[Progress of Immunotherapy in EGFR-mutated Advanced Non-small Cell Lung Cancer].

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC.
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Metabolic reprogramming involves in transition of activated/resting CD4+ memory T cells and prognosis of gastric cancer.

Background: Little is known on how metabolic reprogramming potentially prompts transition of activated and resting CD4+ memory T cells infiltration in tumor microenvironment of gastric cancer (GC). The study aimed to evaluate their interactions and develop a risk model for predicting prognosis in GC. Methods: Expression profiles were obtained from TCGA and GEO databases. An immunotherapeutic IMvigor210 cohort was also enrolled. CIBERSORT algorithm was used to evaluate the infiltration of immune cells. The ssGSEA method was performed to assess levels of 114 metabolism pathways. Prognosis and correlation analysis were conducted to identify metabolism pathways and genes correlated with activated CD4+ memory T cells ratio (AR) and prognosis. An AR-related metabolism gene (ARMG) risk model was constructed and validated in different cohorts. Flow cytometry was applied to validate the effect of all-trans retinoic acid (ATRA) on CD4+ memory T cells. Results: Since significantly inverse prognostic value and negative correlation of resting and activated CD4+ memory T cells, high AR level was associated with favorable overall survival (OS) in GC. Meanwhile, 15 metabolism pathways including retinoic acid metabolism pathway were significantly correlated with AR and prognosis. The ARMG risk model could classify GC patients with different outcomes, treatment responses, genomic and immune landscape. The prognostic value of the model was also confirmed in the additional validation, immunotherapy and pan-cancer cohorts. Functional analyses revealed that the ARMG model was positively correlated with pro-tumorigenic pathways. In vitro experiments showed that ATRA could inhibit levels of activated CD4+ memory T cells and AR. Conclusion: Our study showed that metabolic reprogramming including retinoic acid metabolism could contribute to transition of activated and resting CD4+ memory T cells, and affect prognosis of GC patients. The ARMG risk model could serve as a new tool for GC patients by accurately predicting prognosis and response to treatment.

Integrated Three-Electrode Dual-Mode Detection Chip for Place Cell Analysis: Dopamine Facilitates the Role of Place Cells in Encoding Spatial Locations of Novel Environments and Rewards.

The functioning of place cells requires the involvement of multiple neurotransmitters, with dopamine playing a critical role in hippocampal place cell activity. However, the exact mechanisms through which dopamine influences place cell activity remain largely unknown. Herein, we present the development of the integrated three-electrode dual-mode detection chip (ITDDC), which enables simultaneous recording of the place cell activity and dopamine concentration fluctuation. The working electrode, reference electrode, and counter electrode are all integrated within the ITDDC in electrochemical detection, enabling the real-time in situ monitoring of dopamine concentrations in animals in motion. The reference, working, and counter electrodes are surface-modified using PtNPs and polypyrrole, PtNPs and PEDOT:PSS, and PtNPs, respectively. This modification allows for the detection of dopamine concentrations as low as 20 nM. We conducted dual-mode testing on mice in a novel environment and an environment with food rewards. We found distinct dopamine concentration variations along different paths within a novel environment, implying that different dopamine levels may contribute to spatial memory. Moreover, environmental food rewards elevate dopamine significantly, followed by the intense firing of reward place cells, suggesting a crucial role of dopamine in facilitating the encoding of reward-associated locations in animals. The real-time and in situ recording capabilities of ITDDC offer new opportunities to investigate the interplay between electrophysiology and dopamine during animal exploration and reward-based memory and provide a novel glimpse into the correlation between dopamine levels and place cell activity.

Prognostic utility of TME-associated genes in pancreatic cancer.

Background: Pancreatic cancer (PC) is a deadly disease. The tumor microenvironment (TME) participates in PC oncogenesis. This study focuses on the assessment of the prognostic and treatment utility of TME-associated genes in PC. Methods: After obtaining the differentially expressed TME-related genes, univariate and multivariate Cox analyses and least absolute shrinkage and selection operator (LASSO) were performed to identify genes related to prognosis, and a risk model was established to evaluate risk scores, based on The Cancer Genome Atlas (TCGA) data set, and it was validated by external data sets from the Gene Expression Omnibus (GEO) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Multiomics analyses were adopted to explore the potential mechanisms, discover novel treatment targets, and assess the sensitivities of immunotherapy and chemotherapy. Results: Five TME-associated genes, namely, FERMT1, CARD9, IL20RB, MET, and MMP3, were identified and a risk score formula constructed. Next, their mRNA expressions were verified in cancer and normal pancreatic cells. Multiple algorithms confirmed that the risk model displayed a reliable ability of prognosis prediction and was an independent prognostic factor, indicating that high-risk patients had poor outcomes. Immunocyte infiltration, gene set enrichment analysis (GSEA), and single-cell analysis all showed a strong relationship between immune mechanism and low-risk samples. The risk score could predict the sensitivity of immunotherapy and some chemotherapy regimens, which included oxaliplatin and irinotecan. Various latent treatment targets (LAG3, TIGIT, and ARID1A) were addressed by mutation landscape based on the risk model. Conclusion: The risk model based on TME-related genes can reflect the prognosis of PC patients and functions as a novel set of biomarkers for PC therapy.

Comprehensive analysis for the immune related biomarkers of platinum-based chemotherapy in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is one of the most lethal gynecological malignancies. This study aimed to identify biomarkers that were sensitive to platinum-based chemotherapeutic agents and can be used in immunotherapy and explore the importance of their mechanisms of action. METHODS: RNA-seq profiles and clinicopathological data for OC samples were obtained from The Cancer Genome Atlas (TCGA) and cBioPortal platform, respectively. Platinum-sensitive and platinum-resistant OC samples in the TCGA cohort were selected based on the clinical information. RNA-seq data for 70 OC samples withSingle-sample gene set enrichment analysis (ssGSEA) and unsupervised clustering were used to classify OC patients from the TCGA cohort into clusters with different proportions of infiltrating immune cells. ESTIMATE analysis was used to assess the immune landscape among clusters. Differential expression, univariate Cox regression, and LASSO regression analyses were performed to construct prognostic model. Spearman correlation analysis was conducted to investigate the correlations among immune checkpoint inhibitors (ICIs) and risk score, half-maximal drug inhibitory concentration (IC50) and risk score. RESULTS: Using ssGSEA and unsupervised clustering, OC samples were divided into two clusters with different immune cell infiltration. Then, 1715 differentially expressed immune-related genes (DEIRGs) were identified between two clusters, 984 differentially expressed platinum-sensitive related genes (DEPSRGs) between 149 platinum-sensitive and 63 platinum-resistant OC samples were identified, and 5384 differentially expressed genes (DEGs) between 380 OC and 194 normal samples were detected from the TCGA cohort. Six biomarkers (GMPPB, SRPK1, STC1, PRSS16, HPDL, and SPTSSB) were detected to establish a prognostic model. The OC patients in the TCGA cohort were classified into high- and low-risk groups. The receive operating characteristic (ROC) curve was plotted and demonstrated that the prognostic model performed well with the area under ROC curve (AUC) greater than 0.6. The expressions of 5 ICIs, including CD200, TNFRSF18, CD160, CD200R1, and CD274 (PD-L1), were significantly different between two risk groups, and the risk score was significant negative associated with CTLA4, TNFRSF4, TNFRSF18, and CD274. Moreover, there were significant differences in IC50 of 10 chemo drugs between two risk groups, patients in the high-risk group could be more resistant to po0tinib, dasatinib, and neratinib. CONCLUSION: In summary, this study constructed a novel prognostic model based on six prognostic biomarkers, including GMPPB, SRPK1, STC1, PRSS16, HPDL, and SPTSSB, which can be utilized for predicting the prognosis of OC patients. These biomarkers were the potential therapeutic targets.

Disulfidptosis-associated LncRNAs index predicts prognosis and chemotherapy drugs sensitivity in cervical cancer.

Disulfidptosis is a newly discovered form of cell death. Not yet clearly classified as programmed cell death or accidental cell death. This study aimed to create a novel disulfidptosis-related lncRNA index (DLI) that can be used to predict survival and chemotherapy drugs sensitivity in patients with cervical cancer. First of all, we found lncRNAs associated with disulfidptosis between cervical cancer tissues and normal tissues. By LASSO-Cox analysis, overlapping lncRNAs were then used to construct lncRNA index associated with disulfidptosis, which can be served to predict the prognosis of patients with CC, especially the chemotherapy drugs sensitivity. ROC curves and PCA based on DLI and clinical signatures were developed and demonstrated to have good predictive potential. In addition, differences in immune cell subset infiltration and differences in immune checkpoint expression between high-DLI and low-DLI groups were analyzed, and we investigated the relationship between the DLI and tumor mutation burden (TMB). In summary, we constructed a lncRNA prediction index associated with disulfidptosis. This has important clinical implications, including improving the predictive value of cervical cancer patients and providing a biomarker for cervical cancer guiding individualized treatment.

A lipid metabolism-based prognostic risk model for HBV-related hepatocellular carcinoma.

BACKGROUND: Up to 85% of hepatocellular carcinoma (HCC) cases in China can be attributed to infection of hepatitis B virus (HBV). Lipid metabolism performs important function in hepatocarcinogenesis of HBV-related liver carcinoma. However, limited studies have explored the prognostic role of lipid metabolism in HBV-related HCC. This study established a prognostic model to stratify HBV-related HCC based on lipid metabolisms. METHODS: Based on The Cancer Genome Atlas HBV-related HCC samples, this study selected prognosis-related lipid metabolism genes and established a prognosis risk model by performing uni- and multi-variate Cox regression methods. The final markers used to establish the model were selected through the least absolute shrinkage and selection operator method. Analysis of functional enrichment, immune landscape, and genomic alteration was utilized to investigate the inner molecular mechanism involved in prognosis. RESULTS: The risk model independently stratified HBV-infected patients with liver cancer into two risk groups. The low-risk groups harbored longer survival times (with P < 0.05, log-rank test). TP53, LRP1B, TTN, and DNAH8 mutations and high genomic instability occurred in high-risk groups. Low-risk groups harbored higher CD8 T cell infiltration and BTLA expression. Lipid-metabolism (including "Fatty acid metabolism") and immune pathways were significantly enriched (P < 0.05) in the low-risk groups. CONCLUSIONS: This study established a robust model to stratify HBV-related HCC effectively. Analysis results decode in part the heterogeneity of HBV-related liver cancer and highlight perturbation of lipid metabolism in HBV-related HCC. This study's findings could facilitate patients' clinical classification and give hints for treatment selection.

PPy/SWCNTs-Modified Microelectrode Array for Learning and Memory Model Construction through Electrical Stimulation and Detection of In Vitro Hippocampal Neuronal Network.

The learning and memory functions of the brain remain unclear, which are in urgent need for the detection of both a single cell signal with high spatiotemporal resolution and network activities with high throughput. Here, an in vitro microelectrode array (MEA) was fabricated and further modified with polypyrrole/carboxylated single-walled carbon nanotubes (PPy/SWCNTs) nanocomposites as the interface between biological and electronic systems. The deposition of the nanocomposites significantly improved the performance of microelectrodes including low impedance (60.3 ± 28.8 k Ω), small phase delay (-32.8 ± 4.4°), and good biocompatibility. Then the modified MEA was used to apply learning training and test on hippocampal neuronal network cultured for 21 days through electrical stimulation, and multichannel electrophysiological signals were recorded simultaneously. During the process of learning training, the stimulus/response ratio of the hippocampal learning population gradually increased and the response time gradually decreased. After training, the mean spikes in burst, number of bursts, and mean burst duration increased by 53%, 191%, and 52%, respectively, and the correlation of neurons in the network was significantly enhanced from 0.45 ± 0.002 to 0.78 ± 0.002. In addition, the neuronal network basically retained these characteristics for at least 5 h. These results indicated that we have successfully constructed a learning and memory model of hippocampal neurons on the in vitro MEA, contributing to understanding learning and memory based on synaptic plasticity. The proposed PPy/SWCNTs-modified in vitro MEA will provide a promising platform for the exploration of learning and memory mechanism and their applications in vitro.

Risk factor analysis of bone cement leakage for polymethylmethacrylate-augmented cannulated pedicle screw fixation in spinal disorders.

Objective: To investigate the risk factors of cement leakage (CL) for polymethylmethacrylate-augmented cannulated pedicle screw (CPS) in spinal degenerative diseases and provided technical guidance for clinical surgery. Methods: This study enrolled 276 patients with spinal degenerative disease and osteoporosis who were augmented using CPSs (835 screws in total) from May 2011 to June 2018 in our hospital. The patients' age, sex, bone mineral density (BMD), diagnosis, augmented positions, number of CPS implanted, and CL during surgery were recorded. CL was observed by postoperative computed tomography (CT) and was classified by Yeom typing. Results: A total of 74 (74/835, 8.9%) CPSs in 64 patients leaked (64/276, 23.2%). CL was significantly correlated with the number and position of screws (P < 0.05), but not with sex, age, and BMD (P > 0.05). The position, number of CPSs, fracture, degenerative scoliosis, ankylosing spondylitis, and revision surgery were risk factors for CL (P < 0.05). Augmentation of the thoracic vertebral body, fracture, and ankylosing spondylitis were independent risk factors for Type S. Augmentation of the lumbar vertebral body, lumbar disc herniation, and lumbar spondylolisthesis were independent risk factors for Type B (P < 0.05). Conclusions: CL has a high incidence in clinical practice. High-risk factors for leakage should be addressed to avoid serious complications. Particularly, it is necessary to develop alternative solutions once CPSs can't be used in surgery caused by CL.

Reversed windshield-wiper effect leads to failure of cement-augmented pedicle screw: Biomechanical mechanism analysis by finite element experiment.

The failure mode of cement-augmented pedicle screw (CAPS) was different from common pedicle screw. No biomechanical study of this failure mode named as "reversed windshield-wiper effect" was reported. To investigate the mechanisms underlying this failure mode, a series of finite element models of CAPS and PS were modified on L4 osseous model. Nine models were created according to the cement volume at 0.5 mL interval (range: 1-5 mL). Pullout load and cranio-caudal loads were applied on the screws. Stress and instantaneous rotation center (IRC) of the vertebra were observed. Under cranio-caudal load, the stress concentrated on the screw tip and pedicle region. The maximal stress (MS) at the screw tip region was +2.143 MPa higher than pedicle region. With cement volume increasing, the maximal stress (MS) at the screw tip region decreased dramatically, while MS at pedicle region was not obviously affected. As dose increased to 1.5 mL, the MS at pedicle region became higher than screw tip region and the maximal stress difference was observed at 3.5 mL. IRC of the vertebra located at the facet joint region in PS model. While IRC in CAPS models shifted anteriorly closer to the vertebral body with the increasing of cement volume. Under axial pull-out load, the maximal stress (MS) of cancellous bone in CAPS models was 29.53-50.04% lower than that 2.228 MPa in PS model. MS in the screw-bone interface did not change significantly with cement volume increasing. Therefore, the possible mechanism is that anterior shift of IRC and the negative difference value of MS between screw tip and pedicle region due to cement augmentation, leading to the screw rotate around the cement-screw complex as the fulcrum point.

Role of Posterior Longitudinal Ligament Complex in Spinal Deformity Secondary to Surgical Resection of the Intradural Tumor.

OBJECTIVE: In most cases, complete resection of the intradural tumor is accompanied by long-term neurological complications. Postoperative spinal deformity is the most common complication after surgical resection of intradural tumors, and posterior longitudinal ligament complex (PLC) plays an important role in postoperative spinal deformity. In this study, we investigated the role of PLC in spinal deformity after the surgical treatment of intradural tumors. METHODS: We analyzed the data of 218 consecutive patients who underwent intradural tumor resection from 2000 to 2018 in this retrospective study. Before 2010, patients underwent laminoplasty without maintaining the integrity of PLC (laminoplasty group, n = 155). After 2010, patients performed single-port laminoplasty to maintain the integrity of PLC (laminoplasty retain posterior ligament complex group, n = 63). The score of quality of life, painful cortex, spinal cord movement, progressive kyphosis or scoliosis, perioperative morbidity, and neurological results were analyzed in the laminoplasty group and laminoplasty retain posterior ligament complex group. The distributed variable was shown as mean ± standard deviation and an independent t-test or one-way analysis of variance was calculated. RESULTS: There are 155 patients (71.1%) included in the laminoplasty group, and 63 patients (28.9%) in the laminoplasty retain posterior ligament complex group. The average age of patients was 42 ± 2.3 years, and the average modified McCormick score was 2. There were 158 (72.4%) patients with intramedullary tumors and 115 (52.7%) patients with extramedullary tumors. The length of hospital stays (8 days vs. 6 days; p = 0.023) and discharge to inpatient rehabilitation (48.4% vs. 26.9%; p = 0.012) were significantly lower in the laminoplasty retain posterior ligament complex group than the laminoplasty group. There was no significant difference in the risk of progressive deformity between the two groups at 18 months after surgery (relative risk 0.12; 95% confidence interval [CI] 0.43-1.25; p = 0.258) and at 20 months after surgery (relative risk 0.24; 95% CI 0.21-2.1). CONCLUSION: Laminoplasty retains posterior ligament complex showed no impact on the spinal deformities compared with laminoplasty, but significantly improved the postoperative spinal activity, alleviated pain symptoms, and reduced hospital recovery time.

Circulating Tumor DNA: Less Invasive, More Representative Method to Unveil the Genomic Landscape of Newly Diagnosed Multiple Myeloma Than Bone Marrow Aspirates.

Multiple myeloma (MM) is highly heterogenous and dynamic in its genomic abnormalities. Capturing a representative image of these alterations is essential in understanding the molecular pathogenesis and progression of the disease but was limited by single-site invasive bone marrow (BM) biopsy-based genomics studies. We compared the mutational landscapes of circulating tumor DNA (ctDNA) and BM in 82 patients with newly diagnosed MM. A 413-gene panel was used in the sequencing. Our results showed that more than 70% of MM patients showed one or more genes with somatic mutations and at least half of the mutated genes were shared between ctDNA and BM samples. Compared to the BM samples, ctDNA exhibited more types of driver mutations in the shared driver genes, higher numbers of uniquely mutated genes and subclonal clusters, more translocation-associated mutations, and higher frequencies of mutated genes enriched in the transcriptional regulation pathway. Multivariate Cox analysis showed that age, ctDNA mutations in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival (PFS). Our results demonstrated sequencing of ctDNA provides more thorough information on the genomic instability and is a potential representative biomarker for risk stratification and in newly diagnosed MM than bone marrow.

Osteogenic peptides in periodontal ligament stem cell-containing three-dimensional bioscaffolds promote bone healing.

Bone tissue engineering shows great potential in bone regeneration; however, the lack of bone growth factors with high biocompatibility and efficiency is a major concern. Oligopeptides have drawn great attention due to their high biological efficacy, low toxicity, and low molecular weight. The oligopeptide SDSSD promotes the osteogenesis of human periodontal ligament stem cells (hPDLSCs) in vitro. The SDSSD-modified three-dimensional (3D) bioscaffolds promote osteogenesis and bone formation in the subcutaneous pockets of BALB/c nude mice and facilitate bone healing in vivo. Mechanistically, SDSSD promoted bone formation by binding to G protein-coupled receptors and regulating the AKT signaling pathway. 3D-printing bioscaffolds with SDSSD may be potential bone tissue engineering materials for treating bone defects.

Preparation and characterization of 2-deacetyl-3-O-sulfo-heparosan and its antitumor effects via the fibroblast growth factor receptor pathway.

Heparosan, with a linear chain of disaccharide repeating units of â†’ 4) ß-D-glucuronic acid (GlcA) (1 â†’ 4)-α-D-N-acetylglucosamine (GlcNAc) (1→, is a potential starting chemical for heparin synthesis. However, the chemoenzymatic synthesis of single-site sulfated heparosan and its antitumor activity have not been studied. In this study, 2-deacetyl-3-O-sulfo-heparosan (DSH) was prepared successively by the N-deacetylation chemical reaction and enzymatic modification of human 3-O-sulfotransferase-1 (3-OST-1). Structural characterization of DSH was shown the success of the sulfation with the sulfation degree of 0.87. High performance gel permeation chromatography (HPGPC) analysis revealed that DSH had only one symmetrical sharp peak with a molecular weight of 9.6334 × 104 Da. Biological function studies showed that DSH could inhibit tumor cell (A549, HepG2 and HCT116) viability and induce the apoptosis of A549 cells. Further in vitro mechanistic studies showed that DSH may induce apoptosis via the JNK signaling pathway, and the upstream signal of this process may be fibroblast growth factor receptors. These results indicated that DSH could be developed as one of a potential chemical for tumor treatment.

Pan-cancer multi-omics analyses reveal crosstalk between the Hippo and immune signaling pathways in the tumor microenvironment.

The Hippo signaling pathway is critical for carcinogenesis. However, the roles of the Hippo signaling pathway in the tumor immune microenvironment have been rarely investigated. This study systematically analyzed the relationship between the Hippo signaling pathway and immune cell infiltration across 32 cancer types. Both bioinformatics analyses and biological experiments revealed that the downstream effector of Hippo signaling YAP1 might inhibit CD8+ T cell infiltration by upregulating the expression of the transcription factor CREB1 in uterine corpus endometrial carcinoma. In addition, esophageal carcinoma (ESCA) patients were classified into three subtypes based on the Hippo-immune gene panel. The subtypes of ESCA had distinct characteristics in immune cell infiltration, immune pathways, and prognosis. Thus, this study also reveals a new classification of the immune subtypes with prognostic characteristics in ESCA.

Modified lumbar foraminoplasty using a power-aided reciprocating burr for percutaneous transforaminal endoscopic lumbar discectomy: A technical note and clinical report.

Background: One of the main difficulties in a transforaminal endoscopic lumbar discectomy (TELD), and simultaneously the most critical step, is performing an effective and safe foraminoplasty, which is especially difficult for beginners. To make it safer and faster for beginners to perform, we have used a specially designed power-aided reciprocating burr for TELD and reported the technical details. Methods: From Jan. 2019 to Nov. 2022, 432 patients with single-level, symptomatic L4/5 or L5/S1 disc herniation were treated with TELD using a novel power-aided reciprocating burr. The surgical procedure is described in detail. Magnetic resonance imaging (MRI) was performed the following day and 3 months after the operation. The learning curves of surgeons with different seniority levels are displayed. The Visual Analogue Scale (VAS) score and the Oswestry Disability Index (ODI) were used to measure low back pain, leg pain, and lumbar function. All patients were followed up for at least 1 year. Results: All patients underwent endoscopic surgery successfully. Among the 432 patients, radicular outer membrane damage was observed in 6 cases, and 1 case had hernia of the nerve tract. Except for this patient with aggravation of postoperative numbness, the postoperative neurological symptoms of all patients were significantly improved. The mean VAS scores for low back pain and leg pain and ODI scores were significantly decreased 6 w post-operatively and were maintained until 12 months post-operatively compared to preoperative scores (P < 0.05). All three doctors involved in the study had substantial experience in traditional open spinal surgery. The more operations all three surgeons completed, the more time spent on intervertebral foraminoplasty decreased (P < 0.05). Among them, doctors without experience in TELD surgery became proficient in this technique after accumulating experience in 13 cases. There was no significant difference in foraminoplasty time among these three surgeons during the same growing period (P > 0.05). Conclusions: Current clinical data demonstrated the safety and efficacy of modified TELD using a power-aided reciprocating burr for treating lumbar disc herniation (LDH) and showed that this technique significantly reduces the learning curve for beginners when performing foraminoplasty.

A biomechanical analysis of anterior cervical discectomy and fusion alone or combined cervical fixations in treating compression-extension injury with unilateral facet joint fracture: a finite element study.

BACKGROUND: Compression-extension injury with unilateral facet joint fracture is one of the most devastating injuries of subaxial cervical spine. However, it is not yet clear which fixation technique represents the optimal choice in surgical management. This study aims to assess the construct stability at the operative level (C4/C5 cervical spine) following anterior cervical discectomy and fusion (ACDF) alone and combined fixation techniques (posterior-anterior fixations). METHODS: A previously validated three-dimensional C2-T1 finite element model were modified to simulate surgical procedures via the anterior-only approach (ACDF) and combined cervical approach [(transarticular screw, lateral mass screw, unilateral pedicle screw, bilateral pedicle screw) + ACDF, respectively] for treating compression-extension injury with unilateral facet joint fracture at C4/C5 level. Construct stability (range of rotation, axial compression displacement and anterior shear displacement) at the operative level was comparatively analyzed. RESULTS: In comparison with combined fixation techniques, a wider range of motion and a higher maximum von Mises stress was found in single ACDF. There was no obvious difference in range of motion among transarticular screw and other posterior fixations in the presence of anterior fixation. In addition, the screws inserted by transarticular screw technique had high stress concentration at the middle part of the screw but much less than 500 MPa under different conditions. Furthermore, the variability of von Mises stress in the transarticular screw fixation device was significantly lower than ACDF but no obvious difference compared with other posterior fixations. CONCLUSIONS: Of the five fixation techniques, ACDF has proven poor stability and high structural stress. Compared with lateral and pedicle screw, transarticular screw technique was not worse biomechanically and less technically demanding to acquire in clinical practice. Therefore, our study suggested that combined fixation technique (transarticular screw + ACDF) would be a reasonable treatment option to acquire an immediate stabilization in the management of compression-extension injury with unilateral facet joint fracture. However, clinical aspects must also be regarded when choosing a reconstruction method for a specific patient.

Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome.

Poly (ADPribose) polymerase inhibitors (PARPis) are clinically approved drugs designed according to the concept of synthetic lethality (SL) interaction. It is crucial to expand the scale of patients who can benefit from PARPis, and overcome drug resistance associated with it. Genetic interactions (GIs) include SL and synthetic viability (SV) that participate in drug response in cancer cells. Based on the hypothesis that mutated genes with SL or SV interactions with PARP1/2/3 are potential sensitive or resistant PARPis biomarkers, respectively, we developed a novel computational method to identify them. We analyzed fitness variation of cell lines to identify PARP1/2/3-related GIs according to CRISPR/Cas9 and RNA interference functional screens. Potential resistant/sensitive mutated genes were identified using pharmacogenomic datasets. We identified 41 candidate resistant and 130 candidate sensitive PARPi-response related genes, and observed that EGFR with gain-of-function mutation induced PARPi resistance, and predicted a combination therapy with PARP inhibitor (veliparib) and EGFR inhibitor (erlotinib) for lung cancer. We also revealed that a resistant gene set (TNN, PLEC, and TRIP12) in lower grade glioma and a sensitive gene set (BRCA2, TOP3A, and ASCC3) in ovarian cancer, which were associated with prognosis. Thus, cancer genome-derived GIs provide new insights for identifying PARPi biomarkers and a new avenue for precision therapeutics.

Individualized lncRNA differential expression profile reveals heterogeneity of breast cancer.

Long non-coding RNAs (lncRNAs) play key regulatory roles in breast cancer. However, population-level differential expression analysis methods disregard the heterogeneous expression of lncRNAs in individual patients. Therefore, we individualized lncRNA expression profiles for breast invasive carcinoma (BRCA) using the method of LncRNA Individualization (LncRIndiv). After evaluating the robustness of LncRIndiv, we constructed an individualized differentially expressed lncRNA (IDElncRNA) profile for BRCA and investigated the subtype-specific IDElncRNAs. The breast cancer subtype-specific IDElncRNA showed frequent co-occurrence with alterations of protein-coding genes, including mutations, copy number variation and differential methylation. We performed hierarchical clustering to subdivide TNBC and revealed mesenchymal subtype and immune subtype for TNBC. The TNBC immune subtype showed a better prognosis than the TNBC mesenchymal subtype. LncRNA PTOV1-AS1 was the top differentially expressed lncRNA in the mesenchymal subtype. And biological experiments validated that the upregulation of PTOV1-AS1 could downregulate TJP1 (ZO-1) and E-Cadherin, and upregulate Vimentin, which suggests PTOV1-AS1 may promote epithelial-mesenchymal transition and lead to migration and invasion of TNBC cells. The mesenchymal subtype showed a higher fraction of M2 macrophages, whereas the immune subtype was more associated with CD4 + T cells. The immune subtype is characterized by genomic instability and upregulation of immune checkpoint genes, thereby suggesting a potential response to immunosuppressive drugs. Last, drug response analysis revealed lncRNA ENSG00000230082 (PRRT3-AS1) is a potential resistance biomarker for paclitaxel in BRCA treatment. Our analysis highlights that IDElncRNAs can characterize inter-tumor heterogeneity in BRCA and the new TNBC subtypes indicate novel insights into TNBC immunotherapy.