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Abstract VEXAS syndrome, an uncommon yet severe autoimmune disorder stemming from a mutation in the UBA1 gene, is the focus of this paper. The overview encompasses its discovery, epidemiological traits, genetic underpinnings, and clinical presentations. Delving into whether distinct genotypes yield varied clinical phenotypes in VEXAS patients, and the consequent adjustment of treatment strategies based on genotypic and clinical profiles necessitates thorough exploration within the clinical realm. Additionally, the current therapeutic landscape and future outlook are examined, with particular attention to the potential therapeutic roles of IL-6 inhibitors and JAK inhibitors, alongside an elucidation of prevailing limitations and avenues for further research. This study contributes essential theoretical groundwork and clinical insights for both diagnosing and managing VEXAS syndrome.

Background Miliary Tuberculosis (TB) remains an important infectious disease that threatens human health. The clinical characteristics and prognostic factors of miliary TB are summarized in this study.Methods The clinical information of miliary TB patients between 2010 and 2022 was retrospectively analyzed. Patients with miliary TB were characterized and compared to adverse outcomes cases. Factors independently associated with adverse outcomes were determined via multivariate logistic regression analysis.Results A total of 288 patients were analyzed, including 181 with adverse outcomes. The clinical manifestations are atypical. 88.54% Of them experienced systemic symptoms, whilst 69.79% manifested respiratory symptoms. 40.97% Presented with neurologic symptoms, while 35.07% reported gastrointestinal symptoms. The major comorbidities were pharmacological immunosuppression (21.53%), pneumoconiosis (15.28%), diabetes (10.76%), and pregnancy or postpartum (7.29%). Regarding microbiology, most patients were diagnosed via sputum or Bronchoalveolar Lavage Fluid (BALF), pleural effusion, ascites, cerebrospinal fluid, urine TB-DNA, and tuberculosis culture. Meanwhile, 2.43% of patients were diagnosed via cerebrospinal fluid NGS. Independent risk factors predictive of adverse outcomes were current smoking, leukocytosis, elevated alanine aminotransferase (ALT) levels, and the combination of lymphopenia with bone marrow tuberculosis or tuberculous lymphadenitis. The accuracy of the model was validated by an area under the ROC curve of 0.753 (95% IC 0.697–0.810).Conclusions The clinical manifestations of miliary TB are atypical, and early diagnosis is challenging. The major comorbidities in miliary TB patients were pharmacological immunosuppression, pneumoconiosis, diabetes, pregnancy, and postpartum. Regarding etiological detection, multi-site and multi-type specimens should be collected for a timely diagnosis. Cerebrospinal fluid mNGS test may be a viable choice in some cases. Finally, current smoking, leukocytosis, elevated ALT levels, and the combination of lymphopenia with bone marrow tuberculosis or tuberculous lymphadenitis were identified as independent risk factors for adverse outcomes.

Abstract Objectives The recommended treatment for limited‐stage small‐cell lung cancer (LS‐SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4–6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS‐SCLC who received either 6 cycles or 4–5 cycles of EP chemotherapy combined with TRT. Materials and Methods In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS‐SCLC patients who received 4–6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4–5 cycles. To assess overall survival (OS) and progression‐free survival (PFS), we employed the Kaplan–Meier method after conducting propensity score matching (PSM). Results Among the 265 LS‐SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4–5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4–5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6–53.1 months) vs. 22.7 months (95% CI, 20.8–29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7–30.5 months) vs. 12.0 months (95% CI, 9.8–14.2 months), respectively, p = 0.006]. The two‐year and five‐year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4–5 cycles group, respectively. Conclusion Patients diagnosed with LS‐SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4–5 cycles.

IntroductionTilia miqueliana is an endemic species whose population is declining. The permeability barrier and mechanical constraint of the pericarp (seed coat) are important causes of its seed dormancy. Although there has been considerable research on this subject, questions remain regarding how the permeability barrier and mechanical constraint of the seed coat are eliminated during dormancy release and how water enters the seed. Therefore, protecting the species by improving its germination/dormancy breaking in the laboratory is urgentMethodsIn this study, the changes in the cellular structure, mechanical properties, and components of the Tilia miqueliana seed coat after an H2SO4-gibberellic acid (GA3) treatment were analyzed during dormancy release. Various analyses (e.g., magnetic resonance imaging, scanning electron microscopy, and paraffin section detection) revealed the water gap and water channel.ResultsThe H2SO4 treatment eliminated the blockage at the micropyle and hilum of the seeds. Water entered the seeds through the water gap (micropyle) rather than through the hilum or seed coat, after which it dispersed along the radicle, hypocotyl, and cotyledon to the endosperm. During the cold stratification period, the cellular structure was damaged and an increasing number of holes appeared on the inner and outer surfaces of the seed coat. Vickers hardness tests showed that GA3 decreased the seed coat hardness. Additionally, the seed coat lignin and total phenol contents continuously decreased during the cold stratification period. Notably, the Liquid chromatography–mass spectrometry (LC–MS) analysis of the seed coat detected polyethylene glycol (osmoregulator), which may have destabilized the water potential balance inside and outside the seed and increased the water content to levels required for germination, ultimately accelerating seed dormancy release.DiscussionThis sophisticated and multi-level study reveals how H2SO4 and GA3 eliminate the permeability barrier and mechanical constraints of the seed coat during dormancy release of Tilia miqueliana seeds. This will be beneficial to artificially assist the natural regeneration and population expansion of Tilia miqueliana.

Epidural electrical stimulation is a new treatment method for spinal cord injury (SCI). Its efficacy and safety have previously been reported. Rehabilitation treatment after epidural electrical stimulation is important to ensure and improve the postoperative efficacy of epidural electrical stimulation in patients with SCI. Considering that electromyography (EMG)-induced rehabilitation treatment can accurately match the muscle contraction of patients with SCI, we designed a study protocol for a prospective, randomized controlled trial. In this trial, on the premise of adjusting the spinal cord electrical stimulator to obtain the maximum EMG signal of the target muscle, patients with SCI receiving epidural electrical stimulation will undergo EMG-induced rehabilitation treatment. Recovery of muscle strength of key muscles, quality of life, safety and therapeutic effects will be monitored. Twenty patients with SCI who are scheduled to undergo epidural electrical stimulation in Shanghai Ruijin Rehabilitation Hospital will be randomly divided into two groups with 10 patients per group. The control group will receive conventional rehabilitation treatment. The EMG-induced rehabilitation group will receive EMG-induced rehabilitation treatment of the target muscles of the upper and lower limbs based on conventional rehabilitation treatment. After rehabilitation treatment, follow up for all patients will occur at 2 weeks and 1, 3 and 6 months. The primary outcome measure of this trial will be evaluation of target muscle recovery using the Manual Muscle Testing grading scale. Secondary outcome measures will include modified Barthel Index scores, integrated EMG values, the visual analogue scale, Spinal Cord Independence Measure scores, and modified Ashworth scale scores. The safety indicator will be the incidence of adverse events. This trial will collect data regarding the therapeutic effects of EMG-induced rehabilitation in patients with SCI receiving epidural electrical stimulation for 6 months after rehabilitation treatment. Findings from this trial will help develop rehabilitation methods in patients with SCI after epidural electrical stimulation. This study protocol was approved by Ethics Committee of Shanghai Ruijin Rehabilitation Hospital (Approval No. RKIRB2022-12) on February 15, 2022 and was registered with Chinese Clinical Trial Registry (registration number: ChiCTR2200061674; date: June 30, 2022). Study protocol version: 1.0.

IntroductionCryo treatment of dry seeds is known to attenuate the structure of fruit and seed coats, but little is known about the microstructural impacts of such treatment. The seeds of Tilia miqueliana are dispersed within a hard pericarp, the manual removal (hulling) of which is time-consuming and inefficient. Rapid hulling technology is urgently needed for sustainable production and convenience of edible nuts.MethodsWe explored the mechanistic basis of liquid nitrogen (N)-treatment weakening of the pericarp of T. miqueliana fruits using a range of microscopical, biophysical and chemical approaches.ResultsLiquid N treatment (40 s) resulted in lower pericarp contents of cellulose and hemicellulose, and increased amounts of lignin. Profound changes in cell structure and mechanical properties included the emergence of large holes and gaps between the mesocarp and endocarp cells. Also, the toughness of the pericarp decreased, whilst the hardness and brittleness increased, thereby changing the fracture type from ductile to brittle. Liquid N treatment of dry fruits followed by tapping with a hammer, reduced the number of damaged seeds three-fold and pericarp peeling time four-fold compared with manual hulling, whilst seed viability was not negatively affected.DiscussionComparable findings for the efficient and economical removal of hard covering structures from dispersal units of five more species from three other families following liquid N treatment indicates the potential application of our findings to large-scale production of seeds and seedlings for breeding, forestry and conservation/restoration purposes. Furthermore, it introduces a novel concept for postharvest treatment and pre-treatment of deep processing in nuts.

ObjectiveTo evaluate the predictive value of tumor regression grade assessed by MRI (mr-TRG) after neoadjuvant chemoradiotherapy (neo-CRT) for postoperative pathological TRG (pTRG) and prognosis in patients with locally advanced rectal adenocarcinoma (LARC).Materials and methodsThis was a retrospective study from a single center experience. The patients who were diagnosed with LARC and received neo-CRT in our department between January 2016 and July 2021 were enrolled. The agreement between mrTRG and pTRG was assessed with the weighted κ test. Overall survival (OS), progress-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier analysis and log-rank test.ResultsFrom January 2016 to July 2021, 121 LARC patients received neo-CRT in our department. Among them, 54 patients had complete clinical data, including MRI of pre- and post-neo-CRT, postoperative tumor samples, and follow-up. The median follow-up time was 34.6 months (range: 4.4-70.6 months). The estimated 3-year OS, PFS, LRFS and DMFS were 78.5%, 70.7%, 89.0%, and 75.2%, respectively. The median time from the completion of neo-CRT to preoperative MRI and surgery was 7.1 weeks and 9.7 weeks, respectively. Out of 54 patients, 5 patients achieved mrTRG1 (9.3%), 37 achieved mrTRG2 (68.5%), 8 achieved mrTRG3 (14.8%), 4 achieved mrTRG4 (7.4%), and no patient achieved mrTRG5 after neo-CRT. Regarding pTRG, 12 patients achieved pTRG0 (22.2%), 10 achieved pTRG1 (18.5%), 26 achieved pTRG2 (48.1%), and 6 achieved pTRG3 (11.1%). The agreement between three-tier mrTRG (mrTRG1 vs. mrTRG2-3 vs. mrTRG4-5) and pTRG (pTRG0 vs. pTRG1-2 vs. pTRG3) was fair (weighted kappa=0.287). In a dichotomous classification, the agreement between mrTRG(mrTRG1 vs. mrTRG2-5)and pTRG(pTRG0 vs. pTRG1-3) also resulted in fair agreement (weighted kappa=0.391). The sensitivity, specificity, positive, and negative predictive values of favorable mrTRG (mrTRG 1-2) for pathological complete response (PCR) were 75.0%, 21.4%, 21.4%, and 75.0%, respectively. In univariate analysis, favorable mrTRG (mrTRG1-2) and downstaging N were significantly associated with better OS, while favorable mrTRG (mrTRG1-2), downstaging T, and downstaging N were significantly associated with superior PFS (p

This paper proposes estimating linear dynamic panels by explicitly exploiting the endogeneity of lagged dependent variables and expressing the crossmoments between the endogenous lagged dependent variables and disturbances in terms of model parameters. These moments, when recentered, form the basis for model estimation. The resulting estimator’s asymptotic properties are derived under different asymptotic regimes (large number of cross-sectional units or long time spans), stable conditions (with or without a unit root), and error characteristics (homoskedasticity or heteroskedasticity of different forms). Monte Carlo experiments show that it has very good finite-sample performance.

ObjectiveTo investigate the prognosis of patients with LS-SCLC who responded to chest chemoradiotherapy but did not receive PCI.MethodsA retrospective analysis was conducted on LS-SCLC patients who had achieved complete remission (CR) or partial remission (PR) after definitive chemoradiotherapy but did not receive PCI. The survival rates were calculated using Kaplan–Meier method. The prognosis was analyzed using Cox proportional hazard regression model. The main endpoint was OS.ResultsOf the 500 patients with LS-SCLC admitted between June 2002 and January 2018, 327 achieved CR or PR after definitive chest chemoradiotherapy, 103 did not receive PCI, and 63 of them developed brain metastases (BM). The 1-year and 3-year OS rates in PCI group were 87.5% and 42.3% respectively, versus 70.4% and 20.9% for non-PCI group(P=0.002). The median survival time after BM was 8.7 months (range: 0.3-48.7), and 3-year OS rate was 15.0%, the median survival time of patients without BM was 20.1 months (range: 2.9-79.4), and 3-year OS was 33.4% (P=0.014). Patients with BM were subsequently treated with palliative therapy. Multivariate analysis showed that compared with no treatment, brain radiotherapy alone (HR: 0.131, 95%CI: 0.035-0.491, P=0.003) and radiotherapy combined with chemotherapy (HR: 0.039, 95%CI: 0.008-0.194, P

BackgroundHemiplegic shoulder pain is the most common complication after stroke. It usually occurs during the critical period of stroke recovery and hinders the rehabilitation of upper extremity motor function. However, there are few studies on the risk factors, the development and prognosis of shoulder pain after stroke.ObjectivesThis study aimed to observe the prevalence of post-stroke shoulder pain in the middle-aged and elderly population, find out the risk factors for post-stroke shoulder pain, and explore its effect on stroke outcome.MethodsEligible patients with hemiplegic shoulder pain in the rehabilitation unit were recruited and followed up at 2 and 4 months. The basic clinical information including age, gender, hypertension and atrial fibrillation history, stroke types, stroke location was recorded. Range of motion for shoulder, glenohumeral subluxation, muscle tension, activity of daily living of upper limb were measured. Data from blood test and shoulder ultrasonography were collected.Results480 stroke patients were screened within 1 year, and 239 patients were included in the statistical analysis. The prevalence of hemiplegic shoulder pain was 55.6% (133/239) at admission, 59.4% (142/239) after 2 months, and 55.1% (130/236) after 4 months. We found that shoulder pain was more likely to occur in women, patients with large-area stroke, increased tension of biceps brachii or triceps brachii, subluxation and limited passive range of motion of the shoulder. And the ability of daily living of patients with shoulder pain was significantly lower than that of patients without shoulder pain. Shoulder ultrasonography showed that the most common lesion in patients with shoulder pain was supraspinatus tendon thickening, and the thickness of supraspinatus tendon in the hemiplegic side of patients with shoulder pain was significantly higher than that of unaffected side. In addition, the hospitalization rate of patients with shoulder pain after 2 months and 4 months was significantly higher than that without shoulder pain.ConclusionsHemiplegic shoulder pain has a high prevalence and can last for several months. Multiple risk factors are involved. Moreover, hemiplegic shoulder pain affects the readmission rate of patients. Therefore, we should pay more attention to this problem in our clinical work. The application of various means to relieve shoulder pain will be conducive to the recovery of upper limb motor function and shorten the in-hospital rehabilitation time.

Purpose: To evaluate the effect of the 21-gene recurrence score (RS) assay in breast cancer-specific mortality (BCSM) and decision-making for chemotherapy in older (aged ≥65 years) breast cancer. Methods: We retrospectively included older patients with T1-2N0 and estrogen receptor-positive breast cancer in the Surveillance, Epidemiology, and End Results database. Cox regression model and competing-risks model were used for data analysis. Results: This study included 8524 patients, 1987 (23.3%) had low RS, 5059 (59.4%) had intermediate RS, and 1478 (17.3%) had high RS. Chemotherapy was administrated in 2.0%, 8.6%, and 51.2% for low, intermediate, and high RS cohorts, respectively (P

Abstract Background Non-invasive brain stimulation techniques have been shown in several studies to improve the motor recovery of the affected upper-limbs in stroke patients. This study aims to investigate whether or not cathodal transcranial direct current stimulation (c-tDCS), combined with virtual reality (VR), is superior to VR alone in reducing motor impairment and improving upper limb function and quality of life in stroke patients. Methods Forty patients who suffered ischemic stroke between 2 weeks to 12 months were recruited for this single-blind randomized control trial. The patients were randomly assigned either to an experimental group who receiving c-tDCS and VR, or a control group receiving sham stimulation and VR. The cathodal electrode was positioned over the primary motor cortex (M1) of the unaffected hemisphere. The treatment session consisted of 20 min of daily therapy, for 10 sessions over a 2-week period. The outcome measures were the Fugl-Meyer Upper Extremity (FM-UE), the Action Research Arm Test (ARAT) and the Barthel Index (BI). Results The two groups were comparable in demographic characteristic and motor impairment. After 2 weeks of intervention, both groups demonstrated significant improvement in FM-UE, ARAT and BI scores (P

Abstract Background Soybean cyst nematode (SCN), Heterodera glycines Ichinohe, has been one of the most devastating pathogens affecting soybean production. In the United States alone, SCN damage accounted for more than $1 billion loss annually. With a narrow genetic background of the currently available SCN-resistant commercial cultivars, high risk of resistance breakdown can occur. The objectives of this study were to conduct a genome-wide association study (GWAS) to identify QTL, SNP markers, and candidate genes associated with soybean leaf chlorophyll content tolerance to SCN infection, and to carry out a genomic selection (GS) study for the chlorophyll content tolerance. Results A total of 172 soybean genotypes were evaluated for the effect of SCN HG Type 1.2.3.5.6.7 (race 4) on soybean leaf chlorophyll. The soybean lines were genotyped using a total of 4089 filtered and high-quality SNPs. Results showed that (1) a large variation in SCN tolerance based on leaf chlorophyll content indices (CCI); (2) a total of 22, 14, and 16 SNPs associated with CCI of non-SCN-infected plants, SCN-infected plants, and reduction of CCI SCN, respectively; (3) a new locus of chlorophyll content tolerance to SCN mapped on chromosome 3; (4) candidate genes encoding for Leucine-rich repeat protein, plant hormone signaling molecules, and biomolecule transporters; and (5) an average GS accuracy ranging from 0.31 to 0.46 with all SNPs and varying from 0.55 to 0.76 when GWAS-derived SNP markers were used across five models. This study demonstrated the potential of using genome-wide selection to breed chlorophyll-content-tolerant soybean for managing SCN. Conclusions In this study, soybean accessions with higher CCI under SCN infestation, and molecular markers associated with chlorophyll content related to SCN were identified. In addition, a total of 15 candidate genes associated with chlorophyll content tolerance to SCN in soybean were also identified. These candidate genes will lead to a better understanding of the molecular mechanisms that control chlorophyll content tolerance to SCN in soybean. Genomic selection analysis of chlorophyll content tolerance to SCN showed that using significant SNPs obtained from GWAS could provide better GS accuracy.

Abstract Rationale Our pilot study suggested that noninvasive ventilation (NIV) reduced the need for intubation compared with conventional administration of oxygen on patients with “early” stage of mild acute respiratory distress syndrome (ARDS, PaO2/FIO2 between 200 and 300). Objectives To evaluate whether early NIV can reduce the need for invasive ventilation in patients with pneumonia-induced early mild ARDS. Methods Prospective, multicenter, randomized controlled trial (RCT) of NIV compared with conventional administration of oxygen through a Venturi mask. Primary outcome included the numbers of patients who met the intubation criteria. Results Two hundred subjects were randomized to NIV (n = 102) or control (n = 98) groups from 21 centers. Baseline characteristics were similar in the two groups. In the NIV group, PaO2/FIO2 became significantly higher than in the control group at 2 h after randomization and remained stable for the first 72 h. NIV did not decrease the proportion of patients requiring intubation than in the control group (11/102 vs. 9/98, 10.8% vs. 9.2%, p = 0.706). The ICU mortality was similar in the two groups (7/102 vs. 7/98, 4.9% vs. 3.1%, p = 0.721). Multivariate analysis showed minute ventilation greater than 11 L/min at 48 h was the independent risk factor for NIV failure (OR, 1.176 [95% CI, 1.005–1.379], p = 0.043). Conclusions Treatment with NIV did not reduce the need for intubation among patients with pneumonia-induced early mild ARDS, despite the improved PaO2/FIO2 observed with NIV compared with standard oxygen therapy. High minute ventilation may predict NIV failure. Trial registration NCT01581229. Registered 19 April 2012

With the advantages of high accuracy, high spatial resolution, and long measurement range, LiDAR is considered as the most suitable measurement technique to deliver quantitative imaging of wind fields. However, for complex wind fields, such as monitoring wind turbine wakes where both the temporal resolution and reconstruction speed are of great significance, the conventional LiDAR system lacks the temporal resolution to capture the fast changes of wind turbine wake fields. In this paper, a novel dynamic wind retrieval method is developed to improve temporal resolution using the unsynchronised dual-LiDAR scanning scheme. By exploiting the temporal redundancy information of the LiDAR Line-of-Sight (LoS) data in successive frames, a reduced number of LiDAR scanning points is required for the 2D horizontal wind field retrieval with the help of unsynchronised dual-LiDAR wind scanning scheme, low-rank data up-sampling and a divergence-free regularised wind retrieval algorithm. Numerical simulation is performed to validate the proposed method. Results show that the temporal resolution of LiDAR wind retrieval can be improved by a factor of 2 to 8 and provide acceptable results with good spatial resolution.

Association of both iron/hepcidin and apolipoprotein E (ApoE) with development of Alzheimer disease (AD) and atherosclerosis led us to hypothesize that ApoE might be required for body iron homeostasis. Here, we demonstrated that ApoE knock-out (KO) induced a progressive accumulation of iron with age in the liver and spleen of mice. Subsequent investigations showed that the increased iron in the liver and spleen was due to phosphorylated extracellular regulated protein kinases (pERK) mediated up-regulation of transferrin receptor 1 (TfR1), and nuclear factor erythroid 2-related factor-2 (Nrf2)-dependent down-regulation of ferroportin 1. Furthermore, replenishment of ApoE could partially reverse the iron-related phenotype in ApoE KO mice. The findings imply that ApoE may be essential for body iron homeostasis and also suggest that clinical late-onset diseases with unexplained iron abnormality may partly be related to deficiency or reduced expression of ApoE.

Due to the unsatisfactory robustness of current predictive biomarkers in many cases, application of immunotherapy in advanced cancers with limited treatment options, such as stage IV intrahepatic cholangiocarcinoma (ICC), was quite common. Hence, strategies to enhance the therapeutic effect of immunotherapy or to extend the scope of potential beneficial patients were urgently needed. Combination of radiotherapy and anti-programmed death receptor-1 (PD-1) immunotherapy was a promising one, since they were found to have a synergistic anti-tumor effect in animal models and a couple of patients. We here present a 68-years-old male with chemotherapy-intolerable stage IV ICC, whose primary tumor had low PD-L1 expression level, scarce CD8+ cells in tumor microenvironment, high microsatellite instability (MSI), and high tumor mutation burden (TMB). These biomarkers showed a conflicting prediction of the treatment response and clinical benefit of anti-PD-1 immunotherapy. Combination therapy of anti-PD-1 immunotherapy and radiotherapy was adopted as first-line treatment for the patient. After six cycles of immunotherapy, shrinkage of the primary liver tumor and metastatic lymph nodes happened, alongside with new lung metastasis, which indicated a mixed response. Radiotherapy was then administered to both the liver and lung lesions, accompanied with continued immunotherapy. The combined therapy eventually led to a complete response for both the primary tumor and all metastases without treatment-related adverse effects. The patient has survived for 26 months after the combined therapy and remains tumor-free currently. This case demonstrates the high inconsistency between immunotherapy response biomarkers and the synergetic anti-tumor effect of immunotherapy and radiotherapy in ICC.

Soybean cyst nematode (SCN), Heterodera glycines Ichinohe, is one of the most devastating pathogens affecting soybean production in the U.S. and worldwide. The use of SCN-resistant soybean cultivars is one of the most affordable strategies to cope with SCN infestation. Because of the limited sources of SCN resistance and changes in SCN virulence phenotypes, host resistance in current cultivars has increasingly been overcome by the pathogen. Host tolerance has been recognized as an additional tool to manage the SCN. The objectives of this study were to conduct a genome-wide association study (GWAS), to identify single nucleotide polymorphism (SNP) markers, and to perform a genomic selection (GS) study for SCN tolerance in soybean based on reduction in biomass. A total of 234 soybean genotypes (lines) were evaluated for their tolerance to SCN in greenhouse using four replicates. The tolerance index (TI = 100 × Biomass of a line in SCN infested / Biomass of the line without SCN) was used as phenotypic data of SCN tolerance. GWAS was conducted using a total of 3,782 high quality SNPs. GS was performed based upon the whole set of SNPs and the GWAS-derived SNPs, respectively. Results showed that (1) a large variation in soybean TI to SCN infection among the soybean genotypes was identified; (2) a total of 35, 21, and 6 SNPs were found to be associated with SCN tolerance using the models SMR, GLM (PCA), and MLM (PCA+K) with 6 SNPs overlapping between models; (3) GS accuracy was SNP set-, model-, and training population size-dependent; and (4) genes around Glyma.06G134900, Glyma.15G097500.1, Glyma.15G100900.3, Glyma.15G105400, Glyma.15G107200, and Glyma.19G121200.1 (Table 4). Glyma.06G134900, Glyma.15G097500.1, Glyma.15G100900.3, Glyma.15G105400, and Glyma.19G121200.1 are best candidates. To the best of our knowledge, this is the first report highlighting SNP markers associated with tolerance index based on biomass reduction under SCN infestation in soybean. This research opens a new approach to use SCN tolerance in soybean breeding and the SNP markers will provide a tool for breeders to select for SCN tolerance.

Esophageal squamous cell carcinoma (ESCC) is a frequent malignant tumor with low 5-year overall survival. Targeting ESCC tumor-initiating cells (TICs) may provide a new research avenue to achieve better therapeutic effects of ESCC. However, the identity and characteristics of ESCC TICs remain poorly understood. Through genetic lineage tracing approach, we found that a group of Moloney murine leukemia virus insertion site 1- (Bmi1-) expressing cell populations present in the invasive front of the esophageal epithelium, providing a continuous flow of tumor cells for ESCC. Subsequently, we found that ablation of Bmi1+ cells from mice with ESCC led to inhibition of tumor growth. In addition, our results demonstrated that PTC-209, an inhibitor of Bmi1, was able to inhibit ESCC progression when combined with cisplatin. In summary, our data suggest that Bmi1+ cells serve as TICs in ESCC.

Abstract Despite advances in diagnosis and treatment, the existence of cervical lymph node carcinoma of unknown primary site (CCUP) has always been an urgent problem worldwide. There is still no consensus on the optimal management for CCUP. In this retrospective review, we analyze the clinical characteristics of CCUP patients treated at our institution and examine how these characteristics and treatments were associated with survival. Clinicopathologic features, treatments, and survival outcomes of 154 CCUP patients were collected from the hospital records and analyzed. Survival was estimated by Kaplan–Meier methods and compared by the log‐rank test. Cox proportional hazards regression analysis was used to assess the factors independently associated with overall survival (OS) and progression‐free survival (PFS). Median follow‐up period was 26.44 months (range, 0.53–146.53 months). Multivariate analysis showed N stage, pathologic type, and lymph node extranodal extension (ENE) to be independent prognostic factors for OS in CCUP patients, but not PFS. Subgroup analysis of patients who received radiotherapy showed that radiotherapy to the pharyngeal mucosa was associated with better OS (P = 0.045), but not with better PFS. Advanced N stage, nonsquamous cell carcinoma, and lymph node ENE predict poor prognosis in patients with CCUP. In addition, radiotherapy to suspicious mucosa is accompanied by better OS. These study findings should be useful to clinicians when selecting the treatment approach.

Abstract Circulating plasma Epstein–Barr virus DNA (EBV DNA) is related to tumor recurrence and metastasis and has potential as a dynamic, sensitive, and specific marker in nasopharyngeal carcinoma (NPC). We investigated the clinical significance of assessing plasma EBV DNA load at various time points during treatment. Patients with NPC (n = 949) for whom plasma EBV DNA load was measured by real‐time quantitative polymerase chain reaction (RT‐qPCR) before treatment (pre‐EBV) and at midtreatment (mid‐EBV), end of treatment (end‐EBV), and 3 months after completing treatment (3 m‐EBV) were retrospectively assessed. Receiver operating characteristic (ROC) curve analysis was used to identify the optimal EBV DNA cutoff point for each time point. Overall survival (OS), distant metastasis‐free survival (DMFS), and progression‐free survival (PFS) were compared using Kaplan–Meier estimates. High pre‐EBV, high mid‐EBV, high end‐EBV, and high 3 m‐EBV were all associated with significantly poorer OS, DMFS, and PFS in the entire cohort. Detectable end‐EBV and 3 m‐EBV was associated with significantly poorer OS, DMFS, and PFS. Among patients with detectable end‐EBV, adjuvant therapy significantly improved OS (HR 2.419; 95% CI 1.297–4.51, P = 0.03) and DMFS (HR 2.45; 95% CI 1.243–4.828, P = 0.04), but not PFS (P = 0.17). EBV DNA represents a dynamic biomarker for monitoring treatment and predicting survival in NPC. Assessing plasma EBV DNA before, during, and after chemoradiotherapy could be clinically valuable and enable selection of patients most likely to benefit from additional therapy and improve assessment of treatment response and disease surveillance. Further multicenter prospective investigations are warranted.

Triple-negative breast cancer (TNBC) was regarded as the most aggressive and mortal subtype of breast cancer (BC) since the molecular subtype system has been established. Abundant studies have revealed that epithelial-mesenchymal transition (EMT) played a pivotal role during breast cancer metastasis and progression, especially in TNBC. Herein, we showed that inhibition the expression of replication factor C subunit 3 (RFC3) significantly attenuated TNBC metastasis and progression, which was associated with EMT signal pathway. In TNBC cells, knockdown of RFC3 can down-regulate mesenchymal markers and up-regulate epithelial markers, significantly attenuated cell proliferation, migration and invasion. Additionally, silencing RFC3 expression can decrease nude mice tumor volume, weight and relieve lung metastasis in vivo. Furthermore, we also demonstrated that overexpression of RFC3 in TNBC showed increased metastasis, progression and poor prognosis. We confirmed all of these results by immunohistochemistry analysis in 127 human TNBC tissues and found that RFC3 expression was significantly associated with poor prognosis in TNBC. Taken all these findings into consideration, we can conclude that up-regulation of RFC3 promotes TNBC progression through EMT signal pathway. Therefore, RFC3 could be an independent prognostic factor and therapeutic target for TNBC.

PURPOSE: The incidence of sensorineural hearing loss (SNHL) after treatment with combination of intensity-modulated radiation therapy (IMRT) and cisplatin-based chemotherapy in nasopharyngeal carcinoma (NPC) patients was evaluated, and relationships of SNHL with host factors, treatment-related factors, and radiation dosimetric parameters were investigated. METHODS: Fifty-one NPC patients treated with IMRT from 2004 to 2009 were analyzed. All patients received neoadjuvant, concurrent, or adjuvant use of cisplatin. Pure tone audiometry was performed during the follow-up period with a median time of 60 months, ranging from 28 to 84 months. Correlation of SNHL at low frequencies (pure tone average, 0.5-2 kHz) with a series of factors was analyzed. RESULTS: Among 102 ears, 12.7% had low-frequency SNHL and 42.2% had high-frequency (4 kHz) SNHL. The incidence of low-frequency SNHL was greater in patients with age > 40, with T-stage 4, or who received cumulative cisplatin dose (CCD) > 200 mg/m2 (P = .034, .011, and .003, respectively) and in ears with secretory otitis media (SOM) (P = .002). Several dosimetric parameters were found to be correlated with SNHL. Univariate analysis showed that the minimum radiation dose to 0.1 ml highest dose volume (D0.1 ml) of the cochlea was the best radiation-related predictive parameter. Multivariate analysis indicated that CCD, SOM, and D0.1 ml of cochlea (P = .035, .012, and .022, respectively) were the factors associated with SNHL. CONCLUSION: For NPC patients treated with IMRT and chemotherapy, the incidence of treatment-related SNHL was associated with CCD, D0.1 ml of cochlea, and SOM.

The ordinary least squares (OLS) estimator for spatial autoregressions may be consistent as pointed out by Lee (2002), provided that each spatial unit is influenced aggregately by a significant portion of the total units. This paper presents a unified asymptotic distribution result of the properly recentered OLS estimator and proposes a new estimator that is based on the indirect inference (II) procedure. The resulting estimator can always be used regardless of the degree of aggregate influence on each spatial unit from other units and is consistent and asymptotically normal. The new estimator does not rely on distributional assumptions and is robust to unknown heteroscedasticity. Its good finite-sample performance, in comparison with existing estimators that are also robust to heteroscedasticity, is demonstrated by a Monte Carlo study.

This article shall explore the characteristics of hydro-mechanical transmission in power shift. Based on the double brakes overlapping, the adjustment of the displacement ratio of variable-displacement hydraulic component is considered, and then a new full power shift method is proposed. Models respectively for speed, torque, and power in the power shift process are built. The ideal power shift timing is deduced, with the ratio between speed of fixed-displacement hydraulic component and input speed being the criterion. By combining theoretical analysis and experimental studies, it shows that in power shift process by regulating the displacement ratio of variable-displacement hydraulic component, the interchange between high- and low-pressure sides in closed hydraulic circuit can be completed, and power transition can be thus realized. A new full power shift method is put forward, in which the shift process is divided into five stages: current range, prior stable stage, power transition stage, post stable stage, and target range. Experiments on full power shift process prove that the full power shift method is not only feasible but also can remove the rotational speed fluctuation in power shift process and realize normal full power transmission of output power.

Urban areas usually display better health care services than rural areas, but data about suburban areas in China are lacking. Hence, this cross-sectional study compared the utilization of community basic medical services in Shanghai urban and suburban areas between 2009 and 2014. These data were used to improve the efficiency of community health service utilization and to provide a reference for solving the main health problems of the residents in urban and suburban areas of Shanghai. Using a two-stage random sampling method, questionnaires were completed by 73 community health service centers that were randomly selected from six districts that were also randomly selected from 17 counties in Shanghai. Descriptive statistics, principal component analysis, and forecast analysis were used to complete a gap analysis of basic health services utilization quality between urban and suburban areas. During the 6-year study period, there was an increasing trend toward greater efficiency of basic medical service provision, benefits of basic medical service provision, effectiveness of common chronic disease management, overall satisfaction of community residents, and two-way referral effects. In addition to the implementation effect of hypertension management and two-way referral, the remaining indicators showed a superior effect in urban areas compared with the suburbs (P

Bronchopulmonary dysplasia (BPD) remains the most common and serious chronic lung disease of premature infants. Severe BPD complicated with pulmonary hypertension (PH) increases the mortality of these infants. Riociguat is an allosteric soluble guanylate cyclase stimulator and is approved by the FDA for treating PH in adults. However, it has not been approved for use in neonates due to concern for adverse effects on long bone growth. To address this concern we investigated if administration of riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without side effects on long bone growth in newborn rats. Newborn rats were randomized to normoxia (21% O2) or hyperoxia (85% O2) exposure groups within 24 hours of birth, and received riociguat or placebo by once daily intraperitoneal injections during continuous normoxia or hyperoxia exposure for 9 days. In the hyperoxia control group, radial alveolar count, mean linear intercept and vascular density were significantly decreased, the pathological hallmarks of BPD, and these were accompanied by an increased inflammatory response. There was also significantly elevated vascular muscularization of peripheral pulmonary vessels, right ventricular systolic pressure and right ventricular hypertrophy indicating PH. However, administration of riociguat significantly decreased lung inflammation, improved alveolar and vascular development, and decreased PH during hyperoxia by inducing cGMP production. Additionally, riociguat did not affect long bone growth or structure. These data indicate that riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without affecting long bone growth and structure and hence, suggests riociguat may be a potential novel agent for preventing BPD and PH in neonates.

The central nervous system produces movements by activating specifically programmed muscle synergies that are also altered with injuries in the brain, such as stroke. In this study, we hypothesize that there exists a positive correlation between task-specific muscle synergy and motor functions at joint and task levels in patients following stroke. The purpose here is to define and evaluate neurophysiological metrics based on task-specific muscle synergy for assessing motor functions in patients. A patient group of 10 subjects suffering from stroke and a control group of nine age-matched healthy subjects were recruited to participate in this study. Electromyography (EMG) signals and movement kinematics were recorded in patients and control subjects while performing arm reaching tasks. Muscle synergies of individual patients were extracted off-line from EMG records of each patient, and a baseline pattern of muscle synergy was obtained from the pooled EMG data of all nine control subjects. Peak velocities and movement durations of each reaching movement were computed from measured kinematics. Similarity indices of matching components to those of the baseline synergy were defined by synergy vectors and time profiles, respectively, as well as by a combined similarity of vector and time profile. Results showed that pathological synergies of patients were altered from the characteristics of baseline synergy with missing components, or varied vector patterns and time profiles. The kinematic performance measured by peak velocities and movement durations was significantly poorer for the patient group than the control group. In patients, all three similarity indices were found to correlate significantly to the kinematics of movements for the reaching tasks. The correlation to the Fugl-Meyer score of arm was the highest with the vector index, the lowest with the time profile index, and in between with the combined index. These findings illustrate that the analysis of task-specific muscle synergy can provide valuable insights into motor deficits for patients following stroke, and the task-specific similarity indices are useful neurophysiological metrics to predict the function of neuromuscular control at the joint and task levels for patients.

BACKGROUND:Constraint-induced aphasia therapy (CIAT) has been widely used in post-stroke aphasia rehabilitation. An increasing number of clinical controlled trials have investigated the efficacy of the CIAT for the post-stroke aphasia. PURPOSE:To systematically review the randomized controlled trials (RCTs) concerning the effect of the CIAT in post-stroke patients with aphasia, and to identify the useful components of CIAT in post-stroke aphasia rehabilitation. METHODS:A computerized database search was performed through five databases (Pubmed, EMbase, Medline, ScienceDirect and Cochrane library). Cochrane handbook domains were used to evaluate the methodological quality of the included RCTs. RESULTS:Eight RCTs qualified in the inclusion criteria. Inconsistent results were found in comparing the CIAT with conventional therapies without any component from the CIAT based on the results of three RCTs. Five RCTs showed that the CIAT performed equally well as other intensive aphasia therapies, in terms of improving language performance. One RCT showed that therapies embedded with social interaction were likely to enhance the efficacy of the CIAT. CONCLUSION:CIAT may be useful for improving chronic post-stroke aphasia, however, limited evidence to support its superiority to other aphasia therapies. Massed practice is likely to be a useful component of CIAT, while the role of "constraint" is needed to be further explored. CIAT embedded with social interaction may gain more benefits.

In order to solve the problems of wear and spark of the brush and slip ring in an electrically excited synchronous motor (EESM), based on the principle of magnetic resonance coupling wireless power transfer (MRC-WPT), a resonant wireless excitation system of EESM is designed. By modeling the EESM and analyzing the rotor field oriented control (RFOC) method, a control system of the resonant wireless EESM (RW-EESM) is established. Furthermore, the stator current distribution strategy is analyzed. Finally, a test of the RE-EESM prototype is carried out. The test results show that the motor can realize no-load stable operation, and the test speed is maintained at 85 r/min. The results show that the wireless excitation scheme of EESM is feasible, and the RFOC of RW-EESM motor is reasonable.

Background and objective Controversies exists with regard to target volumes as far as thoracic radiotherapy (TRT) is concerned in the multimodality treatment for limited-stage small cell lung cancer (LSCLC). The aim of this study is to prospectively compare the local control rate, toxicity profiles, and overall survival (OS) between patients received different target volumes irradiation after induction chemotherapy. Methods LSCLC patients received 2 cycles of etoposide and cisplatin (EP) induction chemotherapy and were randomly assigned to receive TRT to either the post- or pre-chemotherapy tumor extent (GTV-T) as study arm and control arm, CTV-N included the positive nodal drainage area for both arms. One to 2 weeks after induction chemotherapy, 45 Gy/30 Fx/19 d TRT was administered concurrently with the third cycle of EP regimen. After that, additional 3 cycles of EP consolidation were administered. Prophylactic cranial irradiation (PCI) was administered to patients with a complete response. Results Thirty-seven and 40 patients were randomly assigned to study arm and control arm. The local recurrence rates were 32.4% and 28.2% respectively (P=0.80); the isolated nodal failure (INF) rate were 3.0% and 2.6% respectively (P=0.91); all INF sites were in the ipsilateral supraclavicular fossa. Medastinal N3 disease was the risk factor for INF (P=0.02, OR=14.13, 95%CI: 1.47-136.13). During radiotherapy, grade I, II weight loss was observed in 29.4%, 5.9% and 56.4%, 7.7% patients respectively (P=0.04). Grade 0-I and II-III late pulmonary injury was developed in 97.1%, 2.9% and 86.4%, 15.4% patients respectively (P=0.07). Median survival time was 22.1 months and 26.9 months respectively. The 1 to 3-year OS were 77.9%, 44.4%, 37.3% and 75.8%, 56.3%, 41.7% respectively (P=0.79). Conclusion The preliminary results of this study indicate that irradiant the post-chemotherapy tumor extent (GTV-T) and positive nodal drainage area did not decrease local control and overall survival while radiation toxicity was reduced. But the current sample size has not met designed requirements, and further investigation is warranted before final conclusions could be drawn.

The potential of association mapping (AM) and genomic selection (GS) has not yet been explored for investigating resistance to soybean cyst nematode (SCN), the most destructive pest affecting soybean. We genotyped 282 representative accessions from the University of Minnesota soybean breeding program using a genome-wide panel of 1536 single nucleotide polymorphism (SNP) markers and evaluated plant responses to SCN HG type 0. After adjusting for population structure, AM detected significant signals at two loci corresponding to and plus a third locus located at the opposite end of chromosome 18. Our analysis also identified a discontinuous long-range haplotype of over 600 kb around locus associated with resistance to SCN HG type 0. The same phenotypic and genotypic datasets were then used to access GS accuracy for prediction of SCN resistance in the presence of major genes through a sixfold cross-validation study. Genomic selection using the full marker set produced average prediction accuracy ranging from 0.59 to 0.67 for SCN resistance, significantly more accurate than marker-assisted selection (MAS) strategies using two -associated DNA makers. Reducing the number of markers to 288 SNPs in the GS training population had little effect on genomic prediction accuracy. This study demonstrates that AM can be an effective genomic tool for identifying genes of interest in diverse germplasm. The results also indicate that improved MAS and GS can enhance breeding efficiency for SCN resistance in existing soybean improvement programs.

BACKGROUND:Hypoxic tumor cells can reduce the efficacy of radiation. Antiangiogenic therapy may transiently "normalize" the tumor vasculature to make it more efficient for oxygen delivery. The aim of this study is to investigate whether the recombinant human endostatin (endostar) can create a "vascular normalization window" to alleviate hypoxia and enhance the inhibitory effects of radiation therapy in human nasopharyngeal carcinoma (NPC) in mice. METHODOLOGY/PRINCIPAL FINDINGS:Transient changes in morphology of tumor vasculature and hypoxic tumor cell fraction in response to endostar were detected in mice bearing CNE-2 and 5-8F human NPC xenografts. Various treatment schedules were tested to assess the influence of endostar on the effect of radiation therapy. Several important factors relevant to the angiogenesis were identified through immunohistochemical staining. During endostar treatment, tumor vascularity decreased, while the basement membrane and pericyte coverage associated with endothelial cells increased, which supported the idea of vessel normalization. Hypoxic tumor cell fraction also decreased after the treatment. The transient modulation of tumor physiology caused by endostar improved the effect of radiation treatment compared with other treatment schedules. The expressions of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14 decreased, while the level of pigment epithelium-derived factor (PEDF) increased. CONCLUSIONS:Endostar normalized tumor vasculature, which alleviated hypoxia and significantly sensitized the function of radiation in anti-tumor in human NPC. The results provide an important experimental basis for combining endostar with radiation therapy in human NPC.

Epilepsy is one of the most common neurological disorders, yet its treatment remains unsatisfactory. Saikosaponin a (SSa), a triterpene saponin derived from Bupleurum chinensis DC., has been demonstrated to have significant antiepileptic activity in a variety of epilepsy models in vivo. However, the electrophysiological activities and mechanisms of the antiepileptic properties of SSa remain unclear. In this study, whole-cell current-clamp recordings were used to evaluate the anticonvulsant activities of SSa in the hippocampal neuronal culture (HNC) models of acquired epilepsy (AE) and status epilepticus (SE). Whole-cell voltage-clamp recordings were used to evaluate the modulation effects of SSa on NMDA-evoked current and sodium currents in cultured hippocampal neurons. We found that SSa effectively terminated spontaneous recurrent epileptiform discharges (SREDs) in the HNC model of AE and continuous epileptiform high-frequency bursts (SE) in the HNC model of SE, in a concentration-dependent manner with an IC(50) of 0.42 µM and 0.62 µM, respectively. Furthermore, SSa significantly reduced the peak amplitude of NMDA-evoked current and the peak current amplitude of I(NaP). These results suggest for the first time that the inhibitions of NMDA receptor current and I(NaP) may be the underlying mechanisms of SSa's anticonvulsant properties, including the suppression of SREDs and SE in the HNC models of AE and SE. In addition, effectively abolishing the refractory SE implies that SSa may be a potential anticonvulsant candidate for the clinical treatment of epilepsy.

Chloritization is a typical middle-low temperature hydrothermal alteration type of early ore-forming stage in Shulouqiu deposit of Changjiang rock mass in southern Zhuguang. In this paper, the chlorite in the horizontal alteration zone around the ore body are studied comprehensively by optical microscopy, electron probe and scanning electron microscopy. Based on the lithological characteristics and genesis of chlorite, they are divided into five types: fissure filling chlorite, biotite altered chlorite, feldspar altered chlorite, dolomite altered chlorite and spherical chlorite. The five types of chlorite are all trioctahedral iron-rich chlorite with the same structure type, belonging to three species: vermicular chlorite, ferromagnesian chlorite and uraninite chlorite. Then, the five types of chlorite may have formed in the same period of fluid action in the early ore-forming period, with the formation temperature between 219 ~ 282°C and log fo2 between -47.74 ~ -43.69. Combined with previous research results in the region, the early ore-forming fluid may be a crust-mantle mixed fluid dominated by mantle-derived materials, with strong reducibility. Its formation is related to the intrusion of regional basic veins, which provides a reducing field for the mineralization system, resulting in the reduction and precipitation of U6+ in the ore-forming fluid. [ABSTRACT FROM AUTHOR]