Kidney transplantation from a systemic lupus erythematosus donor and 1-year follow-up: A case report.

Systemic lupus erythematosus (SLE) is usually regarded as a relative contraindication for deceased kidney donation. The pathological variations because of the changes in the immune environment after kidney transplantation (KT) are unclear, and the recovery of renal function is poorly understood. We present a case of KT from a deceased donor with SLE who was followed-up for one year. Although SLE-related hemangioma developed during the perioperative period, it was cured after interventional treatment. A pre-planned biopsy was performed one year after KT, and it was found that most of the pathological changes and immunofluorescent markers of lupus had resolved. Renal function was stable, and urinary protein and occult blood levels reduced one year after KT.

Mapping and analysis of protein and gene profiles identify the important role of TGF-ß in synovial invasion in pigmented villonodular synovitis.

BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved. METHODS: The expression of synovial genes from six control individuals, seven OA patients, and nineteen PVNS patients was analyzed via RNA sequencing. Protein profiles from five control individuals, ten OA patients, and thirty-two PVNS patients were analyzed using label-free proteomics. Microarray and RT-PCR analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from PVNS tissue. Various signaling pathway inhibitors, siRNAs, and western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed. RESULTS: In total, 522 differentially expressed proteins were identified in the PVNS tissues. By integrating RNA sequencing and microarray analyses, significant changes in the expression of EMT-related genes, including TGFBI, N-cadherin, E-cadherin, SNAIL, and TWIST, were confirmed in the PVNS tissue compared to the control tissue. In vitro, TGF-ß induced EMT and increased epithelial cell migration and invasion. Moreover, TGF-ß not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways. CONCLUSION: This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGF-ß in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy.

Pulmonary granulomas and Mendelson syndrome in an immunocompromised patient.

Granuloma formation is generally correlated with infection. Pulmonary granulomas caused by foreign bodies aspiration are uncommon. The clinical and radiologic features of such cases often lack specificity, which makes it difficult to distinguish from malignancy. Aspiration is usually not considered in the differential diagnosis of patients presenting with mass-like abnormalities on chest imaging. Occult aspiration history, diverse clinical manifestations, atypical imaging findings, and limited availability of pathogen detection techniques make the precise diagnosis a substantial challenge. Herein, we describe an older patient presenting with chest pain and worrisome lung masses/nodules that proved to be pulmonary granulomas caused by foreign matters aspiration. In addition, the patient developed Mendelson syndrome due to acute macroaspiration. Lung tissue metagenomics next-generation sequencing (mNGS) revealed Streptococcus intermedius, a normal flora of the oropharynx. The aim of this case was to underscore the importance of considering aspiration as a potential differential diagnosis of patients presenting with pulmonary granulomas, especially in patients with recurrent pneumonia or predisposing factors. In addition, mNGS act as a potential, rapid, and effective technique for diagnosing aspiration-related syndrome, showing satisfactory performance in identifying pathogens.

Multiple myeloma, IL6, and risk of schizophrenia: A Mendelian randomization, transcriptome, and Bayesian colocalization study.

Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome-wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment-resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation-relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein-coding region of HLA-DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA-DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin-6 (IL-6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA-DRB1 polymorphism, and enhanced IL-6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.

Crosstalk between bone and brain in Alzheimer's disease: Mechanisms, applications, and perspectives.

Alzheimer's disease (AD) is a neurodegenerative disease that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between the brain and bone, but the interaction between bone and brain in AD remains unclear. In this review, we summarize human studies of the association between bone and brain and provide an overview of their interactions and the underlying mechanisms in AD. We review the effects of AD on bone from the aspects of AD pathogenic proteins, AD risk genes, neurohormones, neuropeptides, neurotransmitters, brain-derived extracellular vesicles (EVs), and the autonomic nervous system. Correspondingly, we elucidate the underlying mechanisms of the involvement of bone in the pathogenesis of AD, including bone-derived hormones, bone marrow-derived cells, bone-derived EVs, and inflammation. On the basis of the crosstalk between bone and the brain, we propose potential strategies for the management of AD with the hope of offering novel perspectives on its prevention and treatment. HIGHLIGHTS: The pathogenesis of AD, along with its consequent changes in the brain, may involve disturbing bone homeostasis. Degenerative bone disorders may influence the progression of AD through a series of pathophysiological mechanisms. Therefore, relevant bone intervention strategies may be beneficial for the comprehensive management of AD.

Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines.

High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new click able building blocks remain exceedingly challenging. Here in , we describe a double-click strategy that enables the sequential ligation of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO 2 NCO) via a modular amidation/SuFEx process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO 2 F) and N-acylsulfamides (RCONHSO 2 NR ´ R ´´ ) in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compound s  exhibit high antimicrobial activities against Gram-positive bacterium  S. aureus and drug-resistant MRSA (MIC up to 6.25·µg mL-1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry.

Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the prototypic genomic disorder resulting from deficiency of paternally expressed genes in the human chromosome 15q11-q13 region. The unique molecular mechanism involving epigenetic modifications renders PWS as the most attractive candidate to explore a proof-of-concept of epigenetic therapy in humans. The premise is that epigenetic modulations could reactivate the repressed PWS candidate genes from the maternal chromosome and offer therapeutic benefit. Our prior study identifies an EHMT2/G9a inhibitor, UNC0642, that reactivates the expression of PWS genes via reduction of H3K9me2. However, low brain permeability and poor oral bioavailability of UNC0642 preclude its advancement into translational studies in humans. In this study, a newly developed inhibitor, MS152, modified from the structure of UNC0642, has better brain penetration and greater potency and selectivity against EHMT2/G9a. MS152 reactivated maternally silenced PWS genes in PWS patient fibroblasts and in brain and liver tissues of PWS mouse models. Importantly, the molecular efficacy of oral administration is comparable with the intraperitoneal route. MS152 treatment in newborns ameliorates the perinatal lethality and poor growth, maintaining reactivation in a PWS mouse model at postnatal 90 days. Our findings provide strong support for MS152 as a first-in-class inhibitor to advance the epigenetic therapy of PWS in humans.

Molecular characterization and expression profile of the ALDH1A1 gene and its functions in yak luteal cells.

The ALDH1A1 gene encodes a cytoplasmic member of the aldehyde dehydrogenase 1 family, which plays an important role in regulating animal reproductive performance, including estrus cycle and embryonic development. The aim of this study was to characterize ALDH1A1 activity in ovaries of 3-5 year-old yaks and to determine its effects on cell proliferation, apoptosis, and progesterone secretion in luteal cells (LCs). The coding sequence (CDS) of the ALDH1A1 gene was cloned by reverse transcription-PCR and immunohistochemical analysis was used to confirm localization of the ALDH1A1 protein in the ovary. To assess the activity of ALDH1A1 in regulating progesterone secretion, si-ALDH1A1 was transfected into LCs in vitro and progesterone levels in LC supernatants were measured by ELISA. The interference efficiency was assessed by real-time quantitative PCR (RT-qPCR) and immunofluorescence staining, and cell proliferation and apoptosis were evaluated by EdU and TUNEL staining, respectively. The cloned ALDH1A1 sequence contained 1462 bp, encoding 487 amino acids. Immunohistochemical analysis showed that ALDH1A1 protein expression, which was significantly higher in LCs, was mainly found in antral follicles and the corpus luteum (CL). The expression of ALDH1A1 mRNA in LCs was effectively inhibited by si-ALDH1A1transfection, and progesterone secretion was markedly decreased along with the significant down-regulation of progesterone pathway-related genes, STAR, CYP11A1, CYP19A1, CYP17A1, 3ß-HSD, and HSD17B1. Knockdown of ALDH1A1 mRNA expression decreased cell proliferation and increased apoptosis in LCs. The mRNA expression of the proliferation-related genes, PCNA, CCND1, CCNB1 and CDC25A, was significantly down-regulated, while expression of the apoptosis-promoting CASP3 gene was significantly increased. In summary, we characterized the yak ALDH1A1 gene and revealed that ALDH1A1 knockdown promoted apoptosis, repressed cell proliferation, and decreased progesterone secretion by yak LCs, potentially by regulating the mRNA expression of genes related to proliferation, apoptosis, and progesterone synthesis and secretion.

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Pangenome and multi-tissue gene atlas provide new insights into the domestication and highland adaptation of yaks.

BACKGROUND: The genetic diversity of yak, a key domestic animal on the Qinghai-Tibetan Plateau (QTP), is a vital resource for domestication and breeding efforts. This study presents the first yak pangenome obtained through the de novo assembly of 16 yak genomes. RESULTS: We discovered 290 Mb of nonreference sequences and 504 new genes. Our pangenome-wide presence and absence variation (PAV) analysis revealed 5,120 PAV-related genes, highlighting a wide range of variety-specific genes and genes with varying frequencies across yak populations. Principal component analysis (PCA) based on binary gene PAV data classified yaks into three new groups: wild, domestic, and Jinchuan. Moreover, we proposed a 'two-haplotype genomic hybridization model' for understanding the hybridization patterns among breeds by integrating gene frequency, heterozygosity, and gene PAV data. A gene PAV-GWAS identified a novel gene (BosGru3G009179) that may be associated with the multirib trait in Jinchuan yaks. Furthermore, an integrated transcriptome and pangenome analysis highlighted the significant differences in the expression of core genes and the mutational burden of differentially expressed genes between yaks from high and low altitudes. Transcriptome analysis across multiple species revealed that yaks have the most unique differentially expressed mRNAs and lncRNAs (between high- and low-altitude regions), especially in the heart and lungs, when comparing high- and low-altitude adaptations. CONCLUSIONS: The yak pangenome offers a comprehensive resource and new insights for functional genomic studies, supporting future biological research and breeding strategies.

The effects of IL-27 and IL-35 gene variation and expression levels on the susceptibility and clinical manifestations of pulmonary tuberculosis.

Inflammatory cytokines have crucial roles in the pathogenesis of tuberculosis (TB), and interleukin (IL)-27 and IL-35 have a pro-inflammatory and anti-inflammatory effect on many diseases, including infectious diseases. Therefore, we evaluated the relationship between IL-27 and IL-35 gene polymorphism, expression levels, and pulmonary TB (PTB) susceptibility. Nine single-nucleotide polymorphisms (SNPs) in the IL-27 gene (rs181206, rs153109, and rs17855750) and the IL-35 gene (rs4740, rs428253, rs9807813, rs2243123, rs2243135, and rs568408) were genotyped by the SNPscan technique in 497 patients with PTB and 501 controls. There was no significant difference regarding the genotype and allele frequencies of the above SNPs in the IL-27 and IL-35 genes between patients with PTB and controls. Haplotype analysis showed that the frequency of the GAC haplotype in the IL-35 gene was significantly decreased in patients with PTB when compared to controls (p = 0.036). Stratified analysis suggested that the frequency of the IL-27 rs17855750 GG genotype was significantly increased in patients with PTB with fever. Moreover, the lower frequency of the IL-35 rs568408 GA genotype was associated with drug-induced liver injury in patients with PTB. The IL-35 rs428253 GC genotype, as well as the rs4740 AA genotype and A allele, showed significant relationships with hypoproteinemia in patients with PTB. When compared with controls, the IL-27 level was significantly increased in patients with PTB. Taken together, IL-35 gene variation might contribute to a protective role on the susceptibility to PTB, and IL-27 and IL-35 gene polymorphisms were associated with several clinical manifestations of patients with PTB.

Inhibition of miR-9 Combined With Cisplatin Targeting APE1 Against Angiogenesis in Osteosarcoma.

Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance suggests poor prognosis in OS patients. In this study, the authors discovered that miR-9 has a pro-angiogenic role in OS. The anti-angiogenic effects of cisplatin were greatly increased when miR-9 was suppressed in OS. In addition, the authors demonstrated that miR-9 plays a pro-angiogenic role by targeting apoptosis-inducing factor 1 (APE1) in OS. Importantly, our in vivo experiments showed that inhibition of miR-9 combined with cisplatin could suppress xenograft tumor growth by targeting APE1 and decreasing angiogenesis in OS. In summary, our results suggest that miR-9 plays a role as a tumor promoter, and inhibiting miR-9 and APE1 is a new strategy for inhibiting OS angiogenesis and chemotherapy resistance.

RNA m5C methylation modification: a potential therapeutic target for SARS-CoV-2-associated myocarditis.

The Corona Virus Disease (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has quickly spread worldwide and resulted in significant morbidity and mortality. Although most infections are mild, some patients can also develop severe and fatal myocarditis. In eukaryotic RNAs, 5-methylcytosine (m5C) is a common kind of post-transcriptional modification, which is involved in regulating various biological processes (such as RNA export, translation, and stability maintenance). With the rapid development of m5C modification detection technology, studies related to viral m5C modification are ever-increasing. These studies have revealed that m5C modification plays an important role in various stages of viral replication, including transcription and translation. According to recent studies, m5C methylation modification can regulate SARS-CoV-2 infection by modulating innate immune signaling pathways. However, the specific role of m5C modification in SARS-CoV-2-induced myocarditis remains unclear. Therefore, this review aims to provide insights into the molecular mechanisms of m5C methylation in SARS-CoV-2 infection. Moreover, the regulatory role of NSUN2 in viral infection and host innate immune response was also highlighted. This review may provide new directions for developing therapeutic strategies for SARS-CoV-2-associated myocarditis.

Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study.

BACKGROUND: Acute-on-chronic liver disease (AoCLD) accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases. AIM: To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD. METHODS: Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure (ACLF) study cohort were included in this study. The clinical characteristics and outcomes, and the 90-d survival rate associated with each clinical type of AoCLD were analyzed, using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 3375 patients with AoCLD were enrolled, including 1679 (49.7%) patients with liver cirrhosis acute decompensation (LC-AD), 850 (25.2%) patients with ACLF, 577 (17.1%) patients with chronic hepatitis acute exacerbation (CHAE), and 269 (8.0%) patients with liver cirrhosis active phase (LC-A). The most common cause of chronic liver disease (CLD) was HBV infection (71.4%). The most common precipitants of AoCLD was bacterial infection (22.8%). The 90-d mortality rates of each clinical subtype of AoCLD were 43.4% (232/535) for type-C ACLF, 36.0% (36/100) for type-B ACLF, 27.0% (58/215) for type-A ACLF, 9.0% (151/1679) for LC-AD, 3.0% (8/269) for LC-A, and 1.2% (7/577) for CHAE. CONCLUSION: HBV infection is the main cause of CLD, and bacterial infection is the main precipitant of AoCLD. The most common clinical type of AoCLD is LC-AD. Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.

The novel probiotic preparation based on Lactobacillus spp. mixture on the intestinal bacterial community structure of Cherry Valley duck.

The development and utilization of probiotics have many environmental benefits when they are used to replace antibiotics in animal production. In this study, intestinal lactic acid bacteria were isolated from the intestines of Cherry Valley ducks. Probiotic lactic acid bacterial strains were screened for antibacterial activity and tolerance to produce a Lactobacillus spp. mixture. The effects of the compound on the growth performance and intestinal flora of Cherry Valley ducks were studied. Based on the results of the antibacterial activity and tolerance tests, the highly active strains Lactobacillus casei 1.2435, L. salivarius L621, and L. salivarius L4 from the intestines of Cherry Valley ducks were selected. The optimum ratio of L. casei 1.2435, L. salivarius L621, and L. salivarius L4 was 1:1:2, the amount of inoculum used was 1%, and the fermentation time was 14 h. In vivo experiments showed that compared with the control group, the relative abundances of intestinal Lactobacillus and Blautia were significantly increased in the experimental group fed the lactobacilli compound (P < 0.05); the relative abundances of Parabacteroides, [Ruminococcus]_torques_group, and Enterococcus were significantly reduced (P < 0.05), and the growth and development of the dominant intestinal flora were promoted in the Cherry Valley ducks. This study will provide more opportunities for Cherry Valley ducks to choose microecological agents for green and healthy breeding.

USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK.

Deubiquitinase-targeting chimeras (DUBTACs) have been recently developed to stabilize proteins of interest, which is in contrast to targeted protein degradation (TPD) approaches that degrade disease-causing proteins. However, to date, only the OTUB1 deubiquitinase has been utilized to develop DUBTACs via an OTUB1 covalent ligand, which could unexpectedly compromise the endogenous function of OTUB1 owing to its covalent nature. Here, we show for the first time that deubiquitinase USP7 can be harnessed for DUBTAC development. Based on a noncovalent ligand of USP7, we developed USP7-based DUBTACs that stabilized the ΔF508-CFTR mutant protein as effectively as the previously reported OTUB1-based DUBTAC. Importantly, using two different noncovalent ligands of USP7, we developed the first AMPK DUBTACs that appear to selectively stabilize different isoforms of AMPKß, leading to elevated AMPK signaling. Overall, these results highlight that, in addition to OTUB1, USP7 can be leveraged to develop DUBTACs, thus significantly expanding the limited toolbox for targeted protein stabilization and the development of novel AMPK DUBTACs as potential therapeutics.

MicroRNA-542-3p targets Pten to inhibit the myoblasts proliferation but suppresses myogenic differentiation independent of targeted Pten.

BACKGROUND: Non-coding RNA is a key epigenetic regulation factor during skeletal muscle development and postnatal growth, and miR-542-3p was reported to be conserved and highly expressed in the skeletal muscle among different species. However, its exact functions in the proliferation of muscle stem cells and myogenesis remain to be determined. METHODS: Transfection of proliferative and differentiated C2C12 cells used miR-542-3p mimic and inhibitor. RT-qPCR, EdU staining, immunofluorescence staining, cell counting kit 8 (CCK-8), and Western blot were used to evaluate the proliferation and myogenic differentiation caused by miR-542-3p. The dual luciferase reporter analysis and rescued experiment of the target gene were used to reveal the molecular mechanism. RESULTS: The data shows overexpression of miR-542-3p downregulation of mRNA and protein levels of proliferation marker genes, reduction of EdU+ cells, and cellular vitality. Additionally, knocking it down promoted the aforementioned phenotypes. For differentiation, the miR-542-3p gain-of-function reduced both mRNA and protein levels of myogenic genes, including MYOG, MYOD1, et al. Furthermore, immunofluorescence staining immunized by MYHC antibody showed that the myotube number, fluorescence intensity, differentiation index, and myotube fusion index all decreased in the miR-542-3p mimic group, compared with the control group. Conversely, these phenotypes exhibited an increased trend in the miR-542-3p inhibitor group. Mechanistically, phosphatase and tensin homolog (Pten) was identified as the bona fide target gene of miR-542-3p by dual luciferase reporter gene assay, si-Pten combined with miR-542-3p inhibitor treatments totally rescued the promotion of proliferation by loss-function of miR-542-3p. CONCLUSIONS: This study indicates that miR-542-3p inhibits the proliferation and differentiation of myoblast and Pten is a dependent target gene of miR-542-3p in myoblast proliferation, but not in differentiation.

Clinical Analysis of Microwave Ablation Combined with Decompression and Pedicle Screw Fixation in the Treatment of Spinal Metastases.

OBJECTIVES: There is still controversy over the choice of treatment for end-stage spinal metastases. With the continuous development of microwave technology in spinal tumors, related studies have reported that microwave combined with techniques such as pedicle screw fixation and percutaneous vertebroplasty can achieve the purpose of tumor ablation, relieving spinal cord compression, enhancing spinal stability, effectively relieving pain, and reducing recurrence rates. This study aimed to analyze the effectiveness of microwave ablation combined with decompression and pedicle screw fixation in the palliative management of spinal metastases with pathological fractures. METHODS: This retrospective study enrolled 82 patients with spinal metastases and pathological fractures treated between January 2016 and July 2020, with 44 patients undergoing pedicle screw fixation along with laminectomy (fixation group) and the remaining 38 receiving microwave ablation in addition to the treatment provided to group fixation (MWA group). Before surgery, all patients underwent pain assessment using the visual analogue scale (VAS) and evaluation of spinal cord injury using the Frankel classification. After surgery, the patients' prognoses were assessed using the Tomita score, modified Tokuhashi score system, and progression-free survival. Additionally, we compared operative time and blood loss between the two groups. Survival analysis utilized the Kaplan-Meier method with a log-rank test for group comparisons. Paired t-tests and the Mann-Whitney U test were applied to metric and non-normally distributed data, respectively. Neurological function improvement across groups was evaluated using the χ2 test. RESULTS: All patients were followed up for a median duration of 18 and 20 months in the fixation and MWA groups, respectively, with follow-up periods ranging from 6 to 36 months. Statistically significant reductions in postoperative VAS scores were observed in all patients compared with their preoperative scores. The MWA group exhibited reduced blood loss (t = 2.74, p = 0.01), lower VAS scores at the 1- and 3-month follow-ups (t = 2.34, P = 0.02; t = 2.83, p = 0.006), and longer progression-free survival than the fixation group (p = 0.03). Although the operation times in the MWA group were longer than those in the fixation group, this difference was not statistically significant (t = 6.06, p = 0.12). No statistically significant differences were found regarding improvements in spinal cord function between the two groups (p = 0.77). CONCLUSION: Compared with decompression and pedicle screw fixation for treating spinal metastases with pathological fractures, microwave ablation combined with decompression and pedicle screw fixation showed better outcomes in terms of pain control, longer progression-free survival, and lower blood loss without increasing operative time, which has favorable implications for clinical practice.

Augmenting external control arms using Bayesian borrowing: a case study in first-line non-small cell lung cancer.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab + chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to 1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR = 1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR = 0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR = 1.30; 95% CI: 1.08-1.54, borrowing weight = 1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight = 1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.