Engineering Bimetallic Polyphenol for Mild Photothermal Osteosarcoma Therapy and Immune Microenvironment Remodeling by Activating Pyroptosis and cGAS-STING Pathway.

The immunosuppressive tumor microenvironment (ITME) of osteosarcoma (OS) poses a significant obstacle to the efficacy of existing immunotherapies. Despite the attempt of novel immune strategies such as immune checkpoint inhibitors and tumor vaccines, their effectiveness remains suboptimal due to the inherent difficulty in mitigating ITME simultaneously from both the tumor and immune system. The promotion of anti-tumor immunity through the induction of immunogenic cell death and activation of the cGAS-STING pathway has emerged as potential strategies to counter the ITME and stimulate systemic antitumor immune responses. Here, a bimetallic polyphenol-based nanoplatform (Mn/Fe-Gallate nanoparticles coated with tumor cell membranes is presented, MFG@TCM) which combines with mild photothermal therapy (PTT) for reversing ITME via simultaneously inducing pyroptosis in OS cells and activating the cGAS-STING pathway in dendritic cells (DCs). The immunostimulatory pathways, through the syngeneic effect, exerted a substantial positive impact on promoting the secretion of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, which favors remodeling the immune microenvironment. Consequently, effector T cells led to a notable antitumor immune response, effectively inhibiting the growth of both primary and distant tumors. This study proposes a new method for treating OS using mild PTT and immune mudulation, showing promise in overcoming current treatment limitations.

Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer.

Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.

Myricanol attenuates sepsis-induced inflammatory responses by nuclear factor erythroid 2-related factor 2 signaling and nuclear factor kappa B/mitogen-activated protein kinase pathway via upregulating Sirtuin 1.

Sepsis, a life-threatening condition characterized by dysregulated immune responses, remains a significant clinical challenge. Myricanol, a natural compound, plays a variety of roles in regulating lipid metabolism, anti-cancer, anti-neurodegeneration, and it could act as an Sirtuin 1 (SIRT1) activator. This study aimed to explore the therapeutic potential and underlying mechanism of myricanol in the lipopolysaccharide (LPS)-induced sepsis model. In vivo studies revealed that myricanol administration significantly improved the survival rate of LPS-treated mice, effectively mitigating LPS-induced inflammatory responses in lung tissue. Furthermore, in vitro studies demonstrated that myricanol treatment inhibited the expression of pro-inflammatory cytokines, attenuated signal pathway activation, and reduced oxidative stress in macrophages. In addition, we demonstrated that myricanol selectively enhances SIRT1 activation in LPS-stimulated macrophages, and all of the protective effect of myricanol were reversed through SIRT1 silencing. Remarkably, the beneficial effects of myricanol against LPS-induced sepsis were abolished in SIRT1 myeloid-specific knockout mice, underpinning the critical role of SIRT1 in mediating myricanol's therapeutic efficacy. In summary, this study provides significant evidence that myricanol acts as a potent SIRT1 activator, targeting inflammatory signal pathways and oxidative stress to suppress excessive inflammatory responses. Our findings highlight the potential of myricanol as a novel therapeutic agent for the treatment of LPS-induced sepsis.

Pimpinellin ameliorates macrophage inflammation by promoting RNF146-mediated PARP1 ubiquitination.

Macrophage inflammation plays a central role during the development and progression of sepsis, while the regulation of macrophages by parthanatos has been recently identified as a novel strategy for anti-inflammatory therapies. This study was designed to investigate the therapeutic potential and mechanism of pimpinellin against LPS-induced sepsis. PARP1 and PAR activation were detected by western blot or immunohistochemistry. Cell death was assessed by flow cytometry and western blot. Cell metabolism was measured with a Seahorse XFe24 extracellular flux analyzer. C57, PARP1 knockout, and PARP1 conditional knock-in mice were used in a model of sepsis caused by LPS to assess the effect of pimpinellin. Here, we found that pimpinellin can specifically inhibit LPS-induced macrophage PARP1 and PAR activation. In vitro studies showed that pimpinellin could inhibit the expression of inflammatory cytokines and signal pathway activation in macrophages by inhibiting overexpression of PARP1. In addition, pimpinellin increased the survival rate of LPS-treated mice, thereby preventing LPS-induced sepsis. Further research confirmed that LPS-induced sepsis in PARP1 overexpressing mice was attenuated by pimpinellin, and PARP1 knockdown abolished the protective effect of pimpinellin against LPS-induced sepsis. Further study found that pimpinellin can promote ubiquitin-mediated degradation of PARP1 through RNF146. This is the first study to demonstrate that pimpinellin inhibits excessive inflammatory responses by promoting the ubiquitin-mediated degradation of PARP1.

Accurate de novo peptide sequencing using fully convolutional neural networks.

De novo peptide sequencing, which does not rely on a comprehensive target sequence database, provides us with a way to identify novel peptides from tandem mass spectra. However, current de novo sequencing algorithms suffer from low accuracy and coverage, which hinders their application in proteomics. In this paper, we present PepNet, a fully convolutional neural network for high accuracy de novo peptide sequencing. PepNet takes an MS/MS spectrum (represented as a high-dimensional vector) as input, and outputs the optimal peptide sequence along with its confidence score. The PepNet model is trained using a total of 3 million high-energy collisional dissociation MS/MS spectra from multiple human peptide spectral libraries. Evaluation results show that PepNet significantly outperforms current best-performing de novo sequencing algorithms (e.g. PointNovo and DeepNovo) in both peptide-level accuracy and positional-level accuracy. PepNet can sequence a large fraction of spectra that were not identified by database search engines, and thus could be used as a complementary tool to database search engines for peptide identification in proteomics. In addition, PepNet runs around 3x and 7x faster than PointNovo and DeepNovo on GPUs, respectively, thus being more suitable for the analysis of large-scale proteomics data.

ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers.

Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.

Custom-made semi-joint prosthesis replacement combined ligament advanced reinforcement system (LARS) ligament reconstruction for the limb salvage surgery of malignant tumors in the distal femur in skeletal immature children.

Purpose: To explore the application of Custom-made Semi-joint prosthesis replacement combined with Ligament Advanced Reinforcement System (LARS) ligament reconstruction for the limb salvage surgery (LSS) of malignant tumors in the distal femur and provide selections for the LSS of malignant tumors in skeletal immature children. Methods: A total of 8 children with malignant tumors in the distal femur who underwent Custom-made Semi-joint prosthesis replacement combined LARS ligament reconstruction for LSS from January, 2018 until December, 2019 in our bone and soft tissue tumor center were retrospectively recruited. The prosthesis related complications, oncological prognosis and knee function were observed, and the surgical efficacy was comprehensively evaluated. Results: The average follow-up time was 36.6 months (30-50 months). The average osteotomy length was 13.2 cm (8-20 cm) according to the preoperative imaging results and the length of the customized prosthesis. Two years after operation, the average MSTS-93 score was 24.4 (16-29) which indicated good limb functions. The range of motion of the knee was 0°-120°, with an maximum average of 100°. At last follow-up, the average height of the children increased by 8.4 cm (6-13 cm), and the average limb shortening was 2.7 cm (1.8-4.6 cm). One patient had wound complications in the early postoperative period, wound scab fell off to form superficial ulcer, in whom debridement and suturing were performed. One patient developed hematogenous disseminated prosthesis infection 2 years after surgery, and the prosthesis is now in situ with anti-infection treatment. One patient developed pulmonary metastasis during follow-up, and received chemotherapy and targeted therapy with lesion well controlled. At the last follow-up, there was no local tumor recurrence or prosthesis loosening. Conclusion: Under the premise of appropriate case selection, customized semi-joint prosthesis replacement combined with LARS ligament reconstruction provides a new option for LSS in children with distal femur malignant tumors. LARS ligament reconstruction ensures the stability and range of motion of the knee joint, which maximally preserves the epiphysis of the tibia side and the growth function of the tibia side, reduces the complications of limb length inequality in the long term and creates conditions for limb lengthening or total joint replacement in adults.

IL-1ß Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer.

Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1ß in TAMs. IL-1ß induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1ß antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1ß is an important androgen-responsive immunotherapeutic target for advanced PCa.

Enzyme-catalyzed synthesis of selenium-doped manganese phosphate for synergistic therapy of drug-resistant colorectal cancer.

BACKGROUND: The development of multidrug resistance (MDR) during postoperative chemotherapy for colorectal cancer substantially reduces therapeutic efficacy. Nanostructured drug delivery systems (NDDSs) with modifiable chemical properties are considered promising candidates as therapies for reversing MDR in colorectal cancer cells. Selenium-doped manganese phosphate (Se-MnP) nanoparticles (NPs) that can reverse drug resistance through sustained release of selenium have the potential to improve the chemotherapy effect of colorectal cancer. RESULTS: Se-MnP NPs had an organic-inorganic hybrid composition and were assembled from smaller-scale nanoclusters. Se-MnP NPs induced excessive ROS production via Se-mediated activation of the STAT3/JNK pathway and a Fenton-like reaction due to the presence of manganese ions (Mn2+). Moreover, in vitro and in vivo studies demonstrated Se-MnP NPs were effective drug carriers of oxaliplatin (OX) and reversed multidrug resistance and induced caspase-mediated apoptosis in colorectal cancer cells. OX@Se-MnP NPs reversed MDR in colorectal cancer by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (e.g., ABCB1, ABCC1 and ABCG2). Finally, in vivo studies demonstrated that OX-loaded Se-MnP NPs significantly inhibited proliferation of OX-resistant HCT116 (HCT116/DR) tumor cells in nude mice. CONCLUSIONS: OX@Se-MnP NPs with simple preparation and biomimetic chemical properties represent promising candidates for the treatment of colorectal cancer with MDR.

Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation.

Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated mitophagy. Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on cancer cell plasticity through the regulation of histone lactylation.

Enhanced mild-temperature photothermal therapy by pyroptosis-boosted ATP deprivation with biodegradable nanoformulation.

BACKGROUND: Mild-temperature photothermal therapy (mild PTT) is a safe and promising tumor therapeutic modality by alleviating the damage of healthy tissues around the tumor due to high temperature. However, its therapeutic efficiency is easily restricted by heat shock proteins (HSPs). Thus, exploitation of innovative approaches of inhibiting HSPs to enhance mild PTT efficiency is crucial for the clinical application of PTT. RESULTS: Herein, an innovative strategy is reported: pyroptosis-boosted mild PTT based on a Mn-gallate nanoformulation. The nanoformulation was constructed via the coordination of gallic acid (GA) and Mn2+. It shows an acid-activated degradation and releases the Mn2+ and GA for up-regulation of reactive oxygen species (ROS), mitochondrial dysfunction and pyroptosis, which can result in cellular ATP deprivation via both the inhibiton of ATP generation and incresed ATP efflux. The reduction of ATP and accumulation of ROS provide a powerful approach for inhibiting the expression of HSPs, which enables the nanoformulation-mediated mild PTT. CONCLUSIONS: Our in-vitro and in-vivo results demonstrate that this strategy of pyroptosis-assited PTT can achieve efficient mild PTT efficiency for osteosarcoma therapy.

A Combined Risk Score Model to Assess Prognostic Value in Patients with Soft Tissue Sarcomas.

A study by Tsvetkov et al. recently published a proposed novel form of copper-induced cell death in Science; however, few studies have looked into the possible mechanism in soft tissue sarcoma (STS). Herein, this study sought to investigate the function of cuproptosis-related genes (CRGs) in the development of tumor-associated immune cells and the prognosis of sarcoma. Herein, this study aimed to explore the role of cuproptosis-related genes (CRGs) in the development, tumor-associated immune cells, and the prognosis of sarcoma. METHODS: The prognostic model was established via the least absolute shrinkage and selection operator (LASSO) algorithm as well as multivariate Cox regression analysis. The stromal scores, immune scores, ESTIMA scores, and tumor purity of sarcoma patients were evaluated by the ESTIMATE algorithm. Functional analyses were performed to investigate the underlying mechanisms of immune cell infiltration and the prognosis of CRGs in sarcoma. RESULTS: Two molecular subgroups with different CRG expression patterns were recognized, which showed that patients with a higher immune score and more active immune status were prone to have better prognostic survival. Moreover, GO and KEGG analyses showed that these differentially expressed CRGs were mainly enriched in metabolic/ions-related signaling pathways, indicating that CRGs may have impacts on the immune cell infiltration and prognosis of sarcoma via regulating the bioprocess of mitochondria and consequently affecting the immune microenvironment. The expression levels of CRGs were closely correlated to the immunity condition and prognostic survival of sarcoma patients. CONCLUSIONS: The interaction between cuproptosis and immunity in sarcoma may provide a novel insight into the study of molecular mechanisms and candidate biomarkers for the prognosis, resulting in effective treatments for sarcoma patients.

Transversus abdominis plane block for laparoscopic colorectal surgery: A meta-analysis of randomised controlled trials.

BACKGROUND: The effectiveness of transversus abdominis plane block (TAP) on pain management after laparoscopic colorectal surgery (CRS) remains unclear since the only relevant meta-analysis on this topic did not separate laparoscopic CRS from open CRS. The aim of the study was to compare the analgesic efficacy and safety of TAP with non-TAP in patients undergoing laparoscopic CRS. METHODS: Four databases were searched for randomized controlled trials (RCTs) on this topic using relevant keywords. Two authors independently completed evidence selection, data extraction, and critical appraisal. Available data were pooled in the random-effects model, and point estimates with 95% confidence interval (CI) were reported for postoperative pain at rest and on coughing, opioid consumption, length of hospital stay, and adverse events. RESULTS: A total of 14 RCTs (n = 1216) contributed to the present synthesis. Pooled result showed that patients in the TAP group had lower pain at rest than those in the non-TAP group at postoperative 2-h (mean difference [MD] = -1.42; P < 0.05), 4-h (MD = -0.97; P < 0.05), 12-h (MD = -0.75; P < 0.05), and 24-h (MD = -0.61; P < 0.05). Patients in the TAP group also had lower postoperative pain on coughing than those in the non-TAP group on the first day (MD = -1.02; P < 0.05). Moreover, TAP had lesser postoperative opioid consumption than non-TAP (standardized mean difference, -0.26; P < 0.05; I-square = 20%), and there were non-significant differences in hospital stay and adverse event between the two groups. CONCLUSION: Intraoperative TAP is a safe and feasible pain management for laparoscopic CRS, particularly it is recommended when patient-controlled analgesia is not delivered. Therefore, laparoscopic TAP block might be a favorable administered strategy.

Endoscopic optical coherence tomography angiography using inverse SNR-amplitude decorrelation features and electrothermal micro-electro-mechanical system raster scan.

Background: Angiogenesis is closely associated with tumor development and progression. Endoscopic optical coherence tomography angiography (OCTA) enables rapid inspection of mucosal 3D vasculature of inner organs in the early-stage tumor diagnosis; however, it is limited by instabilities of the optical signal and beam scanning. Methods: In the phase-unstable swept source OCTA (SS-OCTA), amplitude decorrelation was used to compute the motion-induced changes as motion contrast. The influence of the random noise-induced amplitude fluctuations on decorrelation was characterized as a function of inverse signal-to-noise ratio (SNR) with a multi-variate time series (MVTS) model and statistical analysis. Then, the noise-induced decorrelation artifacts in static tissue regions were eliminated by applying a flow mask based on the statistical relation between inverse SNR (iSNR) and amplitude decorrelation (IDa), which was named IDa-OCTA. In addition, a distal stepwise raster scan was realized with a low-voltage electrothermal micro-electro-mechanical system (ET-MEMS)-based catheter for endoscopic imaging, whereby the stable and repeatable B-scans at each step suppressed the decorrelation noise induced by the spatial mismatch between paired scans. Results: The derived IDa relation was validated through numerical simulation and flow phantom experiments. In vivo human buccal mucosa imaging was performed to demonstrate the endoscopic IDa-OCTA imaging. In this, the subsurface structure and vasculature were visualized in a rapid and depth-resolved manner. Conclusions: The rapid 3D vasculature visualization realized by the endoscopic IDa-OCTA improves the diagnosis of early tumors in internal organs.

Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer.

Among the greatest hurdles in clinical management of prostate cancer (PCa) are the progression to lethal castration-resistant prostate cancer (CRPC) and the lack of suitable targeted therapies for advanced disease. Here we identify Gremlin1 as a ligand for fibroblast growth factor receptor 1 (FGFR1), which promotes lineage plasticity and drives castration resistance. Importantly, we generate a specific anti-Gremlin1 therapeutic antibody and demonstrate synergistic effect with androgen deprivation therapy (ADT) in CRPC. GREM1 transcription is suppressed by androgen receptor (AR) and released following ADT. We show that Gremlin1 binds to FGFR1 and activates downstream MAPK signaling. Gremlin1 interacts with FGFR1 differently to its canonical ligand FGF1, as revealed through protein structure docking and mutagenesis experiments. Altogether, our data indicate Gremlin1 as a promising candidate therapeutic target for CRPC.

Development of a Convolutional Neural Network-Based Colonoscopy Image Assessment Model for Differentiating Crohn's Disease and Ulcerative Colitis.

Objective: Evaluation of the endoscopic features of Crohn's disease (CD) and ulcerative colitis (UC) is the key diagnostic approach in distinguishing these two diseases. However, making diagnostic differentiation of endoscopic images requires precise interpretation by experienced clinicians, which remains a challenge to date. Therefore, this study aimed to establish a convolutional neural network (CNN)-based model to facilitate the diagnostic classification among CD, UC, and healthy controls based on colonoscopy images. Methods: A total of 15,330 eligible colonoscopy images from 217 CD patients, 279 UC patients, and 100 healthy subjects recorded in the endoscopic database of Tongji Hospital were retrospectively collected. After selecting the ResNeXt-101 network, it was trained to classify endoscopic images either as CD, UC, or normal. We assessed its performance by comparing the per-image and per-patient parameters of the classification task with that of the six clinicians of different seniority. Results: In per-image analysis, ResNeXt-101 achieved an overall accuracy of 92.04% for the three-category classification task, which was higher than that of the six clinicians (90.67, 78.33, 86.08, 73.66, 58.30, and 86.21%, respectively). ResNeXt-101 also showed higher differential diagnosis accuracy compared with the best performing clinician (CD 92.39 vs. 91.70%; UC 93.35 vs. 92.39%; normal 98.35 vs. 97.26%). In per-patient analysis, the overall accuracy of the CNN model was 90.91%, compared with 93.94, 78.79, 83.33, 59.09, 56.06, and 90.91% of the clinicians, respectively. Conclusion: The ResNeXt-101 model, established in our study, performed superior to most clinicians in classifying the colonoscopy images as CD, UC, or healthy subjects, suggesting its potential applications in clinical settings.

Primary appendiceal diffuse large B-cell lymphoma initially presenting as acute appendicitis: A case report.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 25% of all NHL cases. Primary appendiceal lymphomas (PAL) presenting as acute appendicitis are very rare, occurring in only 0.015% of all cases of gastrointestinal lymphoma. CASE PRESENTATION: A 57-year-old man who was initially presented as acute appendicitis and subsequently underwent interval laparoscopic appendectomy. Pathological examination revealed diffuse large B cell lymphoma with cut end involvement. Whole-body positron emission tomography (PET) scan revealed enlarged right palatine tonsil and raised a suspicion of lymphoma involvement in two right cervical lymph nodes (level II and III); biopsy, however, showed that the lymph nodes were benign, with non-specific cellular changes. Bone marrow biopsy of the iliac crest also did not show lymphoma involvement. Subsequently, a diagnosis of primary appendiceal diffuse large B cell lymphoma (Ann Arbor Stage II) was established. After six courses of definite chemotherapy with cyclophosphamide, doxorubicin HCl, vincristine, and rituximab (R-CHOP), PET/CT showed complete remission of the prior FDG-avid malignancy of appendiceal DLBCL. The patient continued to be stable with no recurrence for fifteen months of regular outpatient department follow-ups. CONCLUSIONS: PAL is rare, and it clinically manifests the signs and symptoms of acute appendicitis. Specific characteristics of lymphoma in CT scans may lead to a more confirmative diagnosis. PET/CT is important for staging the lymphoma. Patients with PAL should be managed with surgical resection followed by R-CHOP-21 for 6 cycles regardless of whether they have localized disease or disseminated disease.

Influence of Patella Position on Soft Tissue Balance and Clinical Outcomes in Patients Undergoing Minimally Invasive Total Knee Arthroplasty, a Randomized Clinical Trial.

BACKGROUND: We hypothesized that subluxating patellar during minimally invasive total knee arthroplasty (MIS-TKA) would affect intraoperative soft tissue balance and postoperative clinical outcome. METHODS: From December 2018 to May 2020, 189 patients receiving primary MIS-TKA were enrolled. The gap-balance technique was used, with patients randomly assigned to undergo osteotomy and balance of soft tissue with patella reduced (group A; n = 93) or subluxated (group B; n = 96). The gap and varus?valgus angle were compared between groups in both extension and flexion position. The gap and varus?valgus angle were also compared before and after reducing patellar in group B. Femoral prosthesis rotation, mechanical femoral axis-to-tibial axis angle, Knee Society Score (KSS), visual analog scale (VAS), and range of motion (ROM) were compared postoperatively between two groups. Follow-up was 12 months. RESULTS: The flexion gap and the varus angle were significantly greater (0.4 mm and 0.7 degree) after patella reduction than before reduction, but the extension joint gap and varus angle were comparable before and after patella reduction. The femoral prosthesis tended to be internally rotated (0.65 degree) in group B. ROM and VAS was better in the group A than in group B at 1 month after surgery, but the differences were not significant at 3, 6 and 12 months. KSS was comparable between the groups after surgery. CONCLUSIONS: During MIS-TKA, as far as possible, soft tissue balance should be achieved with the patella reduced; otherwise, the femoral prosthesis may be installed more internally and, after patella reduction, the flexion gap and varus angle would increase. CLINICAL TRIAL REGISTRATION: Current Controlled Trials ChiCTR2000034106, https://www.chictr.org.cn/hvshowproject.aspx?id=39987.

Photothermal-triggered immunogenic nanotherapeutics for optimizing osteosarcoma therapy by synergizing innate and adaptive immunity.

Inadequate immune response remains a critical cause of immunotherapy failure in various tumor treatments. Herein, we offer a new approach to achieve a cross-talk between innate and adaptive immune responses based on a new nanoplatform for photothermal therapeutics. The nanoplatform was formed by linking titanium carbide MXene with Mn2+-contained ovalbumin (OVA), where it can trigger efficient mt-DNA presentation and the release of OVA and Mn2+ upon the irradiation of near-infrared laser. More importantly, the released mt-DNA and Mn2+ synergistically activate innate immunity via the cGAS-stimulator of the interferon genes signaling pathway, and the OVA and protein antigens from tumor cells enhance adaptive immunity. Furthermore, in an osteosarcoma model, we observed that the proposed nanoplatform leads to the effective presentation of tumor antigens, which boost the maturation of dendritic cells (DCs) to the hilt and thus improve the infiltration of cytotoxic T lymphocyte in primary and distant tumors. Collectively, our work not only demonstrates a method for constructing a new nanoplatform for photothermal therapeutics but also provides a general strategy for synchronously activating innate and adaptive immunities to promote the maturation of DCs for antimetastasis tumor therapy.

High expression of lncRNA HSD11B1-AS1 indicates favorable prognosis and is associated with immune infiltration in cutaneous melanoma.

Cutaneous melanoma is an aggressive malignant cancer associated with poor prognosis. Identification of reliable biomarkers for predicting prognosis of melanoma contributes to improved clinical outcome and disease management. Long non-coding RNAs (lncRNAs) serve a crucial regulatory role of oncogenesis and tumor suppression in melanoma. Using data from The Cancer Genome Atlas database, novel lncRNA 11ß-hydroxysteroid dehydrogenase type 1-antisense RNA 1 (HSD11B1-AS1) was identified, which was significantly downregulated in malignant melanoma and its downregulation was significantly associated with poor clinicopathological characteristics, including advanced T and pathological stage, Clark level, Breslow depth and ulceration and worse prognosis. Multivariate analysis showed that HSD11B1-AS1, as well as N stage and Breslow depth, were independent prognostic factors in cutaneous melanoma, and nomograms suggested a good predictive value of 1-, 3- and 5-year overall survival, progression-free interval and disease-specific survival. In vitro experiments verified the decreased HSD11B1-AS1 expression in melanoma cell lines compared with human epidermal melanocytes. Moreover, cell experiments in vitro, including Cell Counting Kit-8, colony formation, wound healing and Transwell assay, suggested that overexpression of HSD11B1-AS1 significantly inhibited melanoma cell proliferation, migration and invasion. Functional enrichment showed significantly enriched pathways in IFN-γ and -α response, TNF-α signaling via NF-κB and IL-2/STAT-5 and IL-6/JAK/STAT-3 signaling. In addition, immune infiltration analysis demonstrated that HSD11B1-AS1 may function by accelerating immune response regulation and the immune cell infiltration of various immunocytes, especially T, T helper 1, activated dendritic and B cells. The present study revealed HSD11B1-AS1 as a potential therapeutic target and promising biomarker for diagnosis and prognosis of cutaneous melanoma.