrombotic states (27.3%), chronic systemic conditions (24.7%), arteriopathy (16.2%), and cardiac disorders (10.4%). Chronic systemic conditions were more prevalent in patients aged

Abstract Background Allogeneic stem cell transplantation (allo‐HSCT) is the ultimate cure for acute lymphoblastic leukemia (ALL). Aim This study was performed to compare the outcomes of ALL patients receiving busulfan (Bu) with cyclophosphamide (Cy)‐based or total body irradiation (TBI)‐based regimen in a Chinese population. Methods We enrolled 224 adult patients with ALL who received allo‐HSCT at National Taiwan University Hospital between 1997 and 2016. Results The median age at transplantation was 33 years. Before allo‐HSCT, 75.9% of patients attained first or late complete remission. A total of 141 patients (62.9%) received Bu/Cy‐based conditioning, either myeloablative (MA) or reduced‐intensity stem cell transplantation (RIST), and 83 patients received a TBI‐based regimen (MA‐TBI). Patients receiving the MA‐Bu regimen had longer relapse‐free survival (RFS) than those receiving the MA‐TBI regimen (median, 24.1 vs. 6.7 months, p = .044). There was no difference in overall survival (OS, MA‐Bu vs. MA‐TBI vs. RIST‐Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276), treatment‐related mortality (TRM), or incidences of grade 3–4 acute graft‐versus‐host disease (GvHD). Among patients receiving identical GvHD prophylactic regimens, there was no difference between MA‐Bu and MA‐TBI groups regarding the incidence of grade 3–4 acute GvHD, grade 2–4, and all‐grade chronic GvHD. In subgroup analysis, patients receiving oral busulfan had comparable RFS and OS to the intravenous busulfan group (p = .436 and p = .236, respectively), but a higher TRM (25% vs. 9.8%, p = .016). In the multivariable analysis, disease status before allo‐HSCT was the only risk factor impacting RFS and OS. Conclusion In summary, patients receiving Bu/Cy‐based or TBI‐based regimens as conditioning had similar results in terms of OS, TRM, and acute GvHD, whereas the use of myeloablative Bu/Cy resulted in a better RFS. A Bu‐based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Prospective and randomized controlled trials are warranted to validate the long‐term outcomes.

In order to overcome the shortcomings of serious arc drawing and low computational efficiency in the crosswell seismic migration method and the problems of the inaccurate velocity model and sparse distribution of reflection points in the traditional stack imaging method, the article proposes an inverse Fresnel beam XSP-CDP stack imaging method based on first-arrival wave velocity tomography combined with the characteristics of crosswell seismic wave field. Firstly, an accurate crosswell velocity model is established by the first-arrival wave tomography inversion method based on the characteristics of high energy and easy pick-up of the first-arrival wave in crosswell seismic. Secondly, the velocity model is optimized, and the energy contribution weights of effective rays to the receiver point are calculated through the crosswell seismic Fresnel beam wave field forward numerical simulation method. Then, the reflected wave field is dynamically migrated to the reflection points within the first Fresnel zone according to the weight function, and the intensive common reflection point (CRP) gather after normal moveout (NMO) correction is generated. Finally, an appropriate bin is selected for stacking. In this article, the inverse Fresnel beam method is used to decompose the single-channel seismic wave field into the effective reflection points in the Fresnel zone, which makes the fold of the reflection point more uniform and improves the imaging accuracy. The model test and actual data processing results proved the validity and robustness of this method.

Abstract Background Drug resistance is a major obstacle to effective cancer therapy. In order to detect the change in tumor genomic states under drug selection pressure, we use next-generation sequencing technology to investigate the underlying potential mechanisms of drug resistance. Methods In our study, we presented a bladder cancer patient who had been a bona fide responder to first-line gemcitabine plus cisplatin regimen and second-line pazopanib (tyrosine kinase inhibitor (TKI) for FGFR3-TACC3 fusion) but finally had disease progression as an ideal case for showing genomic alteration during drug resistance. We applied whole-exome sequencing and ultra-deep target sequencing to the patient pre- and post- pazopanib resistance. Protein-protein interaction (PPI) network and Gene Ontology (GO) analyses were used to analysis protein interactions and genomic alterations. Patient-derived xenograft (PDX) model was built to test drug sensitivity. Results Twelve mutations scattered in 12 genes were identified by WES pre- pazopanib resistance, while 63 mutations in 50 genes arose post- pazopanib resistance. PPI network showed proteins from multiple epigenetic regulator families were involved post- pazopanib resistance, including subunits of chromatin remodeler SWI/SNF complex ARID1A/1B and SMARCA4, histone acetylation writers CREBBP, histone methylation writer NSD1 and erasers KDM6A/5A. GO enrichment analysis showed pazopanib resistance genes were prominently tagged for chromatin modification, transcription, as well as gland development, leaving genes with the best adaptive FGFR TKI-coping mechanisms. In addition, significantly elevated tumor mutational burden suggested possible utility of immunotherapy. Intriguingly, PDX model suggested that, sensitivity to original chemotherapy regimen (cisplatin) was restored in patient tumor post-pazopanib. Conclusions Epigenetic regulation may play a role in acquired TKI resistance. Our study traced the complete tumor genomic variation course from chemo-resistant but TKI-sensitive to TKI-resistant but chemo-(re) sensitive, revealing the potential complex dynamic drug-driven mechanisms of resistance.

Abstract Background Communication skill is a core competency in neurology residency training. Specific training in this area at the residency level is often lacking, especially regarding difficult conversations. The aim of this study is to evaluate the current state in teaching residents about difficult conversations in 5 Chinese accredited neurology residency training programs and determine whether there is a perceived need for a formalized curriculum in this field. Methods An anonymous, 27-question, cross-sectional online survey addressing difficult conversations for neurological residents were distributed to five grade-A, class-3 hospitals selected from the affiliated teaching hospitals of medical schools qualified to provide neurology residency training in China. Results A total of 182 residents responded to the survey, and the response rate was 67.16% (182/271). Of the participants, 84.6% were female and the average age was 26.8 years. The majority of respondent residents (n = 168; 92.31%) reported being exposed to at least one difficult conversation in their medical careers. Only 43 (23.63%) participants reported having previously received formal communication skills training. In comparison with residents without previous training, those with previous training indicated significantly more confidence (P = 0.003) and were under lower pressure (P = 0.037) in managing difficult conversations. Only 97 (53.3%) residents indicated interest in receiving formal training. Time, lack of enthusiasm, lack of educational materials and faculty expertise were commonly cited barriers to formalized training. Conclusion This survey provides a preliminary assessment of the current status of education on the topic of difficult conversations in five accredited Chinese neurology residency training programs. Our results suggest that there is an unmet need to further develop and implement educational activities by teaching residents to lead difficult conversations. Future efforts should be made to establish and promote a standard and targeted communication curriculum in difficult conversation for Chinese neurological residents.

Abstract Background Delayed post-polypectomy bleeding (PPB) is a major complication of polypectomy. The effect of prophylactic hemoclipping on delayed PPB is uncertain. The aim of this study was to evaluate the effectiveness of prophylactic hemoclipping and identify the risk factors of delayed PPB. Methods Patients with polyps sized 6 to 20 mm underwent snare polypectomy from 2015 to 2017 were retrospectively reviewed. The patients with prophylactic hemoclipping for delayed PPB prevention were included in the clipping group, and those without prophylactic hemoclipping were included in the non-clipping group. The incidence of delayed PPB and time to bleeding were compared between the groups. Multivariate analysis was used to identify the risk factors of delayed PPB. Propensity score matching was used to minimize potential bias. Results After propensity score matching, 612 patients with 806 polyps were in the clipping group, and 576 patients with 806 polyps were in the non-clipping group. There were no significant differences in the incidence of delayed PPB and days to bleeding between two groups (0.8% vs 1.3%, p = 0.4; 3.4 ± 1.94 days vs 4.13 ± 3.39 days, p = 0.94). In the multivariate analysis, the polyp size [Odds ratio (OR):1.16, 95% confidence interval (CI):1.01–1.16, p = 0.03), multiple polypectomies (OR: 4.64, 95% CI:1.24–17.44, p = 0.02) and a history of anticoagulant use (OR:37.52, 95% CI:6.49–216.8, p

Abstract Background There is no current standard rescue treatment for dual drug-resistant strains of Helicobacter pylori (H. pylori). This aim of this study was to investigate the efficacy of rifabutin-based triple therapy for patients infected with dual drug-resistant strains to clarithromycin and levofloxacin. Methods After 2 or 3 H. pylori treatment failures, patients underwent upper endoscopy with tissue biopsies. Phenotypic and genotypic resistances were determined using agar dilution test and polymerase chain reaction with direct sequencing, respectively. Patients infected with dual drug-resistant (clarithromycin and levofloxacin) strains and receiving rifabutin-based triple therapy (rifabutin 150 mg bid, amoxicillin 1 g bid and esomeprazole 40 mg bid for 10 days) were enrolled. Eradication status was determined by 13C-urea breath test 4 weeks after treatment completion. Results A total of 39 patients infected with dual drug-resistant strains were enrolled in this study, with a mean age of 55.9 years. The eradication rate was 79.5% (31/39) (95% confidence intervals: 54.96% ~ 111.40%). Adverse event was reported in 23.1% (9/39) of patients but they were mild and tolerable. In univariate analysis, no factor was identified as an independent predictor of eradication failure. Conclusions Our current study demonstrated that rifabutin-based triple therapy was well tolerated and yielded an acceptable eradication rate for patients infected with dual drug-resistant strains of H. pylori.

Compared to their linear counterparts, cyclic peptides show better biological activities, such as antibacterial, immunosuppressive, and anti-tumor activities, and pharmaceutical properties due to their conformational rigidity. However, cyclic peptides could form numerous putative metabolites from potential hydrolytic cleavages and their fragments are very difficult to interpret. These characteristics pose a great challenge when analyzing metabolites of cyclic peptides by mass spectrometry. This study was to assess and apply a software-aided analytical workflow for the detection and structural characterization of cyclic peptide metabolites. Insulin and atrial natriuretic peptide (ANP) as model cyclic peptides were incubated with trypsin/chymotrypsin and/or rat liver S9, followed by data acquisition using TripleTOF® 5600. Resultant full-scan MS and MS/MS datasets were automatically processed through a combination of targeted and untargeted peak finding strategies. MS/MS spectra of predicted metabolites were interrogated against putative metabolite sequences, in light of a, b, y and internal fragment series. The resulting fragment assignments led to the confirmation and ranking of the metabolite sequences and identification of metabolic modification. As a result, 29 metabolites with linear or cyclic structures were detected in the insulin incubation with the hydrolytic enzymes. Sequences of twenty insulin metabolites were further determined, which were consistent with the hydrolytic sites of these enzymes. In the same manner, multiple metabolites of insulin and ANP formed in rat liver S9 incubation were detected and structurally characterized, some of which have not been previously reported. The results demonstrated the utility of software-aided data processing tool in detection and identification of cyclic peptide metabolites.

Abstract Background Pathogens including duck-origin avian influenza virus (AIV), duck-origin Newcastle disease virus (NDV) and duck Tembusu virus (DTMUV) posed great harm to ducks and caused great economic losses to the duck industry. In this study, we aim to develop a triplex real-time polymerase chain reaction (PCR) assay to detect these three viruses as early as possible in the suspicious duck flocks. Results The detection limit of the triplex real-time PCR for AIV, NDV, and DTMUV was 1 × 101 copies/μL, which was at least 10 times higher than the conventional PCR. In addition, the triplex assay was highly specific, and won’t cross-react with other duck pathogens. Besides, the intra-day relative standard deviation and inter-day relative standard deviation were lower than 4.44% for these viruses at three different concentrations. Finally, a total of 120 clinical samples were evaluated by the triplex real-time PCR, the conventional PCR and virus isolation, and the positive rates for these three methods were 20.83, 21.67, 19.17%, respectively. Taking virus isolation as the gold standard, the diagnostic specificity and positive predictive value of the three viruses were all above 85%, while the diagnostic sensitivity and negative predictive value of the three viruses were all 100%. Conclusion The developed triplex real-time PCR is fast, specific and sensitive, and is feasible and effective for the simultaneous detection of AIV, NDV, and DTMUV in ducks.

Abstract Background Although current guidelines for AKI suggested against the use of furosemide in AKI management, the effect of furosemide on outcomes in real-world clinical settings remains uncertain. The aim of the present study was to investigate the association between furosemide administration and outcomes in critically ill patients with AKI using real-world data. Methods Critically ill patients with AKI were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Propensity score (PS) matched analysis was used to match patients receiving furosemide to those without diuretics treatment. Linear regression, logistic regression model, and Cox proportional hazards model were used to assess the associations between furosemide and length of stay, recovery of renal function, and in-hospital and 90-day mortality, respectively. Results A total of 14,154 AKI patients were included in the data analysis. After PS matching, 4427 pairs of patients were matched between the patients who received furosemide and those without diuretics treatment. Furosemide was associated with reduced in-hospital mortality [hazard ratio (HR) 0.67; 95% CI 0.61–0.74; P

The aim of this study was to investigate the association between nadir platelet count and acute kidney injury (AKI) or 28-day all-cause mortality induced by hemorrhagic shock (HS), and to determine the cutoff value of nadir platelet count in HS clinical practice. This retrospective study included hospitalized patients enrolled in a tertiary-care teaching hospital from January 1, 2010 to December 31, 2015. Clinical data from HS admitted to the intensive care unit (ICU) were evaluated. Nadir platelet count was defined as the lowest values in the first 48 h. Multivariate logistic regression and Cox proportional hazards regression were used to assess the correlation between nadir platelet count and AKI or 28-day all-cause mortality induced by HS, respectively; the area under receiver operating characteristic (AU-ROC) and Youde’s index were used to determine the optimal cutoff value of nadir platelet count. Kaplan-Meier’s method and log-rank test were assessed for the 28-day all-cause mortality in AKI and non-AKI groups. Of 1589 patients screened, 84 patients (mean age,37.1 years; 58 males) were included in the primary analysis in which 30 patients with AKI. Multiple logistic results indicated that nadir platelet count was a risk factor of AKI (OR = 0.71,95% confidence interval [CI] 0.54–0.93, P < 0.05). Cox regression analysis revealed that nadir platelet count was independent risk factors for 28-day all-cause mortality (Hazard ratios [HR]0.89,95%CI 0.76–0.99, P < 0.05). Kaplan-Meier curve showed that 28-day all-cause mortality was significantly higher in patients with AKI than non-AKI (P < 0.001).These results suggest that nadir platelet count in the first 48 h is a new biomarker for AKI and 28-day all-cause mortality induced by HS. Moreover, the risk for AKI and 28-day all-cause mortality in HS patients decreased by 29% and 11%, respectively, for every 10 × 109/L increase in platelet count. Additional studies are needed to investigate whether elevation of nadir platelet count reduces the risk in different genders.

Abstract Sepsis-associated encephalopathy (SAE) is commonly complicated by septic conditions, and is responsible for increased mortality and poor outcomes in septic patients. Uncontrolled neuroinflammation and ischemic injury are major contributors to brain dysfunction, which arises from intractable immune malfunction and the collapse of neuroendocrine immune networks, such as the cholinergic anti-inflammatory pathway, hypothalamic-pituitary-adrenal axis, and sympathetic nervous system. Dysfunction in these neuromodulatory mechanisms compromised by SAE jeopardizes systemic immune responses, including those of neutrophils, macrophages/monocytes, dendritic cells, and T lymphocytes, which ultimately results in a vicious cycle between brain injury and a progressively aberrant immune response. Deep insight into the crosstalk between SAE and peripheral immunity is of great importance in extending the knowledge of the pathogenesis and development of sepsis-induced immunosuppression, as well as in exploring its effective remedies.

The electromagnetic-mechanical wedge brake system (EMWB) is a new structure designed for brake-by-wire system. This structure is composed of a DC motor, an electromagnet device, two wedges, two friction plates, a rotating rod and a brake disk. The presented EMWB system contains two brake actuators such as electromagnetic brake and motor brake. The EMWB system provides a mechanical backup brake model driven by the DC motor when the electromagnetic brake fails. In the braking relief phase, the maximum torque of the DC motor should meet the requirement of separating the friction plates from the brake disk, so the brake performance of EMWB system is simulated with Matlab/Simulink and optimized under the multi-objective constraints, and the simulation results demonstrate that the mechanical backup brake model can meet the brake requirements both for the front axle and the rear axle. Through the multi-objective optimization, the EMWB system can reach an acceptable brake performance and the DC motor can meet the requirement of relieving braking.

This paper proposes a new absorbing boundary condition (ABC) computation approach based on the deep learning technique. Benefited from the sequence dependence feature, the Long Short-Term Memory (LSTM) network is employed to replace the conventional perfectly matched layer (PML) ABC for the Finite-Difference Time-Domain (FDTD) solving process. The newly proposed LSTM based PML model is trained by the electromagnetic field data on the interface of the conventional PML. Different from the conventional PML, the newly proposed model only needs one cell layer as the boundary. Hence, the newly proposed method conveniently reduces both the algorithm's complexity and the area of computation domain of FDTD. Additionally, the newly proposed LSTM based PML model can achieve higher accuracy than the conventional artificial neural network (ANN) based PML, thanks to the sequence dependence feature of the LSTM networks. Numerical examples have illustrated the capability and the accuracy of the proposed LSTM model. The results illustrate that the new method can be compatibly embedded into the FDTD solving process with the high accuracy.

Electromagnetic track brake is increasingly applied to improve emergency braking force together with the main wheel-rail brake system, while larger electromagnetic braking force is demanded. The bottom of pole shoe is designed as the same curved surface like track top in order to achieve a good contact between pole shoe and track and the pole shoe chamfering is also designed to improve electromagnetic attractive force. Three main variables that decide the electromagnetic attractive force are selected in the paper: pole shoe contact width, protection block length and pole shoe length. The reliability of electromagnetic simulation is verified through prototype test and then the electromagnetic attractive force in this study is achieved by electromagnetic simulation. First, the effects of the three variables on electromagnetic attractive force are investigated singly. Then, a uniform design method is employed in this study to further optimize electromagnetic attractive force by researching the interactional effects of the three variables. A regression model is established with pole shoe contact width, protection block length and pole shoe length as the independent variables, and electromagnetic attractive force as the dependent variable. Depending on the regression model, the optimum conditions of the three variables are achieved. In addition, finite element simulation of electromagnetic track brake is developed to investigate electromagnetic attractive force and magnetic field distribution by Ansoft Maxwell. Compared to the existing electromagnetic track brake, the electromagnetic braking force and electromagnetic braking deceleration of the optimized electromagnetic track brake are improved by 6.3% under the optimum conditions, which can greatly improve train safety in emergency. The proposed reinforcement optimizations have two outstanding characteristics. The first is keeping the space usage of electromagnetic track brake unaltered, and the other is its simplicity to conduct.

BackgroundImmune suppression contributes to nosocomial infections (NIs) and poor prognosis in sepsis. Recent studies revealed that CD71+ erythroid cells had unappreciated immunosuppressive functions. This study aimed to investigate the values of CD71+ erythroid cells (CECs) in predicting NIs and prognosis among adult septic patients. The potential factors associated with the expansion of CECs were also explored.MethodsIn total, 112 septic patients and 32 critically ill controls were enrolled. The frequencies of CD71+ cells, CD71+CD235a+ cells, and CD45+ CECs were measured by flow cytometry. The associations between CECs and NIs and 30-day mortality were assessed by ROC curve analysis and Cox and competing-risk regression models. Factors associated with the frequency of CECs were identified by linear regression analysis.ResultsThe percentage of CD71+ cells, CECs, and CD45+ CECs were higher in septic patients than critically ill controls. In septic patients, the percentages of CD71+ cells, CECs, and CD45+ CECs were associated with NI development, while CD71+ cells and CECs were independently associated with 30-day mortality. Linear regression analysis showed that the levels of interleukin (IL)-6 and interferon (IFN)-γ were positively associated with the frequencies of CD71+ cells, CECs, and CD45+ CECs, while IL-10 was negatively associated with them. Additionally, the levels of red blood cells (RBCs) were negatively associated with the percentage of CD45+ CECs.ConclusionsCECs were expanded in sepsis and can serve as independent predictors of the development of NI and 30-day mortality. Low levels of RBCs and high levels of IL-6 and IFN-γ may contribute to the expansion of CECs in sepsis.Trial RegistrationChiCTR, ChiCTR1900024887. Registered 2 August 2019, http://www.chictr.org.cn/showproj.aspx?proj=38645

Efferocytosis is the effective clearance of apoptotic cells by professional and non-professional phagocytes. The process is mechanically different from other forms of phagocytosis and involves the localization, binding, internalization, and degradation of apoptotic cells. Defective efferocytosis has been demonstrated to associate with the pathogenesis of various inflammatory disorders. In the current review, we summarize recent findings with regard to efferocytosis networks and discuss the relationship between efferocytosis and different immune cell populations, as well as describe how efferocytosis helps resolve inflammatory response and modulate immune balance. Our knowledge so far about efferocytosis suggests that it may be a useful target in the treatment of numerous inflammatory diseases.

Accumulating studies have highlighted the biologic significances of ferroptosis modification in tumor progression, but little is known whether ferroptosis modification patterns have potential roles in tumor microenvironment (TME) immune cell infiltration of hepatocellular carcinoma (HCC). In this study, we evaluated 51 ferroptosis regulators and performed consensus clustering algorithm to determine ferroptosis modification patterns and the ferroptosis related gene signature in HCC. Gene set variation analysis (GSVA) was employed to explore biological molecular variations in distinct ferroptosis modification patterns. Single sample gene set enrichment analysis (ssGSEA) algorithm was performed to quantify the relative infiltration levels of various immune cell subsets. Principal component analysis (PCA) algorithm was used to construct the ferroptosisSig score to quantify ferroptosis modification patterns of individual tumors with immune responses. Three distinct ferroptosis modification patterns were identified. GSVA enrichment analysis indicated that three ferroptosis modification subgroups were enriched in different metabolic pathways. ssGSEA analysis determined that 19 of 24 immune infiltrating cells had significant differences in three distinct ferroptosis patterns. A 91-ferroptosis gene signature was constructed to stratify patients into two ferroptosisSig score groups. Patients in the higher ferroptosisSig score were characterized by significantly prolonged survival time compared with patients in the lower ferroptosisSig score group (p < .0001). An immunotherapy cohort confirmed patients with higher ferroptosisSig score determined significant therapeutic advantages and clinical benefits. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of anti-PD/L1 immunotherapy by ferroptosisSig score. Our study indicated the ferroptosis modification played a significant role in TME heterogeneity and complexity. Evaluating the ferroptosis modification pattern of individual tumor could strengthen our cognition of TME infiltration characteristics and guide more effective clinic immunotherapy strategies.