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1.
ACS Appl Mater Interfaces ; 16(14): 17242-17252, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38556729

RESUMO

Protective autophagy and DNA damage repair lead to tumor radio-resistance. Some hypoxic tumors exhibit a low radiation energy absorption coefficient in radiation therapy. High doses of X-rays may lead to side effects in the surrounding normal tissues. In order to overcome the radio-resistance and improve the efficacy of radiotherapy based on the characteristics of the tumor microenvironment, the development of radiosensitizers has attracted much attention. In this study, a Janus ACSP nanoparticle (NP) was developed for chemodynamic therapy and radiosensitization. The reactive oxygen species generated by the Fenton-like reaction regulated the distribution of cell cycles from a radioresistant phase to a radio-sensitive phase. The high-Z element, Au, enhanced the production of hydroxyl radicals (•OH) under X-ray radiation, promoting DNA damage and cell apoptosis. The NP delayed DNA damage repair by interfering with certain proteins involved in the DNA repair signaling pathway. In vivo experiments demonstrated that the combination of the copper-ion-based Fenton-like reaction and low-dose X-ray radiation enhanced the effectiveness of radiotherapy, providing a novel approach for synergistic chemodynamic and radiosensitization therapy. This study provides valuable insights and strategies for the development and application of NPs in cancer treatment.


Assuntos
Nanopartículas , Neoplasias , Radiossensibilizantes , Humanos , Neoplasias/tratamento farmacológico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Microambiente Tumoral , Peróxido de Hidrogênio
2.
Mol Pharm ; 21(4): 1919-1932, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38557163

RESUMO

HER2 status determination is a necessary step for the proper choice of therapy and selection of patients for the targeted treatment of cancer. Targeted radiotracers such as radiolabeled DARPins provide a noninvasive and effective way for the molecular imaging of HER2 expression. This study aimed to evaluate tumor-targeting properties of three 99mTc-labeled DARPin G3 variants containing Gly-Gly-Gly-Cys (G3C), (Gly-Gly-Gly-Ser)3-Cys ((G3S)3C), or Glu-Glu-Glu-Cys (E3C) amino acid linkers at the C-terminus and conjugated to the HYNIC chelating agent, as well as to compare them with the clinically evaluated DARPin G3 labeled with 99mTc(CO)3 using the (HE)3-tag at the N-terminus. The labeling of DARPin G3-HYNIC variants provided radiochemical yields in the range of 50-80%. Labeled variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 0.5-3 nM. There was no substantial influence of the linker and HYNIC chelator on the binding of 99mTc-labeled DARPin G3 variants to HER2 in vitro; however, [99mTc]Tc-G3-(G3S)3C-HYNIC had the highest affinity. Comparative biodistribution of [99mTc]Tc-G3-G3C-HYNIC, [99mTc]Tc-G3-(G3S)3C-HYNIC, [99mTc]Tc-G3-E3C-HYNIC, and [99mTc]Tc-(HE)3-G3 in healthy CD1 mice showed that there was a strong influence of the linkers on uptake in normal tissues. [99mTc]Tc-G3-E3C-HYNIC had an increased retention of activity in the liver and the majority of other organs compared to the other conjugates. The tumor uptake of [99mTc]Tc-G3-(G3S)3C-HYNIC and [99mTc]Tc-(HE)3-G3 in Nu/j mice bearing SKOV-3 xenografts was similar. The specificity of tumor targeting in vivo was demonstrated for both tracers. [99mTc]Tc-G3-(G3S)3C-HYNIC provided comparable, although slightly lower tumor-to-lung, tumor-to spleen and tumor-to-liver ratios than [99mTc]Tc-(HE)3-G3. Radiolabeling of DARPin G3-HYNIC conjugates with 99mTc provided the advantage of a single-step radiolabeling procedure; however, the studied HYNIC conjugates did not improve imaging contrast compared to the 99mTc-tricarbonyl-labeled DARPin G3. At this stage, [99mTc]Tc-(HE)3-G3 remains the most promising candidate for the clinical imaging of HER2-overexpressing cancers.


Assuntos
Proteínas de Repetição de Anquirina Projetadas , Neoplasias , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/patologia , Distribuição Tecidual , Receptor ErbB-2/genética
3.
J Clin Invest ; 134(7)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38557488

RESUMO

While breast cancer 2 (BRCA2) loss of heterozygosity (LOH) promotes cancer initiation, it can also induce death in nontransformed cells. In contrast, mismatch repair gene mutL homolog 1 (MLH1) is a tumor-suppressor gene that protects cells from cancer development through repairing mismatched base pairs during DNA mismatch repair (MMR). Sengodan et al., in this issue of the JCI, reveal an interplay between the 2 genes: MLH1 promoted the survival of BRCA2-deficient cells independently of its MMR function. MLH1 protected replication forks from degradation, while also resolving R-loops, thereby reducing genomic instability. Moreover, MLH1 expression was regulated directly by estrogen, shedding light into the hormone-responsive nature of many BRCA2 mutant breast cancers. These results provide important insight into the genetics that drive the initiation of BRCA2-mutated breast cancers.


Assuntos
Neoplasias da Mama , Proteína 1 Homóloga a MutL , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Instabilidade Genômica , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-38558290

RESUMO

Nanomedicine in oncology has not had the success in clinical impact that was anticipated in the early stages of the field's development. Ideally, nanomedicines selectively accumulate in tumor tissue and reduce systemic side effects compared to traditional chemotherapeutics. However, this has been more successful in preclinical animal models than in humans. The causes of this failure to translate may be related to the intra- and inter-patient heterogeneity of the tumor microenvironment. Predicting whether a patient will respond positively to treatment prior to its initiation, through evaluation of characteristics like nanoparticle extravasation and retention potential in the tumor, may be a way to improve nanomedicine success rate. While there are many potential strategies to accomplish this, prediction and patient stratification via noninvasive medical imaging may be the most efficient and specific strategy. There have been some preclinical and clinical advances in this area using MRI, CT, PET, and other modalities. An alternative approach that has not been studied as extensively is biomedical ultrasound, including techniques such as multiparametric contrast-enhanced ultrasound (mpCEUS), doppler, elastography, and super-resolution processing. Ultrasound is safe, inexpensive, noninvasive, and capable of imaging the entire tumor with high temporal and spatial resolution. In this work, we summarize the in vivo imaging tools that have been used to predict nanoparticle distribution and treatment efficacy in oncology. We emphasize ultrasound imaging and the recent developments in the field concerning CEUS. The successful implementation of an imaging strategy for prediction of nanoparticle accumulation in tumors could lead to increased clinical translation of nanomedicines, and subsequently, improved patient outcomes. This article is categorized under: Diagnostic Tools In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery Emerging Technologies.


Assuntos
Nanopartículas , Neoplasias , Animais , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Ultrassonografia , Imageamento por Ressonância Magnética , Resultado do Tratamento , Nanopartículas/uso terapêutico , Nanomedicina/métodos , Sistemas de Liberação de Medicamentos , Microambiente Tumoral
5.
Elife ; 122024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578269

RESUMO

Background: Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality. Methods: We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors. Results: Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15-38%) higher total mortality, 14% (95% CI, 0-31%) higher cancer mortality, and 31% (95% CI, 10-55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects. Conclusions: Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality. Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


Fatty acids play an essential role in health. Studies have shown that diets high in omega-3 fatty acids found in foods like fish, fish oil, flaxseed and walnuts may be beneficial. Yet some studies have raised concern that too many omega-6 fatty acids in Western diets rich in vegetable oils may be harmful. Some scientists have proposed that the balance of omega-3 and omega-6 in diets is vital to health. They hypothesize that a higher omega-6 to omega-3 fatty acids ratio is detrimental. But, proving that a higher ratio of omega-6 to omega-3 fatty acids is harmful has been difficult. Many studies have found conflicting results. Scientists have struggled to accurately measure fatty acid intake as tracking an individual's dietary intake is challenging and self-reported dietary intake may be incorrect. Additionally, scientists must follow individuals for many years to determine if a high ratio of omega-6 to omega-3 is linked with cancer, heart disease, or death. But, measuring circulating fatty acids in an individual's blood may offer an easier and more reliable approach to studying the health impacts of these vital nutrients. Zhang et al. show that people with higher ratios of omega-6 to omega-3 fatty acids in their blood are at greater risk of dying from cancer, heart disease, or any cause than those with lower ratios. The experiments measured omega-6 and omega-3 fatty acid levels in more than 85,000 participants in the UK Biobank who scientists followed for an average of about 13 years. Participants with the highest ratios of omega-6 to omega-3 fatty acids were 26% more likely to die of any cause, 14% more likely to die of cancer, and 31% more likely to die of heart disease than individuals with the lowest ratios. Individually, high levels of omega-6 fatty acids and high levels of omega-3 fatty acids were both associated with a lower risk of dying. But the protective effects of omega-3 were greater. For example, individuals with the highest levels of omega-6 fatty acids were 23% less likely to die of any cause. By comparison, those with the highest levels of omega-3s were 31% less likely to die. The stronger protection offered by high levels of omega-3s likely explains why having a high ratio of omega-6s to omega-3s was linked to harm. Both are protective. But the protection provided by omega-3s is more robust. The experiments support dietary interventions to raise omega-3 fatty acid levels and maintain a low omega-6 to omega-3 fatty acid ratio to prevent early deaths from cancer, heart disease or other causes. More research is needed to understand the impact of dietary fatty acid intake on other diseases and how genetics may influence the health impact of fatty acids.


Assuntos
Doenças Cardiovasculares , Ácidos Graxos Ômega-3 , Neoplasias , Humanos , Estudos de Coortes , Estudos Prospectivos , 60682 , Bancos de Espécimes Biológicos , Ácidos Graxos Ômega-6 , Neoplasias/epidemiologia
6.
PLoS One ; 19(4): e0301591, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38593144

RESUMO

Multi-layer Complex networks are commonly used for modeling and analysing biological entities. This paper presents the advantage of using COMBO (Combining Multi Bio Omics) to suggest a new role of the chromosomal aberration as a cancer driver factor. Exploiting the heterogeneous multi-layer networks, COMBO integrates gene expression and DNA-methylation data in order to identify complex bilateral relationships between transcriptome and epigenome. We evaluated the multi-layer networks generated by COMBO on different TCGA cancer datasets (COAD, BLCA, BRCA, CESC, STAD) focusing on the effect of a specific chromosomal numerical aberration, broad gain in chromosome 20, on different cancer histotypes. In addition, the effect of chromosome 8q amplification was tested in the same TCGA cancer dataset. The results demonstrate the ability of COMBO to identify the chromosome 20 amplification cancer driver force in the different TCGA Pan Cancer project datasets.


Assuntos
Aberrações Cromossômicas , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Metilação de DNA , Transcriptoma , Epigenoma
8.
Cell Death Dis ; 15(4): 254, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594256

RESUMO

Immunotherapy is emerging as a promising avenue in oncology, gaining increasing importance and offering substantial advantages when compared to chemotherapy or radiotherapy. However, in the context of immunotherapy, there is the potential for the immune system to either support or hinder the administered treatment. This review encompasses recent and pivotal studies that assess the influence of dietary elements, including vitamins, fatty acids, nutrients, small dietary molecules, dietary patterns, and caloric restriction, on the ability to modulate immune responses. Furthermore, the article underscores how these dietary factors have the potential to modify and enhance the effectiveness of anticancer immunotherapy. It emphasizes the necessity for additional research to comprehend the underlying mechanisms for optimizing the efficacy of anticancer therapy and defining dietary strategies that may reduce cancer-related morbidity and mortality. Persistent investigation in this field holds significant promise for improving cancer treatment outcomes and maximizing the benefits of immunotherapy.


Assuntos
Neoplasias , Humanos , Neoplasias/terapia , Imunoterapia , Dieta
9.
Nat Commun ; 15(1): 3063, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594278

RESUMO

Programmed cell death ligand 1 (PDL1), as an important biomarker, is quantified by immunohistochemistry (IHC) with few established histopathological patterns. Deep learning aids in histopathological assessment, yet heterogeneity and lacking spatially resolved annotations challenge precise analysis. Here, we present a weakly supervised learning approach using bulk RNA sequencing for PDL1 expression prediction from hematoxylin and eosin (H&E) slides. Our method extends the multiple instance learning paradigm with the teacher-student framework, which assigns dynamic pseudo-labels for intra-slide heterogeneity and retrieves unlabeled instances using temporal ensemble model distillation. The approach, evaluated on 12,299 slides across 20 solid tumor types, achieves a weighted average area under the curve of 0.83 on fresh-frozen and 0.74 on formalin-fixed specimens for 9 tumors with PDL1 as an established biomarker. Our method predicts PDL1 expression patterns, validated by IHC on 20 slides, offering insights into histologies relevant to PDL1. This demonstrates the potential of deep learning in identifying diverse histological patterns for molecular changes from H&E images.


Assuntos
Destilação , Neoplasias , Humanos , Amarelo de Eosina-(YS) , Hematoxilina , Neoplasias/genética , Biomarcadores , Estudantes
10.
Blood Cancer J ; 14(1): 57, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594285

RESUMO

In 2022, two novel classification systems for myelodysplastic syndromes/neoplasms (MDS) have been proposed: the International Consensus Classification (ICC) and the 2022 World Health Organization (WHO-2022) classification. These two contemporary systems exhibit numerous shared features but also diverge significantly in terminology and the definition of new entities. Thus, we retrospectively validated the ICC and WHO-2022 classification and found that both systems promoted efficient segregation of this heterogeneous disease. After examining the distinction between the two systems, we showed that a peripheral blood blast percentage ≥ 5% indicates adverse survival. Identifying MDS/acute myeloid leukemia with MDS-related gene mutations or cytogenetic abnormalities helps differentiate survival outcomes. In MDS, not otherwise specified patients, those diagnosed with hypoplastic MDS and single lineage dysplasia displayed a trend of superior survival compared to other low-risk MDS patients. Furthermore, the impact of bone marrow fibrosis on survival was less pronounced within the ICC framework. Allogeneic transplantation appears to improve outcomes for patients diagnosed with MDS with excess blasts in the ICC. Therefore, we proposed an integrated system that may lead to the accurate diagnosis and advancement of future research for MDS. Prospective studies are warranted to validate this refined classification.


Assuntos
Síndromes Mielodisplásicas , Neoplasias , Humanos , Estudos Retrospectivos , Consenso , Prognóstico , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/genética , Organização Mundial da Saúde
11.
Sci Rep ; 14(1): 8329, 2024 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594321

RESUMO

Patients with advanced cancer are frequently burdened with a severe sensation of fatigue called cancer-related fatigue (CRF). CRF is induced at various stages and treatments, such as cachexia and chemotherapy, and reduces the overall survival of patients. Objective and quantitative assessment of CRF could contribute to the diagnosis and prediction of treatment efficacy. However, such studies have not been intensively performed, particularly regarding metabolic profiles. Here, we conducted plasma metabolomics of 15 patients with urological cancer. The patients with and without fatigue, including those with cachexia or chemotherapy-induced fatigue, were compared. Significantly lower concentrations of valine and tryptophan were observed in fatigued patients than in non-fatigued patients. In addition, significantly higher concentrations of polyamine pathway metabolites were observed in patients with fatigue and cachexia than in those without cachexia. Patients with exacerbated fatigue due to chemotherapy showed significantly decreased cysteine and methionine metabolism before chemotherapy compared with those without fatigue exacerbation. These findings suggest that plasma metabolic profiles could help improve the diagnosis and monitoring of CRF.


Assuntos
Caquexia , Neoplasias , Humanos , Caquexia/etiologia , Caquexia/diagnóstico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Metabolômica , Metaboloma , Fadiga/etiologia
12.
BMC Palliat Care ; 23(1): 93, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38594658

RESUMO

BACKGROUND: Our aim was to assess temporal trends and compare quality indicators related to Palliative and End-of-Life Care (PEoLC) experienced by people dying of cancer (trajectory I), organ-failure (Trajectory II), and frailty/dementia (trajectory III) in Quebec (Canada) between 2002 and 2016. METHODS: This descriptive population-based study focused on the last month of life of decedents who, based on the principal cause of death, would have been likely to benefit from palliative care. Five PEoLC indicators were assessed: home deaths (1), deaths in acute care beds with no PEoLC services (2), at least one Emergency Room (ER) visit in the last 14 days of life (3), ER visits on the day of death (4) and at least one Intensive Care Unit (ICU) admission in the last month of life (5). Data were obtained from Quebec's Integrated Chronic Disease Surveillance System (QICDSS). RESULTS: The annual percentage of home deaths increased slightly between 2002 and 2016 in Quebec, rising from 7.7 to 9.1%, while the percentage of death during a hospitalization in acute care without palliative care decreased from 39.6% in 2002 to 21.4% in 2016. Patients with organ failure were more likely to visit the ER on the day of death (20.9%) than patients dying of cancer and dementia/frailty with percentages of 12.0% and 6.4% respectively. Similar discrepancies were observed for ICU visits in the last month and ER visits in the last 14 days. CONCLUSION: PEoLC indicators showed more aggressiveness of care for patients with organ failure and highlight the need for more equitable access to quality PEoLC between malignant and non-malignant illness trajectories. These results underline the challenges of providing timely and optimal PEoLC.


Assuntos
Demência , Fragilidade , Neoplasias , Assistência Terminal , Humanos , Quebeque , Cuidados Paliativos , Canadá , Neoplasias/terapia , Estudos Retrospectivos
13.
J Med Case Rep ; 18(1): 167, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38594735

RESUMO

BACKGROUND: Pulmonary inflammatory myofibroblastic tumour (IMT) is a rare condition that usually presents in young individuals and is associated with anaplastic lymphoma kinase (ALK)-translocation. CASE PRESENTATION: We report a case of an 18-year-old Caucasian man with ALK-translocated pulmonary IMT treated with multimodality therapy. The patient presented with breathlessness and was found to have a collapsed left lung. Further investigations revealed an ALK-translocated pulmonary IMT. This is usually treated with an ALK-inhibitor but patient declined after discussing potential side-effects and had repeated rigid bronchoscopic interventions for local disease control. Due to persistent local recurrence, patient received radical external beam radiotherapy (EBRT) with pulse steroids, and one year later started on Ibuprofen, a non-steroidal anti-inflammatory agent (NSAID). Following multimodality treatment, he developed a complete response. He remains treatment-free for the past seven years. Eleven years on from his diagnosis, he remains in remission with a ECOG performance status of zero. CONCLUSIONS: Achieving long-term local control in pulmonary IMT can be challenging. Multimodality treatment is sometimes needed but the overall outlook remains good.


Assuntos
Neoplasias , Inibidores de Proteínas Quinases , Masculino , Humanos , Adolescente , Quinase do Linfoma Anaplásico/genética , Inibidores de Proteínas Quinases/uso terapêutico , Translocação Genética , 60410
14.
Mymensingh Med J ; 33(2): 501-508, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38557533

RESUMO

Palliative care is a valued aspect of clinical care which is an urgent humanitarian need for people worldwide with cancer and other chronic fatal diseases. Patients experience many different symptoms including severe pain in advanced cancer. Palliative care focuses on relief from symptoms, pain and stress by using different analgesics and adjuvant. The goal of palliative care is to improve the quality of life. So, this prospective observational study was carried out to assess pattern of drugs used and their response to pain in cancer patients attending out-patient department of palliative care service in two teaching hospitals of Bangladesh. One hundred forty (140) cancer patients were purposively selected who attended in out-patient department of palliative care unit in Bangabandhu Sheikh Mujib Medical University (BSMMU) and Dhaka Medical College Hospital (DMCH) from July 2018 to June 2019. Outcome variables were commonly presenting complaints, pain intensity, commonly prescribed drugs and analgesic prescription according to WHO three-step analgesic ladder, etc. The mean age ±SD of the respondents was 51.30±15.38 years, male-female ratio 1:1. Common sites of cancer were alimentary origin (20.0%), genitourinary system (17.86%), hepatobiliary system (11.43%), respiratory system (10.71%). The prescribed drugs were analgesics (96.4%), PPIs (74.3%), laxatives (62.1%), anti-emetics (38.6%), multivitamins (32.9%), H2 antagonists (17.1%), sedatives (17.1%), and corticosteroids (8.6%). Level 1 analgesics (Paracetamol or other NSAIDs) were prescribed to 42.65%, level 2 analgesics (Tramadol) were prescribed to 50.00% patients and level 3 analgesics (Morphine) were prescribed to 51.42% patients. The relation between and receiving three levels of analgesic prescriptions was statistically significant. The association between level of analgesic prescription was significant with site of cancer (p<0.001) and intensity of pain (p<0.001). This study showed that morphine was prescribed to more than half of the patients. Other level of analgesics were also used either single or in combination. Younger and male patients were treated more with level III analgesics. Prescribing analgesics were dependent on sites of cancer and intensity of pain.


Assuntos
Neoplasias , Pacientes Ambulatoriais , Feminino , Humanos , Masculino , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Bangladesh , Hospitais de Ensino , Derivados da Morfina/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Dor , Cuidados Paliativos/métodos , Qualidade de Vida , Estudos Prospectivos
15.
Mol Biol Rep ; 51(1): 487, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578532

RESUMO

The stimulator of the interferon genes (STING) signaling pathway plays a crucial role in innate immunity by detecting cytoplasmic DNA and initiating antiviral host defense mechanisms. The STING cascade is triggered when the enzyme cyclic GMP-AMP synthase (cGAS) binds cytosolic DNA and synthesizes the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum adaptor STING, leading to the activation of kinases TBK1 and IRF3 that induce interferon production. Secreted interferons establish an antiviral state in infected and adjacent cells. Beyond infections, aberrant DNA in cancer cells can also activate the STING pathway. Preclinical studies have shown that pharmacological STING agonists like cyclic dinucleotides elicit antitumor immunity when administered intratumorally by provoking innate and adaptive immunity. Combining STING agonists with immune checkpoint inhibitors may improve outcomes by overcoming tumor immunosuppression. First-generation STING agonists encountered challenges like poor pharmacokinetics, limited tumor specificity, and systemic toxicity. The development of the next-generation STING-targeted drugs to realize the full potential of engaging this pathway for cancer treatment can be a solution to overcome the current challenges, but further studies are required to determine optimal applications and combination regimens for the clinic. Notably, the controlled activation of STING is needed to preclude adverse effects. This review explores the mechanisms and effects of STING activation, its role in cancer immunotherapy, and current challenges.


Assuntos
Imunoterapia , Neoplasias , Nucleotidiltransferases , Humanos , Antivirais , DNA/genética , Imunidade Inata , Interferons , Neoplasias/terapia , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo
17.
BMC Cancer ; 24(1): 412, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566032

RESUMO

BACKGROUND: Tumor genomic profiling (TGP) identifies targets for precision cancer treatments, but also secondary hereditary risks. Oncologists are poorly trained to communicate the results of TGP, especially among patients with lower health literacy, poorer genetics knowledge, and higher mistrust. African American (AA) patients are especially vulnerable to poor understanding due to significant cancer disparities and lower uptake of TGP. The goal of this research is to inform the development of an internet-based brief educational support for oncologists to prepare them to provide better decisional support related to TGP for their AA cancer patients. METHODS: This mixed-methods study used semi-structured interviews of oncologists to inform development of an online survey with a convenience sample of US-based oncologists (n = 50) to assess perceptions of the challenges of TGP and communicating results to AA patients. RESULTS: Most interviewed oncologists felt it was important to consider racial/cultural differences when communicating about hereditary risks. Cost, family dynamics, discrimination concerns, and medical mistrust were identified as particularly salient. Survey respondents' views related to AAs and perceptions of TGP were strongly associated with years since completing training, with recent graduates expressing stronger agreement with statements identifying barriers/disadvantages to TGP for AA patients. CONCLUSIONS: Oncologists who had more recently completed training expressed more negative perceptions of TGP and more perceived challenges in communicating about TGP with their AA patients. Focused training for oncologists that addresses barriers specific to AAs may be helpful in supporting improved communication about TGP and improved decisional support for AA patients with cancer considering TGP to evaluate their tumors.


Assuntos
Neoplasias , Humanos , Negro ou Afro-Americano/genética , Genômica , Neoplasias/genética , Oncologistas , Confiança , Fatores de Risco , Comunicação , Relações Médico-Paciente
18.
Front Immunol ; 15: 1330644, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38558804

RESUMO

Background: Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. Objective: To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. Methods: A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. Results: With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. Conclusion: PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.


Assuntos
Antígenos de Superfície da Hepatite B , Neoplasias , Humanos , Vírus da Hepatite B/fisiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Antígenos E da Hepatite B , Estudos Retrospectivos , DNA Viral , Fatores de Risco , Neoplasias/tratamento farmacológico
19.
Mol Oncol ; 18(4): 781-784, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38561242

RESUMO

Oncolytic viruses (OVs) are biological therapeutic agents that selectively destroy cancer cells while sparing normal healthy cells. Besides direct oncolysis, OV infection induces a proinflammatory shift in the tumor microenvironment and the release of tumor-associated antigens (TAAs) that might induce an anti-tumor immunity. Due to their immunostimulatory effect, OVs have been explored for cancer vaccination against specific TAAs. However, this approach usually requires genetic modification of the virus and the production of a new viral vector for each target, which is difficult to implement for low prevalent antigens. In a recent study, Chiaro et al. presented an elegant proof of concept on how to implement the PeptiCRAd vaccination platform to overcome this limitation for the treatment of mesothelioma. Authors showed the feasibility of identifying immunogenic TAAs in human mesothelioma and using them to coat oncolytic adenovirus particles. The result was a customized virus-based cancer vaccine that circumvents time and resource-consuming steps incurred from genetically engineering viruses. Although some questions remain to be addressed, this interesting approach suggests novel strategies for personalized cancer medicine using oncolytic virotherapy.


Assuntos
Mesotelioma Maligno , Mesotelioma , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Adenoviridae/genética , Casamento , Vírus Oncolíticos/genética , Mesotelioma/terapia , Antígenos de Neoplasias , Microambiente Tumoral
20.
BMJ ; 385: q784, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580383
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