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Abstract Type II collagen (CII), a key component of cartilaginous tissues, offers an attractive option for fabricating biomimetic scaffolds that provide mechanical support and biochemical signals to facilitate cell adhesion, proliferation, and differentiation. Advances in fabrication technologies have enabled the creation of intricate and multicellular CII-based scaffolds that more accurately replicate the natural structure of tissues. Here, we review the application of CII in tissue engineering and highlight its crucial contributions to the regeneration of hyaline cartilage and intervertebral discs. Additionally, we discuss the versatile roles of CII in other biomedical applications, including disease modeling, bone regeneration, and the development of artificial immune organs.

The bidirectional relationship between osteochondral defects (OCD) and osteoarthritis (OA), with each condition exacerbating the other, makes OCD regeneration in the presence of OA challenging. Type II collagen (Col2) is important in OCD regeneration and the management of OA, but its potential applications in cartilage tissue engineering are significantly limited. This study investigated the regeneration capacity of Col2 scaffolds in critical-sized OCDs under surgically induced OA conditions and explored the underlying mechanisms that promoted OCD regeneration. Furthermore, the repair potential of Col2 scaffolds was validated in over critical-sized OCD models. After 90 days or 150 days since scaffold implantation, complete healing was observed histologically in critical-sized OCD, evidenced by the excellent integration with surrounding native tissues. The newly formed tissue biochemically resembled adjacent natural tissue and exhibited comparable biomechanical properties. The regenerated OA tissue demonstrated lower expression of genes associated with cartilage degradation than native OA tissue but comparable expression of genes related to osteochondral anabolism compared with normal tissue. Additionally, transcriptome and proteome analysis revealed the hindrance of TGF-β-Smad1/5/8 in regenerated OA tissue. In conclusion, the engrafting of Col2 scaffolds led to the successful regeneration of critical-sized OCDs under surgically induced OA conditions by inhibiting the TGF-β-Smad1/5/8 signaling pathway.

Efficient drug delivery across the blood-brain barrier is imperative for treating glioblastoma (GBM). This study utilized the GBM cell membrane to construct a biomimetic targeted nanosystem (GMNPs@AMD/RAPA) that hierarchically releases the CXCR4 antagonist AMD3100 and the mTOR pathway inhibitor rapamycin (RAPA) for reprogramming the tumor immune microenvironment and suppressing the progression of GBM. By initially inhibiting the CXCL12/CXCR4 axis, the tumor microenvironment (TME) was reprogrammed to enhance the infiltration of cytotoxic T lymphocytes (CTLs) into the TME while suppressing tumor cell survival, proliferation, and angiogenesis. Subsequently, through further cellular uptake and degradation of the nanoparticles, the mTOR pathway inhibitor RAPA was released, further suppressing the tumor progression. This study successfully combined chemotherapy and immunotherapy, achieving effective synergistic therapeutic effects, and suppressing the progression of GBM.

The unique gradient structure and complex composition of osteochondral tissue pose significant challenges in defect regeneration. Restoration of tissue heterogeneity while maintaining hyaline cartilage components has been a difficulty of an osteochondral tissue graft. A novel class of multi-crosslinked polysaccharide-based three-dimensional (3D) printing inks, including decellularized natural cartilage (dNC) and nano-hydroxyapatite, was designed to create a gradient scaffold with a robust interface-binding force. Herein, we report combining a dual-nozzle cross-printing technology and a gradient crosslinking method to create the scaffolds, demonstrating stable mechanical properties and heterogeneous bilayer structures. Biofunctional assessments revealed the remarkable regenerative effects of the scaffold, manifesting three orders of magnitude of mRNA upregulation during chondrogenesis and the formation of pure hyaline cartilage. Transcriptomics of the regeneration site in vivo and scaffold cell interaction tests in vitro showed that printed porous multilayer scaffolds could form the correct tissue structure for cell migration. More importantly, polysaccharides with dNC provided a hydrophilic microenvironment. The microenvironment is crucial in osteochondral regeneration because it could guide the regenerated cartilage to ensure the hyaline phenotype.

Endochondral ossification (ECO) is a form of bone formation whereby the newly deposited bone replaces the cartilage template. A decellularized artificial cartilage graft (dLhCG), which is composed of hyaline cartilage matrixes, has been developed in our previous study. Herein, the osteogenesis of bone marrow-derived MSCs in the dLhCG through chondrogenic differentiation, chondrocyte hypertrophy, and subsequent transdifferentiation induction has been investigated by simulating the physiological processes of ECO for repairing critical-sized bone defects. The MSCs were recellularized into dLhCGs and subsequently allowed to undergo a 14-day proliferation period (mrLhCG). Following this, the mrLhCG constructs were subjected to two distinct differentiation induction protocols to achieve osteogenic differentiation: chondrogenic medium followed by chondrocytes culture medium with a high concentration of fetal bovine serum (CGCC group) and canonical osteogenesis inducing medium (OI group). The formation of a newly developed artificial bone graft, ossified dLhCG (OsLhCG), as well as its capability of aiding bone defect reconstruction were characterized by in vitro and in vivo trials, such as mRNA sequencing, quantitative real-time PCR (qPCR), immunohistochemistry, the greater omentum implantation in nude mice, and repair for the critical-sized femoral defects in rats. The results reveal that the differentiation induction of MSCs in the CGCC group can realize in vitro ECO through chondrogenic differentiation, hypertrophy, and transdifferentiation, while the MSCs in the OI group, as expected, realize ossification through direct osteogenic differentiation. The angiogenesis and osteogenesis of OsLhCG were proved by being implanted into the greater omentum of nude mice. Besides, the OsLhCG exhibits the capability to achieve the repair of critical-size femoral defects.

Dedifferentiation of chondrocyte greatly restricts its function and application, however, it is poorly understood except a small number of canonical markers. The non-cell-adhesive property endows polysaccharide hydrogel with the ability to maintain chondrocyte phenotype, which can serve as a platform to identify new molecular markers and therapeutic targets of chondrocyte dedifferentiation. In this study, the high-throughput RNA sequencing (RNA-seq) was first performed on articular chondrocytes at primary (P0) and passage 1 (P1) stages to explore the global alteration of gene expression along with chondrocyte dedifferentiation. Significantly, several potential marker genes, such as PFKFB3, KDM6B, had been identified via comparatively analyzing their expression in P0 and P1 chondrocytes as well as in 3D constructs (i.e. chondrocyte-laden alginate hydrogel and HA-MA hydrogel) at both mRNA and protein level. Besides, the changes in cellular morphology and enriched pathway of differentially expressed genes during chondrocyte dedifferentiation was studied in detail. This study developed the use of hydrogel as a platform to investigate chondrocyte dedifferentiation; the results provided new molecular markers and potential therapeutic targets of chondrocyte dedifferentiation.

Stable integration of hydrogel implants with host tissues is of critical importance to cartilage tissue engineering. Designing and fabricating hydrogels with high adhesive strength, stability and regeneration potential are major challenges to be overcome. This study fabricated injectable adhesive hyaluronic acid (HA) hydrogel modified by aldehyde groups and methacrylate (AHAMA) on the polysaccharide backbone with multiple anchoring mechanisms (amide bond through the dynamic Schiff base reaction, hydrogen bond and physical interpenetration). AHAMA hydrogel exhibited significantly improved durability and stability within a humid environment (at least 7 days), together with higher adhesive strength (43 KPa to skin and 52 KPa to glass), as compared to commercial fibrin glue (nearly 10 KPa) and HAMA hydrogel (nearly 20 KPa). The results showed that AHAMA hydrogel was biocompatible and could be easily and rapidly prepared in situ. In vitro cell culture experiments showed that AHAMA hydrogel could enhance proliferation (1.2-folds after 3 days) and migration (1.5-folds after 12 h) of bone marrow stem cells (BMSCs), as compared to cells cultured in a culture dish. Furthermore, in a rat osteochondral defect model, implanted AHAMA hydrogel significantly promoted integration between neo-cartilage and host tissues, and significantly improved cartilage regeneration (modified O'Driscoll histological scores of 16.0 ± 4.1 and 18.3 ± 4.6 after 4 and 12-weeks of post-implantation in AHAMA groups respectively, 12.0 ± 2.7 and 12.2 ± 2.8 respectively in HAMA groups, 9.8 ± 2.4 and 11.5 ± 2.1 respectively in untreated groups). Hence, AHAMA hydrogel is a promising adhesive biomaterial for clinical cartilage regeneration and other biomedical applications.

The interactions at the graft–tissue interfaces are critical for the results of engraftments post-implantation. To improve the success rate of the implantations, as well as the quality of the patients' life, understanding the possible reactions between artificial materials and the host tissues is helpful in designing new generations of material-based grafts aiming at inducing specific responses from surrounding tissues for their own reparation and regeneration. To help researchers understand the complicated interactions that occur after implantations and to promote the development of better-designed grafts with improved biocompatibility and patient responses, in this review, the topics will be discussed from the basic reactions that occur chronologically at the graft–tissue interfaces after implantations to the existing and potential applications of the mechanisms of such reactions in designing of grafts. It offers a chance to bring up-to-date advances in the field and new strategies of controlling the graft–tissue interfaces.

AIM: To explore the efficacy of preoperative intravitreal injection of conbercept combined with 25G+ pars plana vitrectomy(PPV)in the treatment of proliferative diabetic retinopathy(PDR).METHODS: The clinical data of 154 patients(176 eyes)with PDR admitted to our hospital from January 2019 to June 2021 were collected for retrospective analysis. According to the treatment methods, 80 patients(92 eyes)in combined treatment group were treated with preoperative intravitreal injection of conbercept combined with 25G+PPV, and 74 patients(84 eyes)in control group were given 25G+PPV only. The postoperative clinical efficacy and levels of adipokines [adiponectin(APN), retinol binding protein 4(RBP4)] before and after surgery were compared between both groups of patients.RESULTS: The combined treatment group showed better clinical efficacy than the control group at 1mo after surgery(P

To compare clinicopathological features and survival outcomes in patients with endometrial cancer, with and without associated adenomyosis. PubMed, Embase and Scopus databases were systematically searched for relevant observational studies. The pooled effect sizes were reported as either hazards ratio (HR) for survival-related outcomes or as odds ratio (OR) for other categorical outcomes. Weighted mean difference (WMD) was reported for continuous outcomes. All the analyses used the random effects model. A total of 21 studies (N = 46,420) were included. Compared to endometrial cancer patients without adenomyosis, patients with associated adenomyosis had improved overall 5-year survival (OS) (HR 0.62, 95% CI: 0.50, 0.79) and disease-free survival (DFS) (HR 0.60, 95% CI: 0.44, 0.82). Disease-specific survival was statistically similar in patients with and without adenomyosis (HR 0.60, 95% CI: 0.35, 1.05). Among patients with adenomyosis, the risk of having an advanced tumour grade (Grade 2 or 3) was lower (OR 0.51, 95% CI: 0.42, 0.62) and a risk of having International Federation of Gynaecology and Obstetrics (FIGO) stage I or II was higher (OR 2.23, 95% CI: 1.65, 3.01). Patients with adenomyosis had lower risk of tumour invasion of adnexa, cervical stromal invasion, deep myometrial involvement (DMI), lympho-vascular space invasion (LVSI) and peritoneal invasion. Presence of adenomyosis in patients with endometrial cancer is associated with favourable tumour characteristics and may improve the survival.

Abstract Aim To review the literature related to symptom management, clinical significance and related theoretical framework systems in adult patients with brain tumours. Background As understanding of symptoms or symptom clusters and underlying biologic mechanisms has grown, it is apparent that symptom science is moving forward. Although some progress has been made in the symptom science of solid tumours such as breast and lung neoplasms, insufficient attention has been paid to symptom management for patients suffering from brain tumours. Further research is needed to achieve effective symptom management for these patients. Design A literature review with a systematic search of symptom management in adult brain tumours. Methods Electronic data bases were searched to obtain relevant published literature on symptom management in adults with brain tumours. This was then analysed and a synthesis of relevant findings is presented. Findings Four significant general themes relating to symptom management of brain tumours in adults were identified: (1) The potential theoretical foundation related to symptom management was revealed. (2) Widely accepted validated scales or questionnaires for the assessment of single symptoms or symptom clusters were recommended. (3) Several symptom clusters and the underlying biologic mechanisms have been reported. (4) Specific symptom interventions for adults with brain tumours were collected and classified as evidence‐based or insufficient evidence. Conclusion There are still many challenges in the effective management of symptoms in adults with brain tumours. The guiding role of theoretical frameworks or models related to symptom management should be utilized in future research. Using the concept of symptom clustering for research into symptoms found in patients with brain tumours, exploring common biological mechanisms for specific symptom clusters and making full use of modern big data resources to build a strong evidence base for an effective intervention or management program may inform the management of symptoms among these patients leading to better results. No Patient or Public Contribution This is a literature review. Implications for Symptom Management The ultimate goal is obviously not only improving the survival rate of patients with brain tumours, but also enhancing their quality of life. Several important findings from our review include the theoretical foundations, validated assessment tools, the assessment of symptom clusters and the underlying biologic mechanism, and the identification of the evidence base for symptom interventions. These are of relevance for managers, researchers and practitioners and may function as a reference to help the effective symptom management for adults with brain tumours.

Proton beam therapy (PBT) can achieve the effect of precision radiotherapy due to its unique Bragg peak. In the process of proton therapy, the peak can be accurately located to the tumor area, which can give the tumor a larger dose of irradiation, reduce the damage to normal tissues and organs, and reduce the occurrence of side effects. Therefore, it is very important to locate the Bragg peak of proton beam in real time in proton therapy. In this paper, a cyclotron is used to generate proton beam, and a diamond detector is used to test the radiation characteristics of proton beam, and the Bragg peak and the beam spot center are measured (0, 35 mm). Thus, accurate Bragg peak value of proton beam was obtained, which guaranteed the accuracy of proton therapy.

Abstract Background Myocardial injury-related cardiogenic shock (MICS) is significantly associated with poor outcomes in patients after cardiac surgery. Herein, we aimed to investigate the risk factor for postoperative MICS. Methods We performed a case-control study on 792 patients undergoing cardiac surgery from 2016 to 2019, including 172 patients with postoperative MICS and 620 age- and sex-matched controls. MICS was defined as composite criteria: a cardiac index of 5 mmol/L at the end of the surgery, a vasoactive-inotropic score of > 40 at the end of the surgery, and a cardiac troponin T (cTnT) level of > 0.8 µg/L on postoperative day 1 (POD1) with an increase of > 10% on POD 2. Results A total of 4671 patients who underwent cardiac surgery in our hospital between 2016 and 2019 were included; of these, 172 (3.68%) had MICS and the remaining 4499 did not. For investigating the risk factors, we selected 620 age- and sex-matched controls. In the univariate analysis, MICS was significantly associated with death (P 2 h (OR: 3.16, 95% CI: 1.94–5.15, P

AIM: To explore the correlation between the expression levels of microRNA-377-3p(miR-377-3p)and microRNA-365-3p(miR-365-3p)in serum and aqueous humor and the degree of diabetes macular edema(DME).METHODS: A total of 60 DME patients(60 eyes)admitted to 363 Hospital from February 2021 to February 2022 were selected in this prospective study(the severe eye was selected if both eyes had DME, while the right eye was selected if the same degree of DME), including 24 mild eyes, 21 moderate eyes and 15 severe eyes. In addition, another 60 patients(60 eyes)with type 2 diabetes(without fundus disease)admitted to our hospital during the same period were selected as the control group. The basic clinical data of all subjects were collected, including body mass index(BMI), smoking history, drinking history, hypertension, hyperlipidemia, the course of diabetes, glycated hemoglobin levels, fasting blood glucose and homocysteine(Hcy); the expression levels of miR-377-3p and miR-365-3p were detected by real-time fluorescent quantitative PCR(qRT-PCR).RESULTS: The course of diabetes, glycosylated hemoglobin, fasting blood glucose and Hcy in DME group were obviously higher than those in control group(all P

Objective Compensation characteristics of spinal sagittal malalignment according to pelvic incidence (PI) have yet to be elucidated. This study aimed to investigate the difference in compensatory segments according to PI in elderly patients with degenerative lumbar spinal stenosis (DLSS). Methods This retrospective study included 196 patients (143 females, 53 males) suffering from DLSS with an average age of 66.73 years in our department. Sagittal parameters were obtained on the whole spinal lateral radiograph, including T1‐T12 slope (T1S‐T12S), Cobb angle (CA) of the functional units of the thoracic spine, thoracic kyphosis (TK), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), PI, the ratio of PT to PI (PT/PI), PI minus LL mismatch (PI‐LL), sagittal vertical axis (SVA). Patients were divided into the low and high PI groups according to the median value of PI. With reference to the value of SVA and PI‐LL, each PI group was further grouped into the balance subgroup (SVA 10°), and imbalance subgroup (SVA ≥50 mm). Independent samples t‐test/Mann–Whitney U test, one‐way ANOVA/Kruskal‐Wallis test, and Person correlation analysis were utilized for statistical test. Results The median value of PI was 47.65°. 96 and 100 patients were assigned to low and high PI groups, respectively. Correlation analysis indicated that the T8‐T12 slope and T10‐T12 slope were associated with PI‐LL in the high and low PI groups, respectively (all, p

Abstract Metastatic breast-cancer is a major cause of death in women worldwide, yet the relationship between oncogenic drivers that promote metastatic versus primary cancer is still contentious. To elucidate this relationship in treatment-naive animals, we hereby describe mammary-specific transposon-mutagenesis screens in female mice together with loss-of-function Rb, which is frequently inactivated in breast-cancer. We report gene-centric common insertion-sites (gCIS) that are enriched in primary-tumors, in metastases or shared by both compartments. Shared-gCIS comprise a major MET-RAS network, whereas metastasis-gCIS form three additional hubs: Rho-signaling, Ubiquitination and RNA-processing. Pathway analysis of four clinical cohorts with paired primary-tumors and metastases reveals similar organization in human breast-cancer with subtype-specific shared-drivers (e.g. RB1-loss, TP53-loss, high MET, RAS, ER), primary-enriched (EGFR, TGFβ and STAT3) and metastasis-enriched (RHO, PI3K) oncogenic signaling. Inhibitors of RB1-deficiency or MET plus RHO-signaling cooperate to block cell migration and drive tumor cell-death. Thus, targeting shared- and metastasis- but not primary-enriched derivers offers a rational avenue to prevent metastatic breast-cancer.

Abstract The effect of plugging the puncture channel with a mixture of hemocoagulase injection on the complications of CT-guided percutaneous transthoracic need biopsy (PTNB) was discussed. The medical records of PTNB were retrospectively studied from June 2017 to May 2022. In the study, the puncture channel of 626 patients were blocked, while remain 681 patients’ were not. The Mantel Haenszel method performed layered analysis and evaluated the correlation of adjusted confounding factors. The Odds Ratio and its 95% confidence interval were calculated using the Woof method. The incidence of high-level pulmonary hemorrhage was significantly reduced in patients with lesions ≤ 2 cm and different needle lengths. Patients with different pleural-needle tip angle and perineedle emphysema were blocked, and the incidence of pneumothorax and thoracic implants was significantly reduced. Through puncture channel plugging, the incidence of pulmonary hemorrhage, pneumothorax and thoracic catheterization of PTNB under CT guidance was reduced.

The effect of spatial heterogeneity on the microbial community and physicochemical properties during the primary fermentation of Daqu were investigated by high-throughput sequencing technology and conventional detection methods. Nongxiangxing baijiu Daqu inoculated with the unique ripe starter obtained by gradually culturing and expanding Daqu treated by cosmic rays was used. The results showed that although the intensity of change in driving factors varied among layer, their trends were the same. The liquefying, saccharifying and esterifying power of Daqu were higher in the bottom layer than in the upper and middle layers at the same fermentation time and the fluctuation was small. The microbial community of Daqu was composed of 12 dominant bacterial genera, including Lactobacillus, Weissella, Bacillus, Kosakonia, Staphylococcu and Thermoactinomyces, and seven dominant fungal genera, such as Pichia, Thermoascus, and Rhizomucor. Principal co-ordinates analysis and hierarchical clustering analysis showed significant differences in the bacterial and fungal community structure among fermentation stages and layers. Procrustes analysis and Mantel test showed that moisture had a significant effect on the bacterial community in Daqu, and acidity had a significant effect on the bacterial community in the middle and bottom layers of Daqu. Moreover, moisture had a significant effect on the fungal community in the upper and middle layers of Daqu. Redundancy analysis showed that moisture and acidity were positively correlated with Lactobacillus and Pichia, while driving factors had different influences on the microbial communities in different layers of Daqu. Therefore, the interaction and co-occurrence patterns of microbial genera in Daqu could change due to the differences in driving factors among different layers of Daqu. These results suggested that regulating driving factors during the Daqu making process is an effective way to improve the microbial community structure and quality of Daqu.

Brain-computer interface (BCI) technology based on motor imagery electroencephalograph (EEG) signals has developed rapidly, and compared with traditional methods, deep learning has achieved competitive results. However, it is still a challenge to design and train an end-to-end network to fully extract the potential features of motor-imaging EEG signals. Based on the temporal and spatial characteristics of EEG, a multi-scale spatiotemporal self-attention network model based on attention mechanism is proposed to classify motor imagery EEG signals into four categories, such as left hand, right hand, foot and tongue/rest. Since the amplitude and response time of motor imagery EEG signal vary with the subjects, it is impossible to determine the most relevant brain region with motor imagery. Therefore, the self-attention mechanism is used to select the best channel by automatically weighting the higher weight to the motion-related channel and the lower weight to the non-motion-related channel in space. And parallel multi-scale TCN layer is used to extract the temporal feature at different scales and to eliminate the noise in time domain. The fusion module fuses the extracted spatial and temporal features, and finally inputs them to the classification module for classification. The model achieves accuracy of 79.26%, 85.90% and 96.96% on the BCI competition datasets IV-2a, IV-2b and HGD dataset. Compared with the baseline method, this method has a higher accuracy in subject classification. The results show that the method has good performance, robustness and transfer learning ability.

A conceptual design of a passive core cooling system (PCCS) was proposed in order to removal residual core heat during accident scenarios. Strong coupling feedback effect exists between natural convective heat transfer of the PCCS and the temperature distribution within the reactor core, which has a significant impact on the heat removal performance of the PCCS and the peak fuel temperature. An integral computational model dedicated to micro gas-cooled reactor, which includes both the PCCS and the reactor core, was developed. Comparisons of results predicted by this model and reference results of two benchmark problem, i.e. exercises of MHTGR and natural convection in a square cavity, show a satisfactory agreement, which thus validate the model. Thereafter, in order to explore the operational characteristics of the PCCS proposed in this work as well as the temperature response of the reactor core, and to assess its mitigative performance during accident scenario, this CFD model was then employed to analyze both the steady state under normal operation condition and the pressurized-loss-of-forced-cooling (PLOFC) accident. The calculation results show that the natural circulation of air is steady and regular during normal operation. The heat loss due to the PCCS is acceptably small, which will not lead to significant impact on the core temperature. During the PLOFC accident, the heat removal power of the PCCS is high in the early phase, whereas its performance gradually decreases as the temperature of the reactor vessel decreases in the long term. In general, the PCCS can effectively remove the residual core heat, thus maintaining the reactor integrity. Consequently, the integral CFD model created in this work can be applied to the design and the safety analysis of the PCCS for the micro gas-cooled reactor.

Benzalkonium chloride is a quaternary ammonium compound with bactericidal activity, which is widely used in domestic and healthcare settings as well as in food processing environments. It plays an important role in the prevention and control of foodborne pathogens. However, the presence of biofilms or improper use of benzalkonium chloride may enable foodborne pathogens to adapt to bactericides, affecting the tolerance to homologous or heterologous biocidal agents. The review summarizes the relationship between the adaptation of foodborne pathogens to benzalkonium chloride and their tolerance to this biocide. The reasons for the increased tolerance to benzalkonium chloride are explained from the perspectives of the expression of efflux pump genes, cell membrane modification, and the formation of the viable but non-cultivable (VBNC) state. Furthermore, the influence of benzalkonium chloride adaptation on the antibiotic resistance of foodborne pathogens is discussed, and the reasons for the increased antibiotic resistance are summarized from the perspectives of biofilm formation, spontaneous mutations, horizontal gene transfer, and the role of efflux pumps in antibiotic resistance. This review could help understand the mechanism of the adaption of foodborne pathogens to benzalkonium chloride and provide a reference for the rational use of biocides and the prevention and control of foodborne pathogens.

Abstract Immune-checkpoint (IC) modulators like the poliovirus receptor (PVR) and programmed death ligand 1 (PD-L1) attenuate innate and adaptive immune responses and are potential therapeutic targets for diverse malignancies, including triple-negative breast cancer (TNBC). The retinoblastoma tumor suppressor, pRB, controls cell growth through E2F1-3 transcription factors, and its inactivation drives metastatic cancer, yet its effect on IC modulators is contentious. Here, we show that RB-loss and high E2F1/E2F2 signatures correlate with expression of PVR, CD274 (PD-L1 gene) and other IC modulators and that pRB represses whereas RB depletion and E2F1 induce PVR and CD274 in TNBC cells. Accordingly, the CDK4/6 inhibitor, palbociclib, suppresses both PVR and PD-L1 expression. Palbociclib also counteracts the effect of CDK4 on SPOP, leading to its depletion, but the overall effect of palbociclib is a net reduction in PD-L1 level. Hydrochloric acid, commonly used to solubilize palbociclib, counteracts its effect and induces PD-L1 expression. Remarkably, lactic acid, a by-product of glycolysis, also induces PD-L1 as well as PVR. Our results suggest a model in which CDK4/6 regulates PD-L1 turnover by promoting its transcription via pRB-E2F1 and degradation via SPOP and that the CDK4/6-pRB-E2F pathway couples cell proliferation with the induction of multiple innate and adaptive immunomodulators, with direct implications for cancer progression, anti-CDK4/6- and IC-therapies.

Abstract Background The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA). Methods Nested in the Health Professionals Follow-up Study, a subcohort of 307 healthy men (mean[SD] age, 70[4] years) provided stool and blood samples in 2012–2013. Data from cohort long-term follow-ups and from the accelerometer, doubly labeled water, and plasma biomarker measurements during the time of stool collection were used to assess long-term and short-term associations of PA with adiposity. The gut microbiome was profiled by shotgun metagenomics and metatranscriptomics. A subcohort of 209 healthy women from the Nurses’ Health Study II was used for validation. Results The microbial species Alistipes putredinis was found to modify the association between PA and body weight. Specifically, in individuals with higher abundance of A. putredinis, each 15-MET-hour/week increment in long-term PA was associated with 2.26 kg (95% CI, 1.53–2.98 kg) less weight gain from age 21 to the time of stool collection, whereas those with lower abundance of A. putredinis only had 1.01 kg (95% CI, 0.41–1.61 kg) less weight gain (p interaction = 0.019). Consistent modification associated with A. putredinis was observed for short-term PA in relation to BMI, fat mass%, plasma HbA1c, and 6-month weight change. This modification effect might be partly attributable to four metabolic pathways encoded by A. putredinis, including folate transformation, fatty acid β-oxidation, gluconeogenesis, and stearate biosynthesis. Conclusions A greater abundance of A. putredinis may strengthen the beneficial association of PA with body weight change, suggesting the potential of gut microbial intervention to improve the efficacy of PA in body weight management. Video Abstract

Background and purpose: The response rate of gastric cancer patients to programmed death-1 (PD-1) inhibitor is relatively low. Establishing a useful efficacy prediction method to screen the superior gastric cancer patients receiving anti-PD-1 therapy could improve the prognosis of patients. This study aimed to explore the value of combined detection of lactate dehydrogenase (LDHA) and programmed death ligand-1 (PD-L1) expressions in predicting the efficacy and prognosis of gastric cancer patients treated with PD-1 inhibitor. Methods: The clinicopathological data of 50 advanced gastric cancer patients treated with PD-1 inhibitor in The First Affiliated Hospital of Wannan Medical College from January 2020 to March 2022 were retrospectively analyzed. The independent risk factors affecting the efficacy of PD-1 inhibitor were analyzed by multivariate logistic regression. The value of combined detection of LDHA and PD-L1 in predicting the efficacy of PD-1 inhibitors in gastric cancer was analyzed by receiver operating characteristic (ROC) curve analysis. Gastric cancer patient survival was analyzed by Kaplan-Meier method. Results: The objective response rate (ORR) of gastric cancer patients receiving PD-1 inhibitor therapy in LDHA low and high expression groups were 59% and 10%, respectively. The disease control rate (DCR) in LDHA low and high expression groups were 83% and 29%, respectively. The difference was statistically significant (P

Platinum-based chemotherapy is one of the predominant strategies for treating ovarian cancer (OC), however, platinum resistance greatly influences the therapeutic effect. Circular RNAs (circRNAs) have been found to participate in the pathogenesis of platinum resistance. Our aim was to explore the involvement of circ_0078607 in OC cell cisplatin (DDP) resistance and its potential mechanisms. Circ_0078607, miR-196b-5p, and growth arrest-specific 7 (GAS7) levels were assessed by qPCR. Circ_0078607 stability was assessed by ribonuclease R digestion and actinomycin D treatment. Cell viability of various conic of DDP treatment was measured by CCK-8. The cell proliferation was determined by CCK-8 and colony formation assay. Western blotting was performed for determining GAS7, ABCB1, CyclinD1 and Bcl-2 protein levels. The direct binding between miR-196b-5p and circ_0078607 or GAS7 was validated by dual-luciferase reporter and RIP assay. DDP resistance in vivo was evaluated in nude mice. Immunohistochemistry staining for detecting Ki67 expression in xenograft tumours. Circ_0078607 and GAS7 was down-regulated, but miR-196b-5p was up-regulated in OC samples and DDP-resistant cells. Overexpression of circ_0078607 inhibited DDP resistance, cell growth and induced apoptosis in DDP-resistant OC cells. Mechanistically, circ_0078607 sequestered miR-196b-5p to up-regulate GAS7. MiR-196b-5p mimics reversed circ_0078607 or GAS7 overexpression-mediated enhanced sensitivity. Finally, circ_0078607 improved the sensitivity of DDP in vivo. Circ_0078607 attenuates DDP resistance via miR-196b-5p/GAS7 axis, which highlights the therapeutic potential of circ_0078607 to counter DDP resistance in OC.

Abstract Objective The aim of this study was to investigate the association between spinal alignment and preoperative patient-reported outcomes (PROs) in patients with degenerative lumbar spondylolisthesis (DLS) and to identify the independent risk factors for worse preoperative PROs. Methods In total, 101 patients suffering from DLS were retrospectively studied within a single medical center. Age, sex, height, weight, and body mass index were uniformly recorded. PRO-related indicators include the Oswestry Disability Index (ODI), the Japanese Orthopedic Association’s (JOA) score, and the visual analog scale (VAS) for back and leg pain. Sagittal alignment, coronal balance, and stability of the L4/5 level were evaluated through whole-spine anteroposterior and lateral radiographs and dynamic lumbar X-ray. Results Increasing age (P = 0.005), higher sagittal vertical axis (SVA) (P

Abstract Purpose To investigate the effect of interlaminar Coflex stabilization (ICS) at various segments in the topping-off procedure on local and global spinal sagittal alignment. Methods Eighty-nine consecutive patients with degenerative lumbar spinal stenosis (DLSS) who underwent ICS and transforaminal lumbar interbody fusion (TLIF) were retrospectively reviewed. They were divided into Group A (L4-L5 ICS + L5-S1 TLIF), Group B (L3-L4 ICS + L4-S1 TLIF), and Group C (L2-L3 ICS + L3-S1 TLIF) according to their fusion levels. The measured local sagittal parameters included the implanted segmental angle (ISA), intervertebral disc angle (IDA), intervertebral foreman height (IFH), and disc height. The assessed global sagittal parameters included thoracic kyphosis, lumbar lordosis (LL), the fused segment angle (FSA), the sacral slope, the pelvic tilt, pelvic incidence, and the sagittal vertical axis. The Oswestry Disability Index (ODI) and visual analog scales (VAS) were recorded to evaluate the clinical outcomes. Results Regarding the local alignment parameters, the ISA and IDA decreased immediately after surgery in Groups A and B, followed by an increase at the last follow-up (all, P

Abstract Background Extracellular vesicles (EVs) released by helminths play an important role in parasite-host communication. However, little is known about the characteristics and contents of the EVs of Fasciola gigantica, a parasitic flatworm that causes tropical fascioliasis. A better understanding of EVs released by F. gigantica will help elucidate the mechanism of F. gigantica-host interaction and facilitate the search for new vaccine candidates for the control and treatment of fascioliasis. Methods Two different populations of EVs (15k EVs and 100k EVs) were purified from adult F. gigantica culture media by ultracentrifugation. The morphology and size of the purified EVs were determined by transmission electron microscopy (TEM) and by the Zetasizer Nano ZSP high performance particle characterization system. With the aim of identifying diagnostic markers or potential vaccine candidates, proteins within the isolated 100k EVs were analyzed using mass spectrometry-based proteomics (LC–MS/MS). Mice were then vaccinated with excretory/secretory products (ESPs; depleted of EVs), 15k EVs, 100k EVs and recombinant F. gigantica heat shock protein 70 (rFg-HSP70) combined with alum adjuvant followed by challenge infection with F. gigantica metacercariae. Fluke recovery and antibody levels were used as measures of vaccine protection. Results TEM analysis and nanoparticle tracking analysis indicated the successful isolation of two subpopulations of EVs (15k EVs and 100k EVs) from adult F. gigantica culture supernatants using differential centrifugation. A total of 755 proteins were identified in the 100k EVs. Exosome biogenesis or vesicle trafficking proteins, ESCRT (endosomal sorting complex required for transport) pathway proteins and exosome markers, heat shock proteins and 14-3-3 proteins were identified in the 100k EVs. These results indicate that the isolated 100k EVs were exosome-like vesicles. The functions of the identified proteins may be associated with immune regulation, immune evasion and virulence. Mice immunized with F. gigantica ESPs, 15k EVs, 100k EVs and rFg-HSP70 exhibited a reduction in fluke burden of 67.90%, 60.38%, 37.73% and 56.6%, respectively, compared with the adjuvant control group. The vaccination of mice with F. gigantica 100k EVs, 15k EVs, ESP and rFg-HSP70 induced significant production of specific immunoglobulins in sera, namely IgG, IgG1 and IgG2a. Conclusion The results of this study suggest that proteins within the exosome-like vesicles of F. gigantica have immunomodulatory, immune evasion and virulence functions. This knowledge may lead to new strategies for immunotherapy, vaccination and the diagnosis of fascioliasis. Graphical Abstract

Abstract Background Recent high-quality trials have shown that the anti-inflammatory effects of colchicine reduce the risk of cardiovascular events in patients suffering post-myocardial infarction and chronic coronary disease. The effect of colchicine in patients undergoing non-coronary artery bypass grafting (non-CABG) with cardiopulmonary bypass remains unclear. We aim to evaluate the effect of colchicine on myocardial protection in patients who underwent non-CABG cardiac surgery. Method Patients were randomly assigned to colchicine or placebo groups starting 72 h before scheduled cardiac surgery and for 5 days thereafter (0.5 mg daily).The primary outcome was the level of cardiac troponin T (cTnT) at postoperative 48 h. The secondary outcomes included troponin I (cTnI) and creatine kinase-MB (CK-MB), inflammatory biomarkers (procalcitonin and interleukin-6, etc.), and adverse events (30-day mortality, stroke, ECMO and IABP use, etc.). Results A total of 132 patients underwent non-CAGB cardiac surgery, 11were excluded because of diarrhea (n = 6) and long aortic cross-clamp time > 2 h (n = 5), 59 were assigned to the colchicine group and 62 to the placebo group. Compared with the placebo group, cTnT (median: 0.3 μg/L, IQR 0.2–0.4 μg/L vs. median: 0.4 μg/L, IQR 0.3–0.6 μg/L, P

Abstract Background Evidence suggests that pediatric tuina, a modality of traditional Chinese medicine (TCM), might have beneficial effects on the symptoms of attention deficit hyperactivity disorder (ADHD), such as overall improvements in concentration, flexibility, mood, sleep quality, and social functioning. This study was conducted to understand the facilitators and barriers in the delivery of pediatric tuina by parents to children with ADHD symptoms. Methods This is a focus group interview embedded in a pilot randomized controlled trial on parent-administered pediatric tuina for ADHD in preschool children. Purposive sampling was employed to invite 15 parents who attended our pediatric tuina training program to participate voluntarily in three focus group interviews. The interviews were audio-recorded and transcribed verbatim. The data were analyzed through template analysis. Results Two themes were identified: (1) facilitators of intervention implementation and (2) barriers to intervention implementation. The theme of the facilitators of intervention implementation included the subthemes of (a) perceived benefits to children and parents, (b) acceptability to children and parents, (c) professional support, and (d) parental expectations of the long-term effects of the intervention. The theme of barriers to intervention implementation included the subthemes of (a) limited benefits for children’s inattention symptoms, (b) manipulation management difficulties, and (c) limitations of TCM pattern identification. Conclusion Perceived beneficial effects on the children’s sleep quality and appetite and parent–child relationships, as well as timely and professional support, mainly facilitated the implementation of parent-administered pediatric tuina. Slow improvements in the children’s inattention symptoms and the possible inaccuracies of online diagnosis were the dominant barriers of the intervention. Parents have high expectations for the provision of long-term professional support during their practice of pediatric tuina. The intervention presented here can be feasibly used by parents.

Abstract Purpose This retrospective cross-sectional study investigated variations in the ratio of cervical lordosis to C7 slope (CL/C7S) at different stages of global sagittal balance to better understand how global sagittal alignment affects cervical alignment. Methods A total of 255 patients with the degenerative lumbar disease were retrospectively studied within a single medical center. Whole spine radiographs were used to evaluate sagittal parameters, mainly including occiput-C2 lordosis (OC2), cervical lordosis (CL), C7 slope (C7S), the ratio of cervical lordosis to C7 slope (CL/C7S), cervical sagittal vertical axis (CSVA), thoracic kyphosis (TK), lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), PI minus LL mismatch (PI–LL), and sagittal vertical axis (SVA). Patients were divided into the balance group (SVA 10°), and imbalance group (SVA > 50 mm). Results Significant correlations were found between CL/C7S and OC2 (r = − 0.334), CSVA (r = − 0.504), PI–LL (r = 0.189), and SVA (r = 0.309). Multivariable linear regression analysis indicated that patients in the hidden imbalance group had lower CL/C7S than those in the balance group (B = − 0.234, P

Abstract Objective: To examine the association between adherence to plant-based diets and mortality. Design: Prospective study. We calculated a plant-based diet index (PDI) by assigning positive scores to plant foods and reverse scores to animal foods. We also created a healthful PDI (hPDI) and an unhealthful PDI (uPDI) by further separating the healthy plant foods from less-healthy plant foods. Setting: The VA Million Veteran Program. Participants: 315 919 men and women aged 19–104 years who completed a FFQ at the baseline. Results: We documented 31 136 deaths during the follow-up. A higher PDI was significantly associated with lower total mortality (hazard ratio (HR) comparing extreme deciles = 0·75, 95 % CI: 0·71, 0·79, P trend < 0·001]. We observed an inverse association between hPDI and total mortality (HR comparing extreme deciles = 0·64, 95 % CI: 0·61, 0·68, P trend < 0·001), whereas uPDI was positively associated with total mortality (HR comparing extreme deciles = 1·41, 95 % CI: 1·33, 1·49, P trend < 0·001). Similar significant associations of PDI, hPDI and uPDI were also observed for CVD and cancer mortality. The associations between the PDI and total mortality were consistent among African and European American participants, and participants free from CVD and cancer and those who were diagnosed with major chronic disease at baseline. Conclusions: A greater adherence to a plant-based diet was associated with substantially lower total mortality in this large population of veterans. These findings support recommending plant-rich dietary patterns for the prevention of major chronic diseases.