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The synthesis and biological assessment of neutral or cationic platinum group metal-based anticancer complexes have been extremely studied, whereas there are few reports on the corresponding zwitterionic complexes. Herein, the synthesis, characterization, and bioactivity of zwitterionic half-sandwich phosphine-imine iridium(III), rhodium(III), and ruthenium(II) complexes were presented. The sulfonated phosphine-imine ligand and a group of zwitterionic half-sandwich

Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma. Approximately 15-20% of RMS cases arise from the bladder and prostate (B/P). The optimal treatment strategy for B/P RMS remains unclear.To retrospectively evaluate the applicability of our procedure performed to treat paediatric patients with B/P RMS.This is a retrospective analysis from a single tertiary referral hospital. From August 2003 to March 2021, 62 children pathologically diagnosed with B/P RMS underwent radical cystectomy and orthotopic detaenial sigmoid neobladder reconstruction in our centre.Surgical procedures included laparoscopic radical cystectomy and detaenial sigmoid neobladder reconstruction, which is demonstrated in the accompanying video.Demographic, clinical, and follow-up data were collected. Perioperative and long-term oncological and functional outcomes were reported. A logistic regression analysis was also performed.All surgeries, including three intracorporeal laparoscopic surgeries, were completed successfully. Of the 62 patients, 54 were alive without evidence of disease recurrence or metastasis at the last follow-up. Five of the 1412-yr-old boys reported that they experienced erections. Two female patients12 yr old reported that they menstruated. However, this was a retrospective study conducted at a single centre with limited surgeon experience.Our results confirmed the safety and feasibility of primary orthotopic sigmoid neobladder reconstruction after radical cystectomy for paediatric patients with B/P RMS. Good outcomes in terms of oncological control and functional recovery were achieved. The high histocompatibility and tissue adaptability of children are inspiring.We describe our stepwise technique of radical cystectomy and detaenial sigmoid neobladder reconstruction for paediatric patients with bladder and prostate rhabdomyosarcoma. With this technique, we were able to achieve good functional recovery without compromising cancer control and significantly increasing complications.

We aimed to evaluate the potential role of antagonistic selection in polygenic diseases: if one variant increases the risk of one disease and decreases the risk of another disease, the signals of genetic risk elimination by natural selection will be distorted, which leads to a higher frequency of risk alleles.We applied local genetic correlations and transcriptome-wide association studies to identify genomic loci and genes adversely associated with at least two diseases. Then, we used different population genetic metrics to measure the signals of natural selection for these loci and genes.First, we identified 2120 cases of antagonistic pleiotropy (negative local genetic correlation) among 87 diseases in 716 genomic loci (antagonistic loci). Next, by comparing with non-antagonistic loci, we observed that antagonistic loci explained an excess proportion of disease heritability (median 6%), showed enhanced signals of balancing selection, and reduced signals of directional polygenic adaptation. Then, at the gene expression level, we identified 31,991 cases of antagonistic pleiotropy among 98 diseases at 4368 genes. However, evidence of altered signals of selection pressure and heritability distribution at the gene expression level is limited.We conclude that antagonistic pleiotropy is widespread among human polygenic diseases, and it has distorted the evolutionary signal and genetic architecture of diseases at the locus level.

Despite the substantial progress made by deep networks in the field of medical image segmentation, they generally require sufficient pixel-level annotated data for training. The scale of training data remains to be the main bottleneck to obtain a better deep segmentation model. Semi-supervised learning is an effective approach that alleviates the dependence on labeled data. However, most existing semi-supervised image segmentation methods usually do not generate high-quality pseudo labels to expand training dataset. In this paper, we propose a deep semi-supervised approach for liver CT image segmentation by expanding pseudo-labeling algorithm under the very low annotated-data paradigm. Specifically, the output features of labeled images from the pretrained network combine with corresponding pixel-level annotations to produce class representations according to the mean operation. Then pseudo labels of unlabeled images are generated by calculating the distances between unlabeled feature vectors and each class representation. To further improve the quality of pseudo labels, we adopt a series of operations to optimize pseudo labels. A more accurate segmentation network is obtained by expanding the training dataset and adjusting the contributions between supervised and unsupervised loss. Besides, the novel random patch based on prior locations is introduced for unlabeled images in the training procedure. Extensive experiments show our method has achieved more competitive results compared with other semi-supervised methods when fewer labeled slices of LiTS dataset are available.

Lorlatinib was found to have activity in ALK-positive NSCLC in a global phase 1 and 2 study. We report an ongoing phase 2 study in Chinese patients with ALK-positive advanced or metastatic NSCLC.Open-label, dual-cohort study (NCT03909971); patients had progressive disease after ALK tyrosine kinase inhibitor treatment (cohort 1: previous crizotinib; cohort 2: one ALK tyrosine kinase inhibitor other than crizotinib [±prior crizotinib]), more than or equal to one unirradiated extracranial target lesion, and Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received oral lorlatinib 100 mg once daily in continuous 21-day cycles. Primary end point: objective response in cohort 1 by independent central radiology (ICR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were based on patients receiving more than or equal to one dose.At data cutoff (August 10, 2020), 109 patients were enrolled (cohort 1: n = 67; cohort 2: n = 42). A total of 47 patients in cohort 1 (70.1%, 95% confidence interval [CI]: 57.7-80.7, p0.0001; primary end point) and 20 patients in cohort 2 (47.6%, 95% CI: 32.0-63.6, secondary end point) achieved objective response by ICR. Median progression-free survival was not reached in cohort 1 and was 5.6 months in cohort 2. In patients with brain lesions at baseline, 29 of 36 patients in cohort 1 (80.6%, 95% CI: 64.0-91.8) and 10 of 21 patients in cohort 2 (47.6%, 95% CI: 25.7-70.2) achieved objective intracranial response by ICR. Hypercholesterolemia (92.7%) and hypertriglyceridemia (90.8%) (cluster terms) were common treatment-related adverse events (TRAEs). Nine patients (8.3%) had serious TRAEs; one permanently discontinued from treatment because of TRAEs.Lorlatinib was found to have a robust and durable response and high intracranial objective response in previously treated Chinese patients with ALK-positive NSCLC.

The SARS-CoV-2 Delta variant has spread rapidly worldwide. To provide data on its virological profile, we here report the first local transmission of Delta in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of quarantined individuals indicated that the viral loads of Delta infections, when they first become PCR-positive, were on average ~1000 times greater compared to lineage A/B infections during the first epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. The estimated transmission bottleneck size of the Delta variant was generally narrow, with 1-3 virions in 29 donor-recipient transmission pairs. However, the transmission of minor iSNVs resulted in at least 3 of the 34 substitutions that were identified in the outbreak, highlighting the contribution of intra-host variants to population-level viral diversity during rapid spread., The SARS-CoV-2 Delta variant has spread rapidly worldwide. Here, the authors characterise a single chain of transmission of Delta in China, and find evidence that it is more infectious and replicates faster during early infection compared to early pandemic lineages.

Hepatocellular carcinoma (HCC) has been the fifth most common malignancy worldwide and is the second most common cause of tumor-related mortality globally. In China, a high proportion of patients with HCC present with an advanced stage of the disease, so HCC is a major challenge to the healthcare system and a substantial socioeconomic burden. The last decade has witnessed an expansion of the treatment landscape for HCC. Various approaches have been explored as potential conversion therapies for advanced HCC. Despite controversies, mounting data have indicated that successful conversion therapy followed by subsequent surgery is achievable in a population of patients with advanced HCC. This conversion therapy is a safe and promising treatment strategy to prolong long-term outcomes. Based on preliminary research, this review has assembled and summarized current clinical experience with and evidence of the efficacy of conversion therapies followed by subsequent surgery for advanced HCC.

The H3K4 demethylase KDM5B is overexpressed in multiple cancer types, and elevated expression levels of KDM5B is associated with decreased survival. However, the underlying mechanistic contribution of dysregulated expression of KDM5B and H3K4 demethylation in cancer is poorly understood. Our results show that loss of KDM5B in multiple types of cancer cells leads to increased proliferation and elevated expression of cancer stem cell markers. In addition, we observed enhanced tumor formation following KDM5B depletion in a subset of representative cancer cell lines. Our findings also support a role for KDM5B in regulating epigenetic plasticity, where loss of KDM5B in cancer cells with elevated KDM5B expression leads to alterations in activity of chromatin states, which facilitate activation or repression of alternative transcriptional programs. In addition, we define KDM5B-centric epigenetic and transcriptional patterns that support cancer cell plasticity, where KDM5B depleted cancer cells exhibit altered epigenetic and transcriptional profiles resembling a more primitive cellular state. This study also provides a resource for evaluating associations between alterations in epigenetic patterning upon depletion of KDM5B and gene expression in a diverse set of cancer cells.

Mitochondrial serine hydroxymethyltransferase (SHMT2) catalyzes the conversion of serine to glycine and concomitantly produces one-carbon units to support cell growth and is upregulated in various cancer cells. SHMT2 knockdown triggers cell apoptosis; however, the detailed mechanism of apoptosis induced by SHMT2 inactivation remains unknown. Here, we demonstrate that SHMT2 supports the proliferation of bladder cancer (BC) cells by maintaining redox homeostasis. SHMT2 knockout decreased the pools of purine and one-carbon units and delayed cell cycle progression in a manner that was rescued by formate, demonstrating that SHMT2-mediated one-carbon units are essential for BC cell proliferation. SHMT2 deficiency promoted the accumulation of intracellular reactive oxygen species (ROS) by decreasing the NADH/NAD

The DNA damage response (DDR) pathway generally protects against genome instability, and defects in DDR have been exploited therapeutically in cancer treatment. We have reported that histone demethylase PHF8 demethylates TOPBP1 K118 mono-methylation (K118me1) to drive the activation of ATR kinase, one of the master regulators of replication stress. However, whether dysregulation of this physiological signalling is involved in tumorigenesis remains unknown. Here, we showed PHF8-promoted TOPBP1 demethylation is clinically associated with breast tumorigenesis and patient survival. Mammary gland tumors from Phf8 knockout mice grow slowly and exhibit higher level of K118me1, lower ATR activity, and increased chromosomal instability. Importantly, we found that disruption of PHF8-TOPBP1 axis suppresses breast tumorigenesis and creates a breast tumor-specific vulnerability to PARP inhibitor (PARPi) and platinum drug. CRISPR/Cas9 mutation modelling of the deleted or truncated mutation of PHF8 in clinical tumor samples demonstrated breast tumor cells expressing the mimetic variants are more vulnerable to PARPi. Together, our study supports the pursuit of PHF8-TOPBP1 signalling pathway as promising avenues for targeted therapies of PHF8-TOPBP1 proficient tumors, and provides proof-of-concept evidence for loss-of-function of PHF8 as a therapeutic indicator of PARPis.

Introduction Anaplastic lymphoma kinase (ALK) gene rearrangements, have been identified in approximately 2-7% of patients with lung adenocarcinoma (LUAD). However, co-occurrence of double ALK fusions in one patient was rare. Herein, we reported two Chinese female LUAD patients with confirmed double ALK fusion variants by next generation sequencing. Case presentation Case 1, a 38-year-old female was diagnosed as peripheral LUAD in left upper lobe with synchronous multiple intrapulmonary metastases (pT2N0M1b, stage IVa). And case 2, a 58-year-old female had left lower lobe primary LUAD and synchronous multiple lung metastases (pT4N2M1b, stage IVa). In both patients, tumor cells displayed strong expression of ALK protein. Genetic profiling by next generation sequencing showed both patients concurrently harbored two types of ALK rearrangements. Case 1 had an unreported ALK-SSH2/EML4-ALK double fusions, and case 2 had an another novel ARID2-ALK/EML4‐ALK double fusions. Both of these patients responded to ALK inhibitor crizotinib. Conclusions Our study reported two novel ALK fusion partners never reported, which expands the knowledge of ALK fusion spectrum and provides insight into therapeutic options for patients with double ALK fusions.

Delay discounting (DD) refers to the phenomenon in which the subjective value of future rewards is reduced over time. There are individual differences in the DD rate, and increased discounting has been observed in those with various psychiatric disorders. Episodic future thinking (EFT) is the act of vividly imagining events that may happen in the future. Studies have shown that EFT could reduce DD, although inconsistent results have been reported. The aim of this meta-analysis was to clarify the efficacy with which EFT reduces DD and to identify potential moderators. Forty-seven studies (including 63 contrasts) were included in the final analysis. EFT was found to significantly reduce DD (Hedges’ g = 0.52). Moderator analysis showed that positive EFT ( g = 0.64) was more effective in reducing DD than EFT with the valence not specifically mentioned ( g = 0.28) and EFT with neutral or negative valence ( g = –0.03). In addition, several factors related to the control task and DD task were related to the efficacy of EFT to reduce DD. These findings have implications for using EFT to reduce DD in the future.

Recent advances have been made in applying convolutional neural networks to achieve more precise prediction results for medical image segmentation problems. However, the success of existing methods has highly relied on huge computational complexity and massive storage, which is impractical in the real-world scenario. To deal with this problem, we propose an efficient architecture by distilling knowledge from well-trained medical image segmentation networks to train another lightweight network. This architecture empowers the lightweight network to get a significant improvement on segmentation capability while retaining its runtime efficiency. We further devise a novel distillation module tailored for medical image segmentation to transfer semantic region information from teacher to student network. It forces the student network to mimic the extent of difference of representations calculated from different tissue regions. This module avoids the ambiguous boundary problem encountered when dealing with medical imaging but instead encodes the internal information of each semantic region for transferring. Benefited from our module, the lightweight network could receive an improvement of up to 32.6% in our experiment while maintaining its portability in the inference phase. The entire structure has been verified on two widely accepted public CT datasets LiTS17 and KiTS19. We demonstrate that a lightweight network distilled by our method has non-negligible value in the scenario which requires relatively high operating speed and low storage usage., Accepted by IEEE TMI, Code Avalivable

HACE1, an E3 ubiquitin-protein ligase, is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer. However, its role in glioma remains elusive. Here, we observed increased expression of HACE1 in gliomas related to control subjects, and found a strong correlation of high HACE1 expression with poor prognosis in patients with WHO grade III and IV as well as low-grade glioma (LGG) patients receiving radiotherapy. HACE1 knockdown obviously suppressed malignant behaviors of glioma cells, while ectopic expression of HACE1 enhanced cell growth in vitro and in vivo. Further studies revealed that HACE1 enhanced protein stability of nuclear factor erythroid 2-related factor 2 (NRF2) by competitively binding to NRF2 with another E3 ligase KEAP1. Besides, HACE1 also promoted internal ribosome entry site (IRES)-mediated mRNA translation of NRF2. These effects did not depend on its E3 ligase activity. Finally, we demonstrated that HACE1 dramatically reduced cellular ROS levels by activating NRF2, thereby decreasing the response of glioma cells to radiation. Altogether, our data demonstrate that HACE1 causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells by activating NRF2, and indicate that it may act as the role of prognostic factor and potential therapeutic target in glioma.

Half-sandwiched structure iridium(III) complexes appear to be an attractive organometallic antitumor agents in recent years. Here, four triphenylamine-modified fluorescent half-sandwich iridium(III) thiosemicarbazone (TSC) antitumor complexes were developed. Because of the "enol" configuration of the TSC ligands, these complexes formed a unique dimeric configuration. Aided by the appropriate fluorescence properties, studies found that complexes could enter tumor cells in an energy-dependent mode, accumulate in lysosomes, and result in the damage of lysosome integrity. Complexes could block the cell cycle, improve the levels of intrastitial reactive oxygen species, and lead to apoptosis, which followed an antitumor mechanism of oxidation. Compared with cisplatin, the antitumor potential in vivo and vitro confirmed that Ir4 could effectively inhibit tumor growth. Meanwhile, Ir4 could avoid detectable side effects in the experiments of safety evaluation. Above all, half-sandwich iridium(III) TSC complexes are expected to be an encouraging candidate for the treatment of malignant tumors.

In recent years, long noncoding RNAs (lncRNAs) have been demonstrated to be important tumor-associated regulatory factors. LncRNA growth arrest-specific transcript 5 (Gas5) acts as an anti-oncogene in most cancers. Whether Gas5 acts as an oncogene or anti-oncogene in hepatocellular carcinoma (HCC) remains unclear. In the present study, the expression and role of Gas5 in HCC were investigated in vitro and in vivo. Lower expression levels of Gas5 were determined in HCC tissues and cells by quantitative reverse transcription-polymerase chain reaction. Overexpressed Gas 5 lentiviral vectors were constructed to analyze their influence on cell viability, migration, invasion, and apoptosis. Fluorescence in situ hybridization was used to identify the subcellular localization of Gas5. Protein complexes that bound to Gas5 were isolated from HepG2 cells through pull-down experiments and analyzed by mass spectrometry. A series of novel Gas5-interacting proteins were identified and bioinformatics analysis was carried out. These included ribosomal proteins, proteins involved in protein folding, sorting, and transportation in the ER, some nucleases and protein enzymes involved in gene transcription, translation, and other proteins with various functions.78 kDa glucose-regulated protein (GRP78) was identified as a direct target of Gas5 by Rip-qPCR and Western blot analysis assay. Gas5 inhibited HepG2 cell growth and induced cell apoptosis via upregulating CHOP to activate the ER stress signaling pathway. Further studies indicated that the knockdown of CHOP by shRNA partially reversed Gas5-mediated apoptosis in HepG2 cells. Magnetic resonance imaging showed that the ectopic expression of Gas5 inhibited the growth of HCC in nude mice. These findings suggest that Gas5 functions as a tumor suppressor and induces apoptosis through activation of ER stress by targeting the CHOP signal pathway in HCC.

Glucose oxidase (GOx)-mediated starvation therapy holds great promise in cancer treatment. However, the worse hypoxia conditions result into low therapeutic efficiency, and undegradability of carriers poses potential threats to living bodies. To address this, herein a bioinspired MnO2 nanosystem with controllable surface was developed for highly efficient starvation/gas synergistic enhanced therapy. Biomimetic design and further surface modification unprecedentedly endowed the nanosystem with ultrahigh loading capacity for GOx and l-Arginine (l-Arg) and special selectivity toward cancer cells. Especially, the dissipative O2 during starvation therapy was well replenished by a positive cycle formed by the nanosystem, which continuously reproduced O2 and accelerated glucose consumption. The abundant H2O2 was further used to oxidize l-Arg into nitric oxide to realize gas therapy. In vitro and in vivo testing confirmed that this new treatment effectively blocked the nutrition and energy sources of cells to obtain excellent therapeutic effect. We reported the first experimental item of this nanosystem for inhibiting cancer cell migration. Considering the novel design concept with facile biomimetic methods, effective co-loading of endogenous substances, and good anti-tumor and anti-migration effects, this work provided new theoretical and experimental basis for starvation therapy and inspired people to design more delicate platform for cancer treatment.

BACKGROUND AND AIMS: Induced pluripotent stem cells (iPSCs) provide an important tool for the generation of patient-derived cells, including hepatocyte-like cells, by developmental cues through an endoderm intermediate. However, most iPSC lines fail to differentiate into endoderm, with induction resulting in apoptosis. APPROACH AND RESULTS: To address this issue, we built upon published methods to develop an improved protocol. We discovered that doxycycline dramatically enhances the efficiency of iPSCs to endoderm differentiation by inhibiting apoptosis and promoting proliferation through the protein kinase B pathway. We tested this protocol in >70 iPSC lines, 90% of which consistently formed complete sheets of endoderm. Endoderm generated by our method achieves similar transcriptomic profiles, expression of endoderm protein markers, and the ability to be further differentiated to downstream lineages. CONCLUSIONS: Furthermore, this method achieves a 4-fold increase in endoderm cell number and will accelerate studies of human diseases in vitro and facilitate the expansion of iPSC-derived cells for transplantation studies.

Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged Opossum and the human genetic disorder Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome. Combining three single-molecule imaging assays in living cells together with genomics and proteomics analysis, we found that SOX18RaOp disrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its target gene selection process. The dominant-negative effect is further amplified by poisoning the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular aetiology of dominant-negative transcription factor function.

Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.

Mutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DNMs and DD has not been well studied. Here we curated developmental delay DNM datasets from the PsyMuKB database and showed that DD patients showed a higher rate and deleteriousness in DNM missense on the PPI interface than sibling control. Next, we identified 302 DD-related PsychiPPIs, defined as PPIs harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from PsychiPPI. We observed that PsychiPPIs preferentially affected the human protein interactome network hub proteins. When analyzing DD candidate genes using gene ontology and gene spatio-expression, we found that PsychiPPI genes carrying PPI interface mutations, such as FGFR3 and ALOX5, were enriched in development-related pathways and the development of the neocortex, and cerebellar cortex, suggesting their potential involvement in the etiology of DD. Our results demonstrated that DD patients carried an excess burden of PPI-truncating DNM, which could be used to efficiently search for disease-related genes and mutations in large-scale sequencing studies. In conclusion, our comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity.

Zhe Liu,1– 3,* Dong Zhou,4,* Xuan Yan,1 Lan Xiao,5,6 Pei Wang,1– 3 Junchao Wei,1– 4 Lan Liao1– 3 1The Affiliated Stomatological Hospital of Nanchang University, Nanchang, People’s Republic of China; 2The Key Laboratory of Oral Biomedicine, Nanchang, People’s Republic of China; 3Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang, People’s Republic of China; 4School of Chemistry and Chemical Engineering, Nanchang University, Nanchang, People’s Republic of China; 5School of Mechanical, Medical & Process Engineering, Centre for Biomedical Technologies, Queensland University of Technology (QUT), Brisbane, Australia; 6Australia China Centre for Tissue Engineering and Regenerative Medicine, Kelvin Grove, Brisbane, Australia*These authors contributed equally to this workCorrespondence: Junchao Wei; Lan Liao, Email weijunchao@ncu.edu.cn; Liaolan5106@ncu.edu.cnPurpose: The translation of nanocarrier-based theranostics into cancer treatment is limited by their poor cellular uptake, low drug-loading capacity, uncontrolled drug release, and insufficient imaging ability.Methods: In this study, novel hybrid nanogels were fabricated as theranostic nanocarriers by modifying chitosan (CTS)/tripolyphosphate (TPP) nanoparticles (NPs) with polyacrylic acid (PAA) and further conjugating cysteine-functionalized gold nanoparticles (AuNPs).Results: The resultant nanogels, referred to as CTS/TPP/PAA@AuNPs (CTPA), exhibited excellent colloidal stability and a high encapsulation rate of 87% for the cationic drug doxorubicin (DOX). In the tumour microenvironment, the acidic pH and overexpression of lysozyme triggered CTPA@DOX to degrade and emit smaller nanoblocks (30– 40 nm), which sequentially released the drug in a tumour-responsive manner. Cellular uptake experiments demonstrated that CTPA facilitates the entry of DOX into the cytoplasm. Furthermore, as visualised through AuNP-mediated computed tomography (CT) imaging, CTPA@DOX enabled favourable accumulation in the tumour. Our in vitro and in vivo data demonstrated that CTPA enabled advanced tumour cell-targeting delivery of DOX, which showed greater anti-tumour activity and biosafety than free DOX.Conclusion: The natural polymer CTS was developed for degradable nanogels, which can precisely track drugs with high antitumour activity. Additionally, the surface adjustment strategy can be assembled to achieve cationic drug loading and high drug-loading capacity, controlled drug release, and sufficient imaging ability. Therefore, multifunctional CTPA enables efficient drug delivery and CT imaging, which is expected to provide a valuable strategy for designing advanced theranostic systems.Keywords: theranostic nanomaterial, degradability, computed tomography imaging, hybrid nanogel

The effect evaluation of the antibiotic susceptibility test based on bacterial solution is of great significance for clinical diagnosis and prevention of antibiotic abuse. Applying a microfluidic chip as the detection platform, the detection method of using microscopic images to observe bacteria under antibiotic can greatly speed up the detection time, which is more suitable for high-throughput detection. However, due to the influence of the depth of the microchannel, there are multiple layers of bacteria under the focal depth of the microscope, which greatly affects the counting and recognition accuracy and increases the difficulty of relocation of the target bacteria, as well as extracting the characteristics of bacterial liquid changes under the action of antibiotics. After the focal depth of the target bacteria is determined, although the z-axis can be controlled with the help of a three-dimensional micro-operator, the equipment is difficult to operate and the long-term changes of the target bacteria cannot be tracked quickly and accurately. In this paper, the YOLOv5 algorithm is adopted to accurately identify bacteria with different focusing states of multi-layer bacteria at the z-axis with any focal depth. In the meantime, a certain amount of microspheres were mixed into bacteria to assist in locating bacteria, which was convenient for tracking the growth state of bacteria over a long period, and the recognition rates of both bacteria and microspheres were high. The recognition accuracy and counting accuracy of bacteria are 0.734 and 0.714, and the two recognition rates of microspheres are 0.910 and 0.927, respectively, which are much higher than the counting accuracy of 0.142 for bacteria and 0.781 for microspheres with the method of enhanced depth of field (EDF method). Moreover, during long-term bacterial tracking and detection, target bacteria at multiple z-axis focal depth positions can be recorded by the aid of microspheres as a positioning aid for 3D reconstruction, and the focal depth positions can be repositioned within 3–10 h. The structural similarity (SSIM) of microscopic image structure differences at the same focal depth fluctuates between 0.960 and 0.975 at different times, and the root-mean-square error (RMSE) fluctuates between 8 and 12, which indicates that the method also has good relocation accuracy. Thus, this method provides the basis for rapid, high-throughput, and long-term analysis of microscopic changes (e.g., morphology, size) of bacteria detection under the addition of antibiotics with different concentrations based on microfluidic channels in the future.

Cancer represents a serious concern for human life and health. Due to drug resistance and the easy metastasis of tumors, there is urgent need to develop new cancer treatment methods beyond the traditional radiotherapy, chemotherapy, and surgery. Bacterial outer membrane vesicles (OMVs) are a type of double-membrane vesicle secreted by Gram-negative bacteria in the process of growth and life, and play extremely important roles in the survival and invasion of those bacteria. In particular, OMVs contain a large number of immunogenic components associated with their parent bacterium, which can be used as vaccines, adjuvants, and vectors to treat diseases, especially in presenting tumor antigens or targeted therapy with small-molecule drugs. Some OMV-based vaccines are already on the market and have demonstrated good therapeutic effect on the corresponding diseases. OMV-based vaccines for cancer are also being studied, and some are already in clinical trials. This paper reviews bacterial outer membrane vesicles, their interaction with host cells, and their applications in tumor vaccines.

The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. In this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives the transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of anchorage independence in lung cancer cells. GFI1 elevated the numbers of circulating and lung-infiltrating tumor cells in xenograft models and predicted poor prognosis of patients with lung cancer. Mechanistically, GFI1 inhibited the expression of multiple adhesion molecules and facilitated substrate detachment. Concomitantly, GFI1 reconfigured the chromatin structure of the RASGRP2 gene and increased its expression, causing Rap1 activation and subsequent sustained ERK activation upon detachment, and this led to ERK signaling dependency in tumor cells. Our studies unveiled a mechanism by which carcinoma cells hijacked a hematopoietic factor to gain anchorage independence and suggested that the intervention of ERK signaling may suppress metastasis and improve the therapeutic outcome of patients with GFI1-positive lung cancer.

Cancer cells at the invasive front directly interact with stromal tissue that provides a microenvironment with mechanical, nutrient, and oxygen supply characteristics distinct from those of intratumoral tissues. It has long been known that cancer cells at the invasive front and cancer cells inside the tumor body exhibit highly differentiated functions and behaviors. However, it is unknown whether cancer cells at different locations exhibit a variety of autophagic flux, an important catabolic process to maintain cellular homeostasis in response to environmental changes. Here, using transmission electron microscopy (TEM), we found that invading cancer cells at the invasive front, which show mesenchymal transcriptomic traits, exhibit higher autophagic flux than cancer cells inside the tumor body in human primary non-small cell lung cancer (NSCLC) tissues. This autophagic feature was further confirmed by a live cell autophagic flux monitoring system combined with a 3D organotypic invasion coculture system. Additionally, the increased autophagic flux endows cancer cells with invasive behavior and positively correlates with the advanced tumor stages and the reduced survival period of lung cancer patients. These findings expand the understanding of autophagic dynamics during cancer invasion.

To study the application of evidence-based nursing in prosthesis postoperative complications.A total of 78 cases of patients who underwent prosthetic breast augmentation were selected from July 2017 to July 2019. All the patients were divided into control group and study group according to the random number table method. The patients in the control group received routine nursing interventions, and the patients in the study group performed evidence-based nursing interventions based on the control group's care. The mental health, external esthetic effects, and complications of the two groups were observed and compared.Before the implementation of nursing intervention, there was no significant difference in mental health indicators (SAS, SDS) between the two groups (p 0.05). After the intervention, the SAS and SDS scores of the two groups were lower than before the intervention, and the study group was lower than the control group, and the difference was statistically significant (p 0.05); before the implementation of nursing intervention, there was no significant difference in the scores of HADS-A and HADS-D between the two groups (p 0.05). After the intervention, the scores of HADS-A and HADS-D of the two groups were lower than those before the intervention, and the scores of the study group were lower than those of the control group, and the difference was statistically significant (p 0.05); 94.9% (37 / 39) was better than 71. 8% (28 / 39) in the control group. The difference was statistically significant (p 0.05), and the total incidence of postoperative complications in the study group was 5.1% (2 / 39), which was lower than 15.4% (6 / 39) in the control group (p 0.05).Evidence-based nursing intervention is effective in preventing postoperative complications of silicone breast augmentation prosthesis. It can effectively reduce postoperative complications, improve external esthetic effects, and improve the level of mental health of patients. It is worthy of clinical promotion and application.

Growing evidence indicates that circular RNAs (circRNAs) are closely involved in tumorigenesis, but the association between circRNAs and pancreatic ductal adenocarcinoma (PDAC) is far from clear. Here, we focused on the functional investigation of circ-0005105, a newly identified circRNA, in PDAC progression. In the present study, we assessed circ-0005105 expression in PDAC tissues and cell lines with quantitative reverse transcription–polymerase chain reaction (qRT-PCR). The biological functions of circ-0005105 in cellular proliferation and invasion were identified through gain- and loss-of-function experiments in vitro and in vivo. The interaction between circ-0005105 and the microRNA (miR)-20a-3p–COL11A1 (collagen type XI alpha 1) axis was examined using luciferase reporter and RNA immunoprecipitation assays. We found that circ-0005105 expression was upregulated in both PDAC tissues and cell lines. Higher circ-0005105 expression correlated positively with the malignant clinical phenotype and poor prognosis of patients with PDAC. Gain- and loss-of-function analysis showed that circ-0005105 facilitated both in vitro and in vivo cellular proliferation and invasion. Mechanistically, circ-000510 served as a competing endogenous RNA (ceRNA) of miR-20a-3p and indirectly modulated COL11A1 expression, leading to activation of epithelial–mesenchymal transition (EMT). Rescue experiments suggested that the oncogenic activity of circ-0005105 was dependent on the modulation of the miR-20a-3p–COL11A1 axis. More importantly, COL11A1 overexpression was significantly associated with poor prognosis in PDAC, and silencing COL11A1 reduced PDAC cell tumorigenicity and metastasis. Taken together, our findings confirm for the first time that circ-0005105 has critical functions by regulating the miR-20a-3p–COL11A1 axis. In the clinic, circ-0005105 can act as a potential prognostic marker and therapeutic target in PDAC.

Pancreatic adenosquamous carcinoma (PASC) - a rare pathological pancreatic cancer (PC) type - has a poor prognosis due to high malignancy. To examine the heterogeneity of PASC, we performed single-cell RNA sequencing (scRNA-seq) profiling with sample tissues from a healthy donor pancreas, an intraductal papillary mucinous neoplasm, and a patient with PASC. Of 9,887 individual cells, ten cell subpopulations were identified, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and cancer cells. Cancer cells were divided into five clusters. Notably, cluster 1 exhibited stem-like phenotypes expressing UBE2C, ASPM, and TOP2A. We found that S100A2 is a potential biomarker for cancer cells. LGALS1, NPM1, RACK1, and PERP were upregulated from ductal to cancer cells. Furthermore, the copy number variations in ductal and cancer cells were greater than in the reference cells. The expression of EREG, FCGR2A, CCL4L2, and CTSC increased in myeloid cells from the normal pancreas to PASC. The gene sets expressed by cancer-associated fibroblasts were enriched in the immunosuppressive pathways. We demonstrate that EGFR-associated ligand-receptor pairs are activated in ductal-stromal cell communications. Hence, this study revealed the heterogeneous variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered intercellular interactions following PASC progression.

To investigate the short-term clinical effect of the cervical anterior Hybrid surgery in the treatment of two-segment and three-segment cervical spondylosis.From January 2018 to January 2019, 108 patients who were performed anterior Hybrid surgery with cervical degenerative diseases were collected. The patients were divided into a two-segment group with 52 patients and a three-segment group with 56 patients according to surgical segments. In two-segment group, there were 24 males and 28 females, aged from 35 to 67 years old with an average of(45.94±14.67) years old. In three-segment group, there were 23 males and 33 females, aged from 32 to 65 years old with an average of (47.54±15.34) years old. The outcome indicators of the two groups were compared. Clinical indicators:neck disability index(NDI) was used to evaluate daily life ability, Japanese Orthopedic Association(JOA) score was used to evaluate neurological function improvement, visual analogue scale(VAS) was used to evaluate pain intensity, and general clinical results were graded according to Odom's score. Cervical range of motion (ROM), fusion and complications were measured by X-ray, CT and MRI.All operations were successfully completed and all patients were followed up for more than 12 months. The operation time of two-segment group and three-segment group were 95 to 180 min with an average of(152.30±44.74) min and 110 to 210 min with an average of (165.18±45.86) mins, the blood loss were 20 to 100 ml with an average of (32.88±8.75) ml and 20 to 150 ml with an average of(34.64±10.63) ml respectively which has no statistical differences between the two groups (The anterior Hybrid surgery in treating multi-level cervical spondylosis could not only improve clinical symptoms of patients but also preserve mobility. Meanwhile, the efficacy and safety of Hybrid surgery in different multi-level cervical disc diseases are confirmed, proving its value in clinical practice.

Autism spectrum disorder (ASD) affects 1–2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN, and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success.

Herein, we present the different coordination modes of half-sandwich iridium(III) and rhodium(III) complexes based on pyridine-amine ligands. The pyridyl-amine iridium(III) and rhodium(III) complexes, the corresponding oxidation pyridyl-imine products, and 16-electron pyridyl-amido complexes can be obtained through the change in reaction conditions (nitrogen/adventitious oxygen atmosphere, reaction time, and solvents) and structural variations in the metal and ligand. Overall, the reaction of pyridine-amine ligands with [(η

Background Malnutrition and muscle wasting are common features frequently observed in pancreatic ductal adenocarcinoma (PDAC) patients with cancer cachexia. They are associated with reduced survival and quality of life. Nutrition therapy is an important part of multimodal cancer care in PDAC. However, due to the complexity of nutrition assessment, only 30–60% of patients with nutritional risks receive nutritional treatment at present. It is important to identify biomarkers that may be used to improve management of PDAC‐associated malnutrition. Serum insulin‐like growth factor binding protein 2 (IGFBP2) has emerged as a potential serum biomarker in a variety of tumours. However, its association with malnutrition and muscle wasting in PDAC is unclear. Methods We evaluated the tumour IGFBP2 expression and serum IGFBP2 level in 98 PDAC patients using immunohistochemistry and enzyme‐linked immunosorbent assay and analysed the correlation between them. Furthermore, we explored the relationship between IGFBP2 of both tumour and serum and nutritional status (Patient‐Generated Subjective Global Assessment and skeletal muscle index). Pan02 IGFBP2 stable transfection cell lines, Pan02 PLV‐IGFBP2 cells, and PLKO‐IGFBP2 cells were injected subcutaneously into the flank of C57BL/6 mouse. Serum IGFBP2 levels, food intake, and body weight of these mice were measured. The degree of muscle atrophy is characterized by haematoxylin and eosin, Oil Red O, and Masson's trichrome staining. The mRNA and protein expression of several essential muscle‐related signal proteins such as atrogin‐1 and muscle RING finger 1 was measured. Results Among 98 patients, we found that tumour IGFBP2 expression is related to plasma IGFBP2 levels (r s = 0.562, P

To support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.

Background ALK rearrangement is a very rare subset of squamous cell carcinoma (SCC) and one of the clinical features in patients is lack of data. Here, we report eight patients diagnosed with SCC of the lung harboring ALK rearrangement. Methods We collected primary NSCLC samples at the Beijing Chest Hospital between January 2012 and December 2018 for Ventana (D5F3) immunohistochemical detection. Among the 148 patients was diagnosed ALK‐rearranged non small cell lung cancer (NSCLC), only eight cases was SCC. We collected patients information from electronic patent records (EPRs). Results The eight cases of SCC were diagnosed by immunohistochemistry (IHC). Two were given crizotinib as second‐line therapy. One patient had stable disease (SD) and progression‐free survival (PFS) of six months. The other patient had progressive disease (PD) but PFS was only one month. The side effects were tolerable. This report identified 31 cases of ALK rearrangement in SCC patients from a literature search (including the eight patients in this study). These fusion genes are often seen in a younger age group (mean age: 55.6 years) and non‐smokers (18/31, 58.1%). A total of 20 cases received an ALK inhibitor as first‐ or second‐line treatment which included 11 with a partial response (PR), four with SD, and five with PD. The DCR and ORR was 75.0% (15/20) and 55.0% (11/20), respectively. The median duration time of therapy was 6.4 ± 4.4 months. Conclusions Patients with ALK‐rearranged SCC obtained clinical benefit from ALK‐inhibitor therapy, especially those who were non‐smokers and whose tumors had been identified by IHC+/FISH+., Clinical benefit was obtained from ALK‐inhibitor treatment in ALK‐rearranged SCC especially in non‐smokers and patients whose tumors had been identified by IHC+/FISH+.

Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy.This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156.A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively.Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

SUMMARYCDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here we use computer-aided drug design to discover a new chemical entity (ARN22089) that targets CDC42 GTPases and blocks CDC42 effector interactions without affecting the binding between closely related GTPases (RAC1, RAS, RAL) and their downstream effectors. Our lead compound has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in three-dimensional vascularized microtumor models (VMT) in vitro. In addition, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. Taken together, this work identifies a promising new class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.

Bladder urothelial carcinoma (BLCA) is a complex disease with high morbidity and mortality. Changes in alternative splicing (AS) and splicing factor (SF) can affect gene expression, thus playing an essential role in tumorigenesis. This study downloaded 412 patients' clinical information and 433 samples of transcriptome profiling data from TCGA. And we collected 48 AS signatures from SpliceSeq. LASSO and Cox analyses were used for identifying survival-related AS events in BLCA. Finally, 1,645 OS-related AS events in 1,129 genes were validated by Kaplan-Meier (KM) survival analysis, ROC analysis, risk curve analysis, and independent prognostic analysis. Finally, our survey provides an AS-SF regulation network consisting of five SFs and 46 AS events. In the end, we profiled genes that AS occurred in pan-cancer and five SFs' expression in tumor and normal samples in BLCA. We selected CLIP-seq data for validation the interaction regulated by RBP. Our study paves the way for potential therapeutic targets of BLCA.

PurposeTo report the demographic, clinical, and laboratory characteristics of ocular syphilis based on a 6-year case series study from an eye center in East-China.MethodsA total of 131 cases (191 eyes) of ocular syphilis and the annual number of total syphilis cases from January 2016 to December 2021, were included in this study. Detailed medical records including systemic and ophthalmic medical history, a complete ophthalmic examination, color fundus photography, B-type ultrasound, fundus fluorescein angiography (FFA), spectral domain optical coherence tomography (SD-OCT), laboratory tests of the serum and cerebrospinal fluid (CSF) samples, as well as visual field test and orbital or cranial MRI in cases with suspected optic neuritis or optic atrophy, were collected and analyzed. Pearson Chi-square or Fisher’s exact tests was used for statistics analysis.ResultsOf the 131 cases with ocular syphilis, 86 cases were in men and 6 cases had a past medical history or systemic manifestation of syphilis. HIV was found in only 2 of 70 cases undergoing serum HIV test. The average age was 54.0 years, ranging from 26–85 years. The average percentage of ocular syphilis out from the total syphilis cases was 5.1%, the average titer of serum rapid plasma regain (RPR) at presentation was 1:32, ranging from 1:1–1:512. The most predominant manifestation of ocular syphilis was posterior uveitis, followed by optic neuritis, optic atrophy, panuveitis, retinal vasculitis, and retinitis. The median of BCVA of all 191 eyes was 20/200 (ranging from no light perception to 20/20), and 20/40 (ranging from no light perception to 20/20) at presentation and final follow-up, respectively. Ocular syphilis with active inflammation responded well to penicillin therapy, no matter the initial visual acuity, ocular disease type, or RPR titers, as long as it was diagnosed early and treated properly and promptly. However, cases with optic atrophy, acute retinal necrosis, late diagnosis, permanent disruption, or loss of outer segment of photoreceptors of macular retina on SD-OCT showed poor visual improvement after therapy.ConclusionsEarly diagnosis of ocular syphilis is still challenging in clinical practice and syphilis tests should be routinely performed in patients with uveitis, retinitis, optic neuritis, and optic atrophy.

Currently, vaccination is the most effective medical measure to improve group immunity and prevent the rapid spread of COVID-19. Since the individual difference of vaccine effectiveness is inevitable, it is necessary to evaluate the vaccine effectiveness of every vaccinated person to ensure the appearance of herd immunity. Here, we developed an artificial intelligent (AI)-assisted colorimetric polydopamine nanoparticle (PDA)-based lateral flow immunoassay (LFIA) platform for the sensitive and accurate quantification of neutralizing antibodies produced from vaccinations. The platform integrates PDA-based LFIA and a smartphone-based reader to test the neutralizing antibodies in serum, where an AI algorithm is also developed to accurately and quantitatively analyze the results. The developed platform achieved a quantitative detection with 160 ng/mL of detection limit and 625-10000 ng/mL of detection range. Moreover, it also successfully detected totally 50 clinical serum samples, revealing a great consistency with the commercial ELISA kit. Comparing with commercial gold nanoparticle-based LFIA, our PDA-based LFIA platform showed more accurate quantification ability for the clinical serum. Therefore, we envision that the AI-assisted PDA-based LFIA platform with sensitive and accurate quantification ability is of great significance for large-scale evaluation of vaccine effectiveness and other point-of-care immunoassays.

Cancer immunoediting is defined as the integration of the immune system's dual host-protective and tumor-promoting roles, including three phases: elimination, equilibrium, and escape. Immune selective pressure causes tumor cells to lose major histocompatibility complex expression or acquire immunosuppressive gene expression, which promotes tumor immune evasion and tumor progression. Interleukin-17D (IL-17D), a member of the IL-17 family of cytokines, plays an important role in the host defense against infection and inflammation. However, the role of IL-17D in the progression of lung cancer remains unclear. In this study, we found that IL-17D was highly expressed in human lung cancer, and increased IL-17D expression was associated with tumor stage and short overall survival. IL-17D overexpression significantly promoted tumor growth in subcutaneous xenograft mouse models but only slightly affected cell proliferation

The radial forearm free flap (RFFF) is one of the commonly used flaps in the repair of head and neck soft tissue defects, especially small and medium-sized defects. The free skin grafts from abdomen are usually used to repair the RFFF donor site wound. This study aims to design a novel V-shaped RFFF, hoping that it might facilitate the direct closure of the forearm donor site wound. From August to December in 2019, 20 patients with oral cancers received radical surgeries, and V-shaped RFFFs were designed to repair the soft defects and the forearm donor site wound was directly closed. The patients were followed up for 6 months to assess the final outcome of repair. The results showed that the pre-designed V-shaped RFFF met the needs of soft tissue defect repair, with the size ranging from 24 cm to 30 cm. Fifteen patients with tongue cancers and four with buccal cancers had satisfactory repair results, and only one patient with buccal cancer had mild limitation of mouth opening. There were 3 patients with a small area of ischemia. The mean postoperative hospital stay was 13.85 ±â€Š1.09 days. In 5 patients, wrist tilt motility decreased compared with that before surgery. The postoperative influence score of wrist exercise on daily life was 2.75 ±â€Š0.44 points. In conclusion, the V-shaped RFFF can meet the needs of small and medium-sized defect repair. This novel design can directly close the forearm donor site wound, which avoids surgical trauma to secondary donor site, and significantly reduces related complications.

Background. An increasing number of studies have indicated that the abnormal expression of certain long noncoding RNAs (lncRNAs) is linked to the overall survival (OS) of patients with myeloma. Methods. Gene expression data of myeloma patients were downloaded from the Gene Expression Omnibus (GEO) database (GSE4581 and GSE57317). Cox regression analysis, Kaplan-Meier, and receiver operating characteristic (ROC) analysis were performed to construct and validate the prediction model. Single sample gene set enrichment (ssGSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to predict the function of a specified lncRNA. Results. In this study, a seven-lncRNA signature was identified and used to construct a risk score system for myeloma prognosis. This system was used to stratify patients with different survival rates in the training set into high-risk and low-risk groups. Test set, the entire test set, the external validation set, and the myeloma subtype achieved the authentication of the results. In addition, functional enrichment analysis indicated that 7 prognostic lncRNAs may be involved in the tumorigenesis of myeloma through cancer-related pathways and biological processes. The results of the immune score showed that IF_I was negatively correlated with the risk score. Compared with the published gene signature, the 7-lncRNA model has a higher C-index (above 0.8). Conclusion. In summary, our data provide evidence that seven lncRNAs could be used as independent biomarkers to predict the prognosis of myeloma, which also indicated that these 7 lncRNAs may be involved in the progression of myeloma.

Summary Background We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. Methods In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov , NCT01982955 , and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. Findings From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9–6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2–6·8; hazard ratio [HR] 0·67, 90% CI 0·35–1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1–37·3) versus 18·7 months in the chemotherapy group (15·9–20·7; HR 0·69, 0·34–1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1–16·6] vs 4·4 months [4·1–6·8]; HR 0·35, 0·17–0·74; median OS 37·3 months [90% CI 24·2–37·3] vs 17·9 months [12·0–20·7]; HR 0·33, 0·14–0·76) or MET amplification (n=19; median PFS 16·6 months [8·3–not estimable] vs 4·2 months [1·4–7·0]; HR 0·13, 0·04–0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25–not estimable]; HR 0·08, 0·01–0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. Interpretation Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration. Funding Merck KGaA.

Objectives The molecular profiles and prognosis of anaplastic lymphoma kinase (ALK) fusion and resectable non-small cell lung cancer (NSCLC) remain unclear. This study aimed to explore the distribution of ALK fusion variants and prognostic factors in patients with surgically resected NSCLC. Material and methods Among the 93 ALK positive surgical patients screened by immunohistochemistry (IHC) or real-time polymerase chain reaction (RT-PCR), 63 patients were confirmed as ALK rearrangement by next-generation sequencing (NGS), including 55 cases of stage I-III and 8 cases of stage IV. Medical records were retrospectively reviewed, the distribution of ALK fusion variants and prognostic factors were analyzed. Results All of the 55 early stage patients were histological adenocarcinoma. No other fusion types were found except for echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase (EML4-ALK). EML4-ALK variant 1 (E13:A20; 25/55, 45.5 %) was the predominant variant type, followed by EML4-ALK variant 3 (E6:A20; 19/55, 34.5 %) and variant 2 (E20:A20; 8/55, 14.5 %). Concomitant mutations occurred in 22 patients (22/55, 40.0 %), which involved in 32 co-mutations from 12 kinds of mutated genes. TP53 mutations were most common in coexisting mutations (13/32, 40.6 %). TP53 mutations were less frequently occurred in variant 1 group (3/25, 12.0 %) than in non-variant 1 group (10/30, 33.3 %, P = 0.064). The median disease-free survival (DFS) of the 55 patients was 22.1 months, and the median overall survival (OS) was not mature at the time of analysis. Multivariable analysis showed that stage T3 and EML4-ALK variant 3 were independent prognostic factors for shorter DFS. Neither TP53 mutations nor any coexisting mutations were related to prognosis. Conclusions This study illustrated the patterns of EML4-ALK fusion variants and gene profiles in patients with resected NSCLC. Advanced T stage and EML4-ALK variant 3 were associated with worse prognosis. The role of TP53 mutations in prognosis is worthy of further study.

Objectives This phase 2 study explored tislelizumab, an anti-PD-1 antibody, in combination with platinum-based chemotherapy as first-line treatment of advanced lung cancer. Material and Methods Eligible patients had histologically/cytologically confirmed advanced/metastatic nonsquamous non-small cell lung cancer (NSQ), squamous NSCLC (SQ), or extensive-stage small cell lung cancer (SCLC). All patients received tislelizumab 200 mg in combination with 4–6 cycles of platinum-doublet. The NSQ cohort received pemetrexed + platinum Q3W for 4 cycles followed by pemetrexed maintenance, the SQ cohort received paclitaxel + platinum (A) or gemcitabine + platinum (B) Q3W, and the SCLC cohort received etoposide + platinum Q3W. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Progression-free survival (PFS) and tolerability profile were secondary endpoints; exploratory endpoints included overall survival (OS) and predictive biomarkers. Results Fifty-four patients (NSQ, n = 16; SQ = 21 [SQ-A, n = 15; SQ-B, n = 6]; SCLC, n = 17) were enrolled; as of February 25, 2019, 14 remained on treatment. Confirmed ORRs were 44% (NSQ), 80% (SQ-A), 67% (SQ-B), and 77% (SCLC). Median PFS were 9.0 months (NSQ), 7.0 months (SQ-A), and 6.9 months (SCLC); PFS in SQ-B are not mature. Median OS was not reached in all cohorts except for SCLC (15.6 months). Common treatment-emergent AEs included anemia (79.6%, n = 43) and decreased white blood cell count (74.1%, n = 40). Gene expression analyses revealed distinct patterns by histology type; lower tumor inflammation signature levels were observed among nonresponding patients with NSQ and SCLC. Conclusions Tislelizumab plus chemotherapy demonstrated encouraging antitumor activity, was generally well tolerated, and distinct immune- and cell cycle–related gene signatures were associated with efficacy across cohorts.

We prospectively assessed 49 coronavirus disease cases in Guangdong, China, to estimate the frequency and duration of detectable severe acute respiratory syndrome coronavirus 2 RNA in human body fluids. The prolonged persistence of virus RNA in various body fluids may guide the clinical diagnosis and prevention of onward virus transmission.

Expanding the palette of fluorescent dyes is vital to push the frontier of biological imaging. Although rhodamine dyes remain the premier type of small-molecule fluorophore owing to their bioavailability and brightness, variants excited with far-red or near-infrared light suffer from poor performance due to their propensity to adopt a lipophilic, nonfluorescent form. We report a framework for rationalizing rhodamine behavior in biological environments and a general chemical modification for rhodamines that optimizes long-wavelength variants and enables facile functionalization with different chemical groups. This strategy yields red-shifted ‘Janelia Fluor’ (JF) dyes useful for biological imaging experiments in cells and in vivo. A general tuning strategy is introduced for improving the utility of rhodamines for biological imaging applications. The strategy yielded bright, versatile and bioavailable far-red and near-infrared ‘Janelia Fluor’ dyes.

Extracellular vesicles (EVs) are important mediators of cell-to-cell communication and have been implicated in several pathologies including those of the central nervous system. They are released by all cell types, including neurons, and are highly heterogenous in size and composition. Yet much remains unknown regarding the biophysical characteristics of different EVs. Here, using cryo-electron microscopy (cryoEM), we analyzed the size distribution and morphology of EVs released from primary cortical neurons. We discovered massive macromolecular clusters on the luminal face of EV membranes. These clusters are predominantly found on medium-sized vesicles, suggesting that they may be specific to microvesicles as opposed to exosomes. We propose that these clusters serve as microdomains for EV signaling and play an important role in EV physiology.

Background/aim: To investigate the correlation between the Glasgow-Blatchford score, shock index, and Forrest classification in patients with peptic ulcer bleeding PUB . Materials and methods: A total of 955 patients with PUB were assessed using the Glasgow-Blatchford score and shock index, as well as the Forrest classification based on their gastroscopy results. The correlation between the Glasgow-Blatchford score and shock index was determined using scatter plot analysis, and the correlation between the Glasgow-Blatchford score or shock index and Forrest classification was determined using Spearman's analysis. Results: Both the Glasgow-Blatchford score and shock index showed the highest values in patients with Forrest class IIa. The GlasgowBlatchford score was significantly higher than patients with Forrest class Ib/IIc/III P < 0.05 , and the shock index was significantly higher than patients with Forrest class Ib/IIb/III P < 0.05 . A positive correlation was observed between the Glasgow-Blatchford score and shock index, at r = 0.427 P < 0.001 . A negative correlation was observed between the Glasgow-Blatchford score and Forrest classification, at r = -0.111 P < 0.01 , and between the shock index and Forrest classification, at r = -0.138 P < 0.01 . Conclusion: A moderate correlation was observed between the Glasgow-Blatchford score and shock index in patients with PUB, and the correlation between the Forrest classification and Glasgow-Blatchford score or shock index was relatively low.