Squalene Epoxidase: Its Regulations and Links with Cancers.

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate-cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.

Structural Characterization and In Vitro Antioxidant Activity of a Novel Polysaccharide from Summer-Autumn Tea.

To enhance the utilization of summer-autumn tea, a water-soluble polysaccharide (D1N1) was isolated through a series of techniques including hot water extraction, ethanol precipitation, and column chromatography. The structure of D1N1 was determined through the utilization of ultraviolet, Fourier-transform infrared, high-performance anion-exchange chromatography, gas chromatography-tandem mass spectrometry, and nuclear magnetic resonance. The results revealed that glucose was the predominant component of D1N1, accounting for 95% of its composition. Additionally, D1N1 also contained galactose, arabinose, and rhamnose. The molecular weight (Mw) of D1N1 was determined to be 224.71 kDa. The backbone of D1N1 consisted of →4)-α-D -Glcp (1→, →3,4)-α-D-Galp-(1→, →4,6)-α-D -Glcp (1→ at a molar ratio of 35:1:1, and branching at the O-3 position of →3,4)-α-D-Galp-(1→ and O-6 position of →4,6)-α-D-Glcp (1→ with α-D -Glcp (1→. In addition, the antioxidant activity of D1N1 was also evaluated. D1N1 exhibited excellent antioxidant bioactivity against the DPPH, superoxide anion radical, and ABTS+ radical. These findings provide a theoretical basis for the application of summer-autumn tea polysaccharide as a potential functional food.

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2.

BACKGROUND: Premature ovarian insufficiency (POI) is a severe disorder leading to female infertility. Genetic mutations are important factors causing POI. TP63-truncating mutation has been reported to cause POI by increasing germ cell apoptosis, however what factors mediate this apoptosis remains unclear. METHODS: Ninety-three patients with POI were recruited from Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Whole-exome sequencing (WES) was performed for each patient. Sanger sequencing was used to confirm potential causative genetic variants. A minigene assay was performed to determine splicing effects of TP63 variants. A TP63-truncating plasmid was constructed. Real-time quantitative PCR, western blot analyses, dual luciferase reporter assays, immunofluorescence staining, and cell apoptosis assays were used to study the underlying mechanism of a TP63-truncating mutation causing POI. RESULTS: By WES of 93 sporadic patients with POI, we found a 14-bp deletion covering the splice site in the TP63 gene. A minigene assay demonstrated that the 14-bp deletion variant led to exon 13 skipping during TP63 mRNA splicing, resulting in the generation of a truncated TP63 protein (TP63-mut). Overexpression of TP63-mut accelerated cell apoptosis. Mechanistically, the TP63-mut protein could bind to the promoter region of CLCA2 and activate the transcription of CLCA2 several times compared to that of the TP63 wild-type protein. Silencing CLCA2 using a specific small interfering RNA (siRNA) or inhibiting the Ataxia Telangiectasia Mutated (ATM) pathway using the KU55933 inhibitor attenuated cell apoptosis caused by TP63-mut protein expression. CONCLUSION: Our findings revealed a crucial role for CLCA2 in mediating apoptosis in POI pathogenesis, and suggested that CLCA2 is a potential therapeutic target for POI.

Activating CD8+ T Cells by Pt(IV) Prodrug-Based Nanomedicine and aPD-L1 Antibody for Enhanced Cancer Immunotherapy.

Recent years have witnessed substantial progress in cancer immunotherapy, specifically T cell-based therapies. However, the application of T cell therapies has been primarily limited to hematologic malignancies, with limited success in the treatment of solid tumors. The main challenge in treating solid tumor is immune escape, which is characterized by reduced antigenicity, diminished immunogenicity, and the development of suppressive tumor immune microenvironments. To address these obstacles and restore T cell-mediated anti-tumor responses, a novel nanoparticle formulation known as PRA@Oxa-c16 is developed. This innovative approach combines retinoic acid and Pt(IV) to specifically target and overcome immune escape. Notably, the therapeutic efficacy of PRA@Oxa-c16 primarily relies on its ability to induce anti-tumor T cell responses, in contrast to the cytotoxicity associated with conventional chemotherapeutic agents. When combined with an immune checkpoint blockade, anti-programmed death-ligand 1 antibody, PRA@Oxa-c16 effectively eliminates solid tumors and induces immune memory responses, which prevent tumor metastasis and recurrence. This promising approach holds great potential for enhancing the treatment of solid tumors with T cell-based immunotherapy.

Transcriptome Sequencing Unveils a Molecular-Stratification-Predicting Prognosis of Sarcoma Associated with Lipid Metabolism.

Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.

Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer.

Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC.

Outcomes following KRASG12C inhibitor treatment in patients with KRASG12C-mutated solid tumors: A systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of FDA-approved KRASG12C inhibitors in patients with KRASG12C-mutated solid tumors. METHODS: We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest. RESULTS: 18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRASG12C-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77). CONCLUSIONS: This study provided a comprehensive understanding of the efficacy and safety of KRASG12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRASG12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRASG12C inhibitor treatment.

Efficacy of the newly designed "SkyWalker" robot compared to the MAKO robotic system in primary total knee arthroplasty: a one-year follow-up study.

PURPOSE: Robot-assisted surgical systems for performing total knee arthroplasty (TKA) have gained significant attention. This study was designed to compare the surgical outcomes in primary TKA surgery between the recently developed "SkyWalker" robot system and the more commonly used MAKO robot. METHODS: A total of 75 patients undergoing primary TKA surgery by the same surgical team were included in this study, with 30 patients in the "SkyWalker" group and 45 patients in the "MAKO" group. We documented the osteotomy plan for both robotic systems. The lower limb alignment angles were evaluated by postoperative radiographic assessment. The operation time, estimated blood loss, postoperative hospital stays, and changes in laboratory indexes were collected during hospitalization. In addition, a comparative evaluation of knee functional assessments and complications was conducted during six month and one year follow-ups. RESULTS: There were no significant differences between the two groups in terms of the accuracy of restoring lower limb alignment, estimated blood loss, or operation time. The knee function assessments at six months and one year postoperatively were similar in both groups. Except for day three after surgery, the level of interleukin-6 (IL-6) and the change in IL-6 (∆IL-6) from preoperative baseline were higher in the "SkyWalker" group than in the MAKO group (median: 20.53 vs. 14.17, P=0.050 and median: 17.30 vs. 10.09, P=0.042, respectively). Additionally, one patient from the MAKO group underwent revision surgery at nine months postoperatively due to ongoing periprosthetic discomfort. CONCLUSIONS: The newly developed "SkyWalker" robot showed comparable efficacy to the MAKO robot in terms of lower limb alignment accuracy and postoperative six month and one year follow-up of clinically assessed resumption of knee function.

The SGLT2 inhibitor empagliflozin attenuates atherosclerosis progression by inducing autophagy.

Cardiovascular disease due to atherosclerosis is one of the leading causes of death worldwide; however, the underlying mechanism has yet to be defined. The sodium-dependent glucose transporter 2 inhibitor (SGLT2i) empagliflozin is a new type of hypoglycemic drug. Recent studies have shown that empagliflozin not only reduces high glucose levels but also exerts cardiovascular-protective effects and slows the process of atherosclerosis. The purpose of this study was to elucidate the mechanism by which empagliflozin ameliorates atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat Western diet to establish an atherosclerosis model. The area and size of atherosclerotic lesions in ApoE-/- mice were then assessed by performing hematoxylin-eosin (HE) staining after empagliflozin treatment. Concurrently, oxidized low-density lipoprotein (oxLDL) was used to mimic atherosclerosis in three different types of cells. Then, following empagliflozin treatment of macrophage cells (RAW264.7), human aortic smooth muscle cells (HASMCs), and human umbilical vein endothelial cells (HUVECs), western blotting was applied to measure the levels of autophagy-related proteins and proinflammatory cytokines, and green fluorescent protein (GFP)-light chain 3 (LC3) puncta were detected using confocal microscopy to confirm autophagosome formation. Oil Red O staining was performed to detect the foaming of macrophages and HASMCs, and flow cytometry was used for the cell cycle analysis. 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), and scratch assays were also performed to examine the proliferation and migration of HASMCs. Empagliflozin suppressed the progression of atherosclerotic lesions in ApoE-/- mice. Empagliflozin also induced autophagy in RAW246.7 cells, HASMCs, and HUVECs via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and it significantly increased the levels of the Beclin1 protein, the LC3B-II/I ratio, and p-AMPK protein. In addition, empagliflozin decreased the expression of P62 and the protein levels of inflammatory cytokines, and it inhibited the foaming of RAW246.7 cells and HASMCs, as well as the expression of inflammatory factors by inducing autophagy. Empagliflozin activated autophagy through the AMPK signaling pathway to delay the progression of atherosclerosis. Furthermore, the results of flow cytometry, EdU assays, CCK-8 cell viability assays, and scratch assays indicated that empagliflozin blocked HASMCs proliferation and migration. Empagliflozin activates autophagy through the AMPK signaling pathway to delay the evolution of atherosclerosis, indicating that it may represent a new and effective drug for the clinical treatment of atherosclerosis.

Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer.

INTRODUCTION: Brain metastasis, with the highest incidence in patients with lung cancer, significantly worsens prognosis and poses challenges to clinical management. To date, how brain metastasis evades immune elimination remains unknown. METHODS: Whole-exome sequencing and RNA sequencing were performed on 30 matched brain metastasis, primary lung adenocarcinoma, and normal tissues. Data from The Cancer Genome Atlas primary lung adenocarcinoma cohort, including multiplex immunofluorescence, were used to support the findings of bioinformatics analysis. RESULTS: Our study highlights the key role of intratumor heterogeneity of genomic alterations in the metastasis process, mainly caused by homologous recombination deficiency or other somatic copy number alteration-associated mutation mechanisms, leading to increased genomic instability and genomic complexity. We further proposed a selection model of brain metastatic evolution in which intratumor heterogeneity drives immune remodeling, leading to immune escape through different mechanisms under local immune pressure. CONCLUSIONS: Our findings provide novel insights into the metastatic process and immune escape mechanisms of brain metastasis and pave the way for precise immunotherapeutic strategies for patients with lung cancer with brain metastasis.

Multiscale spatial relationship-based model for predicting bladder wall dose in pelvic radiotherapy.

PURPOSE: This research aimed to develop a prediction model to assess bladder wall dosimetry during radiotherapy for patients with pelvic tumors, thereby facilitating the refinement and evaluation of radiotherapy treatment plans to mitigate bladder toxicity. METHODS: Radiotherapy treatment plans of 49 rectal cancer patients and 45 gynecologic cancer patients were collected, and multiple linear regression analyses were used to generate prediction models for bladder wall dose parameters ( V 10 - 45 G y ( c m 3 ) ${V_{10 - 45Gy\ }}( {{\mathrm{c}}{{\mathrm{m}}^3}} )$ , D m e a n ( Gy ) ${D_{mean}}( {{\mathrm{Gy}}} )$ ). These models were based on the multiscale spatial relationship between the planning target volume (PTV) and the bladder or bladder wall. The proportion of bladder or bladder wall volume overlapped by the different distance expansions of the PTV was used as an indicator of the multiscale spatial relationship. The accuracy of these models was verified in a cohort of 12 new patients, with further refinement of radiotherapy treatment plans using the predicted values as optimization parameters. Model accuracy was assessed using root mean square error (RMSE) and mean percentage error (MPE). RESULTS: Models derived from individual disease data outperformed those derived from combined datasets. Predicted bladder wall dose parameters were accurate, with the majority of initial calculated values for new patients falling within the 95% confidence interval of the model predictions. There was a robust correlation between the predicted and actual dose metrics, with a correlation coefficient of 0.943. Using the predicted values to optimize treatment plans significantly reduced bladder wall dose (p < $\ < \ $ 0.001), with bladder wall D mean ( G y ) ${D_{{\mathrm{mean}}}}( {Gy} )$ and V 10 - 45 G y ( c m 3 ) ${V_{10 - 45Gy\ }}( {{\mathrm{c}}{{\mathrm{m}}^3}} )$ decreasing by 2.27±0.80 Gy (5.8%±1.8%) and 2.96±2.05 cm3 (7.9%±5.4%), respectively. CONCLUSION: The formulated prediction model provides a valuable tool for predicting and minimizing bladder wall dose and for optimizing and evaluating radiotherapy treatment plans for pelvic tumor patients. This approach holds promise for reducing bladder toxicity and potentially improving patient outcomes.

Clinical significance and predictive risk factors for event-free survival at 24 months in patients with PTCL, NOS.

Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), is a heterogeneous and aggressive type of non-Hodgkin's lymphoma with a bleak prognosis. This study was designed to assess the value of EFS24 as an alternative clinical endpoint and identify prognosis-related factors in PTCL, NOS. Patients diagnosed with PTCL, NOS were retrospectively collected and slides were reviewed by two hematopathologists. EFS was defined as the time from diagnosis to the occurrence of disease progression after initial treatment, retreatment, or death. Subsequent overall survival (OS) was defined from EFS24 or time of progression, if it occurred within 24 months, to the last follow-up or death. 97 cases with complete follow-up were selected. Approximately 66 patients (68.04%) failed to achieve ES24, with the median OS of 12.17 months, and 5-year OS rate of 15.17%. While patients who reached EFS24 had a median OS of 60.57 months and a 5-year OS rate of 68.77%. Multivariate Cox analysis indicated that bone marrow involvement and elevated ß2 Microglobulin (ß2-MG) were associated with a poor prognosis. B symptoms, extranodal involvement more than one site, and a high Ki67 index were significant factors in predicting the failure of EFS24. EFS24 can help stratify the subsequent outcomes of PTCL, NOS. Patients who achieve EFS24 have a favorable prognosis, although it does not reach that of the general population. On the other hand, patients who do not achieve EFS24 have an extremely poor prognosis. Therefore, EFS24 can be used for patient risk stratification, patient counseling, and study design.

Expansion of exhausted CD8+ T cells associates with increased pulmonary fungal infection risk in anti-melanoma differentiation associated gene 5 dermatomyositis.

OBJECTIVES: Anti-MDA5+ dermatomyositis was associated with poor prognosis due to the high incidence of rapid progressive interstitial lung disease, pulmonary infection. The aim of this study is to investigate the abundance and clinical relevance of exhaustion markers on peripheral CD8 T cells from patients with idiopathic inflammatory myopathy (IIM). METHODS: Twenty-nine healthy controls (HCs) and 71 patients with IIM were enrolled, including 42 with anti-MDA5+ and 18 with anti-MDA5- dermatomyositis (DM) and 11 with anti-synthetase syndrome (ASS). Flow cytometry was applied to detect PD-1, TIM-3 and LAG-3 in CD8 T cells. The clinical associations of the CD8 T cell exhaustion phenotype in patients with anti-MDA5+ DM were analysed. RESULTS: CD8 T cells from patients with anti-MDA5+ DM showed significantly increased LAG-3, TIM-3 and PD-1 compared to those from patients with anti-MDA5- IIM (18 with anti-MDA5- DM and 11 with ASS) or HCs (adjusted p all < 0.05). CD8 T cells with distinct exhaustion levels were all significantly increased in anti-MDA5+ DM patients compared with HCs (p all < 0.05). Patients with high level of PD-1+ TIM-3+LAG-3+ CD8+ T cells had a significant higher incidence of pulmonary fungal infections but lower counts of CD4+ and CD8+ T cells. ROC analysis revealed that the frequency of PD-1+TIM-3+LAG-3+CD8+ T cell significantly predicted pulmonary fungal infections (area under the curve: 0.828). CONCLUSIONS: CD8 T cells from patients with anti-MDA5+ DM show significant exhausted phenotype, and increased exhausted CD8 T cells were associated with high risk of pulmonary fungal infection.

Lymphoma Recognition in Histology Image of Gastric Mucosal Biopsy with Prototype Learning.

Lymphomas are a group of malignant tumors developed from lymphocytes, which may occur in many organs. Therefore, accurately distinguishing lymphoma from solid tumors is of great clinical significance. Due to the strong ability of graph structure to capture the topology of the micro-environment of cells, graph convolutional networks (GCNs) have been widely used in pathological image processing. Nevertheless, the softmax classification layer of the graph convolutional models cannot drive learned representations compact enough to distinguish some types of lymphomas and solid tumors with strong morphological analogies on H&E-stained images. To alleviate this problem, a prototype learning based model is proposed, namely graph convolutional prototype network (GCPNet). Specifically, the method follows the patch-to-slide architecture first to perform patch-level classification and obtain image-level results by fusing patch-level predictions. The classification model is assembled with a graph convolutional feature extractor and prototype-based classification layer to build more robust feature representations for classification. For model training, a dynamic prototype loss is proposed to give the model different optimization priorities at different stages of training. Besides, a prototype reassignment operation is designed to prevent the model from getting stuck in local minima during optimization. Experiments are conducted on a dataset of 183 Whole slide images (WSI) of gastric mucosa biopsy. The proposed method achieved superior performance than existing methods.Clinical relevance- The work proposed a new deep learning framework tailored to lymphoma recognition on pathological image of gastric mucosal biopsy to differentiate lymphoma, adenocarcinoma and inflammation.

Development of a duplex PCR for the simultaneous detection of EHP and IHHNV and analysis of the correlation between these two pathogens.

Infectious hypodermal and hematopoietic necrosis virus (IHHNV) is one of the linearly single-stranded DNA viruses. Ecytonucleospora hepatopenaei (EHP) is an intracellular parasitic microsporidian. IHHNV and EHP are pathogens that have been widely prevalent in shrimp farming. Both of them are associated with growth retardation of the penaeid shrimp, which causes serious economic losses to shrimp farming. Shrimp can be co-infected with IHHNV and EHP. In this study, a rapid duplex polymerase chain reaction (PCR) was developed and optimized for the simultaneous detection of EHP and IHHNV. The detection limit of the duplex PCR could reach 1.5 × 102 copies for EHP and IHHNV. A total of 578 Litopenaeus vannamei samples were detected by the established duplex PCR detection method. The results suggested that 398 samples were infected with EHP, 362 samples were infected with IHHNV, and 265 samples were co-infected with EHP and IHHNV. The case-control analysis of the detected shrimp samples showed a certain synergistic effect between EHP and IHHNV.

The invasiveness of robot-assisted total hip replacement is similar to that of conventional surgery.

Robot-assisted total hip arthroplasty (R-THA) is increasingly being performed throughout the world. The invasiveness of this operation is unknown. We retrospectively reviewed the cohort of consecutive osteonecrosis of the femoral head (ONFH) patients who received primary R-THA or manual THA (M-THA) from January 2020 to January 2022 in our institution. One experienced surgeon performed all procedures. We calculated the propensity score to match similar patients in different groups by multivariate logistic regression analysis for each patient. We included confounders consisting of age, sex, body mass index (BMI), and operation time. Preoperative serum markers and Harris hip scores (HHS), postoperative serum markers at first day and third day, complications rate, postoperative HHS and Forgotten Joint Score (FJS) at 6 months after surgery of different cohorts were compared. We analyzed 218 ONFH patients treated with THA (98 R-THA patients, and 120 M-THA patients). After propensity score matching, we generated cohorts of 95 patients in R-THA and M-THA groups. We found no significant difference in preoperative serum markers and HHS. In the R-THA cohort, the PLT count was significantly lower on the postoperative day 1 (192.36 ± 41.72 × 109/L Vs 210.47 ± 72.85 × 109/L, p < 0.05). The Hb level was significantly lower on the postoperative third day in the R-THA cohort (98.52 ± 12.99 g/L Vs 104.74 ± 13.15 g/L, p < 0.05). There was no significant difference in the other serum markers between the cohorts on postoperative day 1 and 3 (p > 0.05). The FJS was significantly higher in the R-THA than M-THA group (p = 0.01). There was no significant difference in the postoperative HHS or complication rate between the groups (p > 0.05). The R-THA is not associated with a serious invasiveness compared to M-THA. Patients who underwent R-THA had a better early function compared to those who underwent M-THA.

Lactate oxidase nanocapsules boost T cell immunity and efficacy of cancer immunotherapy.

Cancer immunotherapy has reshaped the landscape of cancer treatment. However, its efficacy is still limited by tumor immunosuppression associated with the excessive production of lactate by cancer cells. Although extensive efforts have been made to reduce lactate concentrations through inhibition of lactate dehydrogenase, such inhibitors disrupt the metabolism of healthy cells, causing severe nonspecific toxicity. We report herein a nanocapsule enzyme therapeutic based on lactate oxidase, which reduces lactate concentrations and releases immunostimulatory hydrogen peroxide, averting tumor immunosuppression and improving the efficacy of immune checkpoint blockade treatment. As demonstrated in a murine melanoma model and a humanized mouse model of triple-negative breast cancer, this enzyme therapeutic affords an effective tool toward more effective cancer immunotherapy.

Revisional Endoscopic Foraminal Decompression via Modified Interlaminar Approach at L5-S1 after Failed Posterior Instrumented Lumbar Fusion in Elderly Patients.

Elderly people usually have poorer surgical tolerance and a higher incidence of complications when undergoing revision surgery after posterior instrumented lumbar fusion (PILF). Full-endoscopic transforaminal surgery is a safe and effective option, but sometimes, it is difficult to revise L5-S1 foraminal stenosis (FS) after PILF. Therefore, we developed full-endoscopic lumbar decompression (FELD) at the arthrodesis level via a modified interlaminar approach under local anesthesia. This study aimed to describe the technical note and clinical efficacy of the technique. Eleven patients with unilateral lower limb radiculopathy after PILF underwent selective nerve root block and then underwent FELD. Magnetic resonance imaging (MRI) and computer tomography (CT) were performed on the second postoperative day. Their clinical outcomes were evaluated with a Visual analog scale (VAS) of low back pain and sciatica pain, Oswestry disability index (ODI), and the MacNab score. Complete decompression was achieved in every case with FELD without serious complications. Postoperative VAS of sciatica pain and ODI at each time point and VAS of low back pain and ODI after three months postoperatively were significantly improved compared with those preoperative (p < 0.05). According to the MacNab criteria, seven patients (63.6%) had excellent results at the two-year follow-up, and four patients (36.4%) had good results. No patients required further revision surgery. FELD, via a modified interlaminar approach, is effective for treating unilateral L5-S1 FS after PILF in elderly people.

Discovery of a novel small molecule with efficacy in protecting against inflammation in vitro and in vivo by enhancing macrophages activation.

Immune response and inflammation highly contribute to many metabolic syndromes such as inflammatory bowel disease (IBD), ageing and cancer with disruption of host metabolic homeostasis and the gut microbiome. Icariin-1 (GH01), a small-molecule flavonoid derived from Epimedium, has been shown to protect against systemic inflammation. However, the molecular mechanisms by which GH01 ameliorates ulcerative colitis via regulation of microbiota-mediated macrophages polarization remain elusive. In this study, we found that GH01 effectively ameliorated dextran sulfate sodium (DSS)-induced colitis symptoms in mice. Disruption of intestinal barrier function, commensal microbiota and its metabolites were also significantly restored by GH01 in a dose-dependent manner. Of note, we also found that GH01 enhanced phagocytic ability of macrophages and switched macrophage phenotype from M1 to M2 both in vitro and in vivo. Such macrophage polarization was highly associated with intestinal barrier integrity and the gut microbial community. Consequently, GH01 exhibited strong anti-inflammatory capacity by inhibiting TLR4 and NF-κB pathways and proinflammatory factors (IL-6). These findings suggested that GH01 might be a potential nutritional intervention strategy for IBD treatment with the gut microbial community-meditated macrophage as the therapeutic targets.

Technical Notes and Clinical Outcomes of Full-Endoscopic Interbody Fusion Via Transforaminal Approach for Hard Disc Herniations in Thoracolumbar Junction.

OBJECTIVE: Obtaining sufficient decompression and solid fusion and avoiding approach-related injuries simultaneously are still challenging for the treatment of hard disc herniation in thoracolumbar junction. A combined full-endoscopic decompression and interbody fusion via a transforaminal approach was used to achieve this goal. The purpose of this study was to introduce the technical notes and clinical outcomes of this novel technique. METHODS: Twenty segments of hard disc herniations in the thoracolumbar junction of 14 patients treated with full-endoscopic interbody fusion via the transforaminal approach between January 2018 and September 2021 were analyzed. The patients were an average age of 43.3 years. Full-endoscopic interbody fusion and discectomy via the transforaminal approach were performed under local anesthesia, followed by percutaneous pedicle screw system fixation under general anesthesia. Imaging, including magnetic resonance imaging (MRI), computed tomography (CT), and X-ray, was carried out. MRI was performed on the second day and 3 months postoperatively. CT was performed on the second day, 6 months, and 1 year (as needed) postoperatively. Back and radicular pain, neurological function, and thoracic spine function were scored using a visual analog scale, the Nurick scale, and modified Japanese Orthopaedic Association (mJOA) scale, and the Oswestry disability index at 1 week, 3 months, 6 months, and 1 year postoperatively. RESULTS: All the operations were successfully completed, and no intraoperative conversion of the surgical methods occurred. Postoperative thoracolumbar junction MRI and CT examinations of all the patients revealed a sufficiently decompressed spinal cord or cauda equina, without any residual compression. At the 1-year follow-up, all the surgical segments were fused. Back and radicular pain was relieved in all the patients, and neurological function was restored. The average recovery rate of the mJOA was 72.5%, including seven excellent, five good, and two fair cases. Although dural tears occurred in two cases during the operation, no cerebrospinal fluid leakage or pseudomeningocele occurred during follow-up. No other surgical complications were noted. CONCLUSIONS: A combined full-endoscopic decompression and interbody fusion via a transforaminal approach can achieve complete spinal canal decompression and solid interbody fusion with fewer approach-related injuries. It is a safe and effective minimally invasive spine surgery for treating hard disc herniation in the thoracolumbar junction.