scholarly journals Cancer cell membrane-coated nanoparticles for bimodal imaging-guided photothermal therapy and docetaxel-enhanced immunotherapy against cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qiaoqi Chen ◽  
Liang Zhang ◽  
Lin Li ◽  
Mixiao Tan ◽  
Weiwei Liu ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Therapeutic Modality ◽  
Primary Tumors ◽  
Therapeutic Modalities ◽  
Coated Nanoparticles ◽  
Bimodal Imaging ◽  
Rational Combination ◽  
Maturation Rate ◽  
M1 Phenotype ◽  
Immune Adjuvant

Abstract Background Mono-therapeutic modality has limitations in combating metastatic lesions with complications. Although emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. The rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer. Results Poly lactic-co-glycolic acid (PLGA, 50 mg) nanospheres were constructed with photothermal transduction agents (PTAs)-Prussian blue (PB, 2.98 mg) encapsulated in the core and chemotherapeutic docetaxel (DTX, 4.18 mg)/ immune adjuvant-imiquimod (R837, 1.57 mg) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated “M@P-PDR”), which acted as “Nano-targeted cells” to actively accumulate in tumor sites, and were guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by the immune adjuvant R837, the maturation rate of DCs increased by 4.34-fold compared with that of the control. In addition, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving the immunosuppressive TME. The proportion of M2-TAMs decreased from 68.57% to 32.80%, and the proportion of M1-TAMs increased from 37.02% to 70.81%. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased from 17.33% (control) to 35.5%. Primary tumors and metastasis were significantly inhibited when treated with “Nano-targeted cells”-based cocktail therapy. Conclusion “Nano-targeted cells”-based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/recurrence. Graphical Abstract

scholarly journals Artificial “Nano-Targeted Cells” for Bimodal Imaging-Guided Tumor Cocktail Therapy

2021 ◽  
Author(s):  
Qiaoqi Chen ◽  
Liang Zhang ◽  
Lin Li ◽  
Mixiao Tan ◽  
Weiwei Liu ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Therapeutic Modality ◽  
Primary Tumors ◽  
Therapeutic Modalities ◽  
Metastatic Lesions ◽  
Bimodal Imaging ◽  
Rational Combination ◽  
M1 Phenotype ◽  
Immune Adjuvant ◽  
Plga Nanospheres

Abstract Background: Single therapeutic modality always has its limitations in combating metastatic lesions with complicacy. Although the emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. Rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer.Results: Poly lactic-co-glycolic acid (PLGA) nanospheres were constructed with photothermal transduction agents (PTAs)- Prussian blue (PB) encapsulated in the core and chemotherapeutic docetaxel (DTX)/ immune adjuvant- imiquimod (R837) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated as “M@P-PDR”), which acted as “Nano-targeted cells” to actively accumulate in tumor sites, which was guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by immune adjuvant R837, the maturation of DCs were promoted. Besides, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving immunosuppressive TME. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased. The primary tumors and metastasis were significantly inhibited when treated with “Nano-targeted cells” based cocktail therapy.Conclusion: “Nano-targeted cells” based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/ recurrence.

Overcoming resistance to anti-PD-1 with tumor agnostic NBTXR3: From bench to bed side.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2591-2591
Author(s):  
Tanguy Y. Seiwert ◽  
Colette Shen ◽  
Jessica M. Frakes ◽  
Jiaxin Niu ◽  
Jared Weiss ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cell ◽  
Tumor Regression ◽  
Single Agent ◽  
Locally Advanced ◽  
Cd8 T Cell ◽  
Intratumoral Injection ◽  
Post Treatment ◽  
Primary Tumors ◽  
Systemic Control

2591 Background: Despite recent advances, resistance to immune checkpoint inhibitors (ICI), observed in over 80% of treated patients, is currently the main challenge in immuno-oncology. Intense efforts are being made to identify combination therapies that could improve ICI response rates. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase radiation therapy (XRT) dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Here we present evidence that NBTXR3 activated by XRT primes the immune system, producing an anti-tumor response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in mice models and patients. Methods: Abscopal assays were conducted in immunocompetent mice. Anti-PD-1 sensitive or resistant tumor cell lines, were injected in both flanks of mice. Intratumoral injection of NBTXR3 (or vehicle) followed by XRT was performed in right flank (primary) tumors only. Some mice also received anti-PD-1 injections. Tumor growth was monitored, and tumor immune cell infiltrates analyzed by immunohistochemistry (IHC). Separately, in the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+XRT or XRT alone followed by tumor resection. Pre- and post-treatment tumor samples from patients in both groups were analyzed by IHC and Digital Pathology for immune biomarkers. The safety and efficacy (RECIST 1.1/iRECIST) of NBTXR3 plus stereotactic body radiotherapy (SBRT) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers [NCT03589339]. Results: Pre-clinical studies demonstrated that NBTXR3+XRT induces an immune response not observed with XRT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+XRT treated and untreated tumors compared to XRT alone. Similarly, increased CD8+ T-cell and decreased FOXP3+ Treg density (pre- vs post-treatment) was observed in tumor tissues from STS patients treated with NBTXR3+XRT. Furthermore, NBTXR3+XRT in combination with anti-PD-1 improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, as well as reduced the number of spontaneous lung metastases. Preliminary efficacy data from the first in human trial of NBTXR3+XRT in combination with anti-PD-1 showed tumor regression in the majority of patients (8/9). Of note, tumor regression was observed in 6/7 pts who had progressed on prior anti-PD-1. Conclusions: The clinical efficacy of NBTXR3+XRT has been demonstrated as a single agent. We now demonstrate that it potentiates anti-PD-1 treatment to overcome resistance mechanisms. These results highlight the potential of NBTXR3+XRT to positively impact the immuno-oncology field. Clinical trial information: NCT03589339.

scholarly journals Tumor Size Matters—Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 714
Author(s):  
Jean Philippe Nesseler ◽  
Mi-Heon Lee ◽  
Christine Nguyen ◽  
Anusha Kalbasi ◽  
James W. Sayre ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Tumor Regression ◽  
Experimental Models ◽  
Tumor Burden ◽  
Local Regression ◽  
Cell Content ◽  
Primary Tumors ◽  
The Impact

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

scholarly journals Clinicopathologic Characteristics, Therapeutic Modalities and Survival Outcomes of Plasmablastic Lymphoma: A Real-World Study

2021 ◽  
Author(s):  
Yan-Hua Zheng ◽  
Hai-Tao Wang ◽  
Zhuo Wan ◽  
Biao Tian ◽  
Hong-Yuan Shen ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Cox Model ◽  
Plasmablastic Lymphoma ◽  
Therapeutic Modality ◽  
Survival Outcomes ◽  
Rapid Progression ◽  
Clinicopathologic Characteristics ◽  
Therapeutic Modalities ◽  
Risk Of Death ◽  
Ann Arbor

Abstract Introduction: Plasmablastic lymphoma(PBL)，an extremely rare subtype of B-cell non-Hodgkin lymphoma(NHL), is characterized by aggressiveness, rapid progression and bleak prognosis. Neither standardized regimen nor consensus for PBL treatment has been established.Methods: We retrospectively analyzed the clinicopathologic characteristics, therapeutic modalities and survival outcomes of 418 patients registered in the Surveillance, Epidemiology, and End Results (SEER) database from 2008 to 2016 and 21 (19 treated) patients in our institution. Kaplan-Meier survival curves and log-rank test for overall survival (OS) and cancer-specific survival (CSS) were performed to compare each variable. Variables with statistical significance in the univariate Cox regression were incorporated into the multivariate Cox model to determine the independent prognostic factors.Results: In patient cohort from the SEER, PBL has a striking male predilection. The median OS for all PBL patients was 17 months. The 1-year,3-year and 5-year OS rate were 54.4%, 40.4% and 37.2% respectively. Patients who suffered from previous malignancy had a significant survival disadvantage compared to those without previous cancer. Patients with higher Ann Arbor stage at diagnosis were at higher risk of death than those with lower stage. Chemotherapy alone or chemotherapy combined with radiotherapy could significantly reduce the risk of death and extend the patients’ survival, yielding HR of 0.209(95%CI 0.152-0.288) and 0.187(95%CI 0.089-0.394), respectively. Radiation alone seemed useless. All patients from our institution were HIV-negative. The main therapeutic regimens were CHOP or CHOPE, DA-EPOCH, DHAP and ESHAP. Complete response (CR) was achieved in only 3 patients, while partial response (PR) in 10 patients. The median OS was 7 months. Fourteen patients later died of the disease progression.Conclusions: Previous malignancy history, Ann Arbor stage and therapeutic modality were independent prognostic factors. Bortezomib combined with DA-EPOCH may serve as an effective regimen for PBL. The optimal therapeutic modality necessitates further exploration.

scholarly journals Deubiquitinase-Targeting Chimeras for Targeted Protein Stabilization

2021 ◽  
Author(s):  
Nathaniel J. Henning ◽  
Lydia Boike ◽  
Jessica N. Spradlin ◽  
Carl C. Ward ◽  
Bridget Belcher ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Protein Stabilization ◽  
Therapeutic Modality ◽  
Dependent Manner ◽  
Bronchial Epithelial ◽  
Therapeutic Modalities ◽  
Ligand Discovery ◽  
Δf508 Cftr ◽  
Specific Proteins ◽  
Cftr Protein

AbstractTargeted protein degradation is a powerful therapeutic modality that uses heterobifunctional small-molecules to induce proximity between E3 ubiquitin ligases and target proteins to ubiquitinate and degrade specific proteins of interest. However, many proteins are ubiquitinated and degraded to drive disease pathology; in these cases targeted protein stabilization (TPS), rather than degradation, of the actively degraded target using a small-molecule would be therapeutically beneficial. Here, we present the Deubiquitinase-Targeting Chimera (DUBTAC) platform for TPS of specific proteins. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48 ubiquitin-specific deubiquitinase OTUB1. We then developed a heterobifunctional DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-CFTR. We demonstrated proof-of-concept of TPS by showing that this DUBTAC robustly stabilized ΔF508-CFTR in human cystic fibrosis bronchial epithelial cells in an OTUB1-dependent manner. Our study underscores the utility of chemoproteomics-enabled covalent ligand discovery approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS.Editorial summaryWe have developed the Deubiquitinase Targeting Chimera (DUBTAC) platform for targeted protein stabilization. We have discovered a covalent recruiter against the deubiquitinase OTUB1 that we have linked to the mutant ΔF508-CFTR targeting cystic fibrosis drug Lumacaftor to stabilize mutant CFTR protein in cells.

scholarly journals Knowledge of nursing students about the care provided to people with neoplastic wounds

10.3823/2408 ◽  
2017 ◽  
Vol 10 ◽  
Author(s):  
Roseane Ferreira Gomes ◽  
Milca Silícia Pessôa de Morais ◽  
Glenda Agra ◽  
Alana Tamar Oliveira de Sousa ◽  
Matheus Figueiredo Nogueira ◽  
...  
Keyword(s):  
Nursing Students ◽  
Signs And Symptoms ◽  
Skin Neoplasms ◽  
Bachelor's Degree ◽  
Theory And Practice ◽  
Therapeutic Modality ◽  
Care Process ◽  
Exploratory Research ◽  
Therapeutic Modalities ◽  
Education And Health

Objective: To investigate the knowledge of nursing students about the care provided to patients with neoplastic wound. Method: This is an exploratory research of a qualitative nature, which was attended by 15 students of the Bachelor's Degree in Nursing from the Center of Education and Health of the Federal University of Campina Grande, campus Cuité - PB, in the period from October to November 2015. For data collection, we used a form for an interview. The data were analyzed through the Technique of Thematic Analysis of Minayo. Results: From the analysis of the empirical material emerged the following thematic categories: Category 1 - Defining neoplastic wounds; Category 2 - Knowledge incipient on ‘neoplastic wounds’ for academic and professional practice; Category 3 - Envisioning the theme "neoplastic wound" in the Academy; Category 4 - Knowledge about methods of evaluation of neoplastic wounds and Category 5 - Knowledge of therapeutic modalities of neoplastic wounds. Conclusions: The academics know the evaluative method of a patient with neoplastic wound as integralizadora unit of care process; recognize palliative care as the best therapeutic modality for these customers, especially when they are in completion and indicate the products contraindicated in the treatment of these lesions; however, do not mention the covers and recommended substances for the control of the signs and symptoms of these injuries. In this context, it is believed that the creation of academic projects of extension, with the aim of creating opportunities for integration between theory and practice, is one of the ways to improve the knowledge.   Keywords: Knowledge; Students of Nursing; Skin Neoplasms.

Humanized mice (humice) carrying patient-derived xenograft (PDX) as a platform to develop immunotherapy in bladder cancer (BCa).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 381-381 ◽  
Author(s):  
Chong-xian Pan ◽  
Wei Shi ◽  
Ai-Hong Ma ◽  
Hongyong Zhang ◽  
Primo Lara ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Growth ◽  
Immune Cell ◽  
Tumor Regression ◽  
Genetic Alterations ◽  
Therapeutic Modality ◽  
Whole Body ◽  
Flow Cytometry Analysis ◽  
Nsg Mice ◽  
Human Immune

381 Background: Immunotherapy with anti-programmed cell death 1 (PD1) or PD ligand 1 (PD-L1) antibody has emerged as a promising therapeutic modality, but has a response rate of approximately 20% in BCa. There are various drawbacks associated with current animal models. The objective of this study is to establish and characterize humice carrying PDXs in which both the immune cells and BCa cells are derived from humans. Methods: NOD-scid IL2Rgammanull or NSG, mice received CD34+ hematopoietic progenitor cells (HPC) cells i.v. after whole body radiation. PDXs were established through direct implantation of human BCa clinical specimens into NSG mice. Immune cell subpopulations were analyzed through flow cytometry analysis. Humice carrying HLA-unmatched PDXs were treated with an anti-PD1 antibody pemborlizumab (pembro) or in combination with a BKT/ITK inhibitor ibrutinib to determine the anti-tumor efficacy and toxicity. Results: PDXs retained the morphology fidelity and 92-97% of genetic alterations of parental patient cancers. Of the first 8 PDXs tested, 3 had high PD-L1 ( > 10 FPKM) as determined by RNA-seq which was further confirmed with flow cytometry analysis. Major human immune cell sub-populations were reconstituted in humice. No xenograft versus host disease was observed before pembro treatment. In humice with HPC donor 6466, pembro significantly inhibited tumor growth (p = 0.0016 at Day 29) of PDX BL293, but had no effect in another PDX BL440 with the same HPC donor 6466, or with the same PDX BL293 but with a different HPC donor 912. In another set of humice (HPC donor 710) carrying PDX BL293, pembro alone inhibited tumor growth. However, addition of ibrutinib did not potentiate the efficacy of pembro, but increased toxicity. Tumor regression with pembro treatment was associated with decrease of CD4+PD1+, CD8+PD1+ cells at peripheral blood and increased CD45+ and CD8+ cells in PDXs. Conclusions: Humice carrying PDXs reconstitute with human immune system, and can potentially be used to screen for effective immunotherapeutic agents or combinations, and to study resistant mechanisms.

TAMI-33. DYNAMICS OF MICROGLIAL ACTIVATION AND EXPRESSION OF CYTOKINES IN THE SITE OF GLIOBLASTOMA TUMOR RESECTION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi205-vi205
Author(s):  
Jescelica Ortiz-Rivera ◽  
Lilia Kucheryavykh ◽  
Alejandro Albors
Keyword(s):  
Magnetic Beads ◽  
Expression Patterns ◽  
Tumor Resection ◽  
Pcr Analysis ◽  
Vascular Endothelial ◽  
Primary Tumors ◽  
Monocyte Chemoattractant Protein 1 ◽  
M1 Phenotype ◽  
Endothelial Growth Factor ◽  
The Impact

Abstract Glioblastoma (GBM) is the most aggressive type of brain cancer. GBM tumors are made up of a large percentage of microgliawhich support the invasive nature of tumor and the resistance to therapy. In the tumor, microglia cells can polarize into M1 and M2 phenotypes. M1 phenotype is distinguished by its ability to eliminate tumor cells, and secrete proinflammatory cytokines, whileM2 phenotype is associated with tumor cell survival and secrete anti-inflammatory cytokines. Tumor resection is one of the primary steps to treat GBM, thus, resulting in tissue damage and causing microglia activation in the surgical area. The activation state of microglia in the site of resection and the impact of microglia on glioma regrowth is unclear. The purpose of this study is to investigate the state of microglia in the tumor resection area and kinetics of microglial activation.C57BL/6/GL261 mouse glioma implantation model was used. 14 days after in-brain implantation of GL261 cells tumors were surgically resected and then re-grown tumors were analyzed at 0 hours,1, 4, 7, 14 and 21 days after tumor resection, together with the originally resected primary tumors. Microglia were purified from tumors with use of magnetic beads. Western blot analysis of microglia, purified from primary and re-grown tumors, demonstrated increase of CD86 (M1) during the first 7 days after resection and then up-regulation of Arginase (M2) in a period from 14thto 21st days after tumor resection. The cytokine expression analysis revealed significant up-regulation of Vascular Endothelial Growth Factor (VEGF) and Monocyte Chemoattractant Protein 1 (MCP1) in microglia purified from re-grown tumors. PCR analysis confirmed these data, indicating increase of VEGF, MCP1 gene expression in tumor infiltrating microglia in re-grown tumor. We can state that microglia infiltrating primary tumor and tumor re-grown after surgical resection, represent significantly different cytokines expression patterns, favorable to increased vascularization and tumor progression.

High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4021-4021
Author(s):  
Andreas Seeber ◽  
Florian Kocher ◽  
Andreas Pircher ◽  
Alberto Puccini ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Tumor Regression ◽  
Signal Transduction Pathway ◽  
Cxcr4 Expression ◽  
Ductal Adenocarcinoma ◽  
Rna Expression ◽  
Primary Tumors ◽  
Pathway Gene ◽  
Molecular Landscape

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p < 0.0001). CXCR4-high (top quartile: > 59 TPMs), when compared to CXCR4-low (bottom quartile: < 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8+ T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p < 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p < 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p < 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.

A potential protection of melatonin on pathogenesis of oral sub-mucous fibrosis (OSMF) : a current update

2021 ◽  
Vol 4 (1) ◽  
pp. 84-98
Author(s):  
Thodur M Madapusi Balaji ◽  
Saranya Varadarajan ◽  
Debasish Bandyopadhyay ◽  
Raghunathan Jagannathan ◽  
Shankargouda Patil ◽  
...  
Keyword(s):  
Oral Cavity ◽  
Therapeutic Potential ◽  
Mouth Opening ◽  
Therapeutic Modality ◽  
Areca Nut ◽  
Therapeutic Modalities ◽  
Anti Oxidant ◽  
Oral Sub Mucous Fibrosis ◽  
Almost All ◽  
A Current

Oral submucous fibrosisis (OSMF) is a clinical condition of the oral cavity which is caused predominantly by areca nut consumption. This fibrotic condition affects almost all parts of the oral cavity and can cause significant reduction in mouth opening, thereby, resulting in functional impairment. The other potential risk of OSMF is its malignant transformation into oral squamous cell carcinoma, which occurs in a significant number of afflicted patients. Extensive researches have been conducted to understand the pathogenesis of OSMF for identification of tangible therapeutic modalities. To date, there is no effective therapeutic modality for this disorder. It is well known that melatonin has a potent anti-fibrotic, anti-oxidant, and pro-angiogenic effects. The therapeutic potential of melatonin on OSM cannot be ignored. In this article we have explored the potential mechanisms of melatonin as an adjuvant in the prevention and treatment  of OSMF.

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