Air-ventilated normothermic mechanical perfusion improves susceptibility to donation after circulatory death and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis.

End-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis.

Tumor microenvironment activation amplify oxidative stress promoting tumor energy remodeling for mild photothermal therapy and cuproptosis.

Tumor metabolic reprogramming requires high levels of adenosine triphosphate (ATP) to maintain treatment resistance, which poses major challenges to chemotherapy and photothermal therapy. Especially, high levels of ATP promote copper ion efflux for limiting the curative effect of cuproptosis. Here, an H2S-responsive mesoporous Cu2Cl(OH)3-loading chemotherapeutic cisplatin (CDDP) was synthesized, and the final nanoparticle, CDDP@Cu2Cl(OH)3-CDs (CDCuCDs), was encapsulated by electrostatic action with carbon dots (CDs). CDCuCDs reacted with overproduction H2S in colon tumor to produce photothermic copper sulfide for photothermal therapy. CDDP was released by lysis to achieve chemotherapeutic effects. Importantly, CDDP elevated H2O2 levels in cells through a cascade reaction and continuously transforms H2O2 into highly cytotoxic •OH through chemodynamic therapy between H2O2 and Cu+, which enables nanoparticles to generate •OH and improve the chemotherapeutic efficacy. Highly toxic •OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Down-regulated ATP inhibits heat shock protein expression, which promotes the therapeutic effect of mild photothermal therapy and reduces the efflux of intracellular copper ions, thus improving the therapeutic effect of cuproptosis. Our research provides a potential therapeutic strategy using overproduction H2S responses in tumors, allowing tumor microenvironment-activated •OH nanogenerators to promote tumor energy remodeling for cancer treatment.

Multidimensional Fragmentomics Enables Early and Accurate Detection of Colorectal Cancer.

Colorectal cancer is frequently diagnosed in advanced stages, highlighting the need for developing approaches for early detection. Liquid biopsy using cell-free DNA (cfDNA) fragmentomics is a promising approach, but the clinical application is hindered by complexity and cost. This study aimed to develop an integrated model using cfDNA fragmentomics for accurate, cost-effective early-stage colorectal cancer detection. Plasma cfDNA was extracted and sequenced from a training cohort of 360 participants, including 176 patients with colorectal cancer and 184 healthy controls. An ensemble stacked model comprising five machine learning models was employed to distinguish patients with colorectal cancer from healthy controls using five cfDNA fragmentomic features. The model was validated in an independent cohort of 236 participants (117 patients with colorectal cancer and 119 controls) and a prospective cohort of 242 participants (129 patients with colorectal cancer and 113 controls). The ensemble stacked model showed remarkable discriminatory power between patients with colorectal cancer and controls, outperforming all base models and achieving a high area under the receiver operating characteristic curve of 0.986 in the validation cohort. It reached 94.88% sensitivity and 98% specificity for detecting colorectal cancer in the validation cohort, with sensitivity increasing as the cancer progressed. The model also demonstrated consistently high accuracy in within-run and between-run tests and across various conditions in healthy individuals. In the prospective cohort, it achieved 91.47% sensitivity and 95.58% specificity. This integrated model capitalizes on the multiplex nature of cfDNA fragmentomics to achieve high sensitivity and robustness, offering significant promise for early colorectal cancer detection and broad patient benefit. Significance: The development of a minimally invasive, efficient approach for early colorectal cancer detection using advanced machine learning to analyze cfDNA fragment patterns could expedite diagnosis and improve treatment outcomes for patients. See related commentary by Rolfo and Russo, p. 3128.

A domain knowledge-based interpretable deep learning system for improving clinical breast ultrasound diagnosis.

BACKGROUND: Though deep learning has consistently demonstrated advantages in the automatic interpretation of breast ultrasound images, its black-box nature hinders potential interactions with radiologists, posing obstacles for clinical deployment. METHODS: We proposed a domain knowledge-based interpretable deep learning system for improving breast cancer risk prediction via paired multimodal ultrasound images. The deep learning system was developed on 4320 multimodal breast ultrasound images of 1440 biopsy-confirmed lesions from 1348 prospectively enrolled patients across two hospitals between August 2019 and December 2022. The lesions were allocated to 70% training cohort, 10% validation cohort, and 20% test cohort based on case recruitment date. RESULTS: Here, we show that the interpretable deep learning system can predict breast cancer risk as accurately as experienced radiologists, with an area under the receiver operating characteristic curve of 0.902 (95% confidence interval = 0.882 - 0.921), sensitivity of 75.2%, and specificity of 91.8% on the test cohort. With the aid of the deep learning system, particularly its inherent explainable features, junior radiologists tend to achieve better clinical outcomes, while senior radiologists experience increased confidence levels. Multimodal ultrasound images augmented with domain knowledge-based reasoning cues enable an effective human-machine collaboration at a high level of prediction performance. CONCLUSIONS: Such a clinically applicable deep learning system may be incorporated into future breast cancer screening and support assisted or second-read workflows.

Breast cancer is one of the most common cancers, and finding it early can greatly improve patients' chances of survival and recovery. We create a tool based on artificial intelligence (AI)­whereby computer software learns to perform tasks that normally require human thinking­called MUP-Net. MUP-Net can analyze medical images to predict a patient's risk of having breast cancer. To make this AI tool usable in clinical practice, we enabled doctors to see the reasoning behind the AI's predictions by visualizing the key image features it analyzed. We showed that our AI tool not only makes doctors more confident in their diagnosis but also helps them make better decisions, especially for less experienced doctors. With further testing, our AI tool may help clinicians to diagnose breast cancer more accurately and quickly, potentially improving patient outcomes.

An injectable dental pulp-derived decellularized matrix hydrogel promotes dentin repair through modulation of macrophage response.

Maintaining the viability of damaged pulp is critical in clinical dentistry. Pulp capping, by placing dental material over the exposed pulp, is a main approach to promote pulp-dentin healing and mineralized tissue formation. The dental materials are desired to impact on intricate physiological mechanisms in the healing process, including early regulation of inflammation, immunity, and cellular events. In this study, we developed an injectable dental pulp-derived decellularized matrix (DPM) hydrogel to modulate macrophage responses and promote dentin repair. The DPM derived from porcine dental pulp has high collagen retention and low DNA content. The DPM was solubilized by pepsin digestion (named p-DPM) and subsequently injected through a 25G needle to form hydrogel facilely at 37 °C. In vitro results demonstrated that the p-DPM induced the M2-polarization of macrophages and the migration, proliferation, and dentin differentiation of human dental pulp stem cells from deciduous teeth (SHEDs). In a mouse subcutaneous injection test, the p-DPM hydrogel was found to facilitate cell recruitment and M2 polarization during the early phase of implantation. Additionally, the acute pulp restoration in rat models proved that injectable p-DPM hydrogel as a pulp-capping agent had excellent efficacy in dentin regeneration. This study demonstrates that the DPM promotes dentin repair by modulating macrophage responses, and has a potential for pulp-capping applications in dental practice.

H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis.

The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.

Magnetic graphene oxide nanocomposites induce cytotoxicity in ADSCs via GPX4 regulating ferroptosis.

Magnetic graphene oxide nanocomposites (MGO NPs) have been widely studied in biomedical applications. However, their cytotoxicity and underlying mechanisms remain unclear. In this study, the biosafety of MGO NPs was investigated, and the mechanism involved in ferroptosis was further explored. MGO can produce cytotoxicity in ADSCs, which is dependent on their concentration. Ferroptosis was involved in MGO NP-induced ADSC survival inhibition by increasing total ROS and lipid ROS accumulation as well as regulating the expression levels of ferroptosis-related genes and proteins. GPX4 played a critical role in the MGO NP-induced ADSC ferroptosis process, and overexpressing GPX4 suppressed ferroptosis to increase cell survival. This study provides a theoretical basis for the biosafety management of MGO NPs used in the field of biomedical treatment.

Current Perspectives on Paradental Cyst: A Literature Review.

Paradental cyst (PC) is an uncommon type of odontogenic cyst of inflammatory origin, which develops near the cervical margin of the outside of the root of a vital tooth. The category of paradental cyst includes the buccal bifurcation cyst, which is found in the buccal area adjacent to the mandibular first or second molars in children. A conclusive diagnosis of a PC needs to correlate the surgical, radiographic, and histologic findings. When strict diagnosis is neglected, they can be easily misdiagnosed and mistreated. PCs associated with mandibular first and second molars and those associated with the mandibular third molar may have slightly different clinical manifestations but have almost completely different treatment principles due to the distinction in location. For the third molars, removal of both the tooth and the cyst is preferred. However, when the first or second molars are affected, it may be advisable to perform enucleation of the lesion while preserving the associated tooth. There are also more conservative methods to retain vital permanent teeth within the mandibular arch. Additionally, the cyst wall primarily consisted of granulation tissue firmly attached to the periodontal ligament space. The exact origin of these cysts was a subject of ongoing debate, but they were believed to primarily arise from either the reduced enamel epithelium or the inflammatory proliferation of junctional/sulcular epithelium, which originate from the superficial mucosa during tooth eruption. The aim of the present review was to update information on clinical manifestations, diagnosis and treatment strategies of cysts and discuss their pathogenic mechanisms. Raising familiarity with the distinctive features is beneficial for accurately diagnosing these lesions and effectively caring for the patients.

Bioinformatic analysis and verification of a lipid metabolism-related long noncoding RNA prognostic signature for head and neck squamous cell carcinoma.

PURPOSE: Both lipid metabolism reprogramming and lncRNAs exert effects on tumor development. We aimed to predict the prognosis of head and neck squamous cell carcinoma (HNSCC) based on lipid metabolism-related (LR)-lncRNAs. METHODS: LR-lncRNAs were determined from the RNA-ref profiles of HNSCC samples in The Cancer Genome Atlas (TCGA). The prognostic model was established by univariate Cox and Lasso regression analysis. Clinical relevance and predictive accuracy were investigated, and external validation was also performed in the Gene Expression Omnibus (GEO) cohort. Tumor immune infiltration and relevant functional analysis, including the association of autophagy with prognostic signatures, were conducted through single-sample gene set enrichment analysis (ssGSEA). The regulatory network of candidate LR-lncRNAs was investigated via coexpression, ceRNA and cis/trans acting interactions. Potential genes were selected through qRT-PCR analysis, and their effects on tumor biological activities and autophagic activity were explored after gene knockdown. RESULTS: A total of 222 LR-lncRNAs were identified. Among the 41 genes with prognostic significance, 17 lncRNAs were eligible for the risk model. Patients in the high-risk group had a poorer prognosis than those in the low-risk group, and the risk score was found to be positively associated with tumor microenvironment infiltration via multiple algorithms. Furthermore, improved prognosis was found in patients with high autophagic scores and low risk scores, and autophagy-related genes such as PINK1 and CCL2 showed significantly lower expression in the low-risk group. The expression of immune checkpoint genes such as CD28, CTLA4 and PDCD1 decreased dramatically in the high-risk group. The target genes of candidate lncRNAs were confirmed, such as ENO2 and PPAR-gamma. Furthermore, MIR4435-2HG was the most significantly overexpressed lncRNA in HNSCC cell lines and tumor samples, which could promote proliferation and migration and inhibit apoptosis. Additionally, MIR4435-2HG silencing activated autophagy by increasing LC3B expression. CONCLUSION: This study constructed an LR-lncRNA prognostic signature for HNSCC and indicated its relationships with tumor immunity and autophagy, which provides a promising future for LR-lncRNA-oriented prognostic tools and therapeutic targets.

Erratum: EPHB4 Regulates the Proliferation and Metastasis of Oral Squamous Cell Carcinoma through the HMGB1/NF-κB Signalling Pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.59331.].

Regulation of m6A modification on ferroptosis and its potential significance in radiosensitization.

Radiotherapy is often used to treat various types of cancers, but radioresistance greatly limits the clinical efficiency. Recent studies have shown that radiotherapy can lead to ferroptotic cancer cell deaths. Ferroptosis is a new type of programmed cell death caused by excessive lipid peroxidation. The induction of ferroptosis provides a potential therapeutic strategy for radioresistance. As the most common post-transcriptional modification of mRNA, m6A methylation is widely involved in the regulation of various physiopathological processes by regulating RNA function. Dynamic m6A modification controlled by m6A regulatory factors also affects the susceptibility of cells to ferroptosis, thereby determining the radiosensitivity of tumor cells to radiotherapy. In this review, we summarize the mechanism and significance of radiotherapy induced ferroptosis, analyze the regulatory characteristics of m6A modification on ferroptosis, and discuss the possibility of radiosensitization by enhancing m6A-mediated ferroptosis. Clarifying the regulation of m6A modification on ferroptosis and its significance in the response of tumor cells to radiotherapy will help us identify novel targets to improve the efficacy of radiotherapy and reduce or overcome radioresistance.

METTL14 inhibits malignant progression of oral squamous cell carcinoma by targeting the autophagy-related gene RB1CC1 in an m6A-IGF2BP2-dependent manner.

N6-methyladenosine (m6A) plays crucial roles in tumorigenesis and autophagy. However, the underlying mechanisms mediated by m6A and autophagy in the malignant progression of oral squamous cell carcinoma (OSCC) remain unclear. In the present study, we revealed that down-regulated expression of METTL14 was correlated with advanced clinicopathological characteristics and poor prognosis in OSCC. METTL14 knockdown significantly inhibited autophagy and facilitated malignant progression in vitro, and promoted tumor growth and metastasis in vivo. A cell model of rapamycin-induced autophagy was established to identify RB1CC1 as a potential target gene involved in m6A-regulated autophagy in OSCC, through RNA sequencing and methylated RNA immunoprecipitation sequencing (meRIP-seq) analysis. Mechanistically, we confirmed that METTL14 posttranscriptionally enhanced RB1CC1 expression in an m6A-IGF2BP2-dependent manner, thereby affecting autophagy and progression in OSCC, through methylated RNA immunoprecipitation qRT-PCR (meRIP-qPCR), RNA stability assays, mutagenesis assays and dual-luciferase reporter. Collectively, our findings demonstrated that METTL14 serves as an OSCC suppressor by regulating the autophagy-related gene RB1CC1 through m6A modification, which may provide a new insight for the diagnosis and therapy of OSCC.

KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy.

Hepatic ischemia-reperfusion (I/R) injury, a common clinical complication of liver transplantation, gravely affects patient prognosis. Krüppel-like factors (KLFs) constitute a family of C2/H2 zinc finger DNA-binding proteins. KLF6, a member of the KLF protein family, plays crucial roles in proliferation, metabolism, inflammation, and injury responses; however, its role in HIR is largely remains unknown. After I/R injury, we found that KLF6 expression in mice and hepatocytes was significantly upregulated. Mice were then subjected to I/R following injection of shKLF6- and KLF6-overexpressing adenovirus through the tail vein. KLF6 deficiency markedly exacerbated liver damage, cell apoptosis, and activation of hepatic inflammatory responses, whereas hepatic overexpression of KLF6 in mice produced the opposite results. In addition, we knocked out or overexpressed KLF6 in AML12 cells before exposing them to a hypoxia-reoxygenation challenge. KLF6 knockout decreased cell viability and increased hepatocyte inflammation, apoptosis, and ROS, whereas KLF6 overexpression had the opposite effects. Mechanistically, KLF6 inhibited the overactivation of autophagy at the initial stage, and the regulatory effect of KLF6 on I/R injury was autophagy-dependent. CHIP-qPCR and luciferase reporter gene assays confirmed that KLF6 bound to the promoter region of Beclin1 and inhibited its transcription. Additionally, KLF6 activated the mTOR/ULK1 pathway. Finally, we performed a retrospective analysis of the clinical data of liver transplantation patients and identified significant associations between KLF6 expression and liver function following liver transplantation. In conclusion, KLF6 inhibited the overactivation of autophagy via transcriptional regulation of Beclin1 and activation of the mTOR/ULK1 pathway, thereby protecting the liver from I/R injury. KLF6 is expected to serve as a biomarker for estimating the severity of I/R injury following liver transplantation.

Evaluation of apical extrusion of debris and centering ability in different nickel-titanium files during curved root canal preparation.

BACKGROUND: Curved root canals lead to difficulties in cleaning, shaping and filling the root canal system. Apical extrusion of debris and root canal transportation are important factors causing postoperative complications. In clinical practice, commonly selected instruments include multifile NiTi systems, such as M3-Pro PLUS (M3-PRO), Orodeka Plex 2.0 (ODP), Rotate (ROT), and Protaper Gold (PTG), as well as single-file NiTi systems, such as M3-L Platinum 2019 (M3L), Waveone Gold (WOG), and Reciproc Blue (RCB). This study aimed to comprehensively evaluate the differences in the apical extrusion of debris and centering ability of the above NiTi files. METHODS: Seventy 3D-printed resin teeth were used (n = 10). The apically extruded debris was collected in a preweighed centrifuge tube. The resin teeth with or without root canal preparation were cut into separate cross sections at 1 mm, 3 mm, 5 mm, and 7 mm away from the root apex, and then the root canal transportation and centering ratio of each cross section were calculated. RESULTS: Apical extrusion of debris was highest in RCB but lowest in OD-P (P < 0.05). Root call deviation was lowest in ROT at the 3 mm level, in PTG at the 5 mm level, and in PTG and ROT at the 7 mm level (P < 0.05). The centering ratio of NiTi files was highest in the RCB group at the 3 mm level, in the PTG group at the 5 mm level, in the ROT group at the 7 mm level (P < 0.05). CONCLUSIONS: For NiTi files with the same system, the cross-sectional design is the greatest factor affecting the extrusion of debris, and motion mode is the second. In addition, the multifile system could reduce the degree of root canal transportation.

GPX8 deficiency-induced oxidative stress reprogrammed m6A epitranscriptome of oral cancer cells.

Glutathione peroxidase 8 (GPX8) is a key regulator of redox homoeostasis. Whether its antioxidant activity participates in the regulation of m6A modification is a crucial issue, which has important application value in cancer treatment. In this study, MeRIP-seq was used to explore the characteristics of transcriptome-wide m6A modification in GPX8-deficient oral cancer cells. Oxidative stress caused by the lack of GPX8 resulted in 1,279 hyper- and 2,287 hypo-methylated m6A peaks and 2,036 differentially expressed genes in GPX8-KO cells. Twenty-eight differentially expressed genes were related to the cell response to oxidative stress, and half of them changed their m6A modification. In GPX8-KO cells, m6A regulators IGF2BP2 and IGF2BP3 were upregulated, while FTO, RBM15, VIRMA, ZC3H13, and YTHDC2 were downregulated. After H2O2 treatment, the expression changes of RBM15, IGF2BP2, and IGF2BP3 were further enhanced. These data indicated that GPX8-mediated redox homoeostasis regulated m6A modification, thereby affecting the expression and function of downstream genes. This study highlights the possible significance of GPX8 and the corresponding m6A regulatory or regulated genes as novel targets for antioxidant intervention in cancer therapy.

Lack of GPX8 caused oxidative stress of oral cancer cells.Oxidative stress induced by GPX8 deficiency reprogrammed m⁶A epitranscriptome.GPX8 deletion­caused oxidative stress regulated expression of m⁶A regulatory genes.m⁶A modification of antioxidant genes is the adaptive response of cells to oxidative stress.

Influence of preoperative simulation on the reduction quality and clinical outcomes of open reduction and internal fixation for complex proximal humerus fractures.

PURPOSE: Proximal humerus fractures (PHFs) are common. With the development of locking plates, open reduction and internal fixation (ORIF) of the proximal humerus can provide excellent clinical outcomes. The quality of fracture reduction is crucial in the locking plate fixation of proximal humeral fractures. The purpose of this study was to determine the impact of 3-dimensional (3D) printing technology and computer virtual technology assisted preoperative simulation on the reduction quality and clinical outcomes of 3-part and 4-part proximal humeral fractures. METHOD: A retrospective comparative analysis of 3-part and 4-part PHFs undergoing open reduction internal fixation was performed. Patients were divided into 2 groups according to whether computer virtual technology and 3D printed technology were used for preoperative simulation: the simulation group and the conventional group. Operative time, intraoperative bleeding, hospital stay, quality of fracture reduction, Constant scores, American Society for Shoulder and Elbow Surgery (ASES) scores, shoulder range of motion, complications, and revision surgeries were assessed. RESULTS: This study included 67 patients (58.3%) in the conventional group and 48 patients (41.7%) in the simulation group. The patient demographics and fracture characteristics were comparable in these groups. Compared with the conventional group, the simulation group had shorter operation time and less intraoperative bleeding (P < 0.001, both). Immediate postoperative assessment of fracture reduction showed a higher incidence of greater tuberosity cranialization of < 5 mm, neck-shaft angle of 120° to 150°, and head shaft displacement of < 5 mm in the simulation group. The incidence of good reduction was 2.6 times higher in the simulation group than in the conventional group (95% CI, 1.2-5.8). At the final follow-up, the chance of forward flexion > 120° (OR 5.8, 95% CI 1.8-18.0) and mean constant score of > 65 (OR 3.4, 95% CI 1.5-7.4) was higher in the simulation group than the conventional group, as well as a lower incidence of complications in the simulation group was obtained (OR 0.2, 95% CI 0.1-0.6). CONCLUSIONS: This study identified that preoperative simulation assisted by computer virtual technology and 3D printed technology can improve reduction quality and clinical outcomes in treatment of 3-part and 4-part PHFs.

Association of smoking and osteoarthritis in US (NHANES 1999-2018).

Little is currently known about the effect of smoking on osteoarthritis (OA). This study aimed to investigate the relationship between smoking and OA in the United States (US) general population. Cross-sectional study. Level of evidence, 3. 40,201 eligible participants from the National Health and Nutrition Examination Survey 1999-2018 were included and divided into OA and non-arthritis groups. Participants demographics and characteristics were compared between the two groups. Then the participants were divided into non-smokers, former smokers, and current smokers based on their smoking status, also demographics and characteristics among the three groups were compared. Multivariable logistic regression was used to determine the relationship between smoking and OA. The current and former smoking rate in the OA group (53.0%) was significantly higher than that in the non-arthritis group (42.5%; p < 0.001). Multivariable regression analysis including body mass index (BMI), age, sex, race, education level, hypertension, diabetes, asthma and cardiovascular disease showed that smoking was an association for OA. This large national study highlights a positive association between smoking and OA prevalence in the general US population. It is necessary to further study the relationship between smoking and OA in order to determine the specific mechanism of smoking on OA.

Graphdiyne Oxide-Mediated Photodynamic Therapy Boosts Enhancive T-Cell Immune Responses by Increasing Cellular Stiffness.

Purpose: Nanomaterial-based photodynamic therapy (PDT) has been commonly used for the treatment of cancerous tumors. Despite significant achievements made in this field, the intrinsic impact of nanomaterials-based PDT on the mechanical properties of oral squamous cell carcinoma (OSCC) cells is not entirely understood. Here, we used atomic force microscopy (AFM) to measure the stiffness of OSCC cells subjected to PDT in co-culture systems to evaluate the T cell-mediated cancer cell-killing effects. Methods: In this study, AFM was used to assess the stiffness of PDT-subjected cells. The phototoxicity of graphdiyne oxide (GDYO) was assessed using confocal laser scanning microscopy (CLSM), measurements of membrane cholesterol levels, and assessments of the F-actin cytoskeleton. A co-culture system was used to evaluate the effects of CD8+ T cells (cytotoxic T lymphocytes), demonstrating how PDT modulates the mechanical properties of cancer cells and activates T cell responses. The antitumor immunotherapeutic effect of GDYO was further evaluated in a murine xenograft model. Results: GDYO increased the mechanical stiffness of tumor cells and augmented T-cell cytotoxicity and inflammatory cytokine secretion (IFN-γ and TNF-α) under laser in vitro. Furthermore, GDYO-based PDT exerted inhibitory effects on OSCC models and elicited antitumor immune responses via specific cytotoxic T cells. Conclusion: These results highlight that GDYO is a promising candidate for OSCC therapy, shifting the mechanical forces of OSCC cells and breaking through the barriers of the immunosuppressive tumor microenvironment. Our study provides a novel perspective on nanomaterial-based antitumor therapies.

Size-optimized nuclear-targeting phototherapy enhances the type I interferon response for "cold" tumor immunotherapy.

There is growing interest in the effect of innate immune silencing in "cold" tumors, which always fail in the immune checkpoint blockade monotherapy using PD-L1 monoclonal antibodies (aPD-L1). Combination of aPD-L1 with photodynamic therapy, i.e., photoimmunotherapy, is a promising strategy to improve the mono immunotherapy. Nuclear-targeting nanoparticles could elicit a type I interferon (IFN)-mediated innate immune response and reverse the immunosuppressive microenvironment for long-term immunotherapy of "cold" tumors. Photosensitizers such as zinc phthalocyanine (ZnPc) have limited ability to target the nucleus and activate innate sensing pathways to minimize tumor recurrence. Additionally, the relationship between nanoparticle size and nuclear entry capacity remains unclear. Herein, graphene quantum dots (GQDs) were employed as aPD-L1 and ZnPc carriers. Three particle sizes (200 nm, 32 nm and 5 nm) of aPD-L1/ZnPc/GQD-PEG (PZGE) were synthesized and tested. The 5 nm nanoparticles achieved the best nuclear enrichment capacity contributing to their ultrasmall size. Notably, 5 nm PZGE-based photodynamic therapy enabled an amplification of the type I IFN-mediated innate immune response and could convert "immune-cold" tumors into "immune-hot" ones. Utilizing their size advantage to target the nucleus, 5 nm nanoparticles induced DNA damage and activated the type I IFN-mediated innate immune response, subsequently promoting cytotoxic T-lymphocyte infiltration and reversing negative PD-L1 expression. Furthermore, the nanoplatform we designed is promising for the effective suppression of distant oral squamous cell carcinoma. Thus, for the first time, this study presents a size design strategy for nuclear-targeted photo-controlled immune adjuvants and the nuclear-targeted phototherapy-mediated immunomodulatory functions of type I IFN innate immune signalling for "immune-cold" tumors. STATEMENT OF SIGNIFICANCE: The potential of commonly used photosensitizers to activate innate sensing pathways for producing type I IFNs is limited due to the lack of nuclear targeting. Facilitating the nuclear-targeting of photosensitizers to enhance innate immune response and execute long-term tumor killing effect would be a promising strategy for "cold" tumor photoimmunotherapy. Herein, we report an optimal size of PZGE nanoparticles that enable the nuclear-targeting of ZnPc, which reinforces the type I IFN-mediated innate immune response, synergistically reversing "cold tumors" to "hot tumors" for effective primary and distant tumor photoimmunotherapy. This work highlights the marked efficacy of ultrasmall nuclear-located nanocarriers and offers new insight into "immune-cold tumors" via prominent innate immune activation mediated by nuclear-targeting photoimmunotherapy.