Efficacy of surufatinib in the treatment of advanced parathyroid carcinoma: A case report.

Parathyroid cancer is an extremely rare form of neuroendocrine malignancy. Apart from surgery, the effectiveness of chemotherapy and radiotherapy is limited, and the efficacy of targeted drugs remains unclear. In this study, we demonstrate the therapeutic effectiveness and adverse reaction of the targeted drug surufatinib in treating a case of parathyroid cancer, and concurrently review the recent advancements in the treatment of parathyroid cancer. The patient, a 55-year-old male, underwent his first surgery for a "right cervical mass" in May 2011. Postoperative pathology indicated an atypical adenoma of the parathyroid gland. In August 2016, the patient underwent a second surgery for recurrence of the right cervical tumor, with a pathological diagnosis of parathyroid cancer based on clinical history. In November 2017, the patient underwent a third surgery for recurrence of the right cervical tumor. In December 2017, the patient underwent adjuvant external radiation therapy. In August 2022, the patient developed spinal and lung metastases and underwent spinal surgery. Subsequently, the patient received three rounds of chemotherapy on October 5, 2022, October 28, 2022, and November 18, 2022, but the tumor showed slight enlargement. In January 2023, the patient began treatment with surufatinib. After two cycles of treatment, the tumor showed regression. Given the scarcity of systemic treatment options for parathyroid cancer, the targeted drug surufatinib may offer a promising potential treatment option.

Prognostic genome and transcriptome signatures in colorectal cancers.

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFß pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

A disulfidptosis-related glucose metabolism and immune response prognostic model revealing the immune microenvironment in lung adenocarcinoma.

Background: Lung adenocarcinoma accounts for the majority of lung cancer cases and impact survival rate of patients severely. Immunotherapy is an effective treatment for lung adenocarcinoma but is restricted by many factors including immune checkpoint expression and the inhibitory immune microenvironment. This study aimed to explore the immune microenvironment in lung adenocarcinoma via disulfidptosis. Methods: Public datasets of lung adenocarcinoma from the TCGA and GEO was adopted as the training and validation cohort. Based on the differences in the expression of disulfidptosis -related genes, a glucose metabolism and immune response prognostic model was constructed. The prognostic value and clinical relationship of the model were further explored. Immune-related analyses were performed according to CIBERSORT, ssGSEA, TIDE, IPS. Results: We verified that the model could accurately predict the survival expectancy of lung adenocarcinoma patients. Patients with lung adenocarcinoma and a low-risk score had better survival outcomes according to the model. Moreover, the high-risk group tended to have an immunosuppressive effect, as reflected by the immune cell components, phenotypes and functions. We also found that the clinically relevant immune checkpoint CTLA-4 was significantly higher in low-risk group (P<0.05), indicating that the high-risk group may suffer worse tumor immunotherapy efficacy. Finally, we found that this model has accurate predictive value for the efficacy of immune checkpoint blockade in non-small cell lung cancer (P<0.05). Conclusion: The prognostic model demonstrated the feasibility of predicting survival and immunotherapy efficacy via disulfidptosis-related genes and will facilitate the development of personalized anticancer therapy.

Retinal displacement after surgery for idiopathic macular hole.

AIM: To review and summarize the mechanism hypothesis, influencing factors and possible consequences of macular retinal displacement after idiopathic macular hole (IMH) surgery. METHODS: PubMed and Web of Science database was searched for studies published before April 2023 on "Retinal displacement", "Idiopathic macular holes", and "Macular displacement". RESULTS: Recently, more academics have begun to focus on retinal displacement following idiopathic macular holes. They found that internal limiting membrane (ILM) peeling was the main cause of inducing postoperative position shift in the macular region. Moreover, several studies have revealed that the macular hole itself, as well as ILM peeling method, will have an impact on the result. In addition, this phenomenon is related to postoperative changes in macular retinal thickness, cone outer segment tips line recovery, the occurrence of dissociated optic nerve fiber layer (DONFL) and the degree of metamorphopsia. CONCLUSION: As a subclinical phenomenon, the clinical significance of postoperative macular displacement cannot be underestimated as it may affect the recovery of anatomy and function.

A cross-species transcriptomic analysis reveals a novel 2-dimensional classification system explaining the invasiveness heterogeneity of pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine tumors (PanNETs), the second most common type of primary pancreatic tumors, display notable heterogeneity in invasiveness. Current knowledge regarding genomic alterations, including DAXX/ATRX, MEN1 mutations, and copy number variations (CNVs), provides some insights into tumor invasiveness. However, the underlying reasons for the significant variation in invasiveness between insulinoma and other types of PanNETs remain unclear. To construct a comprehensive model for the stratification of prognosis, we employed analysis of both the well-established Rip1-Tag2 (RT2) mouse model of PanNETs and human PanNETs with various functional types. Firstly, by applying single-cell and bulk RNA sequencing in PanNETs from different ages and strains of RT2 mice and human PanNETs, we introduced a 2-dimensional (2D) classification system. Based on the 2-D classification system, human PanNETs were mainly classified as benign insulinomas or non-insulinomas subclusters. Non-insulinomas subtypes mainly included gastrinomas, glucagonomas, VIPomas, and NF-PanNETs, which all exhibited potential invasiveness. In addition, we discovered an enrichment of specific CNV patterns and mutations in corresponding human PanNET subclusters. Then we denoted somatic DAXX/ATRX as the 'second hit' and confounding factors for invasiveness. Finally, by combining the 2D system, DAXX/ATRX mutation status, and tumor diameter, a group of indolent PanNETs with minimal recurrence risk was identified. In conclusion, our current work constructed a comprehensive model to elucidate the heterogeneity of invasiveness in PanNETs and improve prognostic stratification.

Family-based Helicobacter pylori infection control and management strategy and screen-and-treat strategy are highly cost-effective in preventing multiple upper gastrointestinal diseases in Chinese population at national level.

BACKGROUND: The overall benefits of the newly introduced family-based Helicobacter pylori (H. pylori) infection control and management (FBCM) and screen-and-treat strategies in preventing multiple upper gastrointestinal diseases at national level in China have not been explored. We investigate the cost-effectiveness of these strategies in the whole Chinese population. MATERIALS AND METHODS: Decision trees and Markov models of H. pylori infection-related non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), and gastric cancer (GC) were developed to simulate the cost-effectiveness of these strategies in the whole 494 million households in China. The main outcomes include cost-effectiveness, life years (LY), quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). RESULTS: When compared with no-screen strategy, both FBCM and screen-and-treat strategies reduced the number of new cases of NUD, PUD, PUD-related deaths, and the prevalence of GC, and cancer-related deaths. The costs saved by these two strategies were $1467 million and $879 million, quality-adjusted life years gained were 227 million and 267 million, and life years gained were 59 million and 69 million, respectively. Cost-effectiveness analysis showed that FBCM strategy costs -$6.46/QALY and -$24.75/LY, and screen-and-treat strategy costs -$3.3/QALY and -$12.71/LY when compared with no-screen strategy. Compared to the FBCM strategy, the screen-and-treat strategy reduced the incidence of H. pylori-related diseases, added 40 million QALYs, and saved 10 million LYs, but at the increased cost of $588 million. Cost-effectiveness analysis showed that screen-and-treat strategy costs $14.88/QALY and $59.5/LY when compared with FBCM strategy. The robustness of the results was also verified. CONCLUSIONS: Both FBCM and screen-and-treat strategies are highly cost-effective in preventing NUD, PUD, and GC than the no-screen strategy in Chinese families at national level. As FBCM strategy is more practical and efficient, it is expected to play a more important role in preventing familial H. pylori infection and also serves as an excellent reference for other highly infected societies.

The Effect of Hemithyroidectomy in Papillary Thyroid Carcinoma with an Exclusive Involvement of the Recurrent Laryngeal Nerve: A Retrospective Study with a Propensity Score-Matched Analysis.

BACKGROUND: Involvement of the recurrent laryngeal nerve (RLN) in papillary thyroid carcinoma (PTC) is an important prognostic factor and is associated with a higher risk of recurrence. This study aimed to retrospectively analyze the outcomes of patients treated with hemithyroidectomy (HT) in PTC patients with an exclusive RLN invasion who could not tolerate staged surgery, did not wish to undergo another operation, or had other reasons. METHODS: A retrospective review was conducted on 163 patients with PTC and exclusive RLN involvement at our institution between 2013 and 2019. Patients were divided into a total thyroidectomy (TT) group and HT group. The clinicopathologic factors and prognostic outcomes were compared between the two groups. A propensity score-matched analysis was carried out to reduce selection bias, with the following covariates: gender, age, tumor size, multifocality, central lymph node metastasis (CLNM), and RLN resection. The Kaplan-Meier method was used for a comparison of recurrence outcomes. RESULTS: In the baseline data of the 163 PTC patients, tumor size (p < 0.001), multifocality (p = 0.011), CLNM (p < 0.001), and RLN resection (p < 0.008) in the TT and HT groups differed significantly, whereas age and gender did not differ between the two groups. The TT group reported significantly higher temporary and permanent hypoparathyroidism than the HT group (p < 0.001 and p = 0.042, respectively). With 72-month median follow-up, 11 (6.7%) patients developed recurrence. After propensity score matching, 24 patients with HT and 43 patients with TT were included. Recurrence-free survival (RFS) in the matched samples showed no difference between the TT and HT groups (p = 0.092). CONCLUSION: Our results indicate that HT may be a feasible treatment for PTC patients with exclusive RLN involvement in specific circumstances without significantly increasing the risk of recurrence. Performing a thorough preoperative examination is crucial to exclude multifocal tumors and lymph node metastasis before undergoing HT.

Impact of thyroid carcinoma invasion of recurrent laryngeal nerve on cervical lymph node metastasis.

PURPOSE: Papillary thyroid carcinoma (PTC) has a favorable prognosis. However, involvement of the recurrent laryngeal nerve (RLN) significantly increases the risk of recurrence. RLN invasion was an important factor in determining the extent of thyroid surgery. The purpose of this study was to compare clinicopathologic features and characterize risk factors of central and lateral lymph node metastasis (LLNM) of RLN invasion in patients with PTC. METHODS: A retrospective review was conducted of 130 patients with PTCs who had exclusive tumor involvement of the RLN at our institution between January 2014 and February 2019. All patients underwent total thyroidectomy and high-dose radioactive iodine (RAI) therapy. The clinicopathologic factors and prognostic outcomes of the patients with solitary and multiple RLN involvements were compared. Kaplan-Meier method was performed to compare the outcomes of tumor recurrence. Univariate and multivariate logistic regression analyses were used to identify risk factors associated with LLNM. RESULTS: The invasion of the RLN was similar on both sides, with 58.5% on the right, 40.0% on the left, and 1.5% on both sides. Significant differences were observed in tumor size (p < 0.001), lymph node metastasis classification (p = 0.002), RLN resection (p < 0.001), and thyroglobulin (p = 0.010) in the solitary and multiple groups. During the median follow-up of 67 months, 9 (6.9%) patients developed recurrence. There were no statistical differences in recurrence for age, tumor size, gender, multifocality, lymph node metastasis (LNM), and RLN resection. According to receiver operating characteristic (ROC) curve analyses, a cut-off of tumor size > 1.7 cm was identified as the most sensitive and specific predictor of RLN with multiple involvements or LNM invasion. Univariate and multivariate analyses revealed that central lymph node metastasis (CLNM) and RLN invasion by LNM can serve as independent risk factors for LLNM (p = 0.006 and p < 0.001, respectively). CONCLUSION: Our results indicate that recurrence was comparable in patients with solitary and multiple RLN involvements. Multiple RLN involvement was associated with pathological features such as larger tumors, RLN resection, and LLNM. The presence of LNM invading RLN and multiple nerve involvement increases the risk of intraoperative RLN resection. A higher risk of multiple invasion or LNM invasion should be considered when tumor size > 1.7 cm. The presence of CLNM and RLN invaded by LNM were independent predictors for LLNM, which could aid surgeons in deciding on lateral lymph node dissection.

Optical coherence tomography parameters as prognostic factors for stereopsis after vitrectomy for unilateral epiretinal membrane: a cohort study.

This retrospective cohort study explored the relationship between monocular and interocular optical coherence tomography (OCT) parameters and stereopsis in 56 patients undergoing pars plana vitrectomy (PPV) for unilateral idiopathic epiretinal membrane (IERM). IERM impairs visual functions, with symptoms ranging from asymptomatic to severe impairment. Despite established surgical interventions, including PPV with membrane peeling, the impact on advanced three-dimensional visual functions such as stereopsis remains inadequately investigated. All subjects were assessed for stereopsis, visual acuity, and metamorphopsia, alongside spectral domain OCT parameters. These visual functions significantly improved 3-month postoperatively. Central retinal thickness at the fovea, parafovea, and perifovea (CFT, CRT-3 mm, and CRT-6 mm), ectopic inner foveal layer thickness, and retinal layer thickness notably decreased 1 week to 3 months after surgery. The interocular difference in OCT parameters between bilateral eyes was included as a parameter. Baseline CRT-3 mm difference and inner nuclear layer (INL) thickness were independently correlated with postoperative stereopsis on the Titmus Stereo Test, while baseline CRT-6 mm difference and INL thickness were independently related to stereopsis on the TNO stereotest. This study highlights the substantial enhancement in stereopsis post-IERM surgery, with both interocular and monocular OCT parameters independently influencing postoperative stereopsis. These findings underscore the importance of retinal microstructures in assessing and predicting stereopsis in IERM patients after vitrectomy.

Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer.

Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. We describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment, AGITG FORECAST-1 (n = 30 patients). "Resistant" predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. Our findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC.

Methionine can reduce the sublethal risk of Chlorantraniliprole to honeybees (Apis mellifera L.): Based on metabolomics analysis.

Bees, essential for pollination in agriculture and global economic growth. However, the great wax moth (Galleria mellonella, GWM), a Lepidopteran insect, poses a substantial threat to bee colonies, contributing to a global decline in bee populations. Chlorantraniliprole (CH) is one of the primary insecticide used to control GWM due to its efficacy and low toxicity to bees. To improve beekeeping safety and reduce the risk of GWM developing resistance to prolonged use of CH, we investigated the potential of combining methionine (MET) which has been found to have insecticidal activity against certain Lepidoptera pests, with chlorantraniliprole for use in the apiculture industry. This study assessed the combined effects of MET and CH on GWM and honeybees by employing the maximum concentration of MET (1 %, w/w), previously reported as safe for honeybees, and the practical concentration of CH (1 mg/kg) for GWM control. The results revealed limited acute lethal toxicity of MET to GWM and honeybees, whereas the combined chronic exposure of MET and CH (MIX) led to significant synergistic lethal effects on GWM mortality. Nevertheless, the protective effect of MET on honeybees exposed to CH was significant under chronic exposure. Potential mechanisms underlying the synergistic actions of MET and CH may stem from MET-induced protection of the "Cysteine and methionine" and the "Glycine, serine, and threonine" metabolism pathways. Furthermore, immune stress mitigation was also observed in honeybee immune-related gene transcripts treated by the combination of MET and CH under both acute and chronic exposure. The effects of MET on CH activity in GWM and honeybees are likely due to metabolic regulation. This study suggests the potential of developing MET as a promising biopesticide or protective agent in the future.

Applications and Recent Developments of Hydrogels in Ophthalmology.

Hydrogels are a type of functional polymer material with a three-dimensional network structure composed of physically or chemically cross-linked polymers. All hydrogels have two common features: first, their structure contains a large number of hydrophilic groups; therefore, they have a high water content and can swell in water. Second, they have good regulation, and the physical and chemical properties of their cross-linked network can be changed by environmental factors and deliberate modification methods. In recent years, the application of hydrogels in ophthalmology has gradually attracted attention. By selecting an appropriate composition and cross-linking mode, hydrogels can be used in different fields for various applications, such as gel eye drops, in situ gel preparation, intravitreal injection, and corneal contact lenses. This Review provides a detailed introduction to the classification of hydrogels and their applications in glaucoma, vitreous substitutes, fundus diseases, corneal contact lenses, corneal diseases, and cataract surgery.

Pacenta polypeptide injection alleviates the fibrosis and inflammation in cigarette smoke extracts-induced BEAS-2B cells by modulating MMP-9/TIMP-1 signaling.

Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality. Here, we aimed to explore the roles and potential correlation of placenta polypeptide injection (PPI) and MMP-9/TIMP-1 signaling pathway in COPD. BEAS-2B cells were treated with cigarette smoke extract (CSE) to establish a COPD cell model in vitro. The cell survival and cytotoxic effect were measured by CCK-8, LDH release and flow cytometry assays. The inflammatory responses were determined by western blot and ELISA assay. Cell fibrosis was assessed by immunofluorescence and western blot assays. PPI treatment had no cytotoxic effect on BEAS-2B cells until the final concentration reached to 10%. In the range of 0%-8% final concentration, PPI treatment weakened CSE-induced the decrease of cell viability and the increase of LDH level in a concentration-dependent manner. Four percent PPI treatment enhanced cell viability and decreased cell apoptosis of CSE-treated cells in a time-dependent manner. Moreover, 4% PPI treatment significantly decreased inflammatory responses and fibrosis induced by CSE, while AMPA (MMPs agonist) had opposite effects. Notably, AMPA reversed the protective roles of PPI on CSE-induced inflammation and fibrosis. Mechanistically, 4% PPI treatment significantly suppressed MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-19 levels, but enhanced TIMP-1, TIMP-2, TIMP-3, and TIMP-4 levels. Among them, MMP-9 and TIMP-1 might be the main target of PPI. PPI effectively attenuated CSE-induced inflammation and fibrosis in vitro by regulating MMP-9/TIMP-1 signaling pathway.

The Males Absent on the First (MOF) Mediated Acetylation Alters the Protein Stability and Transcriptional Activity of YY1 in HCT116 Cells.

Yin Yang 1 (YY1) is a well-known transcription factor that controls the expression of many genes and plays an important role in the occurrence and development of various cancers. We previously found that the human males absent on the first (MOF)-containing histone acetyltransferase (HAT) complex may be involved in regulating YY1 transcriptional activity; however, the precise interaction between MOF-HAT and YY1, as well as whether the acetylation activity of MOF impacts the function of YY1, has not been reported. Here, we present evidence that the MOF-containing male-specific lethal (MSL) HAT complex regulates YY1 stability and transcriptional activity in an acetylation-dependent manner. First, the MOF/MSL HAT complex was bound to and acetylated YY1, and this acetylation further promoted the ubiquitin-proteasome degradation pathway of YY1. The MOF-mediated degradation of YY1 was mainly related to the 146-270 amino acid residues of YY1. Further research clarified that acetylation-mediated ubiquitin degradation of YY1 mainly occurred through lysine 183. A mutation at the YY1K183 site was sufficient to alter the expression level of p53-mediated downstream target genes, such as CDKN1A (encoding p21), and it also suppressed the transactivation of YY1 on CDC6. Furthermore, a YY1K183R mutant and MOF remarkably antagonized the clone-forming ability of HCT116 and SW480 cells facilitated by YY1, suggesting that the acetylation-ubiquitin mode of YY1 plays an important role in tumor cell proliferation. These data may provide new strategies for the development of therapeutic drugs for tumors with high expression of YY1.

Investigating the impact of tumor location and size on the risk of recurrence for papillary thyroid carcinoma in the isthmus.

BACKGROUND: The purpose of the study was to investigate the ability of new parameters in distinguishing high-risk patients of recurrence from isthmic papillary thyroid carcinomas (iPTCs). METHODS: One hundred sixteen iPTC patients who underwent total thyroidectomy were identified from 3461 PTC patients from 2014 to 2019. Tumor margin to trachea midline distance (TTD), maximum tumor size (TS), and transverse diameter of trachea (TD) were measured on CT images. Cox proportional hazard models served to identify risk factors associated with recurrence-free survival (RFS). The iPTC prognostic formula (IPF = TD/(TTD - TS) - TD/TTD) was evaluated to assess the prognosis. RFS was conducted between the different groups using the Kaplan-Meier analysis. The receiver operating characteristic (ROC) curve of each parameter was drawn to predict recurrence. RESULTS: Central lymph node metastasis (CLNM) and extrathyroidal invasion in iPTC were 58.6% and 31.0%, respectively. Regional recurrence occurred in 16 (13.8%) patients, and no patient died or had distant metastasis. The 3- and 5-year RFS of iPTC were 87.5% and 84.5%, respectively. Gender (p = 0.001) and PLNM (prelaryngeal lymph node metastasis) (p = 0.010) in cPTC (center of iPTC located between two imaginary lines perpendicular to the surface of the skin from the most lateral points of the trachea) and non-cPTC (iPTC patients enrolled in this study excluding cPTC) groups differed significantly. A cut-off point of tumor size >1.1 cm and IPF ≤5.57 were established to have significant differences in prognosis (p = 0.032 and p = 0.005, respectively). Multivariate analysis showed that IPF ≤5.57 was independent prognostic factor for RFS (HR: 4.415, 95%CI: 1.118-17.431, p = 0.034). CONCLUSION: This study indicated the association between IPF and RFS in iPTC patients and established new models to assess risk factors for recurrence pre-operation. IPF ≤5.57 was significantly associated with poor RFS and might be promising parameters for predicting prognosis and surgical decision-making pre-operation.

A review on the oncogenesis of Merkel cell carcinoma: Several subsets arise from different stages of differentiation of stem cell.

Merkel cell carcinoma (MCC), a rare primary cutaneous neuroendocrine neoplasm, is extremely aggressive and has a higher mortality rate than melanoma. Based on Merkel cell polyomavirus (MCPyV) status and morphology, MCCs are often divided into several distinct subsets: pure MCPyV-positive, pure MCPyV-negative, and combined MCC. MCPyV-positive MCC develops by the clonal integration of viral DNA, whereas MCPyV-negative MCC is induced by frequent ultraviolet (UV)-mediated mutations, that are characterized by a high mutational burden, UV signature mutations, and many mutations in TP53 and retinoblastoma suppressor gene (RB1). Combined MCC consists of an intimate mix of MCC and other cutaneous tumor populations, and is usually MCPyV-negative, with rare exceptions. Based on the existing subsets of MCC, it is speculated that there are at least 4 stages in the natural history of stem cell differentiation: primitive pluripotent stem cells, divergent differentiated stem cells, unidirectional stem cells, and Merkel cells (or epidermal/adnexal cells). In the first stage, MCPyV may integrate into the genome of primitive pluripotent stem cells, driving oncogenesis in pure MCPyV-positive MCC. If MCPyV integration does not occur, the stem cells enter the second stage and acquire the ability to undergo multidirectional neuroendocrine and epidermal (or adnexal) differentiation. At this stage, accumulated UV-mediated mutations may drive the development of combined MCC. In the third stage, the stem cells differentiate into unidirectional neuroendocrine stem cells, UV-mediated mutations can induce carcinogenesis in pure MCPyV-negative MCC. Therefore, it has been speculated that several subsets of MCCs arise from different stages of differentiation of common stem cells.

Three-dimension chitosan hydrogel loading melanin composite nanoparticles for wound healing by anti-bacteria, immune activation and macrophage autophagy promotion.

Application of Combined photodynamic therapy (PDT) and photothermal therapy (PTT) has become one of the most promising strategy to replace antibiotics and avoid the epidemic of drug-resistant strains during wound healing. However, high amount of reactive oxygen species (ROS) and high temperature cause severe stress response to normal tissues, leading to potential risks of wound healing. Herein, a three-dimension chitosan hydrogel melanin-glycine-C60 nanoparticles (MGC NPs) were prepared to realized effective anti-bacterial activity, immune activation and macrophage autophagy promotion in three-dimensional wound space without triggering stress response. MGC NP is a composite polymer material composed of natural melanin polymer, oligopeptide and carbon-based material, which showed excellent biological safety. By regulating the peptide length between melanin and C60 and nanoparticle content, a high ROS/heat environment at the upper wound site and a low ROS/heat environment at the lower region adjacent to the wound tissue were established to obtain a three-dimension hydrogel with precise PDT and PTT efficiency in different regions. Highly effective PDT/PTT was used to kill microorganisms in upper region, thus providing a barrier to reduce microbial infection. Mild PDT/PTT in lower region promoted the polarization of M1 macrophage to M2 macrophage and activated autophagy of M2 macrophages, regulating the immune microenvironment and promoting wound repair. In conclusion, the novel three-dimensional PDT/PTT therapy based on natural macromolecules proposed in this study accelerates wound healing through dual pathways on the premise of avoiding wound stress response, which is of great significance for the development of clinical strategies for phototherapy.

Bright future or blind alley? CAR-T cell therapy for solid tumors.

Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a "key-and-lock" relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-target/off-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.

A SNP of the COX4I2 gene associated with environmental adaptation in Chinese cattle.

COX4I2 is an isoform of cytochrome C oxidase subunit IV (COX4), which plays an important role in mitochondrial oxidative phosphorylation. This gene affects heat production and thus affects thermoregulatory capacity in mammals. A splice region variant (rs109072064, NC_037340.1:g.61202988C > T) was identified in COX4I2 by using Ensembl, which transforms the amino acid arginine into cysteine in XP_005214921.1. In this study, we sought to determine the relationship between the mutant locus and the environment in which the cattle are located. We verified that mRNA (XM_005214864.4), which translated XP_005214921.1, is expressed in bovine muscle, fat, heart, liver, kidney, lung and testis tissues. The g.61202988C > T variant was then genotyped in 569 individuals of 34 cattle breeds. Compared with the CC genotype, southern cattle carried more the CT and TT genotypes. Furthermore, the association results carried out that the frequencies of genotypes (CC, CT, TT) and the value of climate parameters (mean annual temperature (T), relative humidity (RH) and temperature humidity index (THI)) were significantly correlated (P < 0.01). Hence, we speculated that the g.61202988C > T variant of COX4I2 gene was associated with the environmental adaptation trait in Chinese cattle and the locus may be considered as a molecular marker for Chinese cattle breeding.

A novel approach for the non-invasive diagnosis of pulmonary nodules using low-depth whole-genome sequencing of cell-free DNA.

Background: Differentiating between benign and malignant pulmonary nodules is a diagnostic challenge, and inaccurate detection can result in unnecessary invasive procedures. Cell-free DNA (cfDNA) has been successfully utilized to detect various solid tumors. In this study, we developed a genome-wide approach to explore the characteristics of cfDNA sequencing reads obtained by low-depth whole-genome sequencing (LD-WGS) to diagnose pulmonary nodules. Methods: LD-WGS was performed on cfDNA extracted from 420 plasma samples from individuals with pulmonary nodules that were no more than 30 mm in diameter, as determined by computed tomography (CT). The sequencing read distribution patterns of cfDNA were analyzed and used to establish a model for distinguishing benign from malignant pulmonary nodules. Results: We proposed the concept of weighted reads distribution difference (WRDD) based on the copy number alterations (CNAs) of cfDNA to construct a benign and malignant diagnostic (BEMAD) algorithm model. In a training cohort of 360 plasma samples, the model achieved an average area under the receiver operating characteristic (ROC) curve (AUC) value of 0.84 in 10-fold cross-validation. The model was validated in an independent cohort of 60 plasma samples, obtaining an AUC value of 0.87. The BEMAD model could distinguish benign from malignant nodules at a sensitivity of 74% and a specificity of 86%. Furthermore, analysis of the critical features of the cfDNA using the BEMAD model identified repeat regions that were associated with microsatellite instability, which is an important indicator of tumorigenesis. Conclusions: This study provides a novel non-invasive diagnostic approach to discriminate between benign and malignant pulmonary nodules to avoid unnecessary invasive procedures.