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UbiquitinC-terminal hydrolase-L1 (UCH-L1) is a cysteine hydrolase. It functions as a ubiquitin hydrolase, stabilizes the ubiquitin monomer, and affects cell division through cell cycle protein deubiquitination. Abnormal UCH-L1 expression is closely related to the occurrence and development of several tumors. Although some in vitro studies have demonstrated the significance of UCH-L1 in non-small-cell lung cancer (NSCLC), only few clinical studies have focused on the UCH-L1 expression in NSCLC, and the results are controversial and non-uniform. We investigated the UCH-L1 expression in 401 cases of surgically resected NSCLC, including 286 cases of adenocarcinoma (ADC) and 65 cases of squamous cell carcinoma. The associations between the UCH-L1 expression and clinicopathological features, programmed cell death-ligand 1 (PD-L1) expression, and prognostic significance were analyzed. For NSCLC, the UCH-L1 expression is associated with sex, smoking history, tumor size (>3 cm), lymphocyte infiltration, advanced pathological stages, and shortened overall survival (OS; 89.72 vs. 114.55 months; P = 0.005), but not PD-L1 expression. The UCH-L1 expression in ADC is associated with advanced pathological stages, pleural invasion, and shortened OS (90.38 vs. 118.55 months; P = 0.010). Multivariate analysis confirmed that UCH-L1 expression was an independent poor prognostic factor for NSCLC (OS: hazard ratio [HR], 1.854; 95% confidence interval [CI], 1.132-3.038; P = 0.014). Our results suggest that the UCH-L1 expression differs across tumors with different clinicopathological features, and it is related to poor prognosis.

At present, there are still no anti-Zika virus (ZIKV) drugs or vaccines approved by FDA with accurate targets and antiviral mechanisms. Considering the RNA G-quadruplex sequences in ZIKV genome, it is very meaningful to develop G-quadruplex binders as potential anti-ZIKV drugs with novel and accurate targets. In this paper, five classical G-quadruplex binders including Ber, Braco 19, NiL, 360A and PDS have been chosen to discuss their interaction with ZIKV RNA G-quadruplexes. PDS shows higher binding affinity and thermal stability than the other G-quadruplex binders. This property is further evidenced in cells by immunofluorescence microscopy. And PDS shows higher anti-ZIKV activity (EC50 = 4.2 ± 0.4 μM) than the other G-quadruplex binders as well as the positive control ribavirin, with a low cytotoxicity. By time-of-addition assay, PDS exerts antiviral activity at the post-entry process of ZIKV replication cycle, thus inhibiting ZIKV mRNA replication and protein expression. Furthermore, PDS combines with ZIKV NS2B-NS3 protease and reduces its catalytic activity. This study suggests that G-quadruplex binder PDS is an effective multi-target ZIKV inhibitor, which provides more guidance to design some novel anti-ZIKV drugs targeting ZIKV RNA G-quadruplexes.

Qian Ye, Ke-Jun Chen, Meng Jia, Sheng Fang Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Sheng FangDepartment of Dermatology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of ChinaEmail fangshengderm@163.comObjective: The aim of this study was to describe the clinical and histopathological characteristics of seborrheic keratosis (SK) with secondary tumor and identify associated factors.Methods: This study was a monocentric retrospective case-control study describing the factors associated with the development of tumors in SK. A total of 1365 patients with SK were admitted to our department between 2018 and 2021. All of the histopathological specimens and medical records of these patients were reviewed. We compared the data of 36 patients with tumors arising in SK with those of the remaining 1329 patients with only SK, which were designated the control group.Results: The incidence of tumors arising in SK that were biopsied was 2.6%. The tumor types included squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and keratoacanthoma (KA). Compared with other patients with SK, elderly patients with immunosuppression, patients presenting surrounding erythema or ulceration, and those with SK in exposed areas had an increased possibility of developing a secondary tumor. Tumors arising within SK have the histopathological features of ulceration, cytologic atypia, mitosis, “malignant horn”, trabecular cell cords, solar elastosis and severe inflammatory infiltration in the dermis.Conclusion: SK can show malignant progression in a small fraction of SK cases that are biopsied. This study is the first report on the clinical and histopathological characteristics of tumors arising in SK and identifies relevant factors in an Asian population.Keywords: seborrheic keratosis, tumor, clinical, histopathological

AIMS Human papilloma virus (HPV)-independent cervical adenocarcinoma (CA) is usually diagnosed at an advanced stage, while the therapeutic options are limited. Therefore, effective treatment options are required. The programmed cell death 1 (PD-1) inhibitor pembrolizumab has been approved for the treatment of patients with recurrent or metastatic cervical squamous cell carcinoma expressing PD-ligand 1 (PD-L1). However, no data regarding PD-L1 expression in HPV-independent CA are available. Thus, we evaluated the association between PD-L1 expression and the clinicopathological characteristics and survival of patients with HPV-independent CA. METHODS We evaluated PD-L1, mismatch repair (MMR) protein expression and the immune stromal features of 44 patients with HPV-independent CA. PD-L1 expression was defined as a combined positive score (CPS) ≥1 and a tumour proportion score (TPS) ≥1%. RESULTS PD-L1 expression was observed in 14 cases (31.8%) with CPS ≥1 and 12 cases (27.3%) with TPS ≥1%. PD-L1 expression, based on either the CPS or the TPS, was associated with a high tumour-infiltrating lymphocyte percentage (CPS = P

Background Intestinal lymphoma is a rare tumor. Contrast-enhanced ultrasound (CEUS) findings of intestinal lymphoma have not been reported previously, and the relationship between CEUS and clinicopathological features and prognostic factors is still unknown. Aim To describe the B-mode US and CEUS features of intestinal lymphoma and investigate the correlation of CEUS and histopathological features. Methods This was a single-center retrospective study. Eighteen patients with histologically confirmed intestinal lymphoma underwent B-mode US and CEUS examinations between October 2016 and November 2019. We summarized the features of B-mode US and CUES imaging of intestinal lymphoma and compared the frequency of tumor necrosis in intestinal lymphomas with reference to different pathological subtypes (aggressive or indolent) and clinical stage (early or advanced). The time-intensity curve parameters of CEUS were also compared between patients with normal and elevated serum lactate dehydrogenase. Results In B-mode imaging, four patterns were observed in intestinal lymphoma: Mass type (12/18, 66.7%), infiltration type (1/18, 5.6%), mesentery type (4/18, 22.2%) and mixed type (1/18, 5.6%). All cases were hypoechoic and no cystic areas were detected. On CEUS, most cases (17/18, 94.4%) showed arterial hyperechoic enhancement. All cases showed arterial enhancement followed by venous wash out. A relatively high rate of tumor necrosis (11/18, 61.1%) was observed in this study. Tumor necrosis on CEUS was more frequent in aggressive subtypes (10/13, 76.9%) than in indolent subtypes (1/5, 20.0%) (P = 0.047). There were no correlations between tumor necrosis and lesion size and Ann Arbor stage. There was no significant difference in time-intensity curve parameters between normal and elevated lactate dehydrogenase groups. Conclusion B-mode US and CEUS findings of intestinal lymphoma are characteristic. We observed a high rate of tumor necrosis, which appeared more frequently in aggressive pathological subtypes of intestinal lymphoma.

Meng Jia, Feng-Zeng Li, Qian Ye, Ke-Jun Chen, Sheng Fang Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Sheng FangDepartment of Dermatology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of ChinaEmail fangshengderm@163.comBackground: Heat shock proteins (HSPs), a group of heat stress proteins, are characterized by highly conserved properties. Malignant transformation is a cellular stress, and the expression of HSPs may be affected during this process. Heat shock protein 105 (HSP105) is a protective protein that has long been observed in many cancer types, but little attention has been given to cutaneous squamous cell carcinoma (CSCC). As such, the objectives of this study were to observe the expression of HSP105 on CSCC and evaluate its correlation with clinicopathological characteristics.Methods: This retrospective study enrolled 60 patients with CSCC. The patients’ clinical data, including sex, age, tumor location, tumor type, and degree of pathological differentiation, were collected. The expression of HSP105 was measured by Western blot and immunohistochemical staining.Results: HSP105 expression was decreased in CSCC (HSCORE=0.65 (0.30, 1.98)) compared with normal skin (HSCORE=2.20 (1.50, 2.80)) (P< 0.001). These results were consistent with the Western blot analysis. HSP105 immunostaining of Bowen disease (HSCORE=1.28 (1.08, 2.40)) revealed higher expression than in verrucous carcinoma (HSCORE=0.30 (0.23, 0.85)), keratoacanthoma (HSCORE=0.53 (0.29, 0.93)) and acantholytic squamous cell carcinoma (HSCORE=0.53 (0.41, 0.68) (P< 0.01)). Poorly differentiated CSCC showed significantly higher expression of HSP105.Conclusion: Our study reveals for the first time that the expression of HSP105 is decreased in CSCC. We suggest that the molecular mechanisms underlying the differential expression of HSP deserve a more rigorous future study, the results of which might explain its role in carcinogenesis and its potential as a target for selective tumor therapy.Keywords: heat shock protein 105, cutaneous, squamous cell carcinoma, expression

BACKGROUND Laryngeal contact granuloma (LCG) is difficult to treat and frequently associated with high persistence and recurrence, despite the availability of both surgical and pharmacological treatment options. An appropriate strategy is therefore needed to help patients with multiple recurrences of LCG to potentially avoid unnecess-ary surgery. CASE SUMMARY We describe the case of a 34-year-old male patient with recurrent LCG in which a good response was achieved through successful management of laryngophar-yngeal reflux disease using a combination pharmacotherapeutic regimen consisting of anti-reflux therapy, pepsin secretion inhibition, bile acid neutralization, and lifestyle modifications. This patient underwent surgery to excise the granuloma, then relapsed, underwent a second surgery, which was followed by a second recurrence. The granuloma then disappeared after 9 mo of combined treatment with ilaprazole enteric-coated capsules (10 mg qd), mosapride tablets (5 mg tid) and compound digestive enzyme capsules (2 tablets). The drug regimen was discontinued after one year, and no recurrence of the lesion has been reported during the one-year follow-up period. CONCLUSION We report a combination of pharmacotherapeutics and lifestyle modifications for the management of laryngopharyngeal reflux disease to address recurring LCG.

This case report describes 26-year-old woman who had multiple clusters of pale-pink lichenoid papules since childhood and the accompanying itching was intense. Skin biopsy revealed obvious fissures had formed under the epidermis. The patient was diagnosed with epidermolysis bullosa pruriginosa and was successfully treated with tofacitinib.

Oral cancer is among the top 10 causes of death due to cancer worldwide. The prognosis for oral cancer patients is not good, with a 5-year survival rate of only 50%. Earlier and more precise classification will help clinicians make a diagnosis and patients survive. With the advancement of technology, computer-aided detection methods are used to help clinicians form therapy strategies. Gray-level co-occurrence matrix (GLCM) feature extraction of images describing the spatial distribution of gray levels is widely used in medical imaging analysis. Scanned laser pico projector (SLPP) has advantages such as high intensity, directivity, coherence, and mono-color with low bandwidth. In this study, GLCM feature extraction and SLPP reflex images were combined to make a small, non-staining, noninvasive classification system. According to the various image characteristics in oral carcinogenesis, SLPP reflex images better define the borders and three-dimensional structures and provide effective GLCM features such as contrast, energy, and homogeneity to classify carcinogenesis in dysplastic oral keratinocyte (DOK) and normal oral keratinocyte (NOK) cells. Moreover, it also reliably classifies highly metastatic (HSC-3) and tongue cancer (CAL-27) cells. A promising computer-aided classification system for oral cancer was developed to build a reliable intraoral examination system for in situ computer-aided diagnosis in normal clinics.

The sarcomatoid variant of anaplastic large cell lymphoma is an extremely rare histologic pattern of anaplastic large cell lymphoma that consists of spindle-shaped neoplastic cells and is easily misdiagnosed as a soft tissue sarcoma. We report a case of the sarcomatoid variant of anaplastic large cell lymphoma that was initially diagnosed as an inflammatory myofibroblastic tumor in our hospital and as liposarcoma after consultation. This article analyzed the features of this entity by reviewing the literature. Only 15 cases have been reported, most of which were misdiagnosed as sarcoma, sarcomatoid carcinoma, or inflammatory myofibroblastic tumor. Most of the reported cases showed a myxoid stroma, with a variable number of inflammatory cells. The hallmark cells usually can be found by careful evaluation of the slides. Immunohistochemistry including CD30, EMA, and ALK are the most useful for diagnosis. Most are III or IV stage, and have a good prognosis after chemotherapy.

Background Treatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy. Glypican-3 (GPC3) is an emerging HCC therapeutic target; therefore, antibodies against GPC3 would be useful tools for developing immunotherapies for HCC. Methods We isolated a novel human monoclonal antibody, 32A9, by phage display technology. We determined specificity, affinity, epitope and anti-tumor activity of 32A9, and developed 32A9-based immunotherapy technologies for evaluating the potency of HCC treatment in vitro or in vivo. Results 32A9 recognized human GPC3 with potent affinity and specificity. The epitope of 32A9 was located in the region of the GPC3 protein core close to the modification sites of the HS chain and outside of the Wnt-binding site of GPC3. The 32A9 antibody significantly inhibited HCC xenograft tumor growth in vivo. We then pursued two 32A9-based immunotherapeutic strategies by constructing an immunotoxin and CAR-T cells. The 32A9 immunotoxin exhibited specific cytotoxicity to GPC3-positive cancer cells, while 32A9 CAR-T cells efficiently eliminated GPC3-positive HCC cells in vitro and caused HCC xenograft tumor regressions in vivo. Conclusions Our study provides a rationale for 32A9 as a promising GPC3-specific antibody candidate for HCC immunotherapy.

Background This study aimed to comprehensively investigate the effect of spread through air spaces (STAS) on clinicopathologic features, molecular characteristics, immunohistochemical expression, and prognosis in lung adenocarcinomas (ADC) and squamous cell carcinomas (SQCC) based on the 8th edition AJCC/UICC staging system. Methods In total, 303 ADC and 121 SQCC cases were assessed retrospectively. Immunohistochemical staining was performed for E-cadherin, vimentin, Ki67, survivin, Bcl-2, and Bim. Correlations between STAS and other parameters were analyzed statistically. Results STAS was observed in 183 (60.4%) ADC and 39 (32.2%) SQCC cases. In ADC, the presence of STAS was associated with wild-type EGFR, ALK and ROS1 rearrangements, low E-cadherin expression, and high vimentin and Ki67 expression. In SQCC, STAS was associated with low E-cadherin expression and high vimentin and survivin expression. Based on univariate analysis, STAS was associated with significantly shorter disease-free survival (DFS) and overall survival (OS) in ADC. In SQCC, STAS tended to be associated with shorter OS. By multivariate analysis, STAS was an independent poor prognostic factor in ADC for DFS but not OS. Stratified analysis showed that STAS was correlated with shorter DFS for stage I, II, IA, IB, and IIA ADC based on univariate analysis and was an independent risk factor for DFS in stage I ADC cases based on multivariate analysis. Conclusions Our findings revealed that STAS is an independent negative prognostic factor for stage I ADC using the new 8th edition AJCC/UICC staging system. Stage I patients with STAS should be followed up more closely and might need different treatment strategies.

Long noncoding RNA (lncRNA) long intergenic nonprotein-coding RNA, p53-induced transcript (LINC-PINT) has shown anti-invasive activity in lung and colon cancer cells. However, the role of LINC-PINT in thyroid cancer is unclear. In the present work, we explored the expression of LINC-PINT in 60 paired thyroid cancer and adjacent normal tissues. The clinical significance and biological function of LINC-PINT in thyroid cancer were determined. LINC-PINT expression was downregulated in thyroid cancer relative to adjacent normal tissues (p = 0.0002). Low expression of LINC-PINT was significantly associated with advanced tumor node metastasis (TNM) stage (p = 0.0306) and lymph node metastasis (p = 0.0359). Ectopic expression of LINC-PINT suppressed the proliferation, invasion, and tumorigenesis of thyroid cancer cells. Mechanistically, LINC-PINT associated with and downregulated microRNA (miR)-767-5p. Moreover, LINC-PINT overexpression relieved miR-767-5p-mediated repression of ten-eleven translocation 2 (TET2). miR-767-5p promoted aggressiveness of thyroid cancer, which was reversed by overexpression of TET2. Coexpression of miR-767-5p or depletion of TET2 rescued the inhibitory effect of LINC-PINT on thyroid cancer cell proliferation and invasion. In addition, there was a negative correlation between miR-767-5p and LINC-PINT in thyroid cancer (r = −0.34772, p = 0.01789). Taken together, LINC-PINT functions as a tumor suppressor in thyroid cancer via the miR-767-5p/TET2 axis, representing a potential therapeutic target for thyroid cancer., Graphical Abstract, Long noncoding RNA LINC-PINT functions as a tumor suppressor in thyroid cancer. Its downregulation contributes to thyroid cancer growth and progression. Restoration of LINC-PINT provides a potential therapeutic strategy against thyroid cancer.

Background Spread through air spaces (STAS) is a spreading phenomenon of lung cancers, which is defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. To date, several articles have reviewed the studies concerning the significance of STAS; however, most articles focused on the prognosis without summarizing the significance of STAS on other aspects. In this review, we comprehensively summarized the current literature related to STAS, so as to explore the clinical significance of STAS from multiple perspectives. Main body This section provided a comprehensive overview of the significance of STAS from multiple perspectives and summarized current controversies and challenges in the diagnosis and clinical application. Conclusion STAS is a conspicuous spreading phenomenon of lung cancers indicating worse prognosis; nevertheless, the treatment strategy for patients with STAS remains to be discussed. Further studies are needed to elaborate whether a STAS-positive patient who underwent limited resection needs a second operation or postoperative adjuvant treatment. Meanwhile, the internal mechanism of STAS formation is largely undiscovered. Whether the capability of detachment-migration-reattachment in STAS tumor cells is achieved at the time of primary tumorigenesis or in the progress of tumor development needs to be studied, and the related signal pathways or genetic alterations need to be explored. With this information, it may be possible to improve the prognosis of patients with STAS-positive lung cancers.

The present study sought to investigate the effect of non-mitogenic acidic fibroblast growth factor (NM-aFGF) loaded PEGylated nanoliposomes (NM-aFGF-PEG-lips) combined with the ultrasound-targeted microbubble destruction (UTMD) technique on modulating diabetic cardiomyopathy (DCM)and the mechanism involved. Animal studies showed that the diabetes mellitus (DM) group exhibited typical myocardial structural and functional changes of DCM. The indexes from the transthoracic echocardiography showed that the left ventricular function in the NM-aFGF-PEG-lips + UTMD group was significantly improved compared with the DM group. Histopathological observation further confirmed that the cardiomyocyte structural abnormalities and mitochondria ultrastructural changes were also significantly improved in the NM-aFGF-PEG-lips + UTMD group compared with DM group. The cardiac volume fraction (CVF) and apoptosis index in the NM-aFGF-PEG-lips + UTMD group decreased to 10.31 ± 0.76% and 2.16 ± 0.34, respectively, compared with those in the DM group (CVF = 21.4 ± 2.32, apoptosis index = 11.51 ± 1.24%). Moreover, we also found significantly increased superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity as well as clearly decreased lipid hydroperoxide levels and malondialdehyde (MDA) activity in the NM-aFGF-PEG-lips + UTMD group compared with those in the DM group (p

BACKGROUND: Given low incidence and high heterogeneity, the treatment strategies of anterior mediastinal masses (AMMs) are diverse based on pathology. The purpose of the study is to evaluate the usefulness of contrast-enhanced ultrasound (CEUS) in transthoracic biopsy of malignant AMMs when compared with that of ultrasound (US) alone and to screen lesions that are more suitable for CEUS evaluation and guidance. METHODS: We reviewed all the US- and CEUS-guided transthoracic core needle biopsy (CNB) of AMMs performed in National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between July 2013 and April 2019. A total of 68 patients (mean age 36 years; male-female ration 1.6:1) who were suspected with malignant AMMs were enrolled in the study. Among them, 20 patients received pre-biopsy CEUS examination (CEUS group); 48 patients underwent conventional US examination and guidance (US group). Demographic, radiologic, pathologic, medical records, and biopsy procedure details were retrospectively reviewed and compared between the two groups. RESULTS: The display of internal necrosis areas was significantly improved when compared with that of the conventional US (70%, 30%; P=0.008). Specifically, CEUS improved the diagnostic accuracy of US-guided transthoracic biopsy (95.0%, 79.2%; P=0.210) and especially for AMMs exceeding 10 cm (100%, 68.2%; P=0.040) and carcinoma (100%, 0%; P=0.048). The number of punctures in US group and CEUS group was 2.6 and 4.4 times, respectively (P

Background Wolbachia wMel is the most commonly used strain in rear and release strategies for Aedes aegypti mosquitoes that aim to inhibit the transmission of arboviruses such as dengue, Zika, Chikungunya and yellow fever. However, the long-term establishment of wMel in natural Ae. aegypti populations raises concerns that interactions between Wolbachia wMel and Ae. aegypti may lead to changes in the host genome, which could affect useful attributes of Wolbachia that allow it to invade and suppress disease transmission. Results We applied an evolve-and-resequence approach to study genome-wide genetic changes in Ae. aegypti from the Cairns region, Australia, where Wolbachia wMel was first introduced more than 10 years ago. Mosquito samples were collected at three different time points in Gordonvale, Australia, covering the phase before (2010) and after (2013 and 2018) Wolbachia releases. An additional three locations where Wolbachia replacement happened at different times across the last decade were also sampled in 2018. We found that the genomes of mosquito populations mostly remained stable after Wolbachia release, with population differences tending to reflect the geographic location of the populations rather than Wolbachia infection status. However, outlier analysis suggests that Wolbachia may have had an influence on some genes related to immune response, development, recognition and behavior. Conclusions Ae. aegypti populations remained geographically distinct after Wolbachia wMel releases in North Australia despite their Wolbachia infection status. At some specific genomic loci, we found signs of selection associated with Wolbachia, suggesting potential evolutionary impacts can happen in the future and further monitoring is warranted.

Background: Rapid and accurate high-throughput estimation of radiation dose aims to help medical rescue in nuclear radiation accident. However, current methods of dose estimation are still lacking of speedy or accuracy. P53 signaling pathway plays an important role in DNA damage repair and cell apoptosis induced by ionizing radiation. The changes of radiation-induced P53 related genes in the early stage of ionizing radiation should compensate for the deficiency of lymphocyte decline and γ-H2AX analysis as novel biomarkers of radiation damage. Methods: Bioinformatic analysis was performed on previous data to find candidate genes from human peripheral blood irradiated in vitro. The radiation sensitivity and baseline levels of candidate genes were verified. The approximate threshold for guiding medical treatment was estimated for each gene, and four genes were combined to construct an effectively early dose estimation model of radiation.Results: Four p53-related genes, DDB2, AEN, TRIAP1 and TRAF4, were screened and verified their significant radiosensitivity. Their expressions were stable without gender or age difference in healthy population, but significantly up-regulated by radiation, with time specificity and dose dependence in 2h-24h after irradiation. Further studies showed these genes can be used as indicators for early medical treatment in acute radiation injury. The effective combination of the four genes could achieve a more accurate dose assessment and injury classification for large-scale wounded patients within 24 hours post exposure.Conclusions: This is the first time to investigate the potential biomarkers of ionizing radiation by systematic study. The effective combination of the four genes provides a new model for dose estimation and injury classification of a large number of exposed population in acute nuclear accidents, and also provides a new idea and method.

Mosquitoes carrying Wolbachia endosymbionts are being released in many countries for arbovirus control. The wMel strain of Wolbachia blocks Aedes-borne virus transmission and can spread throughout mosquito populations by inducing cytoplasmic incompatibility. Aedes aegypti mosquitoes carrying wMel were first released into the field in Cairns, Australia, over a decade ago, and with wider releases have resulted in the near elimination of local dengue transmission. The long-term stability of Wolbachia effects is critical for ongoing disease suppression, requiring tracking of phenotypic and genomic changes in Wolbachia infections following releases. We used a combination of field surveys, phenotypic assessments, and Wolbachia genome sequencing to show that wMel has remained stable in its effects for up to a decade in Australian Ae. aegypti populations. Phenotypic comparisons of wMel-infected and uninfected mosquitoes from near-field and long-term laboratory populations suggest limited changes in the effects of wMel on mosquito fitness. Treating mosquitoes with antibiotics used to cure the wMel infection had limited effects on fitness in the next generation, supporting the use of tetracycline for generating uninfected mosquitoes without off-target effects. wMel has a temporally stable within-host density and continues to induce complete cytoplasmic incompatibility. A comparison of wMel genomes from pre-release (2010) and nine years post-release (2020) populations show few genomic differences and little divergence between release locations, consistent with the lack of phenotypic changes. These results indicate that releases of Wolbachia-infected mosquitoes for population replacement are likely to be effective for many years, but ongoing monitoring remains important to track potential evolutionary changes.Author summaryWolbachia are endosymbionts that can block the transmission of arboviruses by mosquitoes. Aedes aegypti mosquitoes carrying the wMel strain of Wolbachia have been released in ‘population replacement’ interventions, which aim to establish wMel in mosquito populations, thereby reducing their ability to spread disease. Wolbachia population replacement programs began only a decade ago, raising uncertainty about their long-term effectiveness. Here we provide a comprehensive assessment of the long-term stability of wMel from the very first Wolbachia population replacement release. We show that there is no evidence for changes in the phenotypic effects of wMel in mosquitoes, and confirm that the wMel genome has changed very little in the decade since field releases began. wMel remains at high levels within mosquitoes, suggesting that its ability to block virus transmission has been retained. Our data provides confidence that Wolbachia population replacement releases will provide ongoing protection against arbovirus transmission.

Detection of the Wolbachia endosymbiont in Aedes aegypti mosquitoes through real-time polymerase chain reaction assays is widely used during and after Wolbachia releases in dengue reduction trials involving the wMel and wAlbB strains. Although several different primer pairs have been applied in current successful Wolbachia releases, they cannot be used in a single assay to distinguish between these strains. Here, we developed a new diagnostic primer pair, wMwA, which can detect the wMel or wAlbB infection in the same assay. We also tested current Wolbachia primers and show that there is variation in their performance when they are used to assess the relative density of Wolbachia. The new wMwA primers provide an accurate and efficient estimate of the presence and density of both Wolbachia infections, with practical implications for Wolbachia estimates in field collected Ae. aegypti where Wolbachia releases have taken place.

BackgroundAlthough spread through air spaces (STAS) is a robust biomarker in surgically resected lung cancer, its application to biopsies is challenging. Moreover, limited resection is not an effective treatment for STAS-positive lung adenocarcinoma. This study aimed to identify histologic features from preoperative percutaneous transthoracic needle biopsies (PTNBs) to predict STAS status in the subsequently resected specimens, and thus help in selecting the surgical extent.MethodsBetween January 2014 and December 2015, 111 PTNB specimens and subsequent resection specimens from consecutive lung adenocarcinoma patients were retrospectively examined. Histopathologic features of PTNB specimens and presence of STAS in subsequent resection specimens were evaluated and correlations between them were analyzed statistically.ResultsThe study participants had a mean age of 59 years (range, 35–81) and included 50 men and 61 women. Thirty-six patients were positive for STAS whereas 75 were negative. The micropapillary/solid histologic subtypes of lung adenocarcinoma (26 of 39; 66.7%;P P P P P ConclusionsMicropapillary/solid histologic subtype, ITB, and desmoplasia in preoperative PTNB specimens were independently associated with STAS in the subsequent resection specimens. Therefore, these can predict STAS and may help to optimize therapeutic planning.

Repeated morphine exposure has been shown to induce neuronal plasticity in reward-related areas of the brain. miR-132, a CREB-induced and activation-dependent microRNA, has been suggested to be involved in the neuronal plasticity by increasing neuronal dendritic branches and spinogenesis. However, it is still unclear whether miR-132 is related to morphine dependence. Here, we investigate whether miR-132 is involved in morphine dependence and whether it is related to the structural plasticity of the dentate gyrus (DG) neurons. Sprague-Dawley rats are treated with increasing doses of morphine injection for six consecutive days to develop morphine dependence. Our results show that dendritic branching and spinogenesis of the DG neurons of morphine dependent rats are increased. Morphine treatment (24 h) promotes the differentiation of N2a cells stably expressing μ-opioid receptor by up-regulating miR-132 expression. Moreover, inhibiting miR-132 3p (but not 5p) of the DG neurons can reverse the structural plasticity and disrupt the formation of morphine dependence in rats. These findings indicate that miR-132 in the DG neurons is involved in morphine dependence via modifying the neuronal plasticity.

The development of a safe and effective COVID-19 vaccine is of paramount importance to terminate the current pandemic. An adjuvant is crucial for improving the efficacy of the subunit COVID19 vaccine. α-Galactosylceramide (αGC) is a classical iNKT cell agonist which causes the rapid production of Th1- and Th2-associated cytokines; we, therefore, expect that the Th1- or Th2-skewing analogues of αGC can better enhance the immunogenicity of the receptor-binding domain in the spike protein of SARS-CoV-2 fused with the Fc region of human IgG (RBD-Fc). Herein, we developed a universal synthetic route to the Th1-biasing (α-C-GC) and Th2-biasing (OCH and C20:2) analogues. Immunization of mice demonstrated that αGC-adjuvanted RBD-Fc elicited a more potent humoral response than that observed with Alum and enabled the sparing of antigens. Remarkably, at a low dose of the RBD-Fc protein (2 μg), the Th2-biasing agonist C20:2 induced a significantly higher titer of the neutralizing antibody than that of Alum.

Detection of the Wolbachia endosymbiont in Aedes aegypti mosquitoes through real-time PCR assays is widely used during and after Wolbachia releases in dengue reduction trials involving the wMel and wAlbB strains. However, primers applied in current successful Wolbachia releases cannot be used in a single assay to distinguish between these strains. Here, we developed a new diagnostic primer pair wMA which can detect wMel or wAlbB infection in the same assay. We also tested current Wolbachia primers and show that there is variation in their performance when they are used to assess the relative density of Wolbachia. The new wMA primers provide an accurate and efficient estimate of the presence and density of both Wolbachia infections.

Mitochondrial dysfunction is considered as a key mediator in the pathogenesis of diabetic nephropathy (DN). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of DN. In this study, we investigated the role of progranulin (PGRN), a secreted glycoprotein, in mediating mitochondrial homeostasis and its therapeutic potential in DN. We found that the level of PGRN was significantly reduced in the kidney from STZ-induced diabetic mice and patients with biopsy-proven DN compared with healthy controls. In DN model, PGRN-deficient mice aggravated podocyte injury and proteinuria versus wild-type mice. Functionally, PGRN deficiency exacerbated mitochondrial damage and dysfunction in podocytes from diabetic mice. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated high glucose-induced mitochondrial dysfunction in podocytes accompanied by enhanced mitochondrial biogenesis and mitophagy. Inhibition of mitophagy disturbed the protective effects of PGRN in high glucose-induced podocytotoxicity. Mechanistically, we demonstrated that PGRN maintained mitochondrial homeostasis via PGRN-Sirt1-PGC-1α/FoxO1 signaling-mediated mitochondrial biogenesis and mitophagy. Finally, we provided direct evidence for therapeutic potential of PGRN in mice with DN. This study provides new insights into the novel role of PGRN in maintaining mitochondrial homeostasis, suggesting that PGRN may be an innovative therapeutic strategy for treating patients with DN.

Background Immunoglobulin A (IgA) vasculitis with nephritis (IgAVN) and IgA nephropathy (IgAN) are widely considered as related diseases. Considerable evidences support the notion of involvement of complement activation in both IgAVN and IgAN. Our previous studies identified a genetic variant in complement factor H (CFH), rs6677604, as an IgAN-susceptible variant by genome-wide association study, and further confirmed its linkage to CFHR3-1Δ and proved its influence on complement activation and thereby on IgAN susceptibility. Aim To explore the role of rs6677604 in complement activation of IgAVN. Methods In this study, we enrolled 632 patients with IgAVN, 1178 patients with IgAN and 902 healthy controls. The genotype of rs6677604 was measured by TaqMan allele discrimination assays or was extracted from genome-wide association study data. Results The frequency of the rs6677604-A allele was significantly higher in IgAVN than in IgAN. However, no significant differences were observed between IgAVN and the controls. Higher complement factor H (FH) levels were observed in IgAVN than IgAN, and positive correlation between circulating FH and C3 levels was present in IgAVN. In both IgAVN and IgAN, rs6677604-A was associated with less intensity of glomerular C3 deposits. In agreement with the higher frequency of rs6677604-A in IgAVN, the glomerular C3 deposits of patients with IgAVN were less intense than those in IgAN. Conclusion Our findings suggest that genetic variation in CFH (rs6677604) is involved in the phenotype of complement activation in both IgAVN and IgAN. Moreover, rs6677604 might contribute to the difference of complement activation intensity between IgAVN and IgAN.

Anxiety is considered an important protracted abstinence symptom that can aggravate craving and relapse risk in opioid addicts. Although the insular cortex (IC) has been reported to be a key brain region in mediating emotional and motivational alterations induced by drug consumption and withdrawal, the role of IC in anxiety related to protracted abstinence remains elusive. In this study, we found that: (1) anxiety-like behavior in morphine-dependent mice became significant after 28 days of withdrawal, while their physical symptoms became undetectable. (2) Activated glutamatergic neurons in the medial IC, but not the anterior or posterior IC were significantly increased after 28 days of withdrawal. Bilateral lesion of the medial IC, but not the anterior or posterior IC with ibotenic acid (IBO) alleviated the anxiety-like behavior. (3) Expression of Wnt7a in the medial IC was significantly increased after 28 days of withdrawal, and specific down-regulation of Wnt7a with AAV-shWnt7a also alleviated the anxiety-like behavior. The findings reveal the medial IC is involved in mediating anxiety-like behavior related to morphine protracted abstinence, in which Wnt7a plays a critical role.

BACKGROUND: The use of surgery in patients with colorectal cancer (CRC) aged ≥90 years remains controversial. This study aimed to evaluate the short-term postoperative and long-term oncologic outcomes of CRC surgery in patients within this age group. METHODS: A total of 151 consecutive nonagenarian patients who underwent CRC surgery were included from 3 different hospitals. The Comprehensive Complication Index (CCI) was used to grade postoperative complications. Univariate and multivariate analyses were conducted to identify factors associated with CCI and overall survival (OS). RESULTS: The patients had a mean age of 92.8 years (standard deviation ±1.9 years). Forty-six patients (30.5%) underwent emergency surgery, and 105 patients (69.5%) underwent elective surgery. The postoperative complications rate was 66.2% (100/151), and the mean CCI was 26.3 (±30.8). Twenty-three patients (15.2%) died postoperatively, and the perioperative mortality rates for elective surgery and emergency surgery were 7.6% (8/105) and 32.6% (15/46), respectively (P17 were associated with poor OS. CONCLUSIONS: CRC surgery should not be denied to nonagenarian patients. Surgical treatment can be performed with acceptable morbidity and mortality, and achieves long-term survival in a select group.

Bullous scabies (BS) is a rare atypical clinical variant of scabies and is easily confused with bullous disorders. The diagnosis of BS is always a challenge, and physicians often misdiagnose BS patients. Patients with BS admitted from 2012 to 2020 were enrolled in this study. The clinical, dermoscopic, and pathological characteristics of the patients were analyzed retrospectively. Ten patients with BS were enrolled in this study. Seven of the 10 patients were male. The bullae were most commonly found on the thighs and arms (80% of patients). Only 30% of patients (3/10) tested positive for mites and/or eggs by the initial skin scraping, but 100% (5/5) of the patients who received dermoscopy tested positive. Among these 10 patients, only five received a skin biopsy. Subepidermal (4/5) and intraepidermal (1/5) bullae with eosinophil and neutrophil infiltration were observed in five patients. Direct immunofluorescence (DIF) indicated linear deposition of IgG in the basement membrane zone in three patients. Physicians should consider the possibility of BS in patients with blisters, pruritus, and poor response to corticosteroids. Dermoscopy should be prioritized for the differential diagnosis of BS to exclude other bullous disorders. Finally, a biopsy should be performed on each patient with bullae.

BACKGROUND The impact of self-expandable metal stent (SEMS) for malignant right colonic obstruction remains undefined. The aim of this study was to compare short-term postoperative and long-term oncologic outcomes of colonic stenting as a bridge to surgery (SBTS) and urgent colectomy for patients with malignant right-sided obstruction. METHODS A total of 98 consecutive patients who underwent SEMS placement during the period 2004-2015 from three hospitals were included. For comparative analyses, patients were matched (1:2) with 196 patients treated with emergency colectomy from our prospective database. RESULTS The two groups were comparable in terms of demographics and tumor characteristics. The proportion of patients who underwent laparoscopic colectomy was higher in SBTS group than urgent colectomy group (75.5% vs. 37.2%; p

BackgroundGlypican-3 (GPC3), a cell surface glycoprotein that is pathologically highly expressed in hepatocellular carcinoma (HCC), is an attractive target for immunotherapies, including chimeric antigen receptor (CAR) T cells. The serum GPC3 is frequently elevated in HCC patients due to the shedding effect of cell surface GPC3. The shed GPC3 (sGPC3) is reported to block the function of cell-surface GPC3 as a negative regulator. Therefore, it would be worth investigating the potential influence of antigen shedding in anti-GPC3 CAR-T therapy for HCC.MethodsIn this study, we constructed two types of CAR-T cells targeting distinct epitopes of GPC3 to examine how sGPC3 influences the activation and cytotoxicity of CAR-T cells in vitro and in vivo by introducing sGPC3 positive patient serum or recombinant sGPC3 proteins into HCC cells or by using sGPC3-overexpressing HCC cell lines.ResultsBoth humanized YP7 CAR-T cells and 32A9 CAR-T cells showed GPC3-specific antitumor functions in vitro and in vivo. The existence of sGPC3 significantly inhibited the release of cytokines and the cytotoxicity of anti-GPC3 CAR-T cells in vitro. In animal models, mice carrying Hep3B xenograft tumors expressing sGPC3 exhibited a worse response to the treatment with CAR-T cells under both a low and high tumor burden. sGPC3 bound to CAR-T cells but failed to induce the effective activation of CAR-T cells. Therefore, sGPC3 acted as dominant negative regulators when competed with cell surface GPC3 to bind anti-GPC3 CAR-T cells, leading to an inhibitory effect on CAR-T cells in HCC.ConclusionsWe provide a proof-of-concept study demonstrating that GPC3 shedding might cause worse response to CAR-T cell treatment by competing with cell surface GPC3 for CAR-T cell binding, which revealed a new mechanism of tumor immune escape in HCC, providing a novel biomarker for patient enrolment in future clinical trials and/or treatments with GPC3-targeted CAR-T cells.

Parathyroid hormone (PTH)1–34 is an effective peptide drug for osteoporosis therapy. However, the half-life of PTH1–34 in vivo is short, leading to the need for frequent injections of this drug during its treatment. To prolong the half-life of PTH1–34, a novel PTH1–34 analog was generated based on fatty acid generation, and its synthesis process included recombinant protein expression, side-chain modification, and peptide decoration. The PTH1–34 variant was expressed in Escherichia coli, with a single Lys (position 27) retained as a modification site. The side chain, –AEEA-γGlu-C18 diacid, was synthesized using 2-chlorotrityl chloride resin as a solid support, and then was conjugated to the PTH1-34 variant to form PTH-Lys27-AGC. Reversed-phase chromatography confirmed a high final purity (>98%) of the target compound; in vitro bioactivity tests showed that PTH-1 receptor potency of PTH-Lys27-AGC was comparable to that of the native PTH1–34. A competitive human serum albumin binding test demonstrated a high albumin affinity of PTH-Lys27-AGC in comparison to PTH1–34. In summary, we developed a novel PTH1–34 analog, PTH-Lys27-AGC, which may be a long-acting agent for osteoporosis treatment in the future.

In urban rail traction substation, the high-power four quadrant converter can be used to replace the existing 24 pulse rectifier. The four quadrant converter can realize bidirectional flow of energy, provide traction energy when the train is in traction state, and feed the energy back to the AC power grid when the train is braking, so as to achieve the purpose of energy saving. In this paper, a 2MW prototype is designed, and the main circuit topology and parameters are given. When LCL filter is used, two control strategies, passive damping and active damping, are studied, and their effectiveness is verified by Matlab/Simulink. The multiple topology and the corresponding droop control strategy are also given. At last, a 2MW high-power prototype is built, and some experiments have been carried out.

Background: Central and peripheral location as well as thyroid transcription factor-I (TTF-1) expression was reported to be associated with different characteristics and prognosis of small-cell lung cancer (SCLC). This study aimed to investigate differential expression of PD-L1 in different SCLC subtypes, and in biopsy and resection specimens.Methods: We retrospectively analyzed 142 SCLC tumor samples using immunohistochemistry to correlate PD-L1 (22C3) expression with clinicopathologic features and survival data.Results: PD-L1 expression was found in 19.7% SCLCs (28/142) and was more frequent in females than in males (32%, 16/50 vs. 13%, 12/92, p = 0.009), in central type than in peripheral type SCLCs (26%, 26/100 vs. 4.8%, 2/42, p = 0.003), and in TTF-1 positive than in negative SCLCs (23.8%, 25/105 vs. 8.1%, 3/37, p = 0.039). PD-L1 expression was associated with vascular (p = 0.001) and lymphatic invasion (p = 0.001). There was no significant difference in PD-L1 expression between biopsy and resection specimens. On univariate analysis, patients with PD-L1 expression had significantly shorter progression-free survival (PFS; p = 0.026) and overall survival (OS; p = 0.012). Multivariate analysis revealed that PD-L1 expression was an independent prognostic factor for OS (HR, 2.317; 95% CI 1.199–4.478; p = 0.012) and PFS (HR, 1.636; 95% CI 0.990–2.703; p = 0.051) in SCLC.Conclusions: PD-L1 expression was more frequent in central type, TTF-1 positive SCLCs, and predicted a poor clinical outcome in these patients. Therefore, tumor location and TTF-1 expression could predict expression status of PD-L1, and could potentially serve as clinical response to immunotherapy.

Posaconazole (PCZ) is effective in preventing and salvage treatment invasive fungal infections in patients with hematologic disorders. However, PCZ displays highly variable individual pharmacokinetics affecting its efficacy and safety. To investigate the correlation between PCZ concentration and efficacy and safety, the following key influencing factors were explored. A total of 285 trough plasma concentrations (Cmin) of 81 Chinese patients receiving PCZ oral suspension for prophylaxis or treatment of invasive fungal infections were collected in this study. The relationships between Cmin values and clinical response and hepatotoxicity were investigated as well as the incidence of clinical response under different Cmin values of PCZ with a logistic regression model. The concentration of PCZ showed remarkable differences among patients with haematologic disorders. PCZ Cmin values of 0.76 and 1.0 µg/mL were both associated with an over 80% probability of successful response to prophylaxis and treatment of fungal infections, respectively. No association between Cmin values and hepatotoxicity was noted (P > 0.05). Gender, albumin, and co-administration of proton pump inhibitor (PPI) were identified as independent factors influencing PCZ Cmin by multiple linear regression analysis. Furthermore, patients’ C-reactive protein (CRP), albumin, and co-administration of PPI exhibited significant effects on the therapeutic window of patients receiving PCZ for prophylaxis. The plasma concentration is closely associated with therapeutic efficacy of PCZ. It is necessary to adjust the dosing regimens based on PCZ Cmin to obtain an optimal therapeutic response.

Background Immunoglobulin A nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. Previous studies have proved that renal-deposited IgA in IgAN came from circulating IgA1-containing complexes (CICs). Methods To explore the composition of CICs in IgAN, we isolated CICs from IgAN patients and healthy controls and then quantitatively analyzed them by mass spectrometry. Meanwhile, the isolated CICs were used to treat human mesangial cells to monitor mesangial cell injury. Using the protein content and injury effects, the key constituent in CICs was identified. Then the circulating levels of identified key constituent–IgA complex were detected in an independent population by an in-house-developed enzyme-linked immunosorbent assay. Results By comparing the proteins of CICs between IgAN patients and controls, we found that 14 proteins showed significantly different levels. Among them, α1-microglobulin content in CICs was associated with not only in vitro mesangial cell proliferation and monocyte chemoattractant protein 1 secretion, but also in vivo estimated glomerular filtration rate (eGFR) levels and tubulointerstitial lesions in IgAN patients. Moreover, we found α1-microglobulin was prone to bind aberrant glycosylated IgA1. Additionally, elevated circulating IgA-α1-microglobulin complex levels were detected in an independent IgAN population and IgA-α1-microglobulin complex levels were correlated with hypertension, eGFR levels and Oxford T- scores in these IgAN patients. Conclusions Our results suggest that the IgA-α1-microglobulin complex is an important constituent in CICs and that circulating IgA-α1-microglobulin complex detection might serve as a potential noninvasive biomarker detection method for IgAN.

Ovarian cancer is the most malignant of all gynecological cancers. A challenge that deteriorates with ovarian adenocarcinoma in neoplastic disease patients has been associated with the chemoresistance of cancer cells. Cisplatin (CP) belongs to the first-line chemotherapeutic agents and it would be beneficial to identify chemoresistance for ovarian adenocarcinoma cells, especially CP-resistance. Gray level co-occurrence matrix (GLCM) was characterized imaging from a numeric matrix and find its texture features. Serous type (OVCAR-4 and A2780), and clear cell type (IGROV1) ovarian carcinoma cell lines with CP-resistance were used to demonstrate GLCM texture feature extraction of images. Cells were cultured with cell density of 6 &times, 105 in a glass-bottom dish to form a uniform coverage of the glass slide to get the optical images by microscope and DVC camera. CP-resistant cells included OVCAR-4, A2780 and IGROV and had the higher contrast and entropy, lower energy, and homogeneity. Signal to noise ratio was used to evaluate the degree for chemoresistance of cell images based on GLCM texture feature extraction. The difference between wile type and CP-resistant cells was statistically significant in every case (p &lt, 0.001). It is a promising model to achieve a rapid method with a more reliable diagnostic performance for identification of ovarian adenocarcinoma cells with CP-resistance by feature extraction of GLCM in vitro or ex vivo.

In recent decades, the occurrence and distribution of arboviral diseases transmitted by Aedes aegypti mosquitoes has increased. In a new control strategy, populations of mosquitoes infected with Wolbachia are being released to replace existing populations and suppress arboviral disease transmission. The success of this strategy can be affected by high temperature exposure, but the impact of low temperatures on Wolbachia-infected Ae. aegypti is unclear, even though low temperatures restrict the abundance and distribution of this species. In this study, we considered low temperature cycles relevant to the spring season that are close to the distribution limits of Ae. aegypti, and tested the effects of these temperature cycles on Ae. aegypti, Wolbachia strains wMel and wAlbB, and Wolbachia phage WO. Low temperatures influenced Ae. aegypti life-history traits, including pupation, adult eclosion, and fertility. The Wolbachia-infected mosquitoes, especially wAlbB, performed better than uninfected mosquitoes. Temperature shift experiments revealed that low temperature effects on life history and Wolbachia density depended on the life stage of exposure. Wolbachia density was suppressed at low temperatures but densities recovered with adult age. In wMel Wolbachia there were no low temperature effects specific to Wolbachia phage WO. The findings suggest that Wolbachia-infected Ae. aegypti are not adversely affected by low temperatures, indicating that the Wolbachia replacement strategy is suitable for areas experiencing cool temperatures seasonally.

Objective: To study the correlation between high-level free fat acids（FFA）and red blood cell (RBC) injury and to explore the pathological mechanism of hidden blood loss (HBL) after total knee arthroplasty (TKA).Methods: Perioperative blood indexes were tested in 120 patients underwent unilateral total knee replacement for end-stage knee osteoarthritis. Venous blood samples were collected before operation and 24h, 48h, 72h and 120 h after operations. The changes of FFA, hemoglobin (Hb) and red blood cell number in the blood samples were detected by automatic hematology analyzer. The activity of glutathion peroxidase (GSH-Px), total superoxide dismutase (T-SOD) and hydrogen peroxide (H2O2) levels in the blood were measured. Measurement of reactive oxygen species（ROS）was performed by flow cytometry. Meanwhile, the morphological changes of RBC were analyzed under microscope. Results: Significant hidden blood loss was observed for all patients. The Hb content, RBC and hematocrit（Hct）decreased significantly 24 h after surgery (P 2O2 levels significantly decreased compared with preoperative tested samples (P 2O2 levels increased as well. All tested parameters tended to return to normal levels five days after surgery.Conclusion: High levels of FFA in blood can induce oxidative stress and damage RBCs, which in turns causes HBL after surgery.

This study aimed to investigate the relationships between cognitive emotion regulation (CER) strategies, resilience, and insomnia and the underlying mechanism that explains the relationships. Six hundred and fifty-three middle-aged and old people recruited from community service centers in Henan province completed questionnaires related to CER strategies, resilience, and insomnia. Results showed refocus on planning and positive reappraisal negatively predicted insomnia, and catastrophising, rumination and self-blame positively predicted insomnia. Moreover, maladaptive emotion regulation strategies (especially catastrophising) mediated the relationship between resilience and insomnia. The findings suggest the middle-aged and elderly with insomnia tended to employ maladaptive emotion regulation strategies and had lower resilience. Maladaptive emotion regulation strategies buffered the positive effect of resilience on sleep.

Background Tau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status, and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content. Method We systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology, and biomarkers in plasma and brain. Results Male P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205, and astrocyte activation compared to that of wild-type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris water maze and open field test. In addition, we characterized the absence of macrophage-inflammatory protein (MIP-3α) and the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 in the plasma of P301S transgenic mice, which can be served as potential plasma biomarkers in P301S Tg mice. Male P301S transgenic mice expressed more monokine induced by IFN-γ (MIG), tumor necrosis factor-α (TNF-α), IL-10, and IL-13 than those of female P301S mice. Conclusion Our findings highlight sexual dimorphism in the behavior, neuropathology, and plasma proteins in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies, and the MIP-3α may be a new potential plasma biomarker.

Background: Locally advanced breast cancer (LABC) is one of the subgroups of invasive breast cancer. The treatment of LABC is neoadjuvant chemotherapy (NAC) before surgery, which is different from the others. The study aimed to analyze and compare the characteristics of conventional ultrasound, contrast-enhanced ultrasonography (CEUS) and strain elastography (SE) in LABC patients who have different treatment outcomes, and to provide help for LABC in the imaging diagnosis and clinic treatment. Methods: From May 2018 to April 2019, 36 patients (40 lesions) of LABC were enrolled, which diagnosed by puncture biopsy. According to the clinical evaluation, these patients were recommended to undergo pre-operative NAC followed by surgery. All patients underwent conventional ultrasound, CEUS and SE before puncture. According to postoperative pathological grading and follow-up, the patients were divided into effective and ineffective groups. We summarized and compared the features of conventional ultrasound, CEUS and SE of patients in two groups. The correlation between the imaging characteristics and the postoperative pathological grading was also analyzed. Results: Conventional ultrasonic features of LABC: the most lesions of LABC were mass type (32/40, 80.0%), and all lesions were irregular. Most of lesions showed unclear boundaries (39/40, 97.5%), heterogeneous echoes (38/40, 95.0%), and internal calcifications (24/40, 60.0%). Most of lesions had hyperechoic halos (31/40, 77.5%), aspect ratio less than or equal to 1 (34/40, 85.0%), and blood flow grading was III (36/40, 90.0%). CEUS features of LABC: compared with the surrounding normal tissues, all the lesions (40/40,100.0%) were highly enhanced. Most of lesions (35/40, 87.5%) were uneven enhanced. The main enhancement mode was “fast in and slow out” (39/40, 97.5%). There were totally 25 lesions which had “solar sign” (25/40, 62.5%). SE features of LABC: the average visual elastography score of the lesions was 4.28±0.67, the maximum strain rate (E1) of the lesions averaged 4.88±0.54, and the overall strain rate of the lesion averaged 4.14±0.72. There was no significant difference between effective and ineffective groups in the characteristics of conventional ultrasound, CEUS and SE. There was a correlation between the appearance of “solar sign” in CEUS and postoperative pathological grading, and the contingency coefficient was 0.564 (P

Adjuvant chemotherapy after surgery is the standard treatment modality for stage III and part of stage II or stage IV colorectal cancer (CRC) patients. However, the 5-year overall survival (OS) rate remains unsatisfactory. Thus, developing combination therapies is essential to improve the prognosis of patients with CRC. The present study aimed to determine the effect of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with CRC. 122 patients with CRC treated with postoperative adjuvant chemotherapy were retrospectively included in this study. Among them, 62 patients received adjuvant chemotherapy only (control group), while the other 60 patients, with similar demographic and clinical characteristics, received adjuvant chemotherapy and sequential CIK cell immunotherapy (CIK group). Survival analysis showed significantly improved disease free survival (DFS) and OS rates in the CIK group compared with the control group (log-rank test, P = .0024; P = .008, respectively). Univariate and multivariate analyses indicated that sequential CIK cell treatment was an independent prognostic factor for patients’ DFS and OS. Subgroup analyses showed that sequential CIK cell treatment significantly improved the DFS and OS of patients with high-risk T4 stage and insufficient chemotherapy duration. In conclusion, these data indicate that sequential adjuvant CIK cell treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with CRC, particularly for patients with high-risk T4 stage and insufficient chemotherapy duration.

To investigate the function of progranulin on the retina under hypoxic conditions, 8-week-old C57BL/6 mice were divided into normal condition and hypoxic condition groups (n=24 mice/group). The hypoxia model was established through intravitreal injection of 9 mM cobalt chloride. Subsequently, 10 mM progranulin and an equal amount of PBS were injected into the right and left eyes, respectively. Photoreceptor function was examined using electroretinogram (ERG) analysis. Morphological alterations were examined using immunofluorescence co-localization, retinal vascular inflammation was examined using the leukostasis assay, and signaling pathways were screened using immunoblotting. The results revealed that ERG amplitude was significantly lower under hypoxic conditions compared with under normal conditions. Furthermore, the amplitude was significantly reduced in the PBS-injected eyes compared with in the progranulin-injected eyes. Morphological examination demonstrated that the number of rods in the PBS-injected eyes was decreased compared with in the progranulin-injected eyes under hypoxic conditions. In addition, the arrangement of the cones was sparse and the morphology of the outer segments was short and small. Although the number of adherent leukocytes in the progranulin-injected eyes was higher in the hypoxic mice compared with in those under normal conditions, the number was only 52.31% of the number detected in the PBS-injected eyes. Analysis of the signaling pathways demonstrated that the protective effects of progranulin on retinas under hypoxic conditions were regulated by the Toll-like receptor 4 (TLR4)-NADPH oxidase 4 (NOX4) pathway, instead of the caspase and Wnt/β-catenin pathways. In conclusion, progranulin exerted protective effects on the function and morphology of photoreceptors in a hypoxic environment, and could reduce retinal vascular inflammation, through inhibition of the TLR4-NOX4 pathway.

Porcine deltacoronavirus (PDCoV) was first detected in Hong Kong and has recently spread to many countries around the world. PDCoV causes acute diarrhea and vomiting in pigs, resulting in significant economic losses in the global pork industry. In this study, a Chinese PDCoV strain, designated CHN-HG-2017, was isolated from feces of a suckling piglet with severe watery diarrhea on a farm located in central China. Subsequently, the virus was identified by an indirect immunofluorescence assay and electron microscopy. A nucleotide sequence alignment showed that the whole genome of CHN-HG-2017 is 97.6%-99.1% identical to other PDCoV strains. Analysis of potential recombination sites showed that CHN-HG-2017 is a possible recombinant originating from the strains CH/SXD1/2015 and Vietnam/HaNoi6/2015. Furthermore, the pathogenicity of this recombinant PDCoV strain was investigated in 5-day-old piglets by oral inoculation. The challenged piglets developed typical symptoms, such as vomiting, anorexia, diarrhea and lethargy, from 1 to 7 days post-inoculation (DPI). Viral shedding was detected in rectal swabs until 14 DPI in the challenged piglets. Interestingly, high titers of virus-neutralizing antibodies in sera were detected at 21 DPI. Tissues of small intestines from CHN-HG-2017-infected piglets at 4 DPI displayed significant macroscopic and microscopic lesions with clear viral antigen expression. Our analysis of the full genome sequence of a recombinant PDCoV and its virulence in suckling piglets might provide new insights into the pathogenesis of PDCoV and facilitate further investigation of this newly emerged pathogen.

Damage to the zebrafish retina stimulates resident Muller glia to reprogram, reenter the cell cycle, divide asymmetrically, and produce neuronal progenitor cells that amplify and differentiate into the lost neurons. The transition from quiescent to proliferative Muller glia involves both positive and negative regulators. We previously demonstrated that the Notch signaling pathway represses retinal regeneration by maintaining Muller glia quiescence in zebrafish. Here we examine which Notch receptor is necessary to maintain quiescence. Quantitative RT-PCR and RNA-Seq analyses reveal that notch3 is expressed in the undamaged retina and is downregulated in response to light damage. Additionally, Notch3 protein is expressed in quiescent Muller glia of the undamaged retina, is downregulated as Muller glia proliferate, and is reestablished in the Muller glia. Knockdown of Notch3 is sufficient to induce Muller glia proliferation in undamaged retinas and enhances proliferation during light damage. Alternatively, knockdown of Notch1a, Notch1b, or Notch2 decreases the number of proliferating cells during light damage, suggesting that Notch signaling is also required for proliferation during retinal regeneration. We also knockdown the zebrafish Delta and Delta-like proteins, ligands for the Notch receptors, and find that the deltaB morphant possesses an increased number of proliferating cells in the light-damaged retina. As with Notch3, knockdown of DeltaB is sufficient to induce Muller glia proliferation in the absence of light damage. Taken together, the negative regulation of Muller glia proliferation in zebrafish retinal regeneration is mediated by Notch3 and DeltaB.

Metastasis is responsible for 90% of all cancer-related deaths in humans, and the development of a rapid and promising solution for an early diagnosis of metastasis is required. The present study proposed a promising method combined with scanned laser pico-projection technique and typical texture feature (i.e., contrast, correlation, energy, entropy, and homogeneity) extraction of gray-level co-occurrence matrix (GLCM) image processing model to classify the low- and high-metastatic cancer cells using five common cancer adenocarcinoma cell line pairs (i.e., HeLa/HeLa-S3, CL1-0/CL1-5, OVTW59-P0/OVTW59-P4, and CE81T-FNlow/CE81T-FNhigh cell lines). Highly metastatic cancer cells essentially have the highest levels of disorder. Both contrast and entropy refer to the degree of disorder, and energy and homogeneity refer to the degree of uniformity. These four texture features can be effective evaluation indexes for disorder in cancer cells responding to metastatic ability. Texture feature extraction forms reflection images, which are recorded with scanned laser pico-projection system; they effectively bridge the gap in information derived from transmission images. The low- and high-metastatic cancer cells are statistically and effectively classified from the texture feature of GLCM through transmission and reflection images taken with scanned laser pico-projection system. In particular, it only requires several seconds after producing a confluent monolayer of cells and achieves the rapid method with a more reliable diagnostic performance for metastatic ability of cancer cells in vitro or ex vivo.

Background: LncRNA PTCSC3 is a tumor suppressor in thyroid cancer, and its role in drug resistance of anaplastic thyroid cancer (ATC) to chemotherapy drug doxorubicin was investigated in this study. Methods: Expression of RNA and protein was analyzed by qRT-PCR and western blot, respectively. Flow cytometry was used to analyze the expression rate of CD133(+) cells. The endogenous expression of related genes was modulated by recombinant plasmids and cell transfection. Combination condition and interaction between PTCSC3 and STAT3 were determined by RIP and RNA pull-down assay, respectively. MTT assay was performed to detect cytotoxicity. Chromatin immunoprecipitation was conducted to identify interactions between STAT3 and DNA promoter of INO80. Results: LncRNA PTCSC3 was low-expressed in ATC tissues and cells. Over-expressed PTCSC3 inhibited the drug resistance of ATC to doxorubicin. PTCSC3 negatively regulated STAT3, and STAT3 promoted expression of INO80. PTCSC3 regulated INO80 through STAT3. PTCSC3 suppressed stem cells properties and drug resistance of ATC to doxorubicin. Conclusion: LncRNA PTCSC3 inhibits INO80 expression by negatively regulating STAT3, and thereby attenuating drug resistance of ATC to chemotherapy drug doxorubicin.