Effects of tumor derived exosomes on T cells markers expression / Efeitos de exossomos derivados de tumor na expressão de marcadores de células T

Exosomes are 30-120nm bio particles transferred from donor to recipient cells leading to modification in their regulatory mechanisms depending upon the coded message in the form of loaded biomolecule. Cancer cells derived exosomes the true representatives of the parent cells have been found to modify the tumor surrounding/distinct regions and participate in metastasis, angiogenesis and immune suppression. Tis study was aimed to study the effects of tumor mice derived exosomes on the normal mice spleen isolated T cells by using co-culture experiments and flow cytometer analysis. We mainly focused on some of the T cells population and cytokines including IFN-γ, FOXP3+ regulatory T (Treg) cells and KI67 (proliferation marker). Overall results indicated random changes in different set of experiments, where the cancer derived exosomes reduced the IFN-γ expression in both CD4 and CD8 T cells, similarly the Treg cells were also found decreased in the presence of cancer exosomes. No significant changes were observed on the Ki67 marker expression. Such studies are helpful in understanding the role of cancer exosomes in immune cells suppression in tumor microenvironment. Cancer exosomes will need to be validated in vivo and in vitro on a molecular scale in detail for clinical applications.

Os exossomos são biopartículas de 30-120 nm transferidas de células doadoras para células receptoras, levando à modificação em seus mecanismos reguladores, dependendo da mensagem codificada na forma de biomolécula carregada. Verificou-se que exossomos derivados de células cancerosas ­ os verdadeiros representantes das células-mãe ­ modificam as regiões circundantes / distintas do tumor e participam da metástase, angiogênese e imunossupressão. Este estudo teve como objetivo estudar os efeitos de exossomos derivados de camundongos com tumor nas células T isoladas de baço de camundongos normais, usando experimentos de cocultura e análise de citômetro de fluxo. Concentrou-se, principalmente, em algumas populações de células T e citocinas, incluindo IFN-γ, células T reguladoras FOXP3 + (Treg) e KI67 (marcador de proliferação). Os resultados gerais indicaram mudanças aleatórias em diferentes conjuntos de experimentos, em que os exossomos derivados de câncer reduziram a expressão de IFN-γ em células T CD4 e CD8, da mesma forma que as células Treg também foram encontradas diminuídas na presença de exossomos de câncer. Nenhuma mudança significativa foi observada na expressão do marcador Ki67. Esses dados são úteis para a compreensão do papel dos exossomos do câncer na supressão de células do sistema imunológico no microambiente tumoral. Exossomos de câncer precisarão ser validados in vivo e in vitro em escala molecular com detalhes para aplicações clínicas.

Tratamento de odontoma composto e cisto dentígero: relato de caso / Treatment of compound odontoma and dentigeral cyst: case report

Introdução: o odontoma é considerado como um frequente tumor odontogênico benigno, podendo ser classificado em tipo composto ou tipo complexo. O cisto dentígero é o mais comum entre os cistos odontogênicos de desenvolvimento, onde envolve a coroa da unidade dentária no nível da junção amelocementária. Há poucos estudos na literatura do encontro das duas lesões, acometendo o mesmo local na cavidade oral. O diagnóstico pode ser constituído por exame clínico e de imagem. Objetivo: apresentar um caso clínico de odontoma composto e cisto dentígero em região de parassínfise mandibular esquerda abordando as caraterísticas clínicas destas duas lesões e as adequadas formas de tratamento. Relato de caso: paciente do sexo masculino, 16 anos de idade, compareceu ao ambulatório do Centro Odontológico da Escola Bahiana de Medicina e Saúde Pública (Salvador, Bahia), portando encaminhamento de ortodontista, solicitando exodontia da unidade dentária 33 inclusa associada a um odontoma. Ao realizar exames físicos e imaginológicos detectou-se a hipótese diagnóstica de odontoma composto associado a unidade dentária, envolto em folículo pericoronário ou cisto dentígero. Foi realizada biópsia excisional das duas lesões e exodontia da unidade. A análise histopatológica confirmou o diagnóstico para odontoma composto associado a cisto dentígero na unidade 33. Ao acompanhamento de 03 meses, paciente apresentou neoformação óssea da região de parassínfise mandibular, mediante a análise de novos exames imaginológicos. Discussão: há poucos estudos na literatura da associação entre as duas lesões, porém relatos afirmam que o odontoma pode ser encontrado associado aos cistos odontogênicos. Por conta da falta de maiores estudos dessa associação, há escassez de recomendações terapêuticas de acordo com faixa etária e extensão do acometimento das lesões. Considerações finais: lesões comumente assintomáticas, tem o diagnóstico constituído por exame clínico e avaliação de exames de imagem(AU)

Introduction: odontoma is considered a frequent benign odontogenic tumor and can be classified as a compound or complex type. The dentigerous cyst is the most common among developmental odontogenic cysts, where it involves the crown of the dental unit at the level of the cementoenamel junction. There are few studies in the literature on the meeting of the two lesions, affecting the same site in the oral cavity. The diagnosis can be made by clinical and imaging examination. Objective: to present a clinical case of compound odontoma and dentigerous cyst in the left mandibular parasymphysis region, addressing the clinical characteristics of these two lesions and the appropriate forms of treatment. Case report: male patient, 16 years old, attended the outpatient clinic of the Centro Odontológico da Escola Bahiana de Medicina e Saúde Pública (Salvador, Bahia), having been referred by an orthodontist, requesting extraction of the included dental unit 33 associated with an odontoma. Upon physical and imaging examinations, the diagnostic hypothesis of a compound odontoma associated with a dental unit, surrounded by a pericoronal follicle or dentigerous cyst, was detected. Excisional biopsy of the two lesions and extraction of the unit were performed. The histopathological analysis confirmed the diagnosis of compound odontoma associated with dentigerous cyst in unit 33. At the 03-month follow-up, the patient presented bone neoformation in the mandibular parasymphysis region, through the analysis of new imaging exams. Discussion: there are few studies in the literature on the association between the two lesions, but reports state that odontoma can be found associated with odontogenic cysts. Due to the lack of further studies on this association, there is a lack of therapeutic recommendations according to age group and extent of lesion involvement. Final considerations: commonly asymptomatic lesions, the diagnosis consists of clinical examination and evaluation of imaging tests(AU)

Surface-Engineered Monocyte Immunotherapy Combined Graphene Quantum Dots Effective Against Solid Tumor Targets.

Introduction: The immunosuppressive tumor microenvironment (TME) of solid tumors inhibits most drug delivery system-based nanomaterials from achieving deep penetration in tumor tissue and interferes with T cell activity in terms of differentiation and exhaustion, which is becoming a critical therapy hurdle for solid tumors. Therefore, developing a therapeutic strategy with abilities of rapid establishment of tumor-targeted cells, elimination of immune obstacles, and enhanced active immunization is very important, while is still a big challenge. Methods: A new strategy was explored to enhance immune therapy via the conjugation of microRNA155 (miR) to the surface of therapeutic monocyte with graphene quantum dots (GQDs). Results: TME was reversed using surface-engineered monocyte immunotherapy via reprogramming pro-tumoral M2 TAMs into antitumor M1, and thus tumor elimination was dramatically enhanced. Conclusion: Such a surface-engineered monocyte immunotherapy has been demonstrated to be well tolerated to intravenous administration and bio-compatible, showing the potential to be extended for the solid tumor treatment.

Cytoplasmic DNAs: Sources, sensing, and roles in the development of lung inflammatory diseases and cancer.

Cytoplasmic DNA is emerging as a pivotal contributor to the pathogenesis of inflammatory diseases and cancer, such as COVID-19 and lung carcinoma. However, the complexity of various cytoplasmic DNA-related pathways and their crosstalk remains challenging to distinguish their specific roles in many distinct inflammatory diseases, especially for the underlying mechanisms. Here, we reviewed the latest findings on cytoplasmic DNA and its signaling pathways in inflammatory lung conditions and lung cancer progression. We found that sustained activation of cytoplasmic DNA sensing pathways contributes to the development of common lung diseases, which may result from external factors or mutations of key genes in the organism. We further discussed the interplays between cytoplasmic DNA and anti-inflammatory or anti-tumor effects for potential immunotherapy. In sum, this review aids in understanding the roles of cytoplasmic DNAs and exploring more therapeutic strategies.

Type 1 interferon mediated signaling is indispensable for eliciting anti-tumor responses by Mycobacterium indicus pranii.

Introduction: The evolving tumor secretes various immunosuppressive factors that reprogram the tumor microenvironment (TME) to become immunologically cold. Consequently, various immunosuppressive cells like Tregs are recruited into the TME which in turn subverts the anti-tumor response of dendritic cells and T cells.Tumor immunotherapy is a popular means to rejuvenate the immunologically cold TME into hot. Mycobacterium indicus pranii (MIP) has shown strong immunomodulatory activity in different animal and human tumor models and has been approved for treatment of lung cancer (NSCLC) patients as an adjunct therapy. Previously, MIP has shown TLR2/9 mediated activation of antigen presenting cells/Th1 cells and their enhanced infiltration in mouse melanoma but the underlying mechanism by which it is modulating these immune cells is not yet known. Results: This study reports for the first time that MIP immunotherapy involves type 1 interferon (IFN) signaling as one of the major signaling pathways to mediate the antitumor responses. Further, it was observed that MIP therapy significantly influenced frequency and activation of different subsets of T cells like regulatory T cells (Tregs) and CD8+ T cells in the TME. It reduces the migration of Tregs into the TME by suppressing the expression of CCL22, a Treg recruiting chemokine on DCs and this process is dependent on type 1 IFN. Simultaneously, in a type 1 IFN dependent pathway, it enhances the activation and effector function of the immunosuppressive tumor resident DCs which in turn effectively induce the proliferation and effector function of the CD8+ T cells. Conclusion: This study also provides evidence that MIP induced pro-inflammatory responses including induction of effector function of conventional dendritic cells and CD8+ T cells along with reduction of intratumoral Treg frequency are essentially mediated in a type 1 IFN-dependent pathway.

Evaluation of the Anticancer Potential of Morus nigra and Ocimum basilicum Mixture against Different Cancer Cell Lines: An In Vitro Evaluation.

Morus nigra (M) and Ocimum basilicum (O) mixture (MO2) extract was extracted using hexane (MO2H), chloroform (MO2C), ethyl acetate (MO2E), and methanol (MO2M) in a Soxhlet apparatus. The cytotoxicity was evaluated using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The IC50 values of the MO2C-treated cancer cells were 11.31 µg/mL (MDA-MB-231), 15.45 µg/mL (MCF-7), 18.9 µg/mL (HepG2), 26.33 µg/mL (Huh-7), 30.17 µg/mL (LoVo), and 36.76 µg/mL (HCT116). MO2C-treated cells showed cellular and nuclear morphological alterations like chromatin condensation and formation of apoptotic bodies as observed using light and fluorescent microscopy. The antioxidant and anti-inflammatory properties were investigated in vitro using 2,2'-diphenyl-1-picrylhydrazyl (DPPH) and egg albumin denaturation assays. It was evident that the MO2M extract exhibited the highest antioxidant activity (18.13%), followed by the MO2E extract (12.25%), MO2C extract (9.380%), and MO2H extract (6.31%). The highest inhibition percentage of albumin denaturation was observed in MO2H (28.54%), followed by MO2M (4.32%) at 0.2 and 0.1 mg/mL concentrations, respectively. The compounds identified using gas chromatography-mass spectrometry (GC-MS) analysis for MO2C extract were α-trans-bergamotene, germacrene D, selin-4,7(11)-diene, 2 tridecen-1-ol, and 2-decen-1-ol. The present study reveals that MO2C has promising anticancer activity and may serve as a potent polyherbal extract in cancer treatment.

[Research progress on the effect of iron oxide nanoparticles in macrophage polarization].

Macrophages are important immune effector cells with significant plasticity and heterogeneity in the body immune system, and play an important role in normal physiological conditions and in the process of inflammation. It has been found that macrophage polarization involves a variety of cytokines and is a key link in immune regulation. Targeting macrophages by nanoparticles has a certain impact on the occurrence and development of a variety of diseases. Due to its characteristics, iron oxide nanoparticles have been used as the medium and carrier for cancer diagnosis and treatment, making full use of the special microenvironment of tumors to actively or passively aggregate drugs in tumor tissues, which has a good application prospect. However, the specific regulatory mechanism of reprogramming macrophages using iron oxide nanoparticles remains to be further explored. In this paper, the classification, polarization effect and metabolic mechanism of macrophages were firstly described. Secondly, the application of iron oxide nanoparticles and the induction of macrophage reprogramming were reviewed. Finally, the research prospect and difficulties and challenges of iron oxide nanoparticles were discussed to provide basic data and theoretical support for further research on the mechanism of the polarization effect of nanoparticles on macrophages.

Embedding lifestyle interventions into cancer care: has telehealth narrowed the equity gap?

Lifestyle interventions targeting energy balance (ie, diet, exercise) are critical for optimizing the health and well-being of cancer survivors. Despite their benefits, access to these interventions is limited, especially in underserved populations, including older people, minority populations and those living in rural and remote areas. Telehealth has the potential to improve equity and increase access. This article outlines the advantages and challenges of using telehealth to support the integration of lifestyle interventions into cancer care. We describe 2 recent studies, GO-EXCAP and weSurvive, as examples of telehealth lifestyle intervention in underserved populations (older people and rural cancer survivors) and offer practical recommendations for future implementation. Innovative approaches to the use of telehealth-delivered lifestyle intervention during cancer survivorship offer great potential to reduce cancer burden.

Skeletal muscle omics signatures in cancer cachexia: perspectives and opportunities.

Cachexia is a life-threatening complication of cancer that occurs in up to 80% of patients with advanced cancer. Cachexia reflects the systemic consequences of cancer and prominently features unintended weight loss and skeletal muscle wasting. Cachexia impairs cancer treatment tolerance, lowers quality of life, and contributes to cancer-related mortality. Effective treatments for cancer cachexia are lacking despite decades of research. High-throughput omics technologies are increasingly implemented in many fields including cancer cachexia to stimulate discovery of disease biology and inform therapy choice. In this paper, we present selected applications of omics technologies as tools to study skeletal muscle alterations in cancer cachexia. We discuss how comprehensive, omics-derived molecular profiles were used to discern muscle loss in cancer cachexia compared with other muscle-wasting conditions, to distinguish cancer cachexia from treatment-related muscle alterations, and to reveal severity-specific mechanisms during the progression of cancer cachexia from early toward severe disease.

Linking social and built environmental factors to leisure-time physical activity in rural cancer survivors.

BACKGROUND: This study explored associations between social and built environmental factors and leisure-time physical activity (LTPA) in rural cancer survivors (RCS) and whether these associations differed by exercise stage of change (SOC). METHOD: RCS (n = 219) completed questionnaires assessing LTPA, SOC, and social (social status, connectedness, support) and environmental (home environment, neighborhood environment) factors. Linear regression models examined associations between social and built environmental factors and LTPA and tested for moderation by SOC. RESULTS: Half (50.7%) of RCS were physically active, and 49.3% were not active. Social factors positively associated with LTPA included subjective social status in the community (B = 89.0, P = .014) and in the United States (B = 181.3, P < .001), social connectedness (B = 122.3, P = .024), and social support for physical activity from family (B = 41.9, P < .001) and friends (B = 44.3, P < .001). Environmental factors positively associated with LTPA included the home environment (B = 111.2, P < .001), perceived environmental support for PA (B = 355.4, P = .004), and neighborhood attributes, including bicycling infrastructure (B = 191.3, P = .003), proximity to recreation facilities (B = 140.1, P = .021), traffic safety (B = 184.5, P = .025), and aesthetics (B = 342.6, P < .001). SOC statistically significantly moderated the association between social status in the United States and LTPA (B = 160.3, P = .031). CONCLUSIONS: Social and built environmental factors were consistently linked with LTPA and provide context for multilevel interventions promoting LTPA in RCS.

Pharmacokinetics of cancer therapeutics and energy balance: the role of diet intake, energy expenditure, and body composition.

Energy balance accounts for an individual's energy intake, expenditure, and storage. Each aspect of energy balance has implications for the pharmacokinetics of cancer treatments and may impact an individual's drug exposure and subsequently its tolerance and efficacy. However, the integrated effects of diet, physical activity, and body composition on drug absorption, metabolism, distribution, and excretion are not yet fully understood. This review examines the existing literature on energy balance, specifically the role of dietary intake and nutritional status, physical activity and energy expenditure, and body composition on the pharmacokinetics of cancer therapeutics. As energy balance and pharmacokinetic factors can be influenced by age-related states of metabolism and comorbidities, this review also explores the age-related impact of body composition and physiologic changes on pharmacokinetics among pediatric and older adult populations with cancer.

Key takeaways for knowledge expansion of early-career scientists conducting Transdisciplinary Research in Energetics and Cancer (TREC): a report from the TREC Training Workshop 2022.

The overall goal of the annual Transdisciplinary Research in Energetics and Cancer (TREC) Training Workshop is to provide transdisciplinary training for scientists in energetics and cancer and clinical care. The 2022 Workshop included 27 early-to-mid career investigators (trainees) pursuing diverse TREC research areas in basic, clinical, and population sciences. The 2022 trainees participated in a gallery walk, an interactive qualitative program evaluation method, to summarize key takeaways related to program objectives. Writing groups were formed and collaborated on this summary of the 5 key takeaways from the TREC Workshop. The 2022 TREC Workshop provided a targeted and unique networking opportunity that facilitated meaningful collaborative work addressing research and clinical needs in energetics and cancer. This report summarizes the 2022 TREC Workshop's key takeaways and future directions for innovative transdisciplinary energetics and cancer research.

Editorial: Twenty Years On from Sequencing the Human Genome, Personalized/Precision Oncology Prepares to Meet the Challenges of Checkpoint Inhibitor Therapy.

On April 14, 2003, the International Human Genome Project was declared complete after identifying, mapping, and sequencing approximately 92% of the human genome. Significant genetic alterations have now been identified in most human cancers. Personalized, or precision, oncology involves molecular profiling of tumors to identify targetable alterations for drug treatments. T-cell responses to antigens, including tumor-associated antigens, are mediated by the interaction between stimulatory and inhibitory signaling molecules, known as immune checkpoints. Targets of inhibitory checkpoints include programmed death 1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Challenges of checkpoint inhibition therapy include the prevalence and severity of immune-related adverse events (irAEs) and the short duration of response. Also, the beneficial effects in patients with hematologic malignancies other than Hodgkin's lymphoma remain limited. Checkpoint inhibitors are now integrated into standard-of-care for patients with several types of cancer. This Editorial aims to highlight the impact and challenges of checkpoint inhibitors in personalized/precision oncology and how molecular technologies may begin to address these challenges.

Flower-like core-shell nanostructures based on natural asphalt coated with Ni-LDH nanosheets as an electrochemical platform for prostate cancer biomarker sensing.

Flower-like core-shell nanostructures based on natural asphalt (NA) coated with nickel-layered double hydroxide nanosheets (Ni-LDH NSs) were synthesized for the first time. The synthetic nanostructures were successfully used as an efficient platform in the design of sarcosine (SAR) electrochemical aptasensor. SAR is considered an efficient biomarker for prostate cancer (PCa) diagnosis. However, the low concentration of SAR in urine, plasma, and tissue cells has limited the growth of SAR biosensors. The performance of the presented SAR aptasensor is very promising in being applied as a portable device in the identification of PCa. After drawing the calibration curve, the linear concentration range was obtained in two ranges from 5 pM to 100 nM and 100 nM to 7.9 µM, and the limit of detection (LOD) was calculated to be 1.6 pM. This study can provide a basis for wider research in various programs such as developing PCa diagnostic aptasensors and investigating the use of NA nanostructures in other electrochemical applications such as electrocatalysis and energy storage.

Variations in all-cause mortality, premature mortality and cause-specific mortality among persons with diabetes in Ontario, Canada.

INTRODUCTION: Patients with diabetes have a higher risk of mortality compared with the general population. Large population-based studies that quantify variations in mortality risk for patients with diabetes among subgroups in the population are lacking. This study aimed to examine the sociodemographic differences in the risk of all-cause mortality, premature mortality, and cause-specific mortality in persons diagnosed with diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cohort study of 1 741 098 adults diagnosed with diabetes between 1994 and 2017 in Ontario, Canada using linked population files, Canadian census, health administrative and death registry databases. We analyzed the association between sociodemographics and other covariates on all-cause mortality and premature mortality using Cox proportional hazards models. A competing risk analysis using Fine-Gray subdistribution hazards models was used to analyze cardiovascular and circular mortality, cancer mortality, respiratory mortality, and mortality from external causes of injury and poisoning. RESULTS: After full adjustment, individuals with diabetes who lived in the lowest income neighborhoods had a 26% (HR 1.26, 95% CI 1.25 to 1.27) increased hazard of all-cause mortality and 44% (HR 1.44, 95% CI 1.42 to 1.46) increased risk of premature mortality, compared with individuals with diabetes living in the highest income neighborhoods. In fully adjusted models, immigrants with diabetes had reduced risk of all-cause mortality (HR 0.46, 95% CI 0.46 to 0.47) and premature mortality (HR 0.40, 95% CI 0.40 to 0.41), compared with long-term residents with diabetes. Similar HRs associated with income and immigrant status were observed for cause-specific mortality, except for cancer mortality, where we observed attenuation in the income gradient among persons with diabetes. CONCLUSIONS: The observed mortality variations suggest a need to address inequality gaps in diabetes care for persons with diabetes living in the lowest income areas.

Hope in the era of precision oncology: a qualitative study of informal caregivers' experiences.

OBJECTIVES: To explore informal caregivers' perspectives on precision medicine in cancer care. DESIGN: Semi-structured interviews with the informal caregivers of people living with cancer and receiving targeted/immunotherapies. Interview transcripts were analysed thematically using a framework approach. SETTING: Recruitment was facilitated by two hospitals and five Australian cancer community groups. PARTICIPANTS: Informal caregivers (n=28; 16 men, 12 women; aged 18-80) of people living with cancer and receiving targeted/immunotherapies. RESULTS: Thematic analysis identified three findings, centred largely on the pervasive theme of hope in relation to precision therapies including: (1) precision as a key component of caregivers' hope; (2) hope as a collective practice between patients, caregivers, clinicians and others, which entailed work and obligation for caregivers; and (3) hope as linked to expectations of further scientific progress, even if there may be no personal, immediate benefit. CONCLUSIONS: Innovation and change in precision oncology are rapidly reconfiguring the parameters of hope for patients and caregivers, creating new and difficult relational moments and experiences in everyday life and in clinical encounters. In the context of a shifting therapeutic landscape, caregivers' experiences illustrate the need to understand hope as collectively produced, as emotional and moral labour, and as entangled in broader cultural expectations of medical advances. Such understandings may help clinicians as they guide patients and caregivers through the complexities of diagnosis, treatment, emerging evidence and possible futures in the precision era. Developing a better understanding of informal caregivers' experiences of caring for patients receiving precision therapies is important for improving support to patients and their caregivers.

Aggressive giant cell lesion of mandible-confusing to common: true neoplasm versus reactive lesion.

Destructive lesions in the craniofacial region especially in the jawbones, if associated with giant cells, include a spectrum of lesions that pose difficulty in diagnosis. The nature of such a lesion in the jawbones is questionable about whether it is a reactive/benign lesion or aggressive/non-aggressive. Clinical, radiological and histopathological correlation may be a reliable indicator to differentiate between the qualities of the lesion, which directly accounts for effective and individual planning of the treatment. Here we present a case of a woman in her late 20s with an unusual destructive lesion of the mandible.