Human Malignancies Research Articles

Association of interleukin-17A and chemokine/vascular endothelial growth factor-induced angiogenesis in newly diagnosed patients with bladder cancer

BackgroundThe human interleukin-17 (IL-17) family comprises IL-17A to IL-17 F; their receptors are IL-17RA to IL-17RE. Evidence revealed that these cytokines can have a tumor-supportive or anti-tumor impact on human malignancies. The purpose of this study was to assess the expression of CXCR2, IL-17RA, and IL-17RC genes at the mRNA level as well as tissue and serum levels of IL-17A, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) in patients with bladder cancer (BC) compared to control.ResultsThis study showed that gene expression of IL-17RA, IL-17RC, and CXCR2 in the tumoral tissue of BC patients was significantly upregulated compared with normal tissue. The findings disclosed a significant difference in the serum and tissue concentrations of IL-17A, VEGF, and TGF-β between the patient and the control groups, as well as tumor and normal tissues.ConclusionThis study reveals notable dysregulation of CXCR2, IL-17RA, and IL-17RC genes, alongside changes in IL-17A, VEGF, and TGF-β levels in patients with BC than in controls. These findings indicate their possible involvement in BC development and their potential as diagnostic and therapeutic targets.

Computational Analysis of Single Nucleotide Polymorphisms in Human HIC1 Gene.

Background A putative tumor suppressor gene called HIC1 (hypermethylated in cancer) is situated at 17p13.3, a locus where the allelic loss occurs often in human malignancies, including breast cancer. Hypermethylated in cancer 1 protein is a protein that in humans is encoded by the HIC1 gene and it's aHomo sapiens(Human). This gene functions as a growth regulatory and tumor repressor gene. The molecular function of HIC1 gene includes DNA-binding transcription factor activity, sequence-specific DNA binding, DNA binding, histone deacetylase binding, protein binding, metal ion binding, nucleic acid binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription factor activity, RNA polymerase II-specific. The biological process of HIC1 gene includes multicellular organism development, negative regulation of Wnt signaling pathway, positive regulation of DNA damage response, signal transduction by p53 class mediator regulation of transcription, DNA-templated, negative regulation of transcription by RNA polymerase II, Wnt signaling pathway, transcription, DNA-templated, intrinsic apoptotic signaling pathway in response to DNA damage, cellular response to DNA damage stimulus. The study aimed to predict the stability and structure of the protein that will arise from single nucleotide polymorphisms (SNPs) in the human HIC1 gene. Methodology To investigate the possible negative effects associated with these SNPs, bioinformatic analysis is typically essential. The following tools were employed for forecasting harmful SNPs: scale-invariant feature transform (SIFT), Protein Analysis Through Evolutionary Relationships (PANTHER), nonsynonymous SNP by Protein Variation Effect Analyzer (PROVEAN), and nonsynonymous SNP by Single Nucleotide Polymorphism Annotation Platform (SNAP). Results The present study identified a total of 36 SNPs using the SIFT approach, which were shown to have functional significance. Twenty-six were determined to be tolerable, whereas 10 were shown to be detrimental. Out of 20 SNPs, seven (P370A, P646S, R654P, A476T, S400S, D666N, D7V) SNPs were predicted as "Possibly damaging" and seven (L9F, G468R, G490R, L482R, S12W, G489D, S12P) were identified as "probably benign", and six (R725G, G620S, A56V, E463D, D394N, L338V) were identified as "probably damaging" according to the predictions made by PANTHER tools. The majority of the pixels on the strip were red, indicating that the gene changes may have dangerous consequences. These results highlight the need for more research to fully comprehend how these mutations affect the hic1 protein's function, which is essential for the emergence of different types of cancer. Conclusion The current research has provided us with essential information about how SNPs might be used as a diagnostic marker for cancer, given that SNPs may be candidates for cellular changes caused by mutations linked to cancer.

Mucin 1 and venous thrombosis in tumor-bearing mice and patients with cancer

IntroductionMucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer. Materials and methodsWe used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism. Results and discussionMUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer.

Cancer immunity by tissue-resident type 1 innate lymphoid cells and killer innate-like T cells.

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.

MiR-122-IGF-1R signaling allied through the dysregulated lncRNA MALAT-1 expression in gastric carcinoma

MALAT-1 is extremely elevated in human malignancies thus functions as a prognostic biomarker. Nevertheless, limited data has been discovered concerning MALAT's contribution in stomach cancer. MALAT-1 expression appeared considerably greater in gastric cancer (GC) rats with remote miR-122-IGF-1R impact. MALAT-1 depletion inhibited cell cycle development, cell division and invasion, thus boosting death of GC cells. Likewise, miR-122-IGF-1R expression was linked to MALAT-1 deregulations in GC. Biological markers discovery based on biochemical data alongside detailed genome study might enhance prognosis, diagnosis and therapeutic compliance. This article summed up the most recent developments and techniques in GC biomarkers and may have applications for early detection, precise estimation of treatment strategies, and future perspectives according to molecular classification and profiling. In rats, GC was induced by 20-MCA, followed by DOX, Liposomal DOX, and PEGylated-Dox treatment. In addition to histopathological examinations, GC tumor biomarkers such as CEA, CA12–5, KRAS, AKT, PTEN, TP53, JAK-2, lnc- MALAT-1 and miR-122-IGF-1R were tracked. These findings reveal that MALAT-1 may be oncogenic in GC. Prominent MALAT-1 levels may assist as an indicator of metastasis in GC, and that miR-122-IGF-1R expression is associated via reduced MALAT-1 signaling. Finally, PEG-DOX may be an excellent option for GC therapy.

Enhancing m6A modification of lncRNA through METTL3 and RBM15 to promote malignant progression in bladder cancer

Bladder cancer is one of the most prominent malignancies affecting the urinary tract, characterized by a poor prognosis. Our previous research has underscored the pivotal role of m6A methylation in the progression of bladder cancer. Nevertheless, the precise relationship between N6-methyladenosine (m6A) regulation of long non-coding RNA (lncRNA) and bladder cancer remains elusive. This study harnessed sequencing data and clinical records from 408 bladder cancer patients in the TCGA database. Employing R software, we conducted bioinformatics analysis to establish an m6A-lncRNA co-expression network. Analyzing the differences between high and low-risk groups, particularly at the immunological level, and subsequently investigating the primary regulatory factors of these lncRNA, validating the findings through experiments, and exploring their specific cellular functions. We identified 50 m6A-related lncRNA with prognostic significance through univariate Cox regression analysis. In parallel, we employed a LASSO-Cox regression model to pinpoint 11 lncRNA and calculate risk scores for bladder cancer patients. Based on the median risk score, patients were categorized into low-risk and high-risk groups. The high-risk cohort exhibited notably lower survival rates than their low-risk counterparts. Further analysis pointed to RBM15 and METTL3 as potential master regulators of these m6A-lncRNA. Experimental findings also shed light on the upregulated expression of METTlL3 and RBM15 in bladder cancer, where they contributed to the malignant progression of tumors. The experimental findings demonstrated a significant upregulation of METTL3 and RBM15 in bladder cancer specimens, implicating their contributory role in the oncogenic progression. Knockdown of METTL3 and RBM15 resulted in a marked attenuation of tumor cell proliferation, invasion, and migration, which was concomitant with a downregulation in the cellular m6A methylation status. Moreover, these results revealed that RBM15 and METTL3 function in a synergistic capacity, positing their involvement in cancer promotion via the upregulation of m6A modifications in long non-coding RNAs. Additionally, this study successfully developed an N-methyl-N-nitrosourea (MNU)-induced rat model of in situ bladder carcinoma, confirming the elevated expression of RBM15 and METTL3, which paralleled the overexpression of m6A-related- lncRNAs observed in bladder cancer cell lines. This congruence underscores the potential utility of these molecular markers in in vivo models that mirror human malignancies. This study not only offers novel molecular targets,but also enriches the research on m6A modification in bladder cancer, thereby facilitating its clinical translation.

Targeted inhibition of colorectal cancer proliferation: Thedual-modulatory role of 2,4-DTBP on anti-apoptotic Bcl-2 and Survivin proteins.

The anti-apoptotic proteins, Bcl-2 and Survivin, are consistently overexpressed in numerous human malignancies, notably in colorectal cancer. 2,4-Di-tert-butylphenol (2,4-DTBP) is a naturally occurring phenolic compound known for its diverse biological activities, including anti-cancer properties. The mechanism behind 2,4-DTBP-induced inhibition of cell proliferation and apoptosis in human colorectal cancer cells, specifically regarding Bcl-2 and Survivin, remains to be elucidated. In this study, we employed both in silico and invitro methodologies to underpin this interaction at the molecular level. Molecular docking demonstrated a substantial binding affinity of 2,4-DTBP towards Bcl-2 (ΔG = -9.8 kcal/mol) and Survivin (ΔG = -5.6 kcal/mol), suggesting a potential inhibitory effect. Further, molecular dynamic simulations complemented by MM-GBSA calculations confirmed the significant binding of 2,4-DTBP with Bcl-2 (dGbind = -54.85 ± 6.79 kcal/mol) and Survivin (dGbind = -32.36 ± 1.29 kcal/mol). Invitro assays using HCT116 colorectal cancer cells revealed that 2,4-DTBP inhibited proliferation and promoted apoptosis in both a dose- and time-dependent manner. Fluorescence imaging and scanning electron microscopy illustrated the classical features associated with apoptosis upon 2,4-DTBP exposure. Cell cycle analysis through flow cytometry highlighted a G1 phase arrest and apoptosis assay demonstrated increased apoptotic cell population. Notably, western blotting results indicated a decreased expression of Bcl-2 and Survivin post-treatment. Considering the cytoprotective roles of Bcl-2 and Survivin through the inhibition of mitochondrial dysfunction, our findings of disrupted mitochondrial bioenergetics, characterized by reduced ATP production and oxygen consumption, further accentuate the functional impairment of these proteins. Overall, the integration of in silico and invitro data suggests that 2,4-DTBP holds promise as a therapeutic agent targeting Bcl-2 and Survivin in colorectal cancer.

Pan-cancer identified ARPC1B as a promising target for tumor immunotherapy and prognostic biomarker, particularly in READ

ARPC1B encodes the protein known as actin-related protein 2/3 complex subunit 1 B (ARPC1B), which controls actin polymerization in the human body. Although ARPC1B has been linked to several human malignancies, its function in these cancers remains unclear. TCGA, GTEx, CCLE, Xena, CellMiner, TISIDB, and molecular signature databases were used to analyze ARPC1B expression in cancers. Visualization of data was primarily achieved using R language, version 4.0. Nineteen tumors exhibited high levels of ARPC1B expression, which were associated with different tumor stages and significantly affected the prognosis of various cancers. The level of ARPC1B expression substantially connected the narrative of ARPC1B expression with several TMB cancers and showed significant changes in MSI. Additionally, tolerance to numerous anticancer medications has been linked to high ARPC1B gene expression. Using Gene Set Variation Analysis/Gene Set Enrichment Analysisanalysis and concentrating on Rectum adenocarcinoma (READ), we thoroughly examined the molecular processes of the ARPC1B gene in pan-cancer. Using WGCNA, we examined the co-expression network of READ and ARPC1B. Meanwhile, ten specimens were selected for immunohistochemical examination, which showed high expression of ARPC1B in READ. Human pan-cancer samples show higher ARPC1B expression than healthy tissues. In many malignancies, particularly READ, ARPC1B overexpression is associated with immune cell infiltration and a poor prognosis. These results imply that the molecular biomarker ARPC1B may be used to assess the prognosis and immune infiltration of patients with READ.

Quantification of CD3, FoxP3, and granzyme B immunostaining in canine renal cell carcinoma

Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and isassociated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.

Romidepsin exhibits anti-esophageal squamous cell carcinoma activity through the DDIT4-mTORC1 pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common human malignancies worldwide and is associated with high morbidity and mortality. Current treatment options are limited, highlighting the need for development of novel effective agents. Here, a high-throughput drug screening (HTS) was performed using ESCC cell lines in both two- and three-dimensional culture systems to screen compounds that have anti-ESCC activity. Our screen identified romidepsin, a histone deactylase inhibitor, as a potential anti-ESCC agent. Romidepsin treatment decreased cell viability, induced apoptosis and cell cycle arrest in ESCC cell lines, and these findings were confirmed in ESCC cell line-derived xenografted (CDX) mouse models. Mechanically, romidepsin induced transcriptional upregulation of DNA damage-inducible transcript 4 (DDIT4) gene by histone hyperacetylation at its promoter region, leading to the inhibition of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, romidepsin exhibited better efficacy and safety compared to the conventional therapeutic drugs in ESCC patient-derived xenografted (PDX) mouse models. These data indicate that romidepsin may be a novel option for anti-ESCC therapy.

Cellular and clinical impact of protein phosphatase enzyme epigenetic silencing in multiple cancer tissues

BackgroundProtein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mechanisms that tightly regulate intracellular signalling pathways and stimulate cellular responses. In human malignancies, PPE and protein kinases are frequently mutated resulting in uncontrolled kinase activity and PPE suppression, leading to cell proliferation, migration and resistance to anti-cancer therapies. Cancer associated DNA hypermethylation at PPE promoters gives rise to transcriptional silencing (epimutations) and is a hallmark of cancer. Despite recent advances in sequencing technologies, data availability and computational capabilities, only a fraction of PPE have been reported as transcriptionally inactive as a consequence of epimutations.MethodsIn this study, we examined promoter-associated DNA methylation profiles in Protein Phosphatase Enzymes and their Interacting Proteins (PPEIP) in a cohort of 705 cancer patients in five tissues (Large intestine, Oesophagus, Lung, Pancreas and Stomach) in three cell models (primary tumours, cancer cell lines and 3D embedded cancer cell cultures). As a subset of PPEIP are known tumour suppressor genes, we analysed the impact of PPEIP promoter hypermethylation marks on gene expression, cellular networks and in a clinical setting.ResultsHere, we report epimutations in PPEIP are a frequent occurrence in the cancer genome and manifest independent of transcriptional activity. We observed that different tumours have varying susceptibility to epimutations and identify specific cellular signalling networks that are primarily affected by epimutations. Additionally, RNA-seq analysis showed the negative impact of epimutations on most (not all) Protein Tyrosine Phosphatase transcription. Finally, we detected novel clinical biomarkers that inform on patient mortality and anti-cancer treatment sensitivity.ConclusionsWe propose that DNA hypermethylation marks at PPEIP frequently contribute to the pathogenesis of malignancies and within the precision medicine space, hold promise as biomarkers to inform on clinical features such as patient survival and therapeutic response.

Discovery of novel, potent and orally available benzoazipinone derivatives that elicit MKLP2-inhibitory phenotypes

Mitotic kinesin-like protein 2 (MKLP2/KIF20A) is a key mitotic regulator frequently overexpressed in human malignancies and its abundance is positively correlated with poor outcomes of the disease. Despite extensive research on MKLP2 as a potential target for oncology, the development of small-molecule inhibitors specific to MKLP2 remains limited. We have previously identified a benzoazipinone compound, HJ81 as a potent disruptor of Aurora kinase B (AURKB) localization during late mitosis. This study reveals that such disruption results from a failure of AURKB relocation at the onset of anaphase and this phenomenon can be specifically attributed to the disablement of MKLP2, a recognized facilitator of the relocation process. Further optimization of HJ81 leads to identifying compounds such as 12a as promising lead inhibitors of MKLP2-mediated processes, with improved pharmacokinetic properties. 12a inhibits the microtubule-stimulated ATPase activity of the recombinant MKLP2 in vitro. Significant suppression of tumor growth was observed in mice bearing the Calu-6 lung cancer cell line when treated with 12a at a well-tolerated dose. Overall, our findings suggest that benzoazipinone derivatives represent a novel chemical scaffold with the potential to be developed to mimic MKLP2 inhibition for cancer treatment.

Moracin D suppresses cell growth and induces apoptosis via targeting the XIAP/PARP1 axis in pancreatic cancer

BackgroundPancreatic cancer, a tumor with a high metastasis rate and poor prognosis, is among the deadliest human malignancies. Investigating effective drugs for their treatment is imperative. Moracin D, a natural benzofuran compound isolated from Morus alba L., shows anti-inflammation and anti-breast cancer properties and is effective against Alzheimer's disease. However, the effect and mechanism of Moracin D action in pancreatic cancer remain obscure. PurposeTo investigate the function and molecular mechanism of Moracin D action in repressing the malignant progression of pancreatic cancer. MethodsPancreatic cancer cells were treated with Moracin D, and cell proliferation was evaluated by cell counting kit-8 (CCK-8) and immunofluorescence assays. The clonogenicity of pancreatic cancer cells was assessed based on plate colony formation and soft agar assay. Flow cytometry was used to detect cell apoptosis. The expression of proteins related to the apoptosis pathway was determined by Western blot analysis. Moracin D and XIAP were subjected to docking by auto-dock molecular docking analysis. Ubiquitination levels of XIAP and the interaction of XIAP and PARP1 were assessed by co-immunoprecipitation analysis. Moracin D's effects on tumorigenicity were assessed by a tumor xenograft assay. ResultsMoracin D inhibited cell proliferation, induced cell apoptosis, and regulated the protein expression of molecules involved in caspase-dependent apoptosis pathways. Moracin D suppressed clonogenicity and tumorigenesis of pancreatic cancer cells. Mechanistically, XIAP could interact with PARP1 and stabilize PARP1 by controlling its ubiquitination levels. Moracin D diminished the stability of XIAP and decreased the expression of XIAP by promoting proteasome-dependent XIAP degradation, further blocking the XIAP/PARP1 axis and repressing the progression of pancreatic cancer. Moracin D could dramatically improve the chemosensitivity of gemcitabine in pancreatic cancer cells. ConclusionMoracin D repressed cell growth and tumorigenesis, induced cell apoptosis, and enhanced the chemosensitivity of gemcitabine through the XIAP/PARP1 axis in pancreatic cancer. Moracin D is a potential therapeutic agent or adjuvant for pancreatic cancer.

The Role of MUC1 in Renal Cell Carcinoma.

Mucins are a family of high-molecular-weight glycoproteins. MUC1 is widely studied for its role in distinct types of cancers. In many human epithelial malignancies, MUC1 is frequently overexpressed, and its intracellular activities are crucial for cell biology. MUC1 overexpression can enhance cancer cell proliferation by modulating cell metabolism. When epithelial cells lose their tight connections, due to the loss of polarity, the mucins become dispersed on both sides of the epithelial membrane, leading to an abnormal mucin interactome with the membrane. Tumor-related MUC1 exhibits certain features, such as loss of apical localization and aberrant glycosylation that might cause the formation of tumor-related antigen epitopes. Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and it is the most common kidney cancer. The exact role of MUC1 in this tumor is unknown. Evidence suggests that it may play a role in several oncogenic pathways, including proliferation, metabolic reprogramming, chemoresistance, and angiogenesis. The purpose of this review is to explore the role of MUC1 and the meaning of its overexpression in epithelial tumors and in particular in RCC.

GINS2 promotes the progression of human HNSCC by altering RRM2 expression.

GINS2 exerts a carcinogenic effect in multiple human malignancies, while it is still unclear that the potential roles and underlying mechanisms of GINS2 in HNSCC. TCGA database was used to screen out genes with significant differences in expression in HNSCC. Immunohistochemistry and qRT-PCR were used to measure the expression of GINS2 in HNSCC tissues and cells. GINS2 was detected by qRT-PCR or western blot after knockdown or overexpression. Celigo cell counting, MTT, colony formation, and flow cytometric assay were used to check the ability of proliferation and apoptosis. Bioinformatics and microarray were used to screen out the downstream genes of GINS2. GINS2 in HNSCC tissues and cells was up-regulated, which was correlated with poor prognosis. GINS2 gene expression was successfully inhibited and overexpressed in HNSCC cells. Knockdown of GINS2 could inhibit proliferation and increase apoptosis of cells. Meanwhile, overexpression of GINS2 could enhance cell proliferation and colony formation. Knockdown of RRM2 may inhibit HNSCC cell proliferation, while overexpression of RRM2 rescued the effect of reducing GINS2 expression. Our study reported the role of GINS2 in HNSCC for the first time. The results demonstrated that in HNSCC cells, GINS2 promoted proliferation and inhibited apoptosis via altering RRM2 expression. Therefore, GINS2 might play a carcinogen in HNSCC, and become a specific promising therapeutic target.

Co-delivery of siAEG-1 and doxorubicin to treat osteosarcoma via nanomicelles for azide−alkyne “click” conjugation of poly(l-lysine) dendrons onto Zein

Astrocyte elevated gene-1 (AEG-1) oncogene is a notorious and evolving target in a variety of human malignancies including osteosarcoma. The RNA interference (RNAi) has been clinically proven to effectively knock down specific genes. To successfully implement RNAi in vivo, protective vectors are required not only to protect unstable siRNAs from degradation, but also to deliver siRNAs to target cells with controlled release. Here, we synthesized a Zein-poly(l-lysine) dendrons non-viral modular system that enables efficient siRNA-targeted AEG-1 gene silencing in osteosarcoma and encapsulation of antitumor drugs for controlled release. The rational design of the ZDP integrates the non-ionic and low immunogenicity of Zein and the positive charge of the poly(l-lysine) dendrons (DPLL) to encapsulate siRNA and doxorubicin (DOX) payloads via electrostatic complexes and achieve pH-controlled release in a lysosomal acidic microenvironment. Nanocomplexes-directed delivery greatly improves siRNA stability, uptake, and AEG-1 sequence-specific knockdown in 143B cells, with transfection efficiencies comparable to those of commercial lipofectamine but with lower cytotoxicity. This AEG-1-focused RNAi therapy supplemented with chemotherapy inhibited, and was effective in inhibiting the growth in of osteosarcoma xenografts mouse models. The combination therapy is an alternative or combinatorial strategy that can produce durable inhibitory responses in osteosarcoma patients.

Effect of valproic acid on histone deacetylase expression in oral cancer (Review).

Oral squamous cell carcinoma (OSCC) is a frequent human malignancy that demonstrates a range of genetic and epigenetic alterations. Histone deacetylases (HDACs) are key epigenetic regulators of cell-cycle progression, differentiation and apoptosis and their dysregulation is implicated in cancer development. HDACs are promising targets for anticancer therapy through the utilisation of HDAC inhibitors (HDACis). OSCC cells have been shown to have low levels of histone acetylation, suggesting that HDACis may produce beneficial effects in patients with OSCC. Valproic acid (VPA) is a class I and IIa HDACi and, therefore, may be useful in anticancer therapy. VPA has been reported as a chemo-preventive epigenetic agent in individuals with high-risk oral dysplasia (OD) and thus associated with a reduced risk of HNSCC. It is hypothesised that HDAC inhibition by VPA triggers a change in the expression levels of different HDAC family gene-members. The present review summarises the current literature on HDAC expression changes in response to VPA in oral cancer patients and in vitro studies in an effort to better understand the potential epigenetic impact of VPA treatment. The present review outlined the need for exploring supportive evidence of the chemo-preventive role played by VPA-based epigenetic modification in treating oral pre-cancerous lesions and, thus, providing a novel tolerable chemotherapeutic strategy for patients with oral cancer.

Sosialisasi Kesehatan Reproduksi Sebagai Upaya Peningkatan Lifestyle Remaja Yang Sehat dan Unggul Di Desa Tuah Mesade

Period most vulnerable to experiencing reproductive health problems such as early pregnancy, unsafe abortion which can cause the death of mother and child, depression, sexually transmitted infections (STIs) such as Human Immunodeficiency Virus (HIV), sexual harassment, infertility, and malignancies such as cervical cancer. Adolescents begin to focus on behavior that is associated with adult status, namely smoking, drinking alcohol, using drugs, and engaging in promiscuous sexual acts which are quite disturbing. Community Service "Reproductive Health Socialization as an Effort to Improve the Healthy and Excellent Lifestyle of Adolescents in Tuah Mesade Village was held on 9-11 February 2024 with a total of 30 participants. Socialization is provided by the community service team regarding the introduction of male and female reproductive organs, how to care for reproductive organs, nutrition in reproductive health, and sexually transmitted infections. The extension participants seemed enthusiastic about the materials presented by the resource persons and were able to be actively involved, so this extension activity took place in a two-way system and many participants asked questions. The presentation of the counseling material was followed by discussion, ice breaking, and distribution of door prizes in the form of a book with the title "Teaching Book on Nutrition in Reproductive Health" to participants who were active during the discussion activities.
 

In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment

Small molecule-drug conjugates (SMDCs) are increasingly considered as a therapeutic alternative to antibody-drug conjugates (ADCs) for cancer therapy. OncoFAP is an ultra-high affinity ligand of Fibroblast Activation Protein (FAP), a stromal tumor-associated antigen overexpressed in a wide variety of solid human malignancies. We have recently reported the development of non-internalizing OncoFAP-based SMDCs, which are activated by FAP thanks to selective proteolytic cleavage of the -GlyPro- linker with consequent release of monomethyl auristatin E (MMAE) in the tumor microenvironment. In this article, we describe the generation and the in vivo characterization of FAP-cleavable OncoFAP-drug conjugates based on potent topoisomerase I inhibitors (DXd, SN-38, and exatecan) and an anti-tubulin payload (MMAE), which are already exploited in clinical-stage and approved ADCs. The Glycine-Proline FAP-cleavable technology was directly benchmarked against linkers found in Adcetris™, Enhertu™, and Trodelvy™ structures by means of in vivo therapeutic experiments in mice bearing tumors with cellular or stromal FAP expression. OncoFAP-GlyPro-Exatecan and OncoFAP-GlyPro-MMAE emerged as the most efficacious anti-cancer therapeutics against FAP-positive cellular models. OncoFAP-GlyPro-MMAE exhibited a potent antitumor activity also against stromal models, and was therefore selected for clinical development.

Epstein-Barr Virus BRLF1 Induces PD-L1 Expression in Nasopharyngeal Carcinoma Cells.

Nasopharyngeal carcinoma (NPC) is a specific human malignancy with unique geographic distribution and genetic backgrounds. Although early treatment with radio-chemotherapy has been proven effective for NPC therapy, its therapeutic efficacy substantially diminishes in the late stages of this malignancy. In the tumor microenvironment of NPC, PD-L1 has been demonstrated as a critical factor in impairing T cell activation. As an etiological role for NPC development, it is found that Epstein-Barr virus (EBV) latent proteins upregulated PD-L1 expression. However, whether EBV lytic protein affects PD-L1 expression remains unclear. In this study, through monitoring the mRNA expression pattern of lytic genes and PD-L1 in EBV-positive NPC cell line NA, EBV immediately-early gene BRLF1(Rta) was found to have the potential for PD-L1 activation. Furthermore, we identified that Rta expression enhanced PD-L1 expression in mRNA and protein levels through quantitative real-time polymerase chain reaction and western blotting analysis. The luciferase reporter assay revealed that Rta expression enhanced PD-L1 promoter activity. We also demonstrated that Rta-induced PD-L1 expressions could impair interleukin 2 secretion of T cells, and this mechanism may be through ERK activation. These results displayed the importance of EBV Rta in PD-L1 expression in NPC and may give an alternative target for NPC therapy.