Glycosylphosphatidylinositol anchor biosynthesis pathway-based biomarker identification with machine learning for prognosis and T cell exhaustion status prediction in breast cancer.

As the primary component of anti-tumor immunity, T cells are prone to exhaustion and dysfunction in the tumor microenvironment (TME). A thorough understanding of T cell exhaustion (TEX) in the TME is crucial for effectively addressing TEX in clinical settings and promoting the efficacy of immune checkpoint blockade therapies. In eukaryotes, numerous cell surface proteins are tethered to the plasma membrane via Glycosylphosphatidylinositol (GPI) anchors, which play a crucial role in facilitating the proper translocation of membrane proteins. However, the available evidence is insufficient to support any additional functional involvement of GPI anchors. Here, we investigate the signature of GPI-anchor biosynthesis in the TME of breast cancer (BC)patients, particularly its correlation with TEX. GPI-anchor biosynthesis should be considered as a prognostic risk factor for BC. Patients with high GPI-anchor biosynthesis showed more severe TEX. And the levels of GPI-anchor biosynthesis in exhausted CD8 T cells was higher than normal CD8 T cells, which was not observed between malignant epithelial cells and normal mammary epithelial cells. In addition, we also found that GPI -anchor biosynthesis related genes can be used to diagnose TEX status and predict prognosis in BC patients, both the TEX diagnostic model and the prognostic model showed good AUC values. Finally, we confirmed our findings in cells and clinical samples. Knockdown of PIGU gene expression significantly reduced the proliferation rate of MDA-MB-231 and MCF-7 cell lines. Immunofluorescence results from clinical samples showed reduced aggregation of CD8 T cells in tissues with high expression of GPAA1 and PIGU.

Pan-cancer analysis of DCTN2 and its tumour-promoting role in HCC by modulating the AKT pathway.

Dynactin subunit 2 (DCTN2) has been reported to play a role in progression of several tumours; however, the involvement of DCTN2 in potential mechanism or the tumour immune microenvironment among various cancers still remains largely unknown. Therefore, the objective of this study was to comprehensively investigate the expression status and potential function of DCTN2 in various malignancies through different database, such as The Cancer Genome Atlas, the Genotype-Tissue Expression and Gene Expression Omnimus databases. We discovered that DCTN2 expression was high in many type of tumours tissues compared to adjacent non-tumour ones. High DCTN2 signified poor prognosis for patients with tumours. Additionally, Gene Set Enrichment Analysis (GSEA) analysis revealed that DCTN2 was positively correlated with oncogenic pathways, including cell cycle, tumour metastasis-related pathway, while it was negatively with anti-tumour immune signalling pathway, such as INF-γ response. More importantly, we elucidated the functional impact of DCTN2 on hepatocellular carcinoma (HCC) progression and its underlying mechanisms. DCTN2 expression was much higher in HCC tissues than in adjacent non-tumour tissues. Silencing DCTN2 dramatically suppressed the proliferative and metastasis capacities of tumour cell in vitro. Mechanistically, DCTN2 exerted tumour-promoting effects by modulating the AKT signalling pathway. DCTN2 knockdown in HCC cells inhibited AKT phosphorylation and its downstream targets as well. Rescue experiments revealed that the anti-tumour effects of DCTN2 knockdown were partially reversed upon AKT pathway activation. Overall, DCTN2 may be a potent biomarker signifying tumour prognosis and a promising therapeutic target for tumour treatment, particularly in HCC.

Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

Higher serum carotenoid concentrations were associated with the lower risk of cancer-related death: Evidence from the National Health and Nutrition Examination Survey.

The study focuses on the association between serum carotenoids and cancer-related death. Using data from the National Health and Nutrition Examination Survey (2001-2006 and 2017-2018), the study encompasses 10,277 participants older than age 20 years, with recorded baseline characteristics and serum carotenoid concentrations (including α-carotene, trans-ß-carotene, cis-ß-carotene, ß-cryptoxanthin, trans-lycopene, and lutein/zeaxanthin). We hypothesized that serum carotenoid concentrations were negatively associated with cancer-related death. The weighted chi-square analyses indicate significant negative correlations between higher serum concentrations of α-carotene, ß-cryptoxanthin, trans-lycopene, and total carotenoids, and the risk of cancer-related deaths. Using weighted Cox regression analysis, this study confirms that α-carotene, ß-cryptoxanthin, trans-lycopene, and total carotenoids, as continuous or categorical variables, are inversely related to cancer mortality (P < .0001). Furthermore, considering competitive risk events, lower concentrations of serum ß-cryptoxanthin (Fine-Gray P = 1.12e-04), trans-lycopene (P = 5.68e-14), and total carotenoids (P = .03) are associated with an increased risk of cancer-related deaths. The research reveals a crucial inverse relationship between serum carotenoid concentrations and cancer-related death.

Spectral CT vs. diffusion-weighted imaging for the quantitative prediction of pathologic response to neoadjuvant chemotherapy in locally advanced gastric cancer.

OBJECTIVES: To compare the performance of spectral CT and diffusion-weighted imaging (DWI) for predicting pathologic response after neoadjuvant chemotherapy (NAC) in locally advanced gastric cancer (LAGC). MATERIALS AND METHODS: This was a retrospective analysis drawn from a prospective dataset. Sixty-five patients who underwent baseline concurrent triple-phase enhanced spectral CT and DWI-MRI and standard NAC plus radical gastrectomy were enrolled, and those with poor images were excluded. The tumor regression grade (TRG) was the reference standard, and patients were classified as responders (TRG 0 + 1) or non-responders (TRG 2 + 3). Quantitative iodine concentration (IC), normalized IC (nIC), and apparent diffusion coefficient (ADC) were measured by placing a freehand region of interest manually on the maximal two-dimensional plane. Their differences between responders and non-responders were compared. The performances of significant parameters were evaluated by the receiver operating characteristic analysis. The correlations between parameters and TRG status were explored through Spearman correlation coefficient test. Kaplan-Meier survival analysis was adopted to analyze their relationship with patient survival. RESULTS: nICDP and ADC were associated with the TRG and yielded comparable performances for predicting TRG categories, with area under the curve (AUC) of 0.674 and 0.673, respectively. Their combination achieved a significantly increased AUC of 0.770 (p ; 0.05) and was associated with patient disease-free survival, with hazard ratio of 2.508 (1.043-6.029). CONCLUSION: Spectral CT and DWI were equally useful imaging techniques for predicting pathologic response to NAC in LAGC. The combination of nICDP and ADC gained significant incremental benefits and was related to patient disease-free survival. CLINICAL RELEVANCE STATEMENT: Spectral CT and DWI-based quantitative measurements are effective markers for predicting the pathologic regression outcomes of locally advanced gastric cancer patients after neoadjuvant chemotherapy. KEY POINTS: • The pathologic tumor regression grade, the standard criteria for treatment response after neoadjuvant chemotherapy in gastric cancer patients, is difficult to predict early. • The quantitative parameters of normalized iodine concentration at delay phase and apparent diffusion coefficients were correlated with pathologic response; their combination demonstrated incremental benefits and was associated with patient disease-free survival. • Spectral CT and DWI are equally useful imaging modalities for predicting tumor regression grade after neoadjuvant chemotherapy in patients with locally advanced gastric cancer.

Predicting pathologic response to neoadjuvant chemotherapy in locally advanced gastric cancer: The establishment of a spectral CT-based nomogram from prospective datasets.

BACKGROUND: To establish a spectral CT-based nomogram for predicting early neoadjuvant chemotherapy (NAC) response for locally advanced gastric cancer (LAGC). METHODS: This study prospectively recruited 222 cases (177 male and 45 female patients, 9.59 ± 9.54 years) receiving NAC and radical gastrectomy. Triple enhanced spectral CT scans were performed before NAC initiation. According to post-operative tumor regression grade (TRG), patients were classified into responders (TRG = 0 + 1) or non-responders (TRG = 2 + 3), and split into a primary (156) and validation (66) dataset at 7:3 ratio chronologically. We compared clinicopathological data, follow-up information, iodine concentration (IC), normalized ICs (nICs) in arterial/venous/delayed phases (AP/VP/DP) between responders and non-responders. Independent risk factors of response were screened by multivariable logistic regression and adopted for model construction. Model was visualized by nomograms and its capability was determined through receiver operating characteristic (ROC) curves. Log-rank survival analysis was conducted to explore associations between TRG, nomogram and patients' survival. RESULTS: This work identified Borrmann classification, ICDP, and nICDP were independent risk factors of response outcomes. A spectral CT-based nomogram was built accordingly and achieved an area under the curve (AUC) of 0.797 (0.692-0.879) and 0.741(0.661-0.811) for the primary and validation dataset, respectively, higher than AUC of individual parameters alone. The nomogram was related to disease-free survival in the validation dataset (Hazard ratio (HR): 5.19 [1.18-12.93], P = 0.02). CONCLUSIONS: The spectral CT-based nomogram provides an efficient tool for predicting the pathologic response outcomes of GC after NAC and disease-free survival risk stratification.

Reprimo (RPRM) mediates neuronal ferroptosis via CREB-Nrf2/SCD1 pathways in radiation-induced brain injury.

Neuronal ferroptosis has been found to contribute to degenerative brain disorders and traumatic and hemorrhagic brain injury, but whether radiation-induced brain injury (RIBI), a critical deleterious effect of cranial radiation therapy for primary and metastatic brain tumors, involves neuronal ferroptosis remains unclear. We have recently discovered that deletion of reprimo (RPRM), a tumor suppressor gene, ameliorates RIBI, in which its protective effect on neurons is one of the underlying mechanisms. In this study, we found that whole brain irradiation (WBI) induced ferroptosis in mouse brain, manifesting as alterations in mitochondrial morphology, iron accumulation, lipid peroxidation and a dramatic reduction in glutathione peroxidase 4 (GPX4) level. Moreover, the hippocampal ferroptosis induced by ionizing irradiation (IR) mainly happened in neurons. Intriguingly, RPRM deletion protected the brain and primary neurons against IR-induced ferroptosis. Mechanistically, RPRM deletion prevented iron accumulation by reversing the significant increase in the expression of iron storage protein ferritin heavy chain (Fth), ferritin light chain (Ftl) and iron importer transferrin receptor 1 (Tfr1), as well as enhancing the expression of iron exporter ferroportin (Fpn) after IR. RPRM deletion also inhibited lipid peroxidation by abolishing the reduction of GPX4 and stearoyl coenzyme A desaturase-1 (SCD1) induced by IR. Importantly, RPRM deletion restored or even increased the expression of nuclear factor, erythroid 2 like 2 (Nrf2) in irradiated neurons. On top of that, compromised cyclic AMP response element (CRE)-binding protein (CREB) signaling was found to be responsible for the down-regulation of Nrf2 and SCD1 after irradiation, specifically, RPRM bound to CREB and promoted its degradation after IR, leading to a reduction of CREB protein level, which in turn down-regulated Nrf2 and SCD1. Thus, RPRM deletion recovered Nrf2 and SCD1 through its impact on CREB. Taken together, neuronal ferroptosis is involved in RIBI, RPRM deletion prevents IR-induced neuronal ferroptosis through restoring CREB-Nrf2/SCD1 pathways.

Application of intravoxel incoherent motion diffusion-weighted imaging for preoperative knowledge of lymphovascular invasion in gastric cancer: a prospective study.

PURPOSE: To investigate the potential of intravoxel incoherent motion diffusion-weighted imaging (IVIM) for preoperative prediction of lymphovascular invasion (LVI) in gastric cancer (GC). METHODS: This study prospectively enrolled 90 patients (62 males, 28 females, 60.79 ± 9.99 years old) who received radical gastrostomy. Abdominal MRI examinations including IVIM were performed within 1 week before surgery. Patients were divided into LVI-positive and -negative group according to pathological diagnosis after surgery. The apparent diffusion coefficient (ADC) and IVIM parameters, including true diffusion coefficient (D), pseudodiffusion coefficient (D*), and pseudodiffusion fraction (f), were compared between the two groups. The relationship between MRI parameters and LVI was studied by Spearman's correlation analysis. Multivariable logistic regression analysis was used to screen independent predictors of LVI. Receiver-operating characteristic curve analyses were applied to evaluate the efficacy. RESULTS: The ADC, D in LVI-positive group were lower, whereas tumor thickness and f parameter in LVI-positive group were higher than those in LVI-negative group, and they were statistically correlated with LVI (p < 0.05). D, f and tumor thickness were independent risk factors of LVI. The area under the curve of ADC, D, f, thickness, and the combined parameter (D + f + thickness) were 0.667, 0.754, 0.695, 0.792, and 0.876, respectively. The combined parameter demonstrated higher efficacy than any other parameters (p < 0.05). CONCLUSION: The ADC, D, and f can effectively distinguish LVI status of GC. The D, f and thickness were independent predictors. The combination of the three predictors further improved the efficacy.

Research of intelligent reasoning system of Arabidopsis thaliana phenotype based on automated multi-task machine learning.

Traditional machine learning in plant phenotyping research requires the assistance of professional data scientists and domain experts to adjust the structure and hy-perparameters tuning of neural network models with much human intervention, making the model training and deployment ineffective. In this paper, the automated machine learning method is researched to construct a multi-task learning model for Arabidopsis thaliana genotype classification, leaf number, and leaf area regression tasks. The experimental results show that the genotype classification task's accuracy and recall achieved 98.78%, precision reached 98.83%, and classification F 1 value reached 98.79%, as well as the R 2 of leaf number regression task and leaf area regression task reached 0.9925 and 0.9997 respectively. The experimental results demonstrated that the multi-task automated machine learning model can combine the benefits of multi-task learning and automated machine learning, which achieved more bias information from related tasks and improved the overall classification and prediction effect. Additionally, the model can be created automatically and has a high degree of generalization for better phenotype reasoning. In addition, the trained model and system can be deployed on cloud platforms for convenient application.

Spectral CT-based nomogram for preoperative prediction of perineural invasion in locally advanced gastric cancer: a prospective study.

OBJECTIVES: This work focused on developing and validating the spectral CT-based nomogram to preoperatively predict perineural invasion (PNI) for locally advanced gastric cancer (LAGC). METHODS: This work prospectively included 196 surgically resected LAGC patients (139 males, 57 females, 59.55 ± 11.97 years) undergoing triple enhanced spectral CT scans. Patients were labeled as perineural invasion (PNI) positive and negative according to pathologic reports, then further split into primary (n = 130) and validation cohort (n = 66). We extracted clinicopathological information, follow-up data, iodine concentration (IC), and normalized IC values against to aorta (nICs) at arterial/venous/delayed phases (AP/VP/DP). Clinicopathological features and IC values between PNI positive and negative groups were compared. Multivariable logistic regression was performed to screen independent risk factors of PNI. Then, a nomogram was established, and its capability was determined by ROC curves. Its clinical use was evaluated by decision curve analysis. The correlations of PNI and the nomogram with patients' survival were explored by log-rank survival analysis. RESULTS: Borrmann classification, tumor thickness, and nICDP were independent predictors of PNI and used to build the nomogram. The nomogram yielded higher AUCs of 0.853 (0.744-0.928) and 0.782 (0.701-0.850) in primary and validation cohorts than any other parameters (p < 0.05). Both PNI and the nomogram were related to post-surgical treatment planning. Only PNI was associated with disease-free survival in the primary cohort (p < 0.05). CONCLUSION: This work prospectively established a spectral CT-based nomogram, which can effectively predict PNI preoperatively and potentially guide post-surgical treatment strategy in LAGC. KEY POINTS: • The present prospective study established a spectral CT-based nomogram for preoperative prediction of perineural invasion in LAGC. • The proposed nomogram, including morphological features and the quantitative iodine concentration values from spectral CT, had the potential to predict PNI for LAGC before surgery, along with guide post-surgical treatment planning. • Normalized iodine concentration at the delayed phase was the most valuable quantitative parameter, suggesting the importance of delayed enhancement in gastric CT.

Comparison of MRI and CT-Based Radiomics and Their Combination for Early Identification of Pathological Response to Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

BACKGROUND: Current radiomics for treatment response assessment in gastric cancer (GC) have focused solely on Computed tomography (CT). The importance of multi-parametric magnetic resonance imaging (mp-MRI) radiomics in GC is less clear. PURPOSE: To compare and combine CT and mp-MRI radiomics for pretreatment identification of pathological response to neoadjuvant chemotherapy in GC. STUDY TYPE: Retrospective. POPULATION: Two hundred twenty-five GC patients were recruited and split into training (157) and validation dataset (68) in the ratio of 7:3 randomly. FIELD/SEQUENCE: T2-weighted fast spin echo (fat suppressed T2-weighted imaging [fs-T2WI]), diffusion weighted echo planar imaging (DWI), and fast gradient echo (dynamic contrast enhanced [DCE]) sequences at 3.0T. ASSESSMENT: Apparent diffusion coefficient (ADC) maps were generated from DWI. CT, fs-T2WI, ADC, DCE, and mp-MRI Radiomics score (Radscores) were compared between responders and non-responders. A multimodal nomogram combining CT and mp-MRI Radscores was developed. Patients were followed up for 3-65 months (median 19) after surgery, the overall survival (OS) and progression free survival (PFS) were calculated. STATISTICAL TESTS: A logistic regression classifier was applied to construct the five models. Each model's performance was evaluated using a receiver operating characteristic curve. The association of the nomogram with OS/PFS was evaluated by Kaplan-Meier survival analysis and C-index. A P value <0.05 was considered statistically significant. RESULTS: CT Radscore, mp-MRI Radscore and nomogram were significantly associated with tumor regression grading. The nomogram achieved the highest area under the curves (AUCs) of 0.893 (0.834-0.937) and 0.871 (0.767-0.940) in training and validation datasets, respectively. The C-index was 0.589 for OS and 0.601 for PFS. The AUCs of the mp-MRI model were not significantly different to that of the CT model in training (0.831 vs. 0.770, P = 0.267) and validation dataset (0.797 vs. 0.746, P = 0.137). DATA CONCLUSIONS: mp-MRI radiomics provides similar results to CT radiomics for early identification of pathologic response to neoadjuvant chemotherapy. The multimodal radiomics nomogram further improved the capability. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 2.

Efficacy and safety of anlotinib plus programmed death-1 blockade versus anlotinib monotherapy as second or further-line treatment in advanced esophageal squamous cell carcinoma: A retrospective study.

Background: Both anlotinib and programmed death-1 (PD-1) blockade have been approved for the second-line treatment of metastatic esophageal squamous cell carcinoma (ESCC). However, the combination of these two therapies has not been evaluated. This study investigated the efficacy and safety of anlotinib, a novel multitarget tyrosine kinase inhibitor targeting tumor angiogenesis, combined with PD-1 blockade as second or further-line treatment for advanced ESCC. Methods: Between January 2019 and February 2021, 98 advanced ESCC patients receiving anlotinib plus PD-1 blockade or anlotinib monotherapy as second or further-line treatment at Henan Cancer Hospital were retrospectively analyzed. Patients receiving anlotinib plus PD-1 blockade were grouped as cohort A (n=48), while those receiving anlotinib monotherapy were grouped as cohort B (n=50). The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR) and toxicity. Furthermore, independent prognostic factors were identified by Cox regression analysis. A two-sided p-value of <0.05 was considered statistically significant. Results: Data was collected until May 1, 2021, with a median follow-up time of 9.30 months (8.23-10.37 months) in cohort A and11.10months (7.82-14.38 months) in cohort B. For patients with advanced ESCC, cohort A resulted in significantly longer PFS (5.40 vs. 3.00 months, P<0.001) and higher DCR (71.7% vs. 47.9%, P=0.019) than cohort B. The ORR indicated no significant difference between cohort A (23.9%) and cohort B (10.4%) (P=0.082). Adverse reactions were mainly grade1/2 in the two groups. Compared with cohort B, a significantly higher rate of grade 1-2 hypothyroidism was observed in patients in cohort A (P= 0.034). Three patients (6.3%) developed grade 1/2 immune-related pneumonia. There was no significant difference in the incidence of grade 3-4 toxicities. Multivariable Cox regression analysis showed that the drug regimen (P<0.001), Eastern Cooperative Oncology Group Performance Status (P=0.002), distant organ metastasis (P=0.008), and metastatic sites (P=0.032) were independent prognostic factors for PFS. Conclusions: Anlotinib plus PD-1 blockade showed promising anti-tumor activity and manageable toxicity as second or further-line treatment of advanced ESCC.

Dynamic contrast-enhanced and diffusion-weighted MR imaging in early prediction of pathologic response to neoadjuvant chemotherapy in locally advanced gastric cancer.

PURPOSE: To investigate the efficacy of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the early prediction of the pathologic response to neoadjuvant chemotherapy (NAC) in patients with locally advanced gastric cancer (LAGC). METHODS: Fifty patients with LAGC who were treated with NAC followed by radical gastrectomy were enrolled. Uncontrasted and DCE-MRI were performed within 1 week before NAC. According to tumor regression grading (TRG), patients were labeled as responders (TRG = 0 + 1) and non-responders (TRG = 2 + 3). Apparent diffusion coefficients (ADC) and DCE-MRI kinetics (Ktrans, Ve, and Kep) were compared between the two groups. Logistic regression analysis was performed to screen independent factors to predict the NAC efficacy. The relationship between MRI parameters and TRG was studied by Spearman's correlation analysis. Receiver-operating characteristic curve analyses were applied to evaluate the efficacy. RESULTS: ADC, Ktrans, and Kep values were higher in responders than in non-responders (p < 0.05) and correlated with TRG (p < 0.05). The ADC and Kep values were independent markers for predicting TRG. The area under the curve, sensitivities, specificities of ADC, Ktrans, Kep, and ADC + Kep were 0.813, 0.699, 0.709, 0.886;73.64%, 65.54%, 63.21%, 70.37%; 86.47%, 54.97%, 79.47%, 95.65%; respectively. ADC + Kep demonstrated a higher efficacy than Ktrans and Kep (p = 0.012, 0.011), but without improvement compared with ADC (p > 0.05). CONCLUSION: Both DWI and DCE-MRI can effectively predict the pathologic response to NAC in LAGC. A combination of ADC and Kep increased the efficacy, and ADC is the most valuable imaging parameter.

The Biological and Molecular Function of LINC00665 in Human Cancers.

Long non-coding RNAs (lncRNAs) are more than 200 nucleotides in length and are implicated in the development of human cancers, without protein-coding function. Mounting evidence indicates that cancer initiation and progression are triggered by lncRNA dysregulation. Recently, a growing number of studies have found that LINC00665, a long intergenic non-protein coding RNA, may be associated with various cancers, including gastrointestinal tumors, gynecological tumors, and respiratory neoplasms. LINC00665 was reported to be significantly dysregulated in cancers and has an important clinical association. It participates in cell proliferation, migration, invasion, and apoptosis through different biological pathways. In this review, we summarize the current findings on LINC00665, including its biological roles and molecular mechanisms in various cancers. LINC00665 may be a potential prognostic biomarker and novel therapeutic target for cancers.

A high interferon gamma signature of CD8+ T cells predicts response to neoadjuvant immunotherapy plus chemotherapy in gastric cancer.

Background: While the tumor microenvironment (TME) affects immune checkpoint blockade (ICB) efficacy, ICB also reshapes the characteristics of TME. Thus far, studies have focused on the TME evolution during neoadjuvant or adjuvant ICB therapy in gastric cancer (GC). However, the interaction between TME characteristics and neoadjuvant immunotherapy plus chemotherapy remains to be elucidated. Methods: We performed single-cell RNA sequencing on ten GC specimens pre- and post-neoadjuvant camrelizumab plus mFOLFOX6 to determine the impact of the TME on the efficacy of the combination therapy and the remodeling of TME by the therapy. Results: A high baseline interferon gamma (IFN-γ) signature in CD8+ T cells predicts better responses to the combination therapy. We also observed that the IFN-γ signature significantly decreased in multiple cell types, and the exhausted signature of CD8+ T cells was significantly suppressed during the neoadjuvant therapy. Conclusions: Our data reveal interactions between the TME and neoadjuvant immunotherapy plus chemotherapy in GC. Importantly, it also highlights the signature of CD8+ T cells in predicting response to the combination therapy in GC.

Continuing Cetuximab vs Bevacizumab plus chemotherapy after first progression in wild-type KRAS, NRAS and BRAF V600E metastatic colorectal cancer: a randomized phase II trial.

To evaluate the clinical efficacy of continuing cetuximab vs bevacizumab plus chemotherapy crossover after first progression to cetuximab regimen in wild-type KRAS, NRAS and BRAF V600E mCRC, we conducted this prospective, open-label and randomized phase 2 trial in three cancer centers from Oct 1, 2016 to July 1, 2020. Eligibility criteria included documented progressive disease during or after first-line treatment with cetuximab regimen; second biopsy confirmed as KRAS, NRAS and BRAF V600E wild-type mCRC. Patients were randomized to arm A (cetuximab+chemo) or arm B (bevacizumab+chemo) with second-line chemotherapy crossover. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS) and toxicity. Tissue VEGFA, ERBB2 and MET mRNA were examined by real time RT-PCR. A total of 104 patients (53 in arm A and 51 in arm B) were enrolled. Median PFS was 7.7 months (95% CI: 6.5-8.9) for arm A and 6.3 months (95% CI: 4.5-8.1) for arm B (p=0.931). Median OS was 18.2 months (95% CI: 14.5-21.9) for arm A and 16.4 months (95% CI: 14.2-18.6) for arm B (p=0.339). The ORR was 28.3% and 19.6% in arm A and arm B (p=0.31), respectively. MET mRNA was highly expressed in the cetuximab-progressed tumors, but treatment responsiveness to cetuximab or bevacizumab in each arm was not correlated with the MET expression level. The results showed no significant difference in PFS, OS and ORR between the two arms, but a trend in favor of the cetuximab continuation plus chemotherapy crossover was examined in all end points. High expression of MET in cetuximab-progressed tumors may indicate an existence of MET-dependent tumor cell population.

Short-term outcomes of laparoscopic versus open proximal gastrectomy with double-tract reconstruction for Siewert type II and III adenocarcinoma of the esophagogastric junction: a retrospective observational study of consecutive patients.

BACKGROUND: To investigate the safety and merits of laparoscopic proximal gastrectomy with double-tract reconstruction (LPG-DT) for Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). METHODS: Retrospective analysis of the clinical data of 100 consecutive patients with Siewert II and III AEG treated at the Affiliated Tumor Hospital of Zhengzhou University from October 2010 to October 2019 was performed. Out of these patients, 69 underwent open proximal gastrectomy with double-tract reconstruction (OPG-DT), while 31 underwent LPG-DT. The clinicopathological characteristics, perioperative data, and short-term outcomes of the two groups were compared. A P value <0.05 was considered statistically significant. RESULTS: Males accounted for 87% of all patients. Lymph nodes (LNs) count, time to first meal, postoperative length of stay, and postoperative complications were similar between the OPG-DT and LPG-DT group. flatus time was significantly shorter in the LPG-DT group (P<0.05), while the duration of operation was significantly shorter in the the OPG-DT group (P<0.001). Furthermore, the LPG-DT group has less blood loss, shorter flatus time, and lower postoperative-day-5 white blood cell (WBC) count and C-reactive protein (CRP) levels (P<0.05). CONCLUSIONS: Although LPG-DT took longer to perform, its advantages of reduced blood loss and less surgical stress reflected on inflammatory markers supports an acceptable surgical option for Siewert II and III AEG.

Synergism of cisplatin-oleanolic acid co-loaded hybrid nanoparticles on gastric carcinoma cells for enhanced apoptosis and reversed multidrug resistance.

Combined administration of different drugs is a widely acknowledged approach for effective cancer therapy. However, the limited targeting, as well as inferior drug loading capacities of current drug delivery systems (DDS), are still the bottleneck for better performance in cancer treatment. Herein, we successfully developed a cancer cell membrane (CM) decorated calcium carbonate (CC) hybrid nanoparticles (HN) for the co-delivery of cisplatin (CDDP) and oleanolic acid (OA). The physicochemical property of HN/CDDP/OA was evaluated, which revealed that the as-prepared DDS was core-shell structured and well-dispersed nanoparticles with size around 100 nm. The HN/CDDP/OA showed high stability and biocompatibility with pH-responsive drug release. Moreover, the CM modification in HN also demonstrated highly elevated tumor-homing nature than bare CC. Finally, the feasibility of HN/CDDP/OA in the treatment of gastric cancer (MGC-803 cell line) was assessed. HN/CDDP/OA showed better performance than mono systems with enhanced apoptosis and capable of reversing multidrug resistance (MDR) of cancer cells.

PPM1D Functions as Oncogene and is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma.

Mounting evidence has demonstrated that PPM1D participates in the development and progression of a wide variety of tumors. However, its precise roles in esophageal squamous cell carcinoma (ESCC) remain under investigation. Here, UALCAN, an interactive web-portal to perform the expression analyses of PPM1D using TCGA gene expression data, and PPM1D high expression was exhibited in primary esophageal cancer. Further investigation revealed that PPM1D expression was obviously higher in ESCC tissues than in normal tissues (P < 0.01), which was consistent with the results from real-time qPCR and Western blotting in ESCC tissues and paired normal esophageal tissues. Besides, PPM1D expression was closely correlated with TNM staging, tumor differentiation and lymph node metastasis (P < 0.01), but not related to the patients' gender and age (P > 0.05). Notably, PPM1D expression in metastatic ESCC patients was markedly higher than that in non-metastatic ESCC patients (P < 0.01), and the ESCC patients with high PPM1D expression predicted poor prognosis. Multivariate assay demonstrated that PPM1D and lymph node metastasis were considered as independent prognostic factors for the ESCC patients. These findings suggest PPM1D plays a pivotal important role in onset and progression of ESCC, and may be a new biomarker for metastasis and prognosis of the ESCC patients.