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Clinics (Sao Paulo, Brazil) 2024Patients with Human Papillomavirus (HPV+)-associated Laryngeal Squamous Cell Carcinoma (LSCC) exhibit dramatically improved survival relative to those with HPV-Negative...
INTRODUCTION
Patients with Human Papillomavirus (HPV+)-associated Laryngeal Squamous Cell Carcinoma (LSCC) exhibit dramatically improved survival relative to those with HPV-Negative (HPV-) tumors. In this study, the authors aimed to investigate the radiosensitivity of all available confirmed HPV+ and HPV-LSCC cells in vitro and in vivo.
METHODS
Primary LSCC cells were generated from tumor specimens obtained from patients. Real-time PCR was performed to confirm HPV infection and the expression of HPV-related genes (E6 and E7), p53, and pRB. Clonogenic survival assays, western blotting, and flow cytometry were used to assess radiation sensitivity, apoptosis, and the expression of p53 and pRB. p53 and pRB knockout cells were generated using CRISPR/Cas9 technology.
RESULTS
HPV+ LSCC cells displayed enhanced radiation sensitivity compared to HPV- cells. Radiation-induced apoptosis in HPV+ LSCC cells, accompanied by increased levels of p53 and pRB. Knockout of p53 or pRB led to radiation resistance and attenuated radiation-induced apoptosis in HPV+ LSCC cells. In vivo experiments showed similar results, where knockout of p53 or pRB decreased radiosensitivity in tumor-bearing mice.
CONCLUSION
The present findings demonstrated that HPV+ LSCC cells displayed obvious inherent radiation sensitivity, corresponding to increased apoptosis following radiation exposure. Mechanism study showed that the expression of p53 and pRB in HPV+ cells are required for radiation sensitivity. These findings highlight a novel mechanism by which p53 and pRB play key roles in the radiation sensitivity of HPV+ LSCC compared to HPV-LSCC.
Topics: Humans; Laryngeal Neoplasms; Carcinoma, Squamous Cell; Tumor Suppressor Protein p53; Radiation Tolerance; Papillomavirus Infections; Apoptosis; Animals; Cell Line, Tumor; Real-Time Polymerase Chain Reaction; Male; Mice; Flow Cytometry; Blotting, Western; Retinoblastoma Protein
PubMed: 38897099
DOI: 10.1016/j.clinsp.2024.100415 -
Journal of Cellular and Molecular... Jun 2024Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was... (Review)
Review
Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was previously considered a benign self-limiting condition, but it is now known to be associated with substantial short- and long-term morbidity and mortality. Because of the poor understanding of its underlying pathophysiology, there are few evidence-based interventions to treat TTS. The hypotheses formulated so far can be grouped into endogenous adrenergic surge, psychological stress or preexisting psychiatric illness, coronary vasospasm with microvascular dysfunction, metabolic and energetic alterations, and inflammatory mechanisms. Current evidence demonstrates that the infiltration of immune cells such as macrophages and neutrophils play a pivotal role in TTS. At baseline, resident macrophages were the dominant subset in cardiac macrophages, however, it underwent a shift from resident macrophages to monocyte-derived infiltrating macrophages in TTS. Depletion of macrophages and monocytes in mice strongly protected them from isoprenaline-induced cardiac dysfunction. It is probable that immune cells, especially macrophages, may be new targets for the treatment of TTS.
Topics: Takotsubo Cardiomyopathy; Humans; Inflammation; Animals; Macrophages
PubMed: 38896112
DOI: 10.1111/jcmm.18503 -
Biomarker Insights 2024Breast cancer is a heterogeneous disease with diverse histological and molecular subtypes. Luminal breast tumors are the most diagnosed subtype. In luminal breast... (Review)
Review
Breast cancer is a heterogeneous disease with diverse histological and molecular subtypes. Luminal breast tumors are the most diagnosed subtype. In luminal breast cancer, hormone receptors (including ER, PR, HER2) play a diagnostic and prognostic role. Despite the effectiveness of endocrine therapy in luminal breast tumors, tumor recurrence and resistance occur, and this may highlight evolutionary strategies for survival driven by stemness. In this review we thus consider the association between estrogen signaling and stemness in mediating tumor processes. Many studies report stemness as one of the factors promoting tumor progression. Its association with estrogen signaling warrants further investigation and provides an opportunity for the identification of novel biomarkers which may be used for diagnostic, prognostic, and therapeutic purposes. Breast cancer stem cells have been characterized (CD44 CD24) and their role in promoting treatment resistance and tumor recurrence widely studied; however, the complexity of tumor progression which also involve microenvironmental factors suggests the existence of more varied cell phenotypes which mediate stemness and its role in tumor progression.
PubMed: 38895160
DOI: 10.1177/11772719241256798 -
Frontiers in Aging 2024Despite effective control of HIV replication by antiretroviral therapy (ART), a significant number of people living with HIV (PLWH) fail to achieve complete immune...
Despite effective control of HIV replication by antiretroviral therapy (ART), a significant number of people living with HIV (PLWH) fail to achieve complete immune reconstitution and thus are deemed immune non-responders (INRs). Compared with immune responders (IRs) who have restored their CD4 T cell numbers and functions, CD4 T cells from these INRs exhibit prominent mitochondrial dysfunction and premature aging, which play a major role in increasing the incidence of non-AIDS, non-communicable diseases (NCDs). To date, there are no reliable biomarkers that can be used to typify and manage PLWH, especially INRs with non-AIDS NCDs. Growth differential factor-15 (GDF-15) is a transforming growth factor-β (TGF-β) family member known to regulate several biological processes involved in cell aging and stress responses. Since PLWH exhibit premature aging and metabolic dysregulation, here we measured the plasma levels of GDF-15 by ELISA and metabolic proteins by proteomic array and correlated the results with clinical parameters in ART-controlled PLWH (including INRs and IRs) and healthy subjects (HS). We found that GDF-15 levels were significantly elevated in PLWH compared to HS. GDF-15 levels were positively correlated with age and negatively associated with body mass and LDL cholesterol levels in the study subjects. Also, elevated GDF-15 levels were correlated with differential dysregulation of multiple metabolic proteins in PLWH. These results suggest that GDF-15 protein may serve as a biomarker of metabolic dysregulation and aging, and this biomarker will be useful in clinical trials targeting aging and metabolic disorders in ART-treated PLWH.
PubMed: 38895099
DOI: 10.3389/fragi.2024.1414866 -
Frontiers in Genetics 2024Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and... (Review)
Review
Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and or organs. Depending on the underlying physiological pathway affected by pathogenic genetic alterations, overgrowth syndromes are associated with a broad spectrum of neoplasia predisposition, (cardio) vascular and neurodevelopmental anomalies, and dysmorphisms. Pathologic overgrowth may be of prenatal or postnatal onset. It either results from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of cells, an increase in interstitial spaces, or from a combination of all of these. The underlying molecular causes comprise a growing number of genetic alterations affecting skeletal growth and Growth-relevant signaling cascades as major effectors, and they can affect the whole body or parts of it (mosaicism). Furthermore, epigenetic modifications play a critical role in the manifestation of some overgrowth diseases. The diagnosis of overgrowth syndromes as the prerequisite of a personalized clinical management can be challenging, due to their clinical and molecular heterogeneity. Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes. In particular, the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy. With the (future) implementation of next-generation sequencing approaches and further technologies, clinical diagnoses can not only be verified, but they also confirm the clinical and molecular spectrum of overgrowth disorders, including unexpected findings and identification of atypical cases. However, the limitations of the applied assays have to be considered, for each of the disorders of interest, the spectrum of possible types of genomic variants has to be considered as they might require different methodological strategies. Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven selection and interpretation of molecular and physiological data.
PubMed: 38894719
DOI: 10.3389/fgene.2024.1382371 -
Frontiers in Molecular Biosciences 2024p53 deficiency plays a crucial role in chemotherapy resistance through various biological events, including posttranslational modifications (PTMs). Recently, lysine...
p53 deficiency plays a crucial role in chemotherapy resistance through various biological events, including posttranslational modifications (PTMs). Recently, lysine crotonylation (Kcr) has been shown to play a vital role in cancer progression. However, the global p53-regulated crotonylome and the function of these altered Kcr proteins after p53 deficiency remain unclear. In this study, we used a SILAC-based quantitative crotonylome to identify 3,520 Kcr in 1924 crotonylated proteins in response to p53 knockout. We found that increased crotonylation of RRM2 at K283 (RRM2) in the presence of p53 deficiency promoted HCT116 cell resistance to cisplatin. We discovered that SIRT7 could be the decrotonylase of RRM2 and was downregulated after p53 knockout, resulting in increased RRM2. Mechanistically, p53 deficiency inhibited cell apoptosis by upregulating RRM2 protein expression and RRM2-mediated cleaved-PARP1 and cleaved-caspase3 expression, and SIRT7 was downregulated to upregulate crotonylation of RRM2 upon p53 deficiency. In conclusion, our results indicated that p53 deficiency plays a malignant role in colon cancer resistance to cisplatin therapy by regulating RRM2 protein and RRM2 expression. Our findings provide a novel therapeutic target against p53-deficient cancer.
PubMed: 38894712
DOI: 10.3389/fmolb.2024.1423594 -
Pharmacology Research & Perspectives Aug 2024Bioengineering and drug delivery technologies play an important role in bridging the gap between basic scientific discovery and clinical application of therapeutics. To... (Review)
Review
Bioengineering and drug delivery technologies play an important role in bridging the gap between basic scientific discovery and clinical application of therapeutics. To identify the optimal treatment, the most critical stage is to diagnose the problem. Often these two may occur simultaneously or in parallel, but in this review, we focus on bottom-up approaches in understanding basic immunologic phenomena to develop targeted therapeutics. This can be observed in several fields; here, we will focus on one of the original immunotherapy targets-cancer-and one of the more recent targets-regenerative medicine. By understanding how our immune system responds in processes such as malignancies, wound healing, and medical device implantation, we can isolate therapeutic targets for pharmacologic and bioengineered interventions.
Topics: Humans; Animals; Bioengineering; Neoplasms; Immunotherapy; Regenerative Medicine; Drug Delivery Systems
PubMed: 38894611
DOI: 10.1002/prp2.1168 -
Diagnostics (Basel, Switzerland) May 2024Artificial intelligence (AI) can radically change almost every aspect of the human experience. In the medical field, there are numerous applications of AI and... (Review)
Review
Revolutionizing Cardiology through Artificial Intelligence-Big Data from Proactive Prevention to Precise Diagnostics and Cutting-Edge Treatment-A Comprehensive Review of the Past 5 Years.
BACKGROUND
Artificial intelligence (AI) can radically change almost every aspect of the human experience. In the medical field, there are numerous applications of AI and subsequently, in a relatively short time, significant progress has been made. Cardiology is not immune to this trend, this fact being supported by the exponential increase in the number of publications in which the algorithms play an important role in data analysis, pattern discovery, identification of anomalies, and therapeutic decision making. Furthermore, with technological development, there have appeared new models of machine learning (ML) and deep learning (DP) that are capable of exploring various applications of AI in cardiology, including areas such as prevention, cardiovascular imaging, electrophysiology, interventional cardiology, and many others. In this sense, the present article aims to provide a general vision of the current state of AI use in cardiology.
RESULTS
We identified and included a subset of 200 papers directly relevant to the current research covering a wide range of applications. Thus, this paper presents AI applications in cardiovascular imaging, arithmology, clinical or emergency cardiology, cardiovascular prevention, and interventional procedures in a summarized manner. Recent studies from the highly scientific literature demonstrate the feasibility and advantages of using AI in different branches of cardiology.
CONCLUSIONS
The integration of AI in cardiology offers promising perspectives for increasing accuracy by decreasing the error rate and increasing efficiency in cardiovascular practice. From predicting the risk of sudden death or the ability to respond to cardiac resynchronization therapy to the diagnosis of pulmonary embolism or the early detection of valvular diseases, AI algorithms have shown their potential to mitigate human error and provide feasible solutions. At the same time, limits imposed by the small samples studied are highlighted alongside the challenges presented by ethical implementation; these relate to legal implications regarding responsibility and decision making processes, ensuring patient confidentiality and data security. All these constitute future research directions that will allow the integration of AI in the progress of cardiology.
PubMed: 38893630
DOI: 10.3390/diagnostics14111103 -
Diagnostics (Basel, Switzerland) May 2024Surface electromyography (sEMG) has emerged as a valuable tool for assessing muscle activity in various clinical and research settings. This review focuses on the... (Review)
Review
Surface electromyography (sEMG) has emerged as a valuable tool for assessing muscle activity in various clinical and research settings. This review focuses on the application of sEMG specifically in the context of paraspinal muscles. The paraspinal muscles play a critical role in providing stability and facilitating movement of the spine. Dysfunctions or alterations in paraspinal muscle activity can lead to various musculoskeletal disorders and spinal pathologies. Therefore, understanding and quantifying paraspinal muscle activity is crucial for accurate diagnosis, treatment planning, and monitoring therapeutic interventions. This review discusses the clinical applications of sEMG in paraspinal muscles, including the assessment of low back pain, spinal disorders, and rehabilitation interventions. It explores how sEMG can aid in diagnosing the potential causes of low back pain and monitoring the effectiveness of physical therapy, spinal manipulative therapy, and exercise protocols. It also discusses emerging technologies and advancements in sEMG techniques that aim to enhance the accuracy and reliability of paraspinal muscle assessment. In summary, the application of sEMG in paraspinal muscles provides valuable insights into muscle function, dysfunction, and therapeutic interventions. By examining the literature on sEMG in paraspinal muscles, this review offers a comprehensive understanding of the current state of research, identifies knowledge gaps, and suggests future directions for optimizing the use of sEMG in assessing paraspinal muscle activity.
PubMed: 38893614
DOI: 10.3390/diagnostics14111086 -
Molecules (Basel, Switzerland) Jun 2024CDK6 plays a key role in the regulation of the cell cycle and is considered a crucial target for cancer therapy. In this work, conformational transitions of CDK6 were...
CDK6 plays a key role in the regulation of the cell cycle and is considered a crucial target for cancer therapy. In this work, conformational transitions of CDK6 were identified by using Gaussian accelerated molecular dynamics (GaMD), deep learning (DL), and free energy landscapes (FELs). DL finds that the binding pocket as well as the T-loop binding to the Vcyclin protein are involved in obvious differences of conformation contacts. This result suggests that the binding pocket of inhibitors (LQQ and AP9) and the binding interface of CDK6 to the Vcyclin protein play a key role in the function of CDK6. The analyses of FELs reveal that the binding pocket and the T-loop of CDK6 have disordered states. The results from principal component analysis (PCA) indicate that the binding of the Vcyclin protein affects the fluctuation behavior of the T-loop in CDK6. Our QM/MM-GBSA calculations suggest that the binding ability of LQQ to CDK6 is stronger than AP9 with or without the binding of the Vcyclin protein. Interaction networks of inhibitors with CDK6 were analyzed and the results reveal that LQQ contributes more hydrogen binding interactions (HBIs) and hot interaction spots with CDK6. In addition, the binding pocket endures flexibility changes from opening to closing states and the Vcyclin protein plays an important role in the stabilizing conformation of the T-loop. We anticipate that this work could provide useful information for further understanding the function of CDK6 and developing new promising inhibitors targeting CDK6.
Topics: Cyclin-Dependent Kinase 6; Molecular Dynamics Simulation; Protein Binding; Deep Learning; Humans; Protein Conformation; Binding Sites; Protein Kinase Inhibitors; Principal Component Analysis; Thermodynamics; Normal Distribution
PubMed: 38893554
DOI: 10.3390/molecules29112681