Oncology
SLC2A3 is a Potential Factor for Head and Neck Squamous Cancer Development through Tumor Microenvironment Alteration
Tumor immunity has garnered increasing attention in cancer treatment and progression. However there is still a challenge in understanding the mechanisms of specific molecules affecting the clinical prognosis and tumor microenvironment (TME).
Here we applied the ESTIMATE algorithm to calculate the immune and stromal scores in 504 HNSC cases from TCGA. Patients were grouped according to the median value of the immune and stromal. Clinicopathological characteristics and differentially expressed genes (DEG) were analyzed. Subsequently LASSO COX regression survival analysis and clinicopathological characteristics were conducted. Subsequently SLC2A3 was determined as a predictive factor that high expression of SLC2A3 at the mRNA and protein levels predicted a worse clinical prognosis. GSEA25099 was utilized for external validation of immune infiltration while tissue PCR IHC and Western Blot were used to confirm the expression levels of SLC2A3.
A series of immune-infiltration analyses showed that SLC2A3 expression was negatively correlated with CD8+ T cells significantly affecting the survival prognosis of HNSC. In the GSEA analysis the high expression of SLC2A3 was mainly enriched for immune-related biological processes. Meanwhile high expression of SLC2A3 possessed higher TIDE scores and was also strongly positively correlated with a series of immune checkpoints affecting survival prognosis thus causing greater susceptibility to immune escape.
Conclusively SLC2A3 is a potential oncogene and factor of HNSC development notably by an altered state of the immune microenvironment immune-suppressive regulation and immune escape.
Significance of Ribonucleoside-diphosphate Reductase Subunit M2 in Lung Adenocarcinoma
The Ribonucleoside-diphosphate Reductase subunit M2 (RRM2) is known to be overexpressed in various cancers though its specific functional implications remain unclear. This aims to elucidate the role of RRM2 in the progression of Lung Adenocarcinoma (LUAD) by exploring its involvement and potential impact.
RRM2 data were sourced from multiple databases to assess its diagnostic and prognostic significance in LUAD. We evaluated the association between RRM2 expression and immune cell infiltration analyzed its function and explored the effects of modulating RRM2 expression on LUAD cell characteristics through laboratory experiments.
RRM2 was significantly upregulated in LUAD tissues and cells compared to normal counterparts (p < 0.05) with rare genetic alterations noted (approximately 2%). This overexpression clearly distinguished LUAD from normal tissue (area under the curve (AUC): 0.963 95% confidence intervals (CI): 0.946-0.981). Elevated RRM2 expression was significantly associated with adverse clinicopathological characteristics and poor prognosis in LUAD patients. Furthermore a positive association was observed between RRM2 expression and immune cell infiltration. Pathway analysis revealed a critical connection between RRM2 and the cell cycle signaling pathway within LUAD. Targeting RRM2 inhibition effectively suppressed LUAD cell proliferation migration and invasion while promoting apoptosis. This intervention also modified the expression of several crucial proteins including the downregulation of CDC25A CDC25C RAD1 Bcl-2 and PPM1D and the upregulation of TP53 and Bax (p < 0.05).
Our findings highlight the potential utility of RRM2 expression as a biomarker for diagnosing and predicting prognosis in LUAD shedding new light on the role of RRM2 in this malignancy.
Lipid-Based Nanocarriers for Targeted Gene Delivery in Lung Cancer Therapy: Exploring a Novel Therapeutic Paradigm
Lung cancer is a significant cause of cancer-related death worldwide. It can be broadly categorised into small-cell lung cancer (SCLC) and Non-small cell lung cancer (NSCLC). Surgical intervention radiation therapy and the administration of chemotherapeutic medications are among the current treatment modalities. However the application of chemotherapy may be limited in more advanced stages of metastasis due to the potential for adverse effects and a lack of cell selectivity. Although small-molecule anticancer treatments have demonstrated effectiveness they still face several challenges. The challenges at hand in this context comprise insufficient solubility in water limited bioavailability at specific sites adverse effects and the requirement for epidermal growth factor receptor inhibitors that are genetically tailored. Bio-macromolecular drugs including small interfering RNA (siRNA) and messenger RNA (mRNA) are susceptible to degradation when exposed to the bodily fluids of humans which can reduce stability and concentration. In this context nanoscale delivery technologies are utilised. These agents offer encouraging prospects for the preservation and regulation of pharmaceutical substances in addition to improving the solubility and stability of medications. Nanocarrier-based systems possess the notable advantage of facilitating accurate and sustained drug release as opposed to traditional systemic methodologies. The primary focus of scientific investigation has been to augment the therapeutic efficacy of nanoparticles composed of lipids. Numerous nanoscale drug delivery techniques have been implemented to treat various respiratory ailments such as lung cancer. These technologies have exhibited the potential to mitigate the limitations associated with conventional therapy. As an illustration applying nanocarriers may enhance the solubility of small-molecule anticancer drugs and prevent the degradation of bio-macromolecular drugs. Furthermore these devices can administer medications in a controlled and extended fashion thereby augmenting the therapeutic intervention's effectiveness and reducing adverse reactions. However despite these promising results challenges remain that must be addressed. Multiple factors necessitate consideration when contemplating the application of nanoparticles in medical interventions. To begin with the advancement of more efficient delivery methods is imperative. In addition a comprehensive investigation into the potential toxicity of nanoparticles is required. Finally additional research is needed to comprehend these treatments' enduring ramifications. Despite these challenges the field of nanomedicine demonstrates considerable promise in enhancing the therapy of lung cancer and other respiratory diseases.
Role of Non-coding RNAs on the Radiotherapy Sensitivity and Resistance in Cancer Cells
Radiotherapy (RT) is an integral part of treatment management in cancer patients. However one of the limitations of this treatment method is the resistance of cancer cells to radiotherapy. These restrictions necessitate the introduction of modalities for the radiosensitization of cancer cells. It has been shown that Noncoding RNAs (ncRNAs) along with modifiers can act as radiosensitivity and radioresistant regulators in a variety of cancers by affecting double strand break (DSB) wnt signaling glycolysis irradiation induced apoptosis ferroptosis and cell autophagy. This review will provide an overview of the latest research on the roles and regulatory mechanisms of ncRNA after RT in in vitro and preclinical researches.
Theranostic Potential of Bacteriophages against Oral Squamous Cell Carcinoma
Oral Squamous Cell Carcinoma (OSCC) is a widespread and challenging disease that accounts for 94% of cancers of the oral cavity worldwide. Bacteriophages (phages) have shown promise as a potential theranostic agent for the treatment of OSCC. It may offer advantages in overcoming the challenges of conventional methods. Modern high-throughput pyrosequencing techniques confirm the presence of specific bacterial strains associated with OSCC. Bio-panning and filamentous phages facilitate visualization of the peptide on surfaces and show high affinity in OSCC cells. The peptide has the potential to bind integrin (αvβ6) aid in diagnosis and inhibit the proliferation of OSCC cells. Mimotopes of tumor-associated antigens show cytotoxic and immune responses against cancer cells. Biomarker-based approaches such as transferrin enable early OSCC diagnosis. A modified temperate phage introduces CRISPR-Cas3 to target antimicrobial-resistant bacteria associated with OSCC. The research findings highlight the evolving field of phage diagnostics and therapy and represent a new avenue for non-invasive targeted approaches to the detection and treatment of OSCC. However extensive clinical research is required to validate the efficacy of phages in innovative cancer theranostic strategies.
Single-cell and Bulk Transcriptomic Analyses Reveal a Stemness and Circadian Rhythm Disturbance-related Signature Predicting Clinical Outcome and Immunotherapy Response in Hepatocellular Carcinoma
Investigating the impact of stemness-related circadian rhythm disruption (SCRD) on hepatocellular carcinoma (HCC) prognosis and its potential as a predictor for immunotherapy response.
Circadian disruption has been linked to tumor progression through its effect on the stemness of cancer cells.
Develop a novel signature for SCRD to accurately predict clinical outcomes and immune therapy response in patients with HCC.
The stemness degree of patients with HCC was assessed based on the stemness index (mRNAsi). The co-expression circadian genes significantly correlated with mRNAsi were identified and defined as stemness- and circadian-related genes (SCRGs). The SCRD scores of samples and cells were calculated based on the SCRGs. Differentially expressed genes with a prognostic value between distinct SCRD groups were identified in bulk and single-cell datasets to develop an SCRD signature.
A higher SCRD score indicates a worse patient survival rate. Analysis of the tumor microenvironment revealed a significant correlation between SCRD and infiltrating immune cells. Heterogeneous expression patterns functional states genomic variants and cell-cell interactions between two SCRD populations were revealed by transcriptomic genomic and interaction analyses. The robust SCRD signature for predicting immunotherapy response and prognosis in patients with HCC was developed and validated in multiple independent cohorts.
In summary distinct tumor immune microenvironment patterns were confirmed under SCRD in bulk and single-cell transcriptomic and SCRD signature associated with clinical outcomes and immunotherapy response was developed and validated in HCC.
Comprehensive Pan-cancer Analysis of CMPK2 as Biomarker and Prognostic Indicator for Immunotherapy
UMP-CMP kinase 2 (CMPK2) is involved in mitochondrial DNA synthesis which can be oxidized and released into the cytoplasm in innate immunity. It initiates the assembly of NLRP3 inflammasomes and mediates various pathological processes such as human immunodeficiency virus infection and systemic lupus erythematosus. However the role of CMPK2 in tumor progression and tumor immunity remains unclear.
We identified CMPK2 expression patterns in the Genotype Tissue-Expression (GTEx) The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) databases. Validation was performed using immunohistochemical staining data from the Human Protein Atlas (HPA) database and qPCR experiments. Receiver operating characteristic curve analysis and Kaplan-Meier survival analysis were conducted to assess the clinical relevance of CMPK2 expression. The Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) algorithm and the Tumor IMmune Estimation Resource (TIMER) database were used to evaluate the correlation between CMPK2 and immune infiltration in tumors. The Tumor Immune Syngeneic Mouse (TISMO) database and other public datasets were utilized to assess the impact of CMPK2 on immune therapy response. MEXPRESS and MethSurv databases were employed to investigate the effects of methylation on CMPK2 expression.
CMPK2 expression was elevated in 23 cancers and decreased in two cancers. Furthermore CMPK2 expression had a high diagnostic value for 16 cancers. Elevated CMPK2 expression was associated with lower overall survival (OS) disease-specific survival (DSS) and progression-free interval (PFI) in four cancers. Immune microenvironment-related analysis revealed strong associations between CMPK2 expression and immune cell infiltration as well as immune checkpoint expression across various tumors. Notably in four mouse immunotherapy cohorts CMPK2 expression in treated mouse tumors was higher post-treatment. In five clinical immunotherapy cohorts patients with high CMPK2 expression show better responses to immunotherapy. Moreover the methylation level of CMPK2 gene was closely correlated to its expression and tumor prognosis. Among these cancers the clinical and immunological indications of skin cutaneous melanoma (SKCM) are particularly closely related to CMPK2 expression.
Our analysis preliminarily describes the complex function of CMPK2 in cancer progression and immune microenvironment highlighting its potential as a diagnostic and therapeutic target for immunotherapy.
The HGF/Met Receptor Mediates Cytotoxic Effect of Bacterial Cyclodipeptides in Human Cervical Cancer Cells
Human cervix adenocarcinoma (CC) caused by papillomavirus is the third most common cancer among female malignant tumors. Bioactive compounds such as cyclodipeptides (CDPs) possess cytotoxic effects in human cervical cancer HeLa cells mainly by blocking the PI3K/Akt/mTOR pathway and subsequently inducing gene expression by countless transcription regulators. However the upstream elements of signaling pathways have not been well studied.
To elucidate the cytotoxic and antiproliferative responses of the HeLa cell line to CDPs by a transcriptomic analysis previously carried out we identified by immunochemical analyses differential expression of genes related to the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/MET) receptors. Furthermore molecular docking was carried out to evaluate the interactions of CDPs with the EGF and MET substrate binding sites.
Immunochemical and molecular docking analyses suggest that the HGF/MET receptor participation in CDPs cytotoxic effect was independent of the protein expression levels. However protein modulation of downstream Met-targets occurred due to the inhibition of phosphorylation of the HGF/MET receptor. Results suggest that the antiproliferative and cytotoxicity of CDPs in HeLa cells involve the HGF/MET receptor upstream of PI3K/Akt/mTOR pathway; assays with the human breast cancer MCF-7 and MDA-MB-231cell lines supported the finding.
Data provide new insights into the molecular mechanisms involved in CDPs cytotoxicity and antiproliferative effects suggesting that the signal transduction mechanism may be related to the inhibition of the phosphorylation of the EGF/MET receptor at the level of substrate binding site by an inhibition mechanism similar to that of Gefitinib and Foretinib anti-neoplastic drugs.
Solid CaCO3 Formation in Glioblastoma Multiforme and its Treatment with Ultra-Nanoparticulated NPt-Bionanocatalysts
Glioblastoma multiforme (GBM) the most prevalent form of central nervous system (CNS) cancer stands as a highly aggressive glioma deemed virtually incurable according to the World Health Organization (WHO) standards with survival rates typically falling between 6 to 18 months. Despite concerted efforts advancements in survival rates have been elusive. Recent cutting-edge research has unveiled bionanocatalysts with 1% Pt demonstrating unparalleled selectivity in cleaving C-C C-N and C-O bonds within DNA in malignant cells. The application of these nanoparticles has yielded promising outcomes.
The objective of this study is to employ bionanocatalysts for the treatment of Glioblastoma Multiforme (GBM) in a patient followed by the evaluation of obtained tissues through electronic microscopy.
Bionanocatalysts were synthesized using established protocols. These catalysts were then surgically implanted into the GBM tissue through stereotaxic procedures. Subsequently tissue samples were extracted from the patient and meticulously examined using Scanning Electron Microscopy (SEM).
Detailed examination of biopsies via SEM unveiled a complex network of small capillaries branching from a central vessel accompanied by a significant presence of solid carbonate formations. Remarkably the patient subjected to this innovative approach exhibited a three-year extension in survival highlighting the potential efficacy of bionanocatalysts in combating GBM and its metastases.
Bionanocatalysts demonstrate promise as a viable treatment option for severe cases of GBM. Additionally the identification of solid calcium carbonate formations may serve as a diagnostic marker not only for GBM but also for other CNS pathologies.
Tumor-Activated Neutrophils Promote Lung Cancer Progression through the IL-8/PD-L1 Pathway
Lung cancer remains a major global health threat due to its complex microenvironment particularly the role of neutrophils which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer progression.
Employing in vitro experimental models this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-γ secretion apoptosis PD-L1 expression and T-cell proliferation by using techniques such as ELISA flow cytometry immunofluorescence and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and PD-L1.
Lung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils increased PD-L1 expression and suppressed T-cell proliferation and IFN-γ secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS) while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell proliferation.
This study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors such as IL-8 thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.
Mitochondrial Deoxyguanosine Kinase Induces 5-Fluorouracil Chemotherapy Sensitivity through Autophagy
The purpose of this study was to investigate the role of DGUOK in the progression of colorectal cancer (CRC) and its impact on the sensitivity of CRC cells to 5-FU treatment.
We conducted bioinformatics analysis and qRT-PCR to evaluate DGUOK expression in CRC tissues/cells. Cell viability of CRC cells treated with 5-FU was assessed using CCK-8 and colony formation assays. Autophagy levels were determined through immunofluorescence assays and Western blot analysis. Additionally the influence of p-p38 on autophagy was investigated via Western blotting. A rescue assay was performed to confirm whether DGUOK/p38 affects 5-FU sensitivity in CRC cells through autophagy.
Our findings indicate that DGUOK is upregulated in CRC tissues compared to normal tissues correlating with increased cell proliferation and migration. Functionally inhibition of DGUOK enhances autophagy thereby decreasing the sensitivity of CRC cells to 5-FU. This effect is partly mediated by DGUOK's impact on the mitogen-activated protein kinase (MAPK) pathway specifically promoting the phosphorylation of p38 MAPK a crucial regulator in autophagy pathways.
These results suggest that DGUOK could serve as a novel marker for predicting the efficacy of 5-FU in CRC treatment.
L-lysine Increases the Anticancer Effect of Doxorubicin in Breast Cancer by Inducing ROS-dependent Autophagy
Doxorubicin (DOX) is a chemotherapy drug that is widely used in cancer therapy especially in Triple-Negative Breast Cancer (TNBC) patients. Nevertheless cytoprotective autophagy induction by DOX limits its cytotoxic effect and drug resistance induction in patients. Therefore finding a new way is essential for increasing the effectiveness of this drug for cancer treatment.
This study aimed to investigate the effect of L-lysine on DOX cytotoxicity probably through autophagy modulation in TNBC cell lines.
We used two TNBC cell lines MDA-MB-231 and MDA-MB-468 with various levels of autophagy activity. Cell viability after treatment with L-lysine alone and in combination therapy was evaluated by MTT assay. Reactive Oxygen Species (ROS) nitric oxide (NO) concentration and arginase activity were assessed using flow cytometric analysis Griess reaction and arginase activity assay kit respectively. Real-time PCR and western blot analysis were used to evaluate the L-lysine effect on the autophagy-related genes and protein expression. Cell cycle profile and apoptotic assay were performed using flow cytometric analysis.
The obtained data indicated that L-lysine in both concentrations of 24 and 32 mM increased the autophagy flux and enhanced the DOX cytotoxicity especially in MDA-MB-231 which demonstrated higher autophagy activity than MDA-MB-468 by inducing ROS and NO production. Furthermore L-lysine induced G2/M arrest autophagy cell death while significant apoptotic changes were not observed.
These findings suggest that L-lysine can increase DOX cytotoxicity through autophagy modulation. Thus L-lysine in combination with DOX may facilitate the development of novel adjunct therapy for cancer.
Low Expression MCEMP1 Promotes Lung Adenocarcinoma Progression and its Clinical Value
Lung cancer is a highly prevalent tumor with a lack of biological markers that reflect its progression. Mast cell surface membrane protein 1 (MCEMP1 also known as C19ORF59) has not been reported in lung adenocarcinoma (LUAD).
We aimed to investigate the role of MCEMP1 in LUAD.
MCEMP1 expression in LUAD was analyzed using The Cancer Genome Atlas (TCGA) data and conducted univariate and multivariate Cox regression analyses to evaluate the prognostic significance of MCEMP1 expression in TCGA. Tumor Immune Estimation Resource (TIMER) was used for examining the correlation between MCEMP1 expression and immune cell infiltration in LUAD. Furthermore proliferation migration invasion and colony-forming ability were investigated using LUAD cell lines.
MCEMP1 expression in LUAD patient tissues and was correlated with lymph node metastasis differentiation level and tumor status. The Area under Curve (AUC) value of MCEMP1 for the Receiver Operating Characteristic (ROC) curve analysis was 0.984. The immune infiltration analysis revealed a correlation between MCEMP1 expression and the extent of macrophages and neutrophil infiltration in LUAD. Additionally MCEMP1 has low expression in clinical samples MCEMP1 overexpressed in LUAD cells substantially reduced cell growth migration and invasion of malignant cells.
Low expression MCEMP1 promotes LUAD progression which provides new insights and a potential biological target for future LUAD therapies.
The Necroptotic Process-related Signature Predicts Immune Infiltration and Drug Sensitivity in Kidney Renal Papillary Cell Carcinoma
It remains controversial whether the current subtypes of kidney renal papillary cell carcinoma (KIRP) can be used to predict the prognosis independently.
This observational study aimed to identify a risk signature based on necroptotic process-related genes (NPRGs) in KIRP.
In the training cohort LASSO regression was applied to construct the risk signature from 158 NPRGs followed by the analysis of Overall Survival (OS) using the Kaplan-Meier method. The signature accuracy was evaluated by the Receiver Operating Characteristic (ROC) curve which was further validated by the test cohort. Wilcoxon test was used to compare the expressions of immune-related genes neoantigen genes and immune infiltration between different risk groups while the correlation test was performed between NPRGs expressions and drug sensitivity. Gene set enrichment analysis was used to investigate the NPRGs' signature’s biological functions.
We finally screened out 4-NPRGs (BIRC3 CAMK2B PYGM and TRADD) for constructing the risk signature with the area under the ROC curve (AUC) reaching about 0.8. The risk score could be used as an independent OS predictor. Consistent with the enriched signaling the NPRGs signature was found to be closely associated with neoantigen immune cell infiltration and immune-related functions. Based on NPRGs expressions we also predicted multiple drugs potentially sensitive or resistant to treatment.
The novel 4-NPRGs risk signature can predict the prognosis immune infiltration and therapeutic sensitivity of KIRP.
Corrigendum To: PIWIL1 Promotes Malignant Progression of Papillary Thyroid Carcinoma by Inducing EVA1A Expression
Applications of L-Arginine in Pregnancy and Beyond: An Emerging Pharmacogenomic Approach
L-arginine is a semi-essential amino acid that plays a critical role in various physiological processes such as protein synthesis wound healing immune function and cardiovascular regulation. The use of L-arginine in pregnancy has been an emerging topic in the field of pharmacogenomics. L-arginine an amino acid plays a crucial role in the production of nitric oxide which is necessary for proper placental development and fetal growth. Studies have shown that L-arginine supplementation during pregnancy can have positive effects on fetal growth maternal blood pressure and the prevention of preeclampsia. This emerging pharmacogenomic approach involves using genetic information to personalize L-arginine dosages for pregnant women based on their specific genetic makeup. By doing so it may be possible to optimize the benefits of L-arginine supplementation during pregnancy and improve pregnancy outcomes. This paper emphasizes the potential applications of L-arginine in pregnancy and the use of pharmacogenomic approaches to enhance its effectiveness. Nonetheless the emerging pharmacogenomic approach to the application of L-arginine offers exciting prospects for the development of novel therapies for a wide range of diseases.
Development of Cell and Gene Therapies for Clinical Use in the US and EU: Summary of Regulatory Guidelines
Recent decades have seen advancements in the management and treatment of difficult- to-treat diseases such as cancer. A special class of therapeutics called cell and gene therapy has been introduced in the past 10 years. Cell and gene therapy products have strengthened the treatment options for life-threatening diseases with unmet clinical needs and also provided the possibility of a potential cure for the disease in some of the patients. Cell and gene therapy products are gaining recognition and the interest in clinical development of cell and gene therapy products is increasing. Moreover as the class of cell and gene therapy products is relatively new there is a limited regulatory experience in the development and the developers of the cell and gene therapy products can often be puzzled with an array of questions on regulations. The current review intends to provide a basic understanding of regulatory guidelines from the FDA and EMA that are applicable to cell and gene therapy products. Essentials such as which office is responsible for the evaluation of applications which regulatory class/pathway is appropriate for development and what are the quality nonclinical and clinical studies that are needed to support the application are discussed in the article. In addition a summary of regulatory designations and the post-approval requirements such as Risk Evaluation and Mitigation Strategies (REMS) and long-term follow-up is included in the article. Developers (referred to as ‘sponsors’ in this article) of cell and gene therapies can use the respective guidance documents and other specific review articles cited in this review for detailed information on the topics.
HCST Expression Distinguishes Immune-hot and Immune-cold Subtypes in Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent malignancy of the pancreas and the incidence of this disease is approximately equivalent to the mortality rate. Immunotherapy has made a remarkable breakthrough in numerous cancers while its efficacy in PDAC remains limited due to the immunosuppressive microenvironment. Immunotherapy efficacy is highly correlated with the abundance of immune cells particularly cytotoxic T cells. Therefore molecular classifier is needed to identify relatively hot tumors that may benefit from immunotherapy.
In this study we carried out a transcriptome analysis of 145 pancreatic tumors to define the underlying immune regulatory mechanism driving the PDAC immunosuppressive microenvironment. The immune subtype was identified by consensus clustering and the underlying PDAC immune activation mechanism was thoroughly examined using single sample gene set enrichment analysis (ssGSEA). Area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to assess the accuracy of the molecular classifier in differentiating immunological subgroups of PDAC.5
The protein level of molecular classifier was verified by immunohistochemistry in human PDAC tissue. Immune-hot tumors displayed higher levels of immune cell infiltration and immune checkpoint in line with enriched immune escape pathways. Hematopoietic cell signal transducer (HCST) a molecular classifier used to differentiate immunological subtypes of PDAC has shown a substantial link with the expression levels of cytotoxic markers such as CD8A and CD8B. At the single cell level we found that HCST was predominantly expressed in CD8T cells. By immunohistochemistry and survival analysis we further demonstrated the prognostic value of HCST in PDAC.
We identified HCST as a molecular classifier to distinguish PDAC immune subtypes which may be useful for early diagnosis and targeted therapy of PDAC.
Efficacy and Safety of Pembrolizumab Monotherapy or Combined Therapy in Patients with Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Metastatic Triple-negative Breast Cancer (mTNBC) is the most aggressive form of breast cancer with a greater risk of metastasis and recurrence. Research studies have published in-depth analyses of the advantages and disadvantages of pembrolizumab and early data from numerous trials suggests that patients with mTNBC have had remarkable outcomes. This meta-analysis compares the data from numerous relevant studies in order to evaluate the safety and efficacy of pembrolizumab monotherapy or combination therapies for mTNBC.
To identify eligible RCTs a thorough literature search was carried out using electronic databases. CMA software was utilized to perform heterogeneity tests using fixed and random-effects models.
According to our pooled data the median Progression-free Survival (PFS) was 2.66 months and the median overall survival (OS) was 12.26 months. Furthermore by comparing efficacy indicators between PD-L1–positive and PD-L1–negative groups a correlation was found between the overexpression of PD-L1 with OS PFS and ORR. Patients with PD-L1-positive tumors had a higher response rate with an ORR of 21.1% compared to the patients with PD-L1-negative tumors. The ORR for first-line immunotherapy was higher than that of ≥second-line immunotherapy. In addition pembrolizumab plus combination treatment resulted in a pooled incidence of immune-related adverse events of 22.7%.
A modest response to pembrolizumab monotherapy was detected in the mTNBC patients. Furthermore a better outcome from pembrolizumab treatment may be predicted by PD-L1-positive status non-liver/lung metastases combination therapy and first-line immunotherapy. Pembrolizumab in combination with chemotherapy may be more beneficial for patients whose tumors are PD-L1 positive.
Evolution of Prime Editing Systems: Move Forward to the Treatment of Hereditary Diseases
The development of gene therapy using genome editing tools recently became relevant. With the invention of programmable nucleases it became possible to treat hereditary diseases due to introducing targeted double strand break in the genome followed by homology directed repair (HDR) or non-homologous end-joining (NHEJ) reparation. CRISPR-Cas9 is more efficient and easier to use in comparison with other programmable nucleases. To improve the efficiency and safety of this gene editing tool various modifications CRISPR-Cas9 basis were created in recent years such as prime editing – in this system Cas9 nickase is fused with reverse transcriptase and guide RNA which contains a desired correction. Prime editing demonstrates equal or higher correction efficiency as HDR-mediated editing and much less off-target effect due to inducing nick. There are several studies in which prime editing is used to correct mutations in which researchers reported little or no evidence of off-target effects. The system can also be used to functionally characterize disease variants. However prime editing still has several limitations that could be further improved. The effectiveness of the method is not yet high enough to apply it in clinical trials. Delivery of prime editors is also a big challenge due to their size. In the present article we observe the development of the platform and discuss the candidate proteins for efficiency enhancing main delivery methods and current applications of prime editing.