blf and the drl cluster synergistically regulate cell fate commitment during zebrafish primitive hematopoiesis.

Hematopoiesis is a highly coordinated process that generates all the body's blood cells, and perturbations in embryonic hematopoiesis may result in illnesses ranging from fetal anemia to various leukemias. Correct establishment of hematopoietic progenitor cell fate is essential for the development of adequate blood cell subpopulations, although regulators of cell fate commitment have not been fully defined. Here, we show that primary erythropoiesis and myelopoiesis in zebrafish embryos are synergistically regulated by blf and the drl cluster, as simultaneous depletion led to severe erythrocyte aplasia and excessive macrophage formation at the expense of neutrophil development. Integrative analysis of transcriptome- and genome-wide binding data revealed that blf and drl cluster genes are responsible for constraining the expression of vasculogenesis-promoting genes in the intermediate cell mass and monocytopoiesis-promoting genes in the rostral blood island. This indicates that blf and drl cluster genes act as determinants of the fate commitment of erythroid and myeloid progenitor cells. Furthermore, a rescue screen demonstrated that Zfp932 is a potential mammalian functional equivalent to zebrafish blf and drl cluster genes. Our data provide insight into conserved cell fate commitment mechanisms of primitive hematopoiesis.

Hierarchically Assembled Nanofiber Scaffold Guides Long Bone Regeneration by Promoting Osteogenic/Chondrogenic Differentiation of Endogenous Mesenchymal Stem Cells.

Critical-sized segmental long bone defects represent a challenging clinical dilemma in the management of battlefield and trauma-related injuries. The residual bone marrow cavity of damaged long bones contains many bone marrow mesenchymal stem cells (BMSCs), which provide a substantial source of cells for bone repair. Thus, a three-dimensional (3D) vertically aligned nanofiber scaffold (VAS) is developed with long channels and large pore size. The pore of VAS toward the bone marrow cavity after transplantation, enables the scaffolds to recruit BMSCs from the bone marrow cavity to the defect area. In vivo, it is found that VAS can significantly shorten gap distance and promote new bone formation compared to the control and collagen groups after 4 and 8 weeks of implantation. The single-cell sequencing results discovered that the 3D nanotopography of VAS can promote BMSCs differentiation to chondrocytes and osteoblasts, and up-regulate related gene expression, resulting in enhancing the activities of bone regeneration, endochondral ossification, bone trabecula formation, bone mineralization, maturation, and remodeling. The Alcian blue and bone morphogenetic protein 2 (BMP-2) immunohistochemical staining verified significant cartilage formation and bone formation in the VAS group, corresponding to the single-cell sequencing results. The study can inspire the design of next-generation scaffolds for effective long-bone regeneration is expected by the authors.

Elevated Glucose on Admission Was an Independent Risk Factor for 30-Day Major Adverse Cardiovascular Events in Patients with STEMI but Not NSTEMI.

Background: The purpose of this study was to evaluate the impact of glucose levels on admission, on the risk of 30-day major adverse cardiovascular events (MACEs) in patients with acute myocardial infarction (AMI), and to assess the difference in outcome between ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) patients. Methods: This study was a post hoc analysis of the Acute Coronary Syndrome Quality Improvement in Kerala Study, and 13,398 participants were included in the final analysis. Logistic regression models were used to assess the association between glucose levels on admission and the risk of 30-day MACEs, adjusting for potential confounders. Results: Participants were divided according to the glucose quintiles. There was a positive linear association between glucose levels at admission and the risk of 30-day MACEs in AMI patients [adjusted OR (95% CI): 1.05 (1.03, 1.07), p < 0.001]. Compared to participants with an admission glucose between 5.4 and 6.3 mmol/L, participants with the highest quintile of glucose level ( ≥ 10.7 mmol/L) were associated with increased risk of 30-day MACEs in the fully adjusted logistic regression model [adjusted OR (95% CI): 1.82 (1.33, 2.50), p < 0.001]. This trend was more significant in patients with STEMI (p for interaction = 0.036). Conclusions: In patients with AMI, elevated glucose on admission was associated with an increased risk of 30-day MACEs, but only in patients with STEMI.

Quantum Dots Mediated Heterojunction Coupling MoSe2 Photoanode for Photoelectrochemical Water Splitting.

Graphene quantum dots (GQDs) possess the photosensitive absorption for photoelectrochemical hydrogen evolution owing to special band structures, whereas they usually confront with photo-corrosion or undesired charge recombination during photoelectrochemical reactions. Hence, we establish the heterojunction between GQDs and MoSe2 sheets via a hydrothermal process for improved stability and performance. Photoanodic water splitting with hydrogen evolution boosted by the heteroatom doped N,S-GQDs/MoSe2 heterojunction has been attained due to the abundant active sites, promoted charge separation and transfer kinetics with reduced energy barriers. Diphasic 1T and 2H MoSe2 sheet-hybridized quantum dots contribute to the Schottky heterojunction, which can play a key role in expedited carrier transport to inhibit accumulative photo-corrosion and increase photocurrent. Heteroatom dopants lead to favored energy band matching, bandgap narrowing, stronger light absorption and high photocurrent density. The external quantum efficiency of the doped heterojunction has been elevated twofold over that of the non-doped pristine heterojunction. Modification of the graphene quantum dots and MoSe2 heterojunction demonstrate a viable and adaptable platform toward photoelectrochemical hydrogen evolution processes.

Autologous osteoperiosteal transplantation for cystic osteochondral lesions of the talus: Bone reconstruction is essential.

PURPOSE: Autologous osteoperiosteal transplantation (AOPT) is one of the most feasible and effective techniques for cystic osteochondral lesions of the talus (OLT). However, few reports have been reported about the process of graft-host bone healing and bone articular surface reconstruction, which help us to further understand the actual situation of bone healing and modify surgical methods. METHODS: We retrospectively evaluated 33 osteochondral lesions in 30 patients undertaking AOPT for OLT with subchondral cysts from December 2016 to October 2021. According to CT observation, we used 4 variables to describe the bony articular repair, including the integration of the articular surface, the height of the bone filling, the status of bone union, and the appearance of bone resorption or cystic change. We also analyzed the demographic data and clinical function. Descriptive statistics were used for demographic and clinical variables. Normally distributed data were presented as mean ± SD, and non-normally distributed data were presented as median (Q1, Q3). Associations between these variables and the primary clinical outcomes were examined using t-test or one-way ANOVA test for continuous variables. RESULTS: The patients' mean age was (41.7 ± 14.0) years old and the mean follow-up time was (29.6 ± 17.8) months. The chondral lesion size was (14.3 ± 4.1) mm. The cyst depth was (10.9 ± 3.7) mm. Significant improvements were observed in functional outcomes (according to the numeric rating scale for pain when walking and the American orthopedic foot and ankle society score) between the preoperative and latest follow-up evaluations, from 4.2 ± 2.1 to 2.2 ± 2.0 (p < 0.001), and from 66.8 ± 12.9 to 83.2 ± 10.4, respectively (p < 0.001). The overall satisfaction reached 8.3 of 10 points. All patients returned to sports and their median daily steps reached 8000 steps with 27 (81.8%) patients walking over 6000 steps daily. According to CT observation, "discontinuous bony articular surface and gap > 1 mm" was found in 27 grafts (81.8%), and "below the level of the adjacent articular surface, ≤ 1 mm" in a third of the grafts. Abnormal height of bone filling affected numeric rating scale score (p = 0.049) and American Orthopedic Foot and Ankle Society score (p = 0.027). Of note, bone resorption or cystic changes appeared in up to 13 autografts (39.4%). CONCLUSIONS: AOPT is an effective and acceptable technique for cystic OLT. Bone reconstruction is essential for large cystic OLT. How to get better bony articular reconstruction and avoid cyst recurrence should still be paid more attention.

HPV16 infection promotes the malignant transformation of the esophagus and progression of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) may be correlated with HPV infection, and the mechanism underlying the ESCC formation induced by HPV16 infection remains elusive. Here, we overexpressed HPV16 E6 and E7 and coordinated the overexpression of these two genes in EPC2 and ESCC cells. We found that E7 and coordinated expression of E6 and E7 promoted the proliferation of EPC2 cells, and upregulation of shh was responsible for cell proliferation since the use of vismodegib led to the failure of organoid formation. Meanwhile, overexpression of E6 and E7 in ESCC cells promoted cell proliferation, migration, and invasion in vitro. Importantly, E6 and E7 coordinately increased the capability of tumor growth in nude mice, while vismodegib slowed the growth of tumors in NCG mice. Moreover, a series of genes and proteins changed in cell lines after overexpression of the E6 and E7 genes, the potential biological processes and pathways were systematically analyzed using a bioinformatics assay. Together, these findings suggest that the activation of the hedgehog pathway induced by HPV16 infection may initially transform basal cells in the esophagus and promote following malignant processes in ESCC cells. The application of hedgehog inhibitors may represent a therapeutic avenue for ESCC treatment.

Opposing actions of CRF-R1 and CB1 receptor on facial stimulation-induced MLI-PC plasticity in mouse cerebellar cortex.

BACKGROUND: Corticotropin-releasing factor (CRF) is the major neuromodulator orchestrating the stress response, and is secreted by neurons in various regions of the brain. Cerebellar CRF is released by afferents from inferior olivary neurons and other brainstem nuclei in response to stressful challenges, and contributes to modulation of synaptic plasticity and motor learning behavior via its receptors. We recently found that CRF modulates facial stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission via CRF type 1 receptor (CRF-R1) in vivo in mice, suggesting that CRF modulates sensory stimulation-evoked MLI-PC synaptic plasticity. However, the mechanism of how CRF modulates MLI-PC synaptic plasticity is unclear. We investigated the effect of CRF on facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological methods. RESULTS: Facial stimulation at 1 Hz induced LTD of MLI-PC synaptic transmission under control conditions, but not in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by application of a selective CRF-R1 antagonist, BMS-763,534 (200 nM), but it was not restored by application of a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Blocking cannabinoid type 1 (CB1) receptor abolished the facial stimulation-induced MLI-PC LTD, and revealed a CRF-triggered MLI-PC long-term potentiation (LTP) via CRF-R1. Notably, either inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca2+ with cyclopiazonic acid (100 µM), completely prevented CRF-triggered MLI-PC LTP in mouse cerebellar cortex in vivo. CONCLUSIONS: The present results indicated that CRF blocked sensory stimulation-induced opioid-dependent MLI-PC LTD by triggering MLI-PC LTP through CRF-R1/PKC and intracellular Ca2+ signaling pathway in mouse cerebellar cortex. These results suggest that activation of CRF-R1 opposes opioid-mediated cerebellar MLI-PC plasticity in vivo in mice.

Reconstruction of iliac crest defect after autogenous harvest with bone cement and screws reduces donor site pain.

BACKGROUND: The iliac crest is the most common autogenous bone graft donor site, although associated with postoperative pain, functional disability, cosmesis, morphology and surgical satisfaction. We assessed each aspect above by comparing iliac crest reconstruction with bone cement and screws following harvest with no reconstruction. METHODS: We evaluated patients who underwent large iliac crest harvesting, including ten patients who underwent iliac crest defect reconstruction with bone cement and cancellous screws (R group) and ten randomly matched patients without reconstruction (NR group) were evaluated prospectively in the same period. Local pain, cosmesis and other complications were assessed postoperatively at 1 week, 6 weeks, 3 months and 6 months. RESULTS: Pain, cosmesis and satisfaction of patients significantly differed between the two groups. The R group exhibited less complications and lower pain visual analogue scores at postoperative 1 week (p < 0.001), 6 weeks (p < 0.001) and 3 months (p < 0.01) but not at 6 months, at which time patients reported almost no pain. One patient reported pain for more than 1 year in the NR group. The R group exhibited better cosmesis, morphology and satisfaction than the NR group. In the NR group, one patient suffered pain when sitting up and another when wearing a belt. CONCLUSION: Postoperative pain can be reduced and cosmesis can be improved through reconstructing the iliac crest defects after autogenous harvesting with bone cement and cancellous screws. The technique is simple, safe and easy to implement.

Autologous Costal Chondral/Osteochondral Transplantation and Costa-Derived Chondrocyte Implantation for Articular Cartilage Repair: Basic Science and Clinical Applications.

There has been increasing application of autologous costal chondral/osteochondral transplantation (ACCT/ACOT) and costa-derived chondrocyte implantation (ACCI) for articular cartilage repair over the past three decades. This review presents the major evidence on the properties of costal cartilage and bone and their qualifications as grafts for articular cartilage repair, the major clinical applications, and the risks and strategies for costal chondral/osteochondral graft(s) harvest. First, costal cartilage has many specific properties that help restore the articular surface. Costa, which can provide abundant cartilage and cylindrical corticocancellous bone, preserves permanent chondrocyte and is the largest source of hyaline cartilage. Second, in the past three decades, autologous costal cartilage-derived grafts, including cartilage, osteochondral graft(s), and chondrocyte, have expanded their indications in trauma and orthopaedic therapy from small to large joints, from the upper to lower limbs, and from non-weight-bearing to weight-bearing joints. Third, the rate of donor-site complications of ACCT or ACOT is low, acceptable, and controllable, and some skills and accumulated experience can help reduce the risks of ACCT and ACOT. Costal cartilage-derived autografting is a promising technique and could be an ideal option for articular chondral lesions with or without subchondral cysts. More high-quality clinical studies are urgently needed to help us further understand the clinical value of such technologies.

Aligned cryogel fibers incorporated 3D printed scaffold effectively facilitates bone regeneration by enhancing cell recruitment and function.

Reconstructing extensive cranial defects represents a persistent clinical challenge. Here, we reported a hybrid three-dimensional (3D) printed scaffold with modification of QK peptide and KP peptide for effectively promoting endogenous cranial bone regeneration. The hybrid 3D printed scaffold consists of vertically aligned cryogel fibers that guide and promote cell penetration into the defect area in the early stages of bone repair. Then, the conjugated QK peptide and KP peptide further regulate the function of the recruited cells to promote vascularization and osteogenic differentiation in the defect area. The regenerated bone volume and surface coverage of the dual peptide-modified hybrid scaffold were significantly higher than the positive control group. In addition, the dual peptide-modified hybrid scaffold demonstrated sustained enhancement of bone regeneration and avoidance of bone resorption compared to the collagen sponge group. We expect that the design of dual peptide-modified hybrid scaffold will provide a promising strategy for bone regeneration.

Comprehensive analysis of effects of magnetic nanoparticles on aerobic granulation and microbial community composition: From the perspective of acyl-homoserine lactones mediated communication.

As dosing additives benefit for aerobic granular sludge (AGS) cultivation, effects of different concentrations (0, 10, 50 and 100 mg/L) of magnetic nanoparticles (Fe3O4 NPs) on aerobic granulation, contaminant removal and potential microbial community evolution related to acyl-homoserine lactones (AHLs) mediated bacterial communication were investigated with municipal wastewater. Results showed that the required time to achieve granulation ratio > 70 % was reduced by 60, 90 and 30 days in phase II with addition of 10, 50, 100 mg/L Fe3O4 NPs, respectively. 50 mg/L Fe3O4 NPs can improve contaminant removal efficiency. The promotion of relative abundance of AHLs-producing and AHLs-producing/quenching populations and AHLs-related functional genes accompanied with faster granulation. Iron-cycling-related bacteria were closely related with AHLs-related bacteria during AGS formation. Co-occurrence network analyses showed that AHLs-mediated communication may play an important role in coordinating microbial community composition and functional bacteria participating in nitrogen and polyphosphate metabolisms during aerobic granulation process.

A novel approach to chiral separation: thermo-sensitive hydrogel membranes.

The application of membrane technology for separating chiral compounds is hindered due to the restricted availability of chiral recognition sites on the membrane surface. In this study, we propose a novel approach for chiral separation through a selector (bovine serum albumin, BSA) mediated thermo-sensitive membrane system. A thermo-sensitive hydrogel-coated membrane (termed PDTAN) was developed by anchoring poly(N-isopropylacrylamide) (PNIPAm) onto a polyethersulfone (PES) membrane through an adhesive and hydrophilic dopamine hydrochloride (PDA)/tannic acid (TA)/chitosan (Chi) intermediate layer. The results demonstrate outstanding chiral separation efficiency, achieving αL/D = 3.30 for D-phenylalanine (D-Phe) rejection at 40 °C on a BSA-mediated PDTAN membrane system, with significant stability and minimal fouling, surpassing previous findings. Moreover, the PDTAN membrane altered the selective properties of recognition sites in BSA, transitioning from rejecting L-Phe to rejecting D-Phe. Analysis using fourth-order derivative UV-vis, circular dichroism (CD), and in situ Fourier transform infrared spectroscopy (FTIR) techniques revealed a transition in the secondary structure of BSA from α-helix to ß-sheet as the temperature increased. This transition, facilitated by hydrogen bonding between BSA and PNIPAm, enabled selective recognition of D-Phe, demonstrating a distinct shift in chiral recognition properties. Importantly, with D-Phe adsorbed onto ß-sheet structures of BSA, hydrogen-bond interactions between BSA and the PDTAN membrane were significantly reduced, thereby minimizing membrane fouling and achieving the durability of membrane-based chiral separation.

TREM1+ tumor-associated macrophages secrete CCL7 to promote hepatocellular carcinoma metastasis.

PURPOSE: Tumor-associated macrophages (TAMs) play a critical role in hepatocellular carcinoma (HCC) progression and metastasis. Systematic investigation of the cross-talk between TAMs and HCC may help in searching for the critical target to guard against HCC metastasis. METHODS AND RESULTS: Herein, we found that TREM1 highly expressed in HCC tissue by analyzing the data obtain from GEO database. Interestingly, the results indicated that TREM1 was primarily expressed by monocytes. Immune infiltration studies further validated that TREM1 expression was positively related with increased infiltration of macrophages in HCC tissues. In vitro, we observed that TREM1 knockdown significantly abrogated the effect of TAMs in promoting the metastasis and epithelial-mesenchymal transition (EMT) of HCC cells. Additionally, cytokine array detection identified CCL7 as the main responsive cytokine following with TREM1 knockdown in TAMs. CONCLUSION: Taken together, our findings strongly suggested that high expression of TREM1 was positively associated with metastasis and poor prognosis of HCC. Furthermore, TAMs expressing TREM1 contribute to EMT-based metastasis through secreting CCL7. These results provide a novel insight into the potential development of targeting the TREM1/CCL7 pathway for preventing metastatic HCC.

Clinical Outcomes for Arthroscopic Anterior Talofibular Ligament Repair After Suture Anchor Insertion Through the Anterolateral Portal vs the Lateral Accessory Portal.

BACKGROUND: Two types of suture anchor insertion pathways (anterolateral portal vs lateral accessory portal) are used in arthroscopic anterior talofibular ligament (ATFL) repair. However, it is not clear which one is the better choice. This study aims to compare the clinical outcomes of these 2 suture anchor insertion pathways when performing arthroscopic ATFL lasso-loop repair for the treatment of chronic lateral ankle instability (CLAI). METHODS: From 2019 to 2021, patients with CLAI who underwent arthroscopic ATFL lasso-loop repair were retrospectively reviewed and divided into the anterolateral portal (ALP) group and the lateral accessory portal (LAP) group. A 1:1 propensity score matching was used to control confounding factors based on age, sex, body mass index, follow-up duration, preoperative visual analog scale (VAS) score, and Tegner score (ALP group, n = 26; LAP group, n = 26). Karlsson score, VAS score, Tegner score, operation time, anterior drawer test results, patient symptoms, and magnetic resonance (MR) evaluation of ATFL quality were used to describe the outcomes. RESULTS: The patient characteristics and follow-up durations were similar between the 2 groups. After a mean follow-up duration of 28.8 ± 2.3 months, the ALP group had significantly better Karlsson score, VAS score, and Tegner score improvement than the LAP group, with fewer symptoms. Seven patients in the LAP group still had a feeling of ankle instability, and 3 of them exhibited ankle laxity. CONCLUSION: In this study, we found that inserting the suture anchor through the anterolateral portal was associated with better outcomes compared to that through the lateral accessory portal when performing arthroscopic ATFL lasso-loop repair for CLAI patients. The improvement was greater for pain relief and function and was associated with a lower frequency of subjective ankle instability.

High energy-efficiency decomplexation of metal-complexes by H*-mediated electro-reduction on hydroxyphenyl Co-porphyrin catalysts.

Electrochemical reduction of metal-organic complex pollutants has been recognized as an environmental benign method that operates at mild condition. However, the selective reduction of metal complexes and energy consumption in cathodic process are still a big challenge. Herein, we found that hydroxyphenyl Co-porphyrin catalyst (CoTH@NG) realizes the highly selective decomplexation of metal-organic complexes by H* -mediated reduction, and simultaneously the impressive recovery efficiency of metal ions. Density functional theory (DFT) confirms the generation and capturing ability of H* on CoTH@NG, verifying the dominant role of H* -mediated reduction in the selective decomplexation of Cu-EDTA. CoTH@NG realizes the superior energy efficiency for Cu-EDTA removal (279.3 g kWh-1 of EEOCu-EDTA) and Cu recovery (48.6 g kWh-1 of EEOCu), which are remarkably 3.3 × 102 and 9.7 × 102 times higher than traditional carbon cloth electrode. Moreover, the recovered Cu0(s) nanowires on the electrode surface can be efficiently regenerated in HCOOH by a galvanic reaction through the electron channel of CoTH@NG, regenerating catalytic electrode. This is one of the pioneer studies on H* -mediated electro-reduction decomplexation of metal-complexes, metal recovery, and electrode regeneration on CoTH@NG, which providing a technical strategy for developing efficient electrocatalytic system for pollution control. Environmental Implication Metal complexes is a dramatic increase in the electroplating and mining industries, and seriously affect both public health and environmental sustainability. Our work reported a new hydroxyphenyl Co-porphyrin catalyst (CoTH@NG) which achieves the selective decomplexation of metal-organic complexes, and simultaneously the recovery of metal ions. CoTH@NG realizes the superior energy efficiency for Cu-EDTA removal (279.3 g kWh-1) and Cu0(s) recovery (48.6 g kWh-1), which are remarkably 3.3 × 102 and 9.7 × 102 times higher than traditional carbon cloth electrode. Moreover, the recovered Cu0(s) can be efficiently regenerated in HCOOH by a galvanic reaction through the electron channel of CoTH@NG, regenerating catalytic electrode.

Immunotherapy Improves the Survival of Stage 4 Non-Small Cell Lung Cancer Patients at the US Population Level: The Real-World Evidence.

INTRODUCTION: Immunotherapy has revolutionized the management of lung cancer and improved lung cancer survival in trials, but its real-world impact at the population level remains unclear. METHODS: Using data obtained from eight Surveillance, Epidemiology, and End Results (SEER) registries from 2004 through 2019, we addressed the long-term trends in the incidence, incidence-based mortality (IBM), and survival of lung cancer patients in the United States. RESULTS: The incidence and IBM of both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) all significantly decreased steadily from 2004 to 2019. The 1-year survival (1-YS) of both NSCLC and SCLC improved over time, with the best improvement observed for Stage 4 NSCLC. Two significant turning points of Stage 4 NSCLC 1-YS were observed over the years: 0.63% (95% confidence interval [CI]: 0.33%-0.93%) from 2004 to 2010, 0.81% (95% CI: 0.41%-1.21%) from 2010 to 2014 and a striking 2.09% (95% CI: 1.70%-2.47%) from 2014 to 2019. The same two turning points in 1-YS were pronounced for Stage 4 NSCLC in women, which were coincident with the introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immunotherapy. However, for Stage 4 NSCLC in men, only one significant turning point in the 1-YS starting in 2014 was found, which might only correspond to immunotherapy. Significant period effects in reduced IBM were also observed for both Stage 4 AD and Stage 4 SQCC during the period. CONCLUSION: This SEER analysis found that immunotherapy improved the survival of Stage 4 NSCLC patients at the population level in the United States. This real-world evidence confirms that immunotherapy has truly revolutionized the management of lung cancer.

Peptidylprolyl isomerase D circular RNA sensitizes breast cancer to trastuzumab through remodeling HER2 N4-acetylcytidine modification.

Human epidermal growth factor receptor 2 (HER2) overexpression and activation are crucial for trastuzumab resistance in HER2-positive breast cancer; however, the potential regulatory mechanism of HER2 is still largely undetermined. In this study, a novel circular RNA derived from peptidylprolyl isomerase D (PPID) is identified as a negative regulator of trastuzumab resistance. Circ-PPID is highly stable and significantly downregulated in trastuzumab-resistant cells and tissues. Restoration of circ-PPID markedly enhances HER2-positive breast cell sensitivity to trastuzumab in vitro and in vivo. Circ-PPID directly binds to N-acetyltransferase 10 (NAT10) in the nucleus and blocks the interaction between NAT10 and HER2 mRNA, reducing N4-acetylcytidine (ac4C) modification on HER2 exon 25, leading to HER2 mRNA decay. Intriguingly, the subcellular localization of circ-PPID differs between trastuzumab-sensitive and -resistant cells. Circ-PPID in trastuzumab-resistant cells is located more in the cytoplasm, mainly due to the upregulation of Exportin 4 (XPO4), which results in the loss of spatial conditions for circ-PPID to bind to nuclear NAT10. Taken together, our data suggest that circ-PPID is a previously unappreciated ac4C-dependent HER2 epigenetic regulator, providing a promising therapeutic direction for overcoming trastuzumab resistance in clinical setting.

Biological characteristics and clinical treatment of pulmonary sarcomatoid carcinoma: a narrative review.

Background and Objective: Pulmonary sarcomatoid carcinoma (PSC) is a subset of non-small cell lung cancer (NSCLC) with highly malignant, aggressive, and heterogeneous features. Patients with this disease account for approximately 0.1-0.4% of lung cancer cases. The absence of comprehensive summaries on the basic biology and clinical treatments for PSC means there is limited systematic awareness and understanding of this rare disease. This paper provides an overview of the biological characteristics of PSC and systematically summarizes various treatment strategies available for patients with this disease. Methods: For this narrative review, we have searched literature related to the basic biology and clinical treatment approaches of PSC by searching the PubMed database for articles published from July 16, 1990 to August 29, 2023. The following keywords were used: "pulmonary sarcomatoid carcinoma", "genetic mutations", "immune microenvironment", "hypoxia", "angiogenesis", "overall survival", "surgery", "radiotherapy", "chemotherapy", and "immune checkpoint inhibitors". Key Content and Findings: Classical PSC comprises epithelial and sarcomatoid components, with most studies suggesting a common origin. PSC exhibits a higher tumor mutational burden (TMB) and mutation frequency than other types of NSCLC. The tumor microenvironment (TME) of PSC is characterized by hypoxia, hypermetabolism, elevated programmed cell death protein 1/programmed cell death-ligand 1 expression, and high immune cell infiltration. Treatment strategies for advanced PSC are mainly based on traditional NSCLC treatments, but PSC exhibits resistance to chemotherapy and radiotherapy. The advancement of genome sequencing has introduced targeted therapies as an option for mutation-positive PSC cases. Moreover, due to the characteristics of the immune microenvironment of PSC, many patients positively respond to immunotherapy, demonstrating its potential for the management of PSC. Conclusions: Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.

IFN-α/ß/IFN-γ/IL-15 pathways identify GBP1-expressing tumors with an immune-responsive phenotype.

Immunotherapy is widely used in cancer treatment; however, only a subset of patients responds well to it. Significant efforts have been made to identify patients who will benefit from immunotherapy. Successful anti-tumor immunity depends on an intact cancer-immunity cycle, especially long-lasting CD8+ T-cell responses. Interferon (IFN)-α/ß/IFN-γ/interleukin (IL)-15 pathways have been reported to be involved in the development of CD8+ T cells. And these pathways may predict responses to immunotherapy. Herein, we aimed to analyze multiple public databases to investigate whether IFN-α/ß/IFN-γ/IL-15 pathways could be used to predict the response to immunotherapy. Results showed that IFN-α/ß/IFN-γ/IL-15 pathways could efficiently predict immunotherapy response, and guanylate-binding protein 1 (GBP1) could represent the IFN-α/ß/IFN-γ/IL-15 pathways. In public and private cohorts, we further demonstrated that GBP1 could efficiently predict the response to immunotherapy. Functionally, GBP1 was mainly expressed in macrophages and strongly correlated with chemokines involved in T-cell migration. Therefore, our study comprehensively investigated the potential role of GBP1 in immunotherapy, which could serve as a novel biomarker for immunotherapy and a target for drug development.

Cancer drug indication approvals in China and the United States: a comparison of approval times and clinical benefit, 2001-2020.

Background: Perceived delays in cancer drug approvals have been a major concern for policymakers in China. Policies have been implemented to accelerate the launch of new cancer drugs and indications. This study aimed to assess similarities and differences between China and the United States in the approvals, timing, and clinical benefit evidence of cancer drug indications between 2001 and 2020. Methods: This study retrospectively identified all cancer drugs and indications approved in both China and the United States from January 1st, 2001 to December 31, 2020, and described differences in approval times as well as in submission and review times. Information on the availability of overall survival benefit evidence by December 31, 2020, was collected. Univariate and multiple logistic regression analyses were used to assess whether evidence of benefit and other factors affected the propensity and timing of approvals of cancer drug indications in China. Findings: Between 2001 and 2020, 229 indications corresponding to 145 cancer drugs approved in the United States were identified. Of those, 80 indications (34.9%) were also approved in China by the end of 2020. Cancer drug indications were approved in China at a median of 1273.5 days after approval in the United States. The median submission and review time differences for cancer drug indications in China were 1198.0 days and 180.0 days respectively. Submission time differences accounted for most of the approval time differences (p < 0.001). Indications supported by overall survival benefit evidence had shorter median review time differences (145.0 days) than those without such evidence (235.0 days, p = 0.008). Indications with overall survival benefit evidence were 3.94 times more likely to be approved in China compared to those without such evidence (p = 0.001), controlling for approval year, cancer type, and the prevalence of cancer by site. Interpretation: FDA-approved cancer drug indications demonstrating a survival benefit were more likely to receive approvals in China with shorter regulatory review times compared to indications without such evidence. Given that manufacturer submission times were the main driver of cancer drug approval times in China, factors influencing submission timing should be explored. Funding: No funding.