Biology
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.
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.
Gene Therapy for Skin Aging
Extrinsic and intrinsic factors contribute to skin aging; nonetheless they are intertwined. Moreover intrinsic skin aging mirrors age-related declines in the entire human body's internal organs. There is evidence that skin appearance is an indicator of the general health of somebody or a visual certificate of health. Earlier it was apparent that the intrinsic factors are unalterable but the sparkling of skin aging gene therapy on the horizon is changing this narrative. Skin aging gene therapy offers tools for skin rejuvenation natural beauty restoration and therapy for diseases affecting the entire skin. However skin aging gene therapy is an arduous and sophisticated task relying on precise interim stimulation of telomerase to extend telomeres and wend back the biological clock in the hopes to find the fountain of youth while preserving cells innate biological features. Finding the hidden fountain of youth will be a remarkable discovery for promoting aesthetics medicine genecosmetics and healthy aging. Caloric restriction offers ultimate health benefits and a reproducible way to promote longevity in mammals while delaying age-related diseases. Moreover exercise further enhances these health benefits. This article highlights the potential of skin aging gene therapy and foretells the emerging dawn of the genecosmetics era.
Advancements in CRISPR-Based Therapies for Genetic Modulation in Neurodegenerative Disorders
Neurodegenerative disorders pose significant challenges in the realm of healthcare as these conditions manifest in complex multifaceted ways often attributed to genetic anomalies. With the emergence of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology a new frontier has been unveiled in the quest for targeted precise genetic manipulation. This abstract explores the recent advancements and potential applications of CRISPR-based therapies in addressing genetic components contributing to various neurodegenerative disorders. The review delves into the foundational principles of CRISPR technology highlighting its unparalleled ability to edit genetic sequences with unprecedented precision. In addition it talks about the latest progress in using CRISPR to target specific genetic mutations linked to neurodegenerative diseases like Huntington's disease Alzheimer's disease amyotrophic lateral sclerosis (ALS) and Parkinson's disease. It talks about the most important studies and trials that show how well and safely CRISPR-based therapies work. This shows how this technology can change genetic variants that cause diseases. Notably the discussion emphasizes the challenges and ethical considerations associated with the implementation of CRISPR in clinical settings including off-target effects delivery methods and long-term implications. Furthermore the article explores the prospects and potential hurdles in the widespread application of CRISPR technology for treating neurodegenerative disorders. It touches upon the need for continued research improved delivery mechanisms and ethical frameworks to ensure responsible and equitable access to these groundbreaking therapies.
Human Umbilical Cord Mesenchymal Stem Cells Alleviate Chronic Salpingitis by Modulating Macrophage-Associated Inflammatory Factors
Introduction: Mesenchymal stem cells (MSCs) have been widely studied because of their established anti-inflammatory properties. During chronic salpingitis (CS) infiltrated macrophages have vital roles in inflammation and tissue remodeling. Methods: We employed the type of MSCs human umbilical cord (huc) MSCs in an experimental CS model and therapeutic efficacy was assessed. hucMSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hucMSCs on the macrophage macrophage line RAW264.7 markers were analyzed under LPS stimulation with or without co-culturing with hucMSCs for 12h and 24h. In addition flow cytometry analysis was applied to reveal the interaction of co-culture. For animal studies CS was induced by the MoPn strain Chlamydia trachomatis (CT) hucMSCs were intravaginally injected in the CS and we analyzed the infiltrated macrophage by immunofluorescence. Results: We found the markers IL-10 was markedly increased and IL-1β caspase-1 was notably downregulated after co-culturing with hucMSCs by RT-PCR. hucMSCs promote macrophage line RAW264.7 apoptosis. We also found that hucMSCs treatment can alleviate CS by decreasing the mRNA expression of IL-1β caspase-1 and MCP-1 in the tubal tissue by RT-PCR and decreasing the protein expression of IL-1β caspase-1 and TGF-β by western blotting. Conclusion: These results suggest that macrophage function may be related to the immune-modulating characteristics of hucMSCs that contribute to CS.
Enhancing the Regenerative Potential of Adipose-Derived Mesenchymal Stem Cells Through TLR4-Mediated Signaling
Introduction: Toll-like receptor 4 (TLR4) is a receptor that traditionally plays an important role in immunomodulation (regulation of the immune system) and the initiation of proinflammatory responses. TLR4 is used in the body to recognize molecular patterns of pathogens or damaged cells from outside. However in recent years it has also become clear that TLR4 can affect the immune system and the function of stem cells especially mesenchymal stem cells. Therefore understanding how TLR4 signaling works at the cellular and molecular level and using this knowledge in regenerative medicine could be potentially useful especially in the treatment of adipose- derived mesenchymal stem cells (ADMSCs). How these cells can use TLR4 signaling when used to increase their regenerative potential and repair tissues is an area of research. Aims: This study aims to elucidate the multifaceted role of TLR4-mediated signaling in ADMSCs. Methods: Employing a comprehensive set of assays including MTT for cell viability flow cytometry for surface marker expression and gene expression analysis we demonstrate that TLR4 activation significantly modulates key aspects of ADMSC biology. Specifically TLR4 signaling was found to regulate ADMSCs proliferation surface marker expression and regenerative capacity in a dose- and time-dependent manner. Furthermore TLR4 activation conferred cytoprotective effects against Doxorubicin (DOX)-induced cellular apoptosis. Results: These findings suggest that TLR4 signaling could be used to enhance the regenerative abilities of ADMSCs and enable ADMSC-based therapies to be used more effectively for tissue engineering and therapeutic purposes. Conclusion: However it is important to note that research in this area needs more details and clinical studies.
Enhancing Spermatogenesis in Non-obstructive Azoospermia Through Mesenchymal Stem Cell Therapy22
Stem cells hold great promise as novel and encouraging therapeutic tools in the treatment of degenerative disorders due to their differentiation potential while maintaining the capability to self-renewal and their unlimited ability to divide and regenerate tissue. A variety of different types of stem cells can be used in cell therapy. Among these mesenchymal stem cell (MSC) therapy has gradually established itself as a novel method for treating damaged tissues that need restoration and renewal. Male infertility is an important health challenge affecting approximately 8-12% of people around the world. This abnormality can be caused by primary congenital acquired or idiopathic reasons. Men with no sperm in their semen have a condition called azoospermia caused by non-obstructive (NOA) causes and post-testicular obstructive causes. Accumulating evidence has shown that various types of MSCs can differentiate into germ cells and improve spermatogenesis in the seminiferous tubules of animal models. In addition recent studies in animal models have exhibited that extracellular vesicles derived from MSCs can stimulate the progression of spermatogenesis and germ cell regeneration in the recipient testes. In spite of the fact that various improvements have been made in the treatment of azoospermia disorder in animal models by MSC or their extracellular vesicles no clinical trials have been carried out to test their therapeutic effect on the NOA. In this review we summarize the potential of MSC transplantation for treating infertility caused by NOA.
Evaluation of Pancreatic β-cell Differentiation Efficiency of Human iPSC Lines for Clinical Use2212
Background: Transplantation of pancreatic β-cells generated from human induced pluripotent stem cells (hiPSCs) has great potential as a root treatment for type 1 diabetes. However their current level of efficiency to differentiate into β-cells is still not at par for clinical use. Previous research has shown that differentiation efficiency varies among human embryonic stem cells and mouse-induced pluripotent stem cell lines. Therefore selecting a suitable cell line for efficient induction into desired tissues and organs is crucial. Methods: In this study we have evaluated the efficiency of 15 hiPSC lines available for clinical use to differentiate into pancreatic β-cells. Results: Our investigation has revealed induction efficiency to differ among the hiPSC lines even when derived from the same donor. Among the hiPSC lines tested the 16A01 cell line exhibited the highest Insulin expression and low Glucagon expression suggesting that this cell line is suitable for differentiation into β-cells. Conclusion: Our study has demonstrated the importance of selecting a suitable hiPSC line for effective differentiation into β-cells.
Mechanisms of Stem Cells and Their Secreted Exosomes in the Treatment of Autoimmune Diseases
Stem cells play a therapeutic role in many diseases by virtue of their strong self-renewal and differentiation abilities especially in the treatment of autoimmune diseases. At present the mechanism of the stem cell treatment of autoimmune diseases mainly relies on their immune regulation ability regulating the number and function of auxiliary cells anti-inflammatory factors and proinflammatory factors in patients to reduce inflammation. On the other hand the stem cell- derived secretory body has weak immunogenicity and low molecular weight can target the site of injury and can extend the length of its active time in the patient after combining it with the composite material. Therefore the role of secretory bodies in the stem cell treatment of autoimmune diseases is increasingly important.