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Background & Aims: To develop and validate the CoRC model at conventional MRI for diagnosing clinically significant liver fibrosis (≥ F2) and necroinflammation (≥ G2). Materials and methods: This retrospective cohort study recruited 537 patients with biopsy-proven liver fibrosis and necroinflammation at center 1 from May 2015 to Aug 2020 and center 2 between Jan 2011 and Jan 2021. 394 patients were randomly allocated into training (n = 276) and internal test (n = 118) cohorts at center 1.. Automated entire liver segmentation used ResUNet-based Human-in-the-Loop approach. Radiomics features were extracted from the mask on fat-suppressed T2-weighted and delayed enhanced T1-weighted images separately. Radiomics signatures were generated using logistic regression. Radiomics-scores and optimal clinical biomarkers as independent risk factors were integrated into the CoRC models in the training cohort with multivariate logistic regression. Models were tested in independent temporal test cohort at center 1 (n = 96) and an external test cohort from center 2 (n = 47). Diagnostic performance was evaluated by area under the curve, calibrations and decision curve analysis. Results: In the internal, temporal, and external test cohorts, CoRC model 1 yielded AUCs of 0.79, 0.82 , and 0.83 for ≥ F2, meanwhile, CoRC model 2 showed AUCs of 0.86, 0.79, and 0.89 for ≥ G2. ,We compared CoRC models with transient elastography-based liver stiffness measurement (TE-LSM) subgrouply (AUC 0.78 vs.0.79, P = 0.86/0.82 vs. 0.73, P = 0.14 for ≥ F2, whereas 0.88 vs. 0.81, P = 0.16/0.79 vs. 0.74, P = 0.49 for ≥ G2). Conclusions CoRC models exhibited promising diagnostic performances for ≥ F2 and ≥ G2, which could be a potential alternative when TE-LSM is unavailable.

BackgroundMETamplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine–kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method forMETamplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS inMETamplification remains uncertain.MethodsForty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment.METamplification by FISH was defined as a MET/CEP7 ratio of > 2.0 and/or copy number (CN) > 5.METamplification by NGS was defined as gene copy number (GCN) ≥ 5.ResultsThe concordance rate among FISH and NGS was 62.5% (25/40).METamplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 withMETamplification) vs. 6.7% (1/15 withoutMETamplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P METamplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0% (6/10, withMETGCN ≥ 5) vs. 40.0% (12/30, withMETGCN ConclusionsMETamplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.

As the lesions in pulmonary nodules (PNs) are small and the clinical manifestations lack specificity, the etiology of PNs is complex, predisposing them to misdiagnoses missed diagnoses. Thus, the diagnosis and treatment of PNs remains challenging and an important clinical problem.This study prospectively enrolled 156 patients with computed tomography (CT)-diagnosed PNs who underwent circulating genetically abnormal cell (CAC) testing between January 2020 and December 2021. We collected data on clinical features closely related to the nature of PNs, such as age, smoking history, and type of nodule. All internal regions of interest (ROIs) of PNs in this study were segmented. Radiomic feature extraction was performed on the ROIs, and a radiomics model was constructed using least absolute shrinkage and selection operator (LASSO) regression to obtain a radiomics score (Rad-score). A comprehensive model combining clinical features, Rad-score, and liquid biopsy was constructed using logistic regression analysis. The diagnostic performance of the model was evaluated using receiver operating characteristic (ROC) curves.In this study, 5 radiomics features were screened for model construction. The area under the ROC curve (AUC) of the radiomics model was 0.844 [95% confidence interval (CI): 0.766-0.915] in the training set. The Rad-score, clinical features, and CAC were further combined to construct a multidimensional analysis model. The AUC of the synthesized model was 0.943 (95% CI: 0.881-0.978) in the training set.A multidimensional model is an effective tool for the noninvasive diagnosis of malignant PNs. The validation and combination of multiple diagnostic methods is a productive avenue of research trend for the identification of malignant PNs.

The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiOsub2/sub@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiOsub2/subnanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiOsub2/sub@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiOsub2/sub@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4sup+/supand CD8sup+/supT lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiOsub2/sub@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.

BACKGROUND Computed tomography (CT) and magnetic resonance imaging (MRI) are both capable of predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). However, which modality is better is unknown. PURPOSE To intraindividually compare CT and MRI for predicting MVI in solitary HCC and investigate the added value of radiomics analyses. STUDY TYPE Retrospective. SUBJECTS Included were 402 consecutive patients with HCC (training set:validation set = 300:102). FIELD STRENGTH/SEQUENCE T2-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging MRI at 3.0T and contrast-enhanced CT. ASSESSMENT CT- and MR-based radiomics signatures (RS) were constructed using the least absolute shrinkage and selection operator regression. CT- and MR-based radiologic (R) and radiologic-radiomics (RR) models were developed by univariate and multivariate logistic regression. The performance of the RS/models was compared between two modalities. To investigate the added value of RS, the performance of the R models was compared with the RR models in HCC of all sizes and 2-5 cm in size. STATISTICAL TESTS Model performance was quantified by the area under the receiver operating characteristic curve (AUC) and compared using the Delong test. RESULTS Histopathologic MVI was identified in 161 patients (training set:validation set = 130:31). MRI-based RS/models tended to have a marginally higher AUC than CT-based RS/models (AUCs of CT vs. MRI, P: RS, 0.801 vs. 0.804, 0.96; R model, 0.809 vs. 0.832, 0.09; RR model, 0.835 vs. 0.872, 0.54). The improvement of RR models over R models in all sizes was not significant (P = 0.21 at CT and 0.09 at MRI), whereas the improvement in 2-5 cm was significant at MRI (P

Background Here we present a rare case of localized amyloidosis involving the nasolacrimal duct and lacrimal sac which was managed by endoscopic surgery. Case summary A 50-year-old man whose medical history included bilateral ventricular fold and vocal cord amyloidosis complained of bilateral epiphora. Magnetic resonance imaging revealed a neoplasm within the nasolacrimal sac. Characteristic positivity for Congo red staining and birefringence under a polarized microscope proved the diagnosis of amyloidosis. Dacryocystorhinostomy via an endoscope obtained a favorable result. A one-year follow-up found no recurrence. Conclusion There are few reports on amyloidosis involving the lacrimal outflow system, and management and outcome are not clear. Endoscopic dacryocystorhinostomy can be a choice to relieve symptoms. Regular follow-up and monitoring of systemic diseases are highly recommended.

Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non-small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs.Whole-exome sequencing, RNA sequencing, and multiplex immunohistochemistry (mIHC) staining were conducted to analyze 24 spatially segregated tumor samples from eight patients who were pathologically diagnosed with T4N0M0 (diameter ≥ 7 cm) NSCLCs. The adjacent normal tissues and peripheral blood served as controls.In total, 35.2% of mutations and 91.1% of somatic copy number alterations were classified as subclonal events, which exhibited widespread genetic intratumoral heterogeneity. In contrast, a low degree of CIN was observed. None of the patients had genome doubling. The burden of loss of heterozygosity, aneuploidy, and the genome instability index of these tumors were significantly lower than those in the TRACERx cohort. Expression profiles revealed significantly upregulated expression of cell division-related signals and the G2/M checkpoint pathway. In addition, a similar expression pattern of the immune microenvironment was observed in different regions of the tumor, which was confirmed by mIHC profiles.Our study indicates the presence of intratumoral genetic heterogeneity and immune microenvironmental heterogeneity features in T4N0M0 NSCLCs, and the low degree of CIN may be related to the low metastatic capability.

We aimed to investigate the additional significance of cerebral small vessel disease (SVD) beyond collaterals in determining the clinical outcome after acute ischemic stroke (AIS).We retrospectively reviewed large vessel-involved stroke patients who had baseline CTA within 24 h after symptom onset and had an MRI scan 5 days after admission from October 1, 2018, to October 31, 2021. Collaterals and SVD markers (including atrophy, leukoaraiosis, lacunes, and perivascular space) were graded on CT angiography and MR images, respectively. Modified Rankin Scale (mRS) score at 90 days was recorded, and mRS ≤ 2 was regarded as a good clinical outcome. The associations between SVD markers, collaterals, and mRS were analyzed using logistic and causal mediation regression.We finally enrolled 119 patients (70 ± 13 years). The multivariable regression showed atrophy (evidence: OR 0.05 [95% CI 0.01-0.31], p = 0.002; severe: OR 0.08 [95% CI 0.01-0.44], p = 0.007) and evidence of lacune (OR 0.30 [95% CI 0.08-0.96], p = 0.049) were associated with poor clinical outcomes after correcting covariables. Collaterals mediated 25.74% of the effect of atrophy on poor clinical outcomes (p0.001), while lacune impacted clinical outcomes without collaterals' mediation effect (p = 0.54). The classification model with atrophy and lacune had a significantly higher AUC than without markers to distinguish good and poor outcomes (p = 0.036).Beyond collaterals, brain frailty, specifically assessed by atrophy and lacune, was essential in evaluating stroke patients and could additionally improve the stroke outcome prediction.• Beyond collaterals, brain frailty, specifically assessed by brain atrophy and lacune, was still an independent risk factor of unfavorable clinical outcomes after AIS. • Adding brain atrophy and lacune into the model has an extra benefit in predicting stroke outcomes. • The effect of atrophy on stroke outcomes was proportionally mediated through collaterals, but about three-quarters of the effect of brain atrophy and the total effect of lacune directly impacted stroke outcomes without a mediation effect of collaterals.

The coleopteran parasitoid Dastarcus helophoroides (Fairmaire) (Coleoptera: Bothrideridae) is considered an efficient preventative method against the damage caused by a large number of cerambycid pests in China and other East Asian countries. Mass rearing of this parasitoid depends on screening appropriate factitious hosts. In this paper, the fitness-related traits of this parasitic beetle were explored using pupae of the two tenebrionid beetles, Tenebrio molitor Linnaeus and Zophobas morio Fabricius (Coleoptera: Tenebrionidae) as factitious hosts. The results showed that in dual-choice trials, D. helophoroides larvae preferred to attack Z. morio pupae. In no-choice trials, D. helophoroides reared on Z. morio pupae displayed significantly higher pupation and emergence rate, longer developmental duration of larval and larval–pupal stages, larger adult body size, shorter preoviposition period, more egg masses and egg production, and higher relative expected reproduction than those reared on T. molitor pupae. These results demonstrate that Z. morio is a more suitable factitious host for mass rearing of D. helophoroides.

The self-crosslinked hyaluronic acid (scHA) and steroids are considered as efficient factors for postoperative management after chronic rhinosinusitis (CRS) nasal surgery. This randomized clinical trial is designed to investigate the efficacy and potential of scHA gel as a topical drug sustained release carrier for steroid of budesonide. The study is performed with 30 patients of chronic rhinosinusitis with nasal polyps (CRSwNP) who underwent functional endoscopic sinus surgery (FESS). The single application of scHA was assessed in the control patient group for postoperative recovery. In the treatment patient group, the combination of scHA/budesonide was applied for postoperative management. The patients are followed up in 2 weeks, 4 weeks and 12 weeks after surgery. The combination of scHA/budesonide results in better endoscopic scoring and mucus evaluation than the single scHA application. The results indicate that the combination of scHA/budesonide is a valuable treatment for the FESS postoperative management and implies the potential of scHA gel as a topical drug sustained release scaffold.

A new mealybug species Atrococcus rushuiensis Zhang, sp. nov., collected under the leaf sheath of Sporobolus fertilis (Poaceae) in Fuzhou City, Jiangxi Province, China, is described and illustrated. A new combination is introduced, transferring Allotrionymus shanxiensis Wu to the genus Atrococcus as A. shanxiensis (Wu), comb. nov. A key is presented for the species of Atrococcus recorded from China.

Background In previous studies, the predictive role of BIM deletion polymorphism with respect to responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) has been controversial. The potential reasons for these inconsistent findings were unknown. Methods Data from CTONG0901 clinical trial and medical records of Guangdong Lung Cancer Institute (GLCI) were retrospectively pooled. A total of 194 and 141 EGFR‐mutant non‐small cell lung cancer (NSCLC) patients treated with first‐ and second‐generation EGFR‐TKIs were examined in the CTONG0901 and GLCI cohorts, respectively. Sixty‐eight patients were treated with third‐generation EGFR‐TKIs in the GLCI cohort. The BIM gene status was examined by next‐generation sequencing. Results The frequency of BIM deletion polymorphism was 11.3% and 17.0% in CTONG0901 and GLCI cohorts, respectively. For first‐ and second‐generation EGFR‐TKIs in CTONG0901 cohort, objective response (ORR) was 54.5% in BIM deletion group versus 56.4% in wild‐type BIM group (P = .87); disease control rate (DCR) was 90.9% versus 88.4% (P = 1.00); progression‐free survival (PFS) was 10.5 versus 11.2 months (P = .59); and overall survival (OS) was 20.5 versus 20.5 months (P = .73). In GLCI cohort, ORR was 54.2% versus 60.7% (P = .55); DCR was 91.7% versus 96.6% (P = .27); PFS was 10.1 versus 11.6 months (P = .63); and OS was 58.5 versus 45.0 months (P = .93). For third‐generation EGFR‐TKIs, ORR was 18.2% versus 63.2% (P = .02); DCR was 81.8% versus 96.5%, (P = .12); PFS was 5.8 versus 9.0 months (P = .13); and OS was 30.0 versus 24.8 months (P = .85). Cox regression analysis showed that concomitant genetic alterations could adversely affect the response to EGFR‐TKIs, but not BIM deletion. Conclusions The presence of BIM deletion showed no relation to an impaired response to first‐, second‐, and third‐generation EGFR‐TKIs in NSCLC patients. The factors influencing the response of EGFR‐TKIs were concomitant genetic alterations, but not BIM deletion.

Introduction: Lung cancer is the most prevalent malignant tumors worldwide. Over the past decade, the emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has ushered in a new era of lung cancer treatment. Therefore, clinical trials investigating the efficacy and safety of these drugs are important.Areas covered: This review provides an overview on the safety of three classes of EGFR-TKIs and discusses the adverse events (AEs) and reactions reported in the literature.Expert opinion: EGFR-TKIs significantly improve progression-free survival and overall survival in non-small cell lung cancer (NSCLC) patients with an activating mutation of EGFR. However, EGFR-TKIs also block the EGFR-regulating pathways in the skin and gastrointestinal tract and cause AEs, including diarrhea, liver toxicity, skin disease, stomatitis, interstitial lung disease, and ocular toxicity, which have detrimental effects on quality of life and drug compliance. Clinicians should understand how to prevent and control these adverse reactions, which can often be achieved by dose reduction, discontinuation of treatment, or switching to another drug.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide. Checkpoint blockade immunotherapy has made tremendous progress in the treatment of a variety of cancers in recent years. Costimulatory molecules constitute the foundation of cancer immunotherapies and are deemed to be promising targets for cancer treatment. This study attempted to evaluate the potential value of costimulatory molecule genes (CMGs) in HNSCC.Materials and MethodsBased on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset, we identified the prognostic value of CMGs in HNSCC. Subsequently, CMGs-based signature (CMS) to predict overall survival of HNSCC patients was established and validated. The differences of downstream pathways, clinical outcomes, immune cell infiltration, and predictive immunotherapy responses between different CMS subgroups were investigated via bioinformatic algorithms. We also explored the biological functions of TNFRSF12A, one risk factor of CMS, by in vitro experiments.ResultsAmong CMGs, 22 genes were related to prognosis based on clinical survival time in HNSCC. Nine prognosis-related CMGs were selected to establish CMS. CMS was an independent risk factor and could indicate the survival of HNSCC patients, the component of tumor-infiltrating lymphocytes, and the immunotherapy response rate. Functional enrichment analysis confirmed that CMS might involve immune-relevant processes. Additionally, TNFRSF12A was related to poor prognosis and enhanced malignant phenotype of HNSCC.ConclusionCollectively, CMS could accurately indicate prognosis, evaluate the tumor immune microenvironment, and predict possible immunotherapy outcomes for HNSCC patients.

Current anatomic TNM stage classification fails to capture the immune heterogeneity of oral squamous cell carcinoma (OSCC). Increasing evidence indicates the strong association between epithelial-mesenchymal transition (EMT) and tumor immune response. In this study, we employed an EMT signature to classify OSCC patients into epithelial- (E-) and mesenchymal- (M-) phenotypes using TCGA and GSE41613 transcriptome data. The ESTIMATE and CIRBERSORT analyses implied that the EMT signature genes originated from the stroma of the bulk tissue. The M-subtype tumors were characterized as “immune-hot” with more immune cell infiltration than the E-subtype ones. The low infiltration of active immune cells, the high infiltration of inactive immune cells, and the high expressions of immune checkpoints demonstrated an immunosuppressive characteristic of the M-subtype tumors. Moreover, we developed and validated a novel prognostic classifier based on the EMT score, the expressions of seven immune checkpoints, and the TNM stages, which could improve the prediction efficiency of the current clinical parameter. Together, our findings provide a better understanding of the tumor immune heterogeneity and may aid guiding immunotherapy in OSCC.

Background and Purpose: Ipsilateral thalamic diaschisis (ITD) initially describes functional depression of the thalamus ipsilateral to a supratentorial lesion, but accumulating evidence has shown morphological changes also occur. Therefore, we aimed to characterize thalamic perfusion and diffusion related to ITD over time and their inter-relationships after middle cerebral artery infarction. Methods: Eighty-five patients with middle cerebral artery infarction who underwent diffusion kurtosis imaging and arterial spin labeling were retrospectively included. ITD was diagnosed as ipsilateral thalamic hypoperfusion present on ≥2 cerebral blood flow maps. The thalamic asymmetrical index was calculated as (ipsilateral value−contralateral value)/contralateral value×100%. Finally, the inter-relationships of thalamic perfusion and diffusion were analyzed. Results: ITD was present in 56/85 patients (65.9%, ITD+). In ITD+ patients, larger abnormal perfusion volume, higher perfusion-infarct mismatch and lower rates of focal hyperperfusion were observed than ITD− patients. Infarction affecting the corona radiata were more frequent among ITD+ patients. Mean kurtosis were slightly but significantly increased within the ipsilateral thalamus compared with the contralateral one in ITD+ patients of subacute and chronic groups, while fractional anisotropy was significantly increased in subacute group but decreased in chronic group for both ITD+ and ITD− patients. Mean diffusivity was significantly increased in ITD+ patients of chronic group. Furthermore, the AI CBF was negatively and significantly correlated with AI MK and AI FA in ITD+ patients in subacute group, and AI MD , even after adjustment for abnormal perfusion volume and days from symptoms onset, in chronic group. ITD+ patients had significantly higher National Institutes of Health Stroke Scale and modified Rankin Scale scores at admission and discharge and also showed a trend to independent association with clinical outcome at discharge. Conclusions: The combination of arterial spin labeling and diffusion kurtosis imaging can reveal early, time-specific thalamic perfusion and diffusion changes after middle cerebral artery infarction. ITD-related hypoperfusion was significantly correlated with underlying microstructural alterations.

The ectoparasitoid beetle, Dastarcus helophoroides (Fairmaire) (Coleoptera: Bothrideridae), has been widely used as a biological control agent for many cerambycid beetles in China, Korea, and Japan. However, much less is known about its phototactic behavior to visual stimuli. In this paper, the phototactic behavioral response of D. helophoroides to 27 monochromatic lights and to nine illumination intensities of the most attractive light was evaluated using light-emitting diodes (LEDs) as light sources. The results showed that in dual choice between darkness and individual LED light, D. helophoroides adults exhibited a positively phototactic response to all wavelengths ranging from 300 to 860 nm. The near-infrared light (NIR, ranging from 700 to 760 nm) elicited stronger phototactic behavioral response, showing a preference for NIR wavelengths light. In paired choice among four preferred NIR lights, D. helophoroides adults displayed a significantly more favorable response to NIR light at 700 nm. Furthermore, the beetles expressed varying levels of sensitivity to illumination intensities from 1 to 600 lux under NIR light at 700 nm. The phototactic response was strongest at 7 lux and a statistically significant downward trend was found with increasing or decreasing the illumination intensities. These findings clearly demonstrate that D. helophoroides is a positively phototactic insect and its phototactic behavior is significantly influenced by light wavelength and illumination intensity, among which NIR light with peak wavelength at 700 nm and an intensity at 7 lux are most suitable in attracting D. helophoroides adults.

Computed tomography (CT) and magnetic resonance imaging (MRI) are both capable of predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). However, which modality is better is unknown.To intraindividually compare CT and MRI for predicting MVI in solitary HCC and investigate the added value of radiomics analyses.Retrospective.Included were 402 consecutive patients with HCC (training set:validation set = 300:102).T2-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging MRI at 3.0T and contrast-enhanced CT.CT- and MR-based radiomics signatures (RS) were constructed using the least absolute shrinkage and selection operator regression. CT- and MR-based radiologic (R) and radiologic-radiomics (RR) models were developed by univariate and multivariate logistic regression. The performance of the RS/models was compared between two modalities. To investigate the added value of RS, the performance of the R models was compared with the RR models in HCC of all sizes and 2-5 cm in size.Model performance was quantified by the area under the receiver operating characteristic curve (AUC) and compared using the Delong test.Histopathologic MVI was identified in 161 patients (training set:validation set = 130:31). MRI-based RS/models tended to have a marginally higher AUC than CT-based RS/models (AUCs of CT vs. MRI, P: RS, 0.801 vs. 0.804, 0.96; R model, 0.809 vs. 0.832, 0.09; RR model, 0.835 vs. 0.872, 0.54). The improvement of RR models over R models in all sizes was not significant (P = 0.21 at CT and 0.09 at MRI), whereas the improvement in 2-5 cm was significant at MRI (P 0.05) but not at CT (P = 0.16).CT and MRI had a comparable predictive performance for MVI in solitary HCC. The RS of MRI only had significant added value for predicting MVI in HCC of 2-5 cm.3 TECHNICAL EFFICACY: Stage 2.

Background Olfactory neuroblastoma (ONB) is a rare malignancy arising in the nasal vault. Endoscopic resection has been reported to improve overall survival (OS). At present, clinicopathological predictors of the prognosis of ONB remain undefined. Methods Data including demographics, clinical characteristics and follow-up information of ONB patients treated with endoscopic surgery were collected. Risk factors on OS rates were investigated by LASSO and Cox analyses. A nomogram was developed and evaluated with internal validation. Risk groups were established according to patients’ points in the nomogram. Findings 154 ONB patients treated with surgery were included in this single center study. A nomogram based on multivariate Cox regression model including multiple tumor history, orbital invasion, carotid canal invasion, modified Kadish stage, delivery sequence of RT and surgery, sequence of chemotherapy and surgery was developed. The bias-corrected C-index (0.886 [95% CI: 0.843-0.943]) was significantly higher than of conventional staging classifications. The AUC of nomogram regarding 1-, 2- and 5-year OS probabilities reached 0.912, 0.929 and 0.957, respectively. The risk levels based on nomogram points were more discriminative than conventional classifications. Interpretation Validation analysis showed good predictive accuracy and discriminative ability of the nomogram. Therefore, the nomogram could be utilized to individually predict survival probability for ONB patients after endoscopic resection. Funding This study was funded by the Chinese Academy of Medical Sciences (No. 2019-I2M-5-003), the Shanghai Science and Technology Commission (No. 19411950600), the Shanghai Hospital Development Center (No. SHDC12018118) and the Eye, Ear, Nose and Throat Hospital of Fudan University (No. SYB202006).

Highlights • Predictive power of PD response for ICIs was superior than traditional biomarkers; • Predictive efficacy was improved by integrating tumor-immune-related features; • When tumor-specific feature was replaced, the model has pan-cancer applicability. • NRAS and PDPK1 have the potential to induce primary resistance to ICIs., Background Treatment by immune checkpoint blockade (ICB) provides a remarkable survival benefit for multiple cancer types. However, disease aggravation occurs in a proportion of patients after the first couple of treatment cycles. Methods RNA sequencing data was retrospectively collected. 6 tumour-immune related features were extracted and combined to build a lung cancer-specific predictive model to distinguish responses as progression disease (PD) or non-PD. This model was trained by 3 public pan-cancer datasets and a lung cancer cohort from our institute, and generated a lung cancer-specific integrated gene expression score, which we call LITES. It was finally tested in another lung cancer dataset. Results LITES is a promising predictor for checkpoint blockade (area under the curve [AUC]=0.86), superior to traditional biomarkers. It is independent of PD-L1 expression and tumour mutation burden. The sensitivity and specificity of LITES was 85.7% and 70.6%, respectively. Progression free survival (PFS) was longer in high-score group than in low-score group (median PFS: 6.0 vs. 2.4 months, hazard ratio=0.45, P=0.01). The mean AUC of 6 features was 0.70 (range=0.61-0.75), lower than in LITES, indicating that the combination of features had synergistic effects. Among the genes identified in the features, patients with high expression of NRAS and PDPK1 tended to have a PD response (P=0.001 and 0.01, respectively). Our model also functioned well for patients with advanced melanoma and was specific for ICB therapy. Conclusions LITES is a promising biomarker for predicting an impaired response in lung cancer patients and for clarifying the biological mechanism underlying ICB therapy.

Immunotherapy has been demonstrated as a promising strategy in controlling head and neck squamous cell carcinoma (HNSC). The AID/APOBEC family is well characterized as DNA mutator and considered to play critical roles in immune responses in HNSC. However, the expression pattern and deamination-dependent demethylation roles of AID/APOBECs in HNSC are unclear. In this study, the RNA-seq and DNA methylation profiles of HNSC from TCGA database and cell-based experiments were applied to analyze the relationships between AID/APOBEC expression levels, patients’ clinical outcomes, methylation alterations, and immune responses. Here, we found that APOBEC3H was abnormally upregulated in HNSC patients. HPV+ patients tended to have higher APOBEC3H levels than HPV- patients. Remarkably, patients with high APOBEC3H levels showed a favorable overall survival. Furthermore, tumors with high APOBEC3H levels exhibited a genome-wide DNA hypomethylation pattern. APOBEC3H was identified to demethylate and upregulate CXCL10 and improve CD8+ T cell tumor infiltration in the tumor microenvironment. Collectively, APOBEC3H plays critical roles in CD8+ T cell immune infiltration and activation in HNSC, which may be a potential biomarker for oncoimmunotherapy in HNSC.

Background The KRAS mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients. At the 2019th World Conference of Lung Cancer, the KRAS G12C-specific inhibitor AMG510 showed promising results in the phase I clinical trial. However, the frequency, clinical characteristics, and prognostic significance of the KRAS G12C mutation in Chinese NSCLC patients are rarely reported. Methods Next-generation sequencing was used to confirm the KRAS mutation status in 40,804 NSCLC patients from multiple centers (mCohort). Survival data were collected retrospectively from 1456 patients at one of the centers, the Guangdong Lung Cancer Institute (iCohort). Results In the mCohort, 3998 patients (9.8%) were confirmed to harbor a KRAS mutation, of whom 1179 (29.5%) had the G12C subtype. In the iCohort, 130 NSCLC patients (8.9%) had a KRAS mutation and 42 (32.3%) had the G12C subtype. The G12C subgroup included more male patients (85.2% vs 67.4%, P P = 0.02) than did the non-G12C subgroup. Both the KRAS mutation group and KRAS G12C mutation subgroup were associated with a shorter median overall survival (OS) than wildtype tumors (15.1 vs 26.7 months, hazard ratio [HR]KRAS = 1.50, P = 0.002; 18.3 vs 26.7 months, HRG12C = 1.66, P = 0.007). In Cox regression analysis, smoking (HR = 1.39, P = 0.05) and stage IV disease (HR = 2.72, P KRAS mutation (HR = 1.30, P = 0.07) and KRAS G12C mutation (HR = 1.47, P = 0.07) reached borderline significance. Conclusions In the largest sample used thus for, our study found that approximately 10% of Chinese NSCLC patients had KRAS mutations. Of these, nearly 30% harbored the KRAS G12C mutation subtype, which was most common in male smokers. The KRAS G12C mutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved by G12C-specific inhibitors in the future. (296 words)

The camphor sawfly, Mesoneura rufonota Rohwer, is an economically important leaf-chewing pest of the genus Cinnamomum Trew. However, little is known about the range of species that it can infest within this genus or whether larvae show preferences for particular species. We conducted preference and performance experiments under laboratory conditions to assess larval host preference and suitability as a host plant of five congeneric trees species: C. camphora (Linn) Presl, C. bodinieri Levl., C. burmanni (Nees et T. Nees) Blume, C. pauciflorum Nees, and C. micranthum (Hay.) Hay. In no-choice, two-choice and multiple-choice feeding trials, significantly higher feeding rates were found on C. camphora, followed by C. bodinieri, compared to those on the other three tree species. In two-choice behavior trials, larvae moved to occupy leaves of C. camphora faster and more frequently, followed by C. bodinieri, than when offered the other three tree species. In no-choice fitness trials, the survival of larval and pupal stage was the highest, the developmental duration of larval and pupal stage was the shortest, the pupal body weight was the heaviest and adults lived the longest on C. camphora followed by C. bodinieri, while M. rufonota did not complete development on C. burmanni, C. pauciflorum or C. micranthum. Our results demonstrate that larvae consistently prefer and perform better on C. camphora leaves, that they can utilize C. bodinieri, but it is less preferred, and that C. burmanni, C. pauciflorum, and C. micranthum appear to be unsuitable as a host for M. rufonota.

Renal function varies according to the nature and stage of diseases. Renal functional magnetic resonance imaging (fMRI), a technique considered superior to the most common method used to estimate the glomerular filtration rate, allows for noninvasive, accurate measurements of renal structures and functions in both animals and humans. It has become increasingly prevalent in research and clinical applications. In recent years, renal fMRI has developed rapidly with progress in MRI hardware and emerging postprocessing algorithms. Function-related imaging markers can be acquired via renal fMRI, encompassing water molecular diffusion, perfusion, and oxygenation. This review focuses on the progression and challenges of the main renal fMRI methods, including dynamic contrast-enhanced MRI, blood oxygen level-dependent MRI, diffusion-weighted imaging, diffusion tensor imaging, arterial spin labeling, fat fraction imaging, and their recent clinical applications. Level of evidence 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:863-881.

Background Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. Methods An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. Findings The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. Interpretation Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. Funding The study was supported by Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU)

Bimetallic gold-copper nanochain networks (AuCu NCNs) were prepared by a single-step wet-chemical approach using metformin as a growth-directing agent. The formation mechanism was investigated in detail, and the AuCu NCNs were characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). The nanocrystals were deposited on glassy carbon electrode and this resulted in a highly sensitive sensor for nitrite. Features include a low working potential (best at 0.684 V vs. SCE), fair sensitivity (17.55 μA mM−1), a wide linear range (0.01 to 4.0 mM), a low detection limit (0.2 μM, S/N = 3), and superior selectivity as compared to other sensors.

Renal function varies according to the nature and stage of diseases. Renal functional magnetic resonance imaging (fMRI), a technique considered superior to the most common method used to estimate the glomerular filtration rate, allows for noninvasive, accurate measurements of renal structures and functions in both animals and humans. It has become increasingly prevalent in research and clinical applications. In recent years, renal fMRI has developed rapidly with progress in MRI hardware and emerging postprocessing algorithms. Function-related imaging markers can be acquired via renal fMRI, encompassing water molecular diffusion, perfusion, and oxygenation. This review focuses on the progression and challenges of the main renal fMRI methods, including dynamic contrast-enhanced MRI, blood oxygen level-dependent MRI, diffusion-weighted imaging, diffusion tensor imaging, arterial spin labeling, fat fraction imaging, and their recent clinical applications.5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:863-881.

In the supply chain system, the inventory is the main object of supply chain management, the level of inventory is high or low not only affects the comprehensive cost of a single enterprise, but also restricts the performance of entire supply chain.To realize the difference between inventory management under the supply chain environment and the traditional supply chain management, to establish stock corresponding to uncertain market needs and how to overcome the existing problems is the important issues the enterprise managers must consider when they improve and optimize the supply chain . This article is based on that researching the problem of inventory management under the environment of supply chain,analyzing the challenges it faces, maintaining the good performance of the supply chain under the premise of normal operation of each link. At the sane time,it interprets the connotation of the supply chain and the inventory management under the environment of supply chain, and points out the several kinds of inventory management mode under environment of supply chain enterprises can take.

At present, as an emerging service industry customer service and the third profit source of enhancing the competitiveness of the enterprise market, the logistics industry gets the attention of more and more enterprises. In the enterprise total cost, reasonable decomposition and calculating the logistics cost, seriously affect the profits of the enterprise. Therefore, how to make enterprise logistics cost accounting becomes the focus concern of enterprises to improve market competitiveness. This topic comes from the basic theory of homework cost method, the enterprise logistics cost accounting based on homework cost method are analyzed. This paper expounds the homework cost method based the thinking of enterprise logistics cost accounting, by the process of resource to homework cost object cost allocation, and the activity-based cost method of enterprise logistics cost accounting methods are analyzed on focus.

The proportion of aged population nowadays almost rises acutely in each countries, which resulted from the increasing life expectancy and falling fertility rates. The impairment of mobility is a major health concern for the elderly. While the more decline of daily activities, more dangerous the elderly would be. The design of an image-based surveillance system for tracking elderly's activities in home was proposed in this paper, and the algorithm of shadow elimination was applied to reduce the effect of the subject's shadow for regional segmentation. The HOG-SVM algorithm-based image segmentation technique was recommended to analyze the gradient orientations of segmented objects to follow the trail of the subject movement. The accuracy of this method is almost 96.3%. We hope this designed construction system can be applied in the clinical application for the elderly in the respects of health care and home care in the future.

This study aims to understand the special expression patterns of angiotensin-II receptor (AT 1 R and AT 2 R) in nodose ganglia and nucleus of tractus solitary of baroreflex afferent pathway and their contribution in sex difference of neurocontrol of blood pressure regulation. In this regard, action potentials were recorded in baroreceptor neurons (BRNs) using whole-cell patch techniques; mRNA and protein expression of AT 1 R and AT 2 R in nodose ganglia and nucleus of tractus solitary were evaluated using real time–polymerase chain reaction, Western blot, and immunohistochemistry at both tissue and single-cell levels. The in vivo effects of 17β-estradiol on blood pressure and AT 2 R expression were also tested. The data showed that AT 2 R, rather than AT 1 R, expression was higher in female than age-matched male rats. Moreover, AT 2 R was downregulated in ovariectomized rats, which was restored by the administration of 17β-estradiol. Single-cell real time–polymerase chain reaction data indicated that AT 2 R was uniquely expressed in Ah-type BRNs. Functional study showed that long-term administration of 17β-estradiol significantly alleviated the blood pressure increase in ovariectomized rats. Electrophysiological recordings showed that angiotensin-II treatment increased the neuroexcitability more in Ah- than C-type BRNs, whereas no such effect was observed in A-types. In addition, angiotensin-II treatment prolonged action potential duration, which was not further changed by iberiotoxin. The density of angiotensin-II–sensitive K + currents recorded in Ah-types was equivalent with iberiotoxin-sensitive component. In summary, the unique, sex- and afferent-specific expression of AT 2 R was identified in Ah-type BRNs, and AT 2 R-mediated KCa1.1 inhibition in Ah-type BRNs may exert great impacts on baroreflex afferent function and blood pressure regulation in females.

Objective/Background: Phosphatidylserine (PS) exposure on the outer membrane surface is a known storage lesion of red blood cells (RBCs). Procoagulant activity (PCA) of PRBC units has been shown to increase during storage. However, the PCA and the relation to PS of banked RBCs remain unknown. The aim of this study is to investigate the PCA and the correlation with PS exposure on banked RBCs. Materials and Methods: Human normal leucodepleted RBC concentrates were stored in saline–adenine–glucose–mannitol (SAGM) solution at 4 °C for up to 42 days. PS exposure was measured by lactadherin and annexin V. PCA of RBCs was determined by one-step recalcification assay and further determined by prothrombinase and tenase assays. The correlation between PCA and PS exposure of RBCs was measured by inhibition tests with lactadherin or annexin V. Results: Lactadherin detected 1·5% PS-positive stored RBCs vs 0·5% for annexin V after 14 days of storage, which significantly reached 18·4 vs 4·5% after 42 days of storage. Potent PCA was observed on day 14 and continuously increased. PCA of RBCs on day 42 was inhibited 94% by lactadherin vs 45% by annexin V. Incubation at 37 °C in fresh heparinised plasma partially reversed PS exposure and PCA of RBCs stored for 14 days but had no effect on these parameters for cells stored for 42 days. Conclusions: PCA and PS exposure of stored RBCs increased during storage and showed significant positive correlation. PCA of long-term stored RBCs may not be reversed by transfusion.

Developing new nanomaterials is of key importance to improve the analytical performances of electrochemical biosensors. In this work, palladium–copper alloyed nanocages supported on reduced graphene oxide (RGO–PdCu NCs) were facilely prepared by a simple one-pot solvothermal method. A novel phenol biosensor based on laccase has been constructed for rapid detection of catachol, using RGO–PdCu NCs as electrode material. The as-developed phenol biosensor greatly enhanced the electrochemical signals for catechol. Under the optimal conditions, the biosensor has two linear ranges from 0.005 to 1.155 mM and 1.655 to 5.155 mM for catachol detection at 0.6 V, the sensitivity of 12.65 µA mM−1 and 5.51 µA mM−1, respectively. This biosensor showed high selectivity, low detection limit, good reproducibility, and high anti-interference ability.

Introduction The diagnosis of lymphoid malignancies is often challenging in paucicellular specimens. PCR may also be limited by insufficient cells for DNA isolation and incomplete coverage of gene rearrangements. This study aims to evaluate a PCR method for IgH clonality using direct cell lysates. Methods PCR amplification used cell lysate from detergent-based lysis and BIOMED-2 primers. CSF specimens were tested for 20 patients with primary CNS lymphoma or systemic lymphoma suspected for CNS involvement. Cytology and flow cytometry analysis was performed in parallel with PCR. Results Direct lysis produced a better yield than the column-based method for DNA isolation. PCR using lysate showed an efficiency of clonality detection from a minimum of 20 tumor cells. PCR clonality was found in nine of the 20 CSFs, and positive PCR was concordant with both cytology and flow cytometry in seven cases. There were two cases positive for PCR, but indeterminate for flow cytometry because of insufficient cell events. Of the eleven PCR-negative cases, two were considered as false negative, as flow cytometry showed positive for malignant cells. The PCR was also performed successfully with a specimen from the anterior chamber of the eye. Conclusion PCR clonality with direct cell lysis of CSF is feasible, and it may overcome the limitation of DNA isolation. This PCR method may be particularly useful for small volume and low cell CSF when flow cytometry is inconclusive.

Hyperpolarization-activated currents (Ih) mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate excitability of myelinated A- and Ah-type visceral ganglion neurons (VGN). Whether alterations in Ih underlie the previously reported reduction of excitability of myelinated Ah-type VGNs following ovariectomy (OVX) has remained unclear. Here we used the intact nodose ganglion preparation in conjunction with electrophysiological approaches to examine the role of Ih remodeling in altering Ah-type neuron excitability following ovariectomy in adult rats. Ah-type neurons were identified based on their afferent conduction velocity. Ah-type neurons in nodose ganglia from non-OVX rats exhibited a voltage 'sag' as well as 'rebound' action potentials immediately following hyperpolarizing current injections, which both were suppressed by the Ih blocker ZD7288. Repetitive spike activity induced afterhyperpolarizations lasting several hundreds of milliseconds (termed post-excitatory membrane hyperpolarizations, PEMHs), which were significantly reduced by ZD7288, suggesting that they resulted from transient deactivation of Ih during the preceding spike trains. Ovariectomy reduced whole-cell Ih density, caused a hyperpolarizing shift of the voltage-dependence of Ih activation, and slowed Ih activation. OVX-induced Ih remodeling was accompanied by a flattening of the stimulus frequency/response curve and loss of PEMHs. Also, HCN1 mRNA levels were reduced by ∼30% in nodose ganglia from OVX rats compared with their non-OVX counterparts. Acute exposure of nodose ganglia to 17beta-estradiol partly restored Ih density and accelerated Ih activation in Ah-type cells. In conclusion, Ih plays a significant role in modulating the excitability of myelinated Ah-type VGNs in adult female rats.

Objective To investigate ultrastructural changes in pulmonary tissue of a rat model of pulmonary fibrosis following treatment with compound Carapax trionycis ( C. trionycis ; Biejia in Chinese) formula. Methods Sixty male Sprague-Dawley rats were randomly divided into four groups ( n =15): compound C. trionycis formula high-, middle-, and low-dose groups as well as model group. Pulmonary fibrosis was induced by bleomycin. Five rats from each group were sacrificed on day 7, 14 and 28 of the drug treatment, respectively. The pulmonary tissue was harvested followed by hematoxylin-eosin staining and subsequent transmission electron microscopy. The Szapiel's method was used to assess the degree of alveolitis and pulmonary fibrosis. Results Compared with the model group, the compound C. trionycis formula groups had slighter pulmonary alveolitis after the 7-day treatment and also had alleviated alveolar inflammation and pulmonary fibrosis after the 14-day treatment. After the 28-day treatment, the compound C. trionycis formula groups showed deposition of a small amount of fibrous tissue and lesions occupying less than 21% of the whole lung area, while the model group showed focal or diffuse fibrous deposition, narrow alveolar cavity, disordered lung structure, and lesions in larger than 51% of the whole lung area. Conclusions The compound C. trionycis formula can inhibit the proliferation of collagen fibers and resist pulmonary fibrosis.