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British Journal of Haematology Dec 2023Molecular and clinical stratification of patients with angioimmunoblastic T-cell lymphoma (AITL) is unsatisfactory, which hinders the development of personalized...
Molecular and clinical stratification of patients with angioimmunoblastic T-cell lymphoma (AITL) is unsatisfactory, which hinders the development of personalized therapies. This study aimed to identify molecular biomarkers for AITL based on peripheral cell-free DNA (cfDNA) that could be used to predict prognosis and guide treatment non-invasively. A customized panel containing 46 genes was used to study pretreatment cfDNA and paired tumour tissues in 64 Chinese AITL patients from three clinical centres, and gene mutations in cfDNA and tumour tissue were assessed for concordance (34 paired samples). Then, the association of gene mutations and prognosis was analysed, and a functional enrichment analysis was performed. The sequencing results showed good consistency between cfDNA samples and paired tissue samples. KDM5A, STAT1, FANCM, ERBB4, PIK3R5 and NSD1 were identified as novel recurrent mutations. Mutations in FANCM or combinations of RHOA, KDM5A and FAT1 were associated with poor prognosis. Additionally, functional analysis revealed that RHOA might serve as a predictive biomarker of PD-1 blockade respondence. Our findings confirmed the role of cfDNA as a liquid biopsy in AITL, and revealed novel molecular determinants that can stratify patients and guide treatment options.
Topics: Humans; Lymphoma, T-Cell; Prognosis; Cell-Free Nucleic Acids; DNA Fingerprinting; Immunoblastic Lymphadenopathy; Mutation; Lymphoma, T-Cell, Peripheral; Retinoblastoma-Binding Protein 2; DNA Helicases
PubMed: 37646306
DOI: 10.1111/bjh.19089 -
Asia-Pacific Journal of Ophthalmology... 2024Retinoblastoma stands as a paradigm of success in treating malignancies among pediatric patients. Over recent decades, the approach to managing retinoblastoma has... (Review)
Review
Retinoblastoma stands as a paradigm of success in treating malignancies among pediatric patients. Over recent decades, the approach to managing retinoblastoma has evolved significantly, transitioning from the preservation of patients' lives to the preservation of eyes and vision while minimizing treatment-related complications. Chemotherapy, administered through diverse routes, has solidified its role as the cornerstone of retinoblastoma treatment. In addition to intravenous chemotherapy (IVC), alternative administration routes, including intraarterial (IAC), intravitreal, intracameral, and periocular delivery, have emerged as promising modalities for retinoblastoma management. Numerous studies have demonstrated outstanding outcomes, achieving nearly 100% salvage rates for eyes classified under groups A-C. However, for advanced intraocular retinoblastoma (groups D and E eyes), IAC appears to offer superior local control rates compared to IVC. Intravitreal injection of chemotherapeutic agents, when administered in a controlled and secure manner, holds promise in averting the need for enucleation and radiotherapy in advanced retinoblastoma cases presenting with vitreous seeds. The optimal chemotherapy strategy remains meticulously tailored based on numerous factors. This review provides a comprehensive update on chemotherapy across various routes, encompassing key considerations, dosages, administration methods, treatment outcomes, and potential complications. Furthermore, it explores emerging potential treatments and outlines future directions aimed at enhancing treatment outcomes.
Topics: Retinoblastoma; Humans; Retinal Neoplasms; Antineoplastic Agents; Intravitreal Injections
PubMed: 38641204
DOI: 10.1016/j.apjo.2024.100061 -
PeerJ. Computer Science 2023Retinoblastoma, the most prevalent pediatric intraocular malignancy, can cause vision loss in children and adults worldwide. Adults may develop uveal melanoma. It is a...
Retinoblastoma, the most prevalent pediatric intraocular malignancy, can cause vision loss in children and adults worldwide. Adults may develop uveal melanoma. It is a hazardous tumor that can expand swiftly and destroy the eye and surrounding tissue. Thus, early retinoblastoma screening in children is essential. This work isolated retinal tumor cells, which is its main contribution. Tumors were also staged and subtyped. The methods let ophthalmologists discover and forecast retinoblastoma malignancy early. The approach may prevent blindness in infants and adults. Experts in ophthalmology now have more tools because of their disposal and the revolution in deep learning techniques. There are three stages to the suggested approach, and they are pre-processing, segmenting, and classification. The tumor is isolated and labeled on the base picture using various image processing techniques in this approach. Median filtering is initially used to smooth the pictures. The suggested method's unique selling point is the incorporation of fused features, which result from combining those produced using deep learning models (DL) such as EfficientNet and CNN with those obtained by more conventional handmade feature extraction methods. Feature selection (FS) is carried out to enhance the performance of the suggested system further. Here, we present BAOA-S and BAOA-V, two binary variations of the newly introduced Arithmetic Optimization Algorithm (AOA), to perform feature selection. The malignancy and the tumor cells are categorized once they have been segmented. The suggested optimization method enhances the algorithm's parameters, making it well-suited to multimodal pictures taken with varying illness configurations. The proposed system raises the methods' accuracy, sensitivity, and specificity to 100, 99, and 99 percent, respectively. The proposed method is the most effective option and a viable alternative to existing solutions in the market.
PubMed: 38077613
DOI: 10.7717/peerj-cs.1681 -
JCO Global Oncology Jun 2024Stigma is an understudied barrier to health care acceptance in pediatric oncology. We sought to explore the stigma experience, including its impact on cancer treatment...
PURPOSE
Stigma is an understudied barrier to health care acceptance in pediatric oncology. We sought to explore the stigma experience, including its impact on cancer treatment decision making, and identify strategies to mitigate stigma for patients with osteosarcoma and retinoblastoma in Guatemala, Jordan, and Zimbabwe.
METHODS
Participants included caregivers, adolescent patients (age 12-19 years), and health care clinicians. A semistructured interview guide based on The Health Stigma and Discrimination Framework (HSDF) was adapted for use at each site. Interviews were conducted in English, Spanish, Arabic, or Shona, audio-recorded, translated, and transcribed. Thematic analysis focused on stigma practices, experiences, outcomes, drivers, mitigators, and interventions.
RESULTS
We conducted 56 interviews (28 caregivers, 19 health care clinicians, nine patients; 20 in Guatemala, 21 in Jordan, 15 in Zimbabwe). Major themes were organized into categories used to adapt the HSDF to global pediatric cancer care. Themes were described similarly across all sites, ages, and diagnoses, with specific cultural nuances noted. Pediatric cancer stigma was depicted as an isolating and emotional experience beginning at diagnosis and including internalized and associative stigma. Stigma affected decision making and contributed to negative outcomes including delayed diagnosis, treatment abandonment, regret, and psychosocial fragility. Overcoming stigma led to positive outcomes including resilience, treatment adherence, pride, and advocacy. Identified stigma drivers and mitigators were linked to potential interventions.
CONCLUSION
Participants describe a shared stigma experience that transcends geography, cultural context, age, and diagnosis. Stigma manifestations have the potential to impact medical decision making and affect long-term psychological outcomes. Stigma assessment tools and interventions aimed at stigma mitigation including educational initiatives and support groups specific to pediatric cancer should be the focus of future research.
Topics: Humans; Social Stigma; Adolescent; Guatemala; Child; Female; Male; Zimbabwe; Retinoblastoma; Young Adult; Osteosarcoma; Adult; Caregivers
PubMed: 38905576
DOI: 10.1200/GO.24.00017 -
Frontiers in Medicine 2023To analyze causes and prognostic factors for death among Retinoblastoma (Rb) patients treated at a single specialized tertiary cancer center in Jordan.
PURPOSE
To analyze causes and prognostic factors for death among Retinoblastoma (Rb) patients treated at a single specialized tertiary cancer center in Jordan.
METHODS
We reviewed the mortality causes for all Rb patients who have been treated at the King Hussein Cancer Center between 2003 and 2019 and were followed for at least 3 years after diagnosis. The main outcome measures included demographics, laterality, tumor stage, treatment modalities, metastasis, survival, and causes of death.
RESULTS
Twenty-four (5%) of the 478 patients died from retinoblastoma and 5-year survival was 94%. The mean age at diagnosis was 15 months (median, 18 months; range, 4-38 months); eight (33%) received diagnoses within the first year of life. Eleven (46%) were boys, 16 (67%) had bilateral disease, and 3 (13%) had a positive family history. The stage for the worst eye was C for 1 (4%) patient, D in 6 (25%) patients, and E (T3) in 15 (63%) patients. Two patients had extraocular Rb at diagnosis, and four of the patients who had intraocular Rb at diagnosis refused treatment and then came back with extraocular Rb. In total, extraocular disease was encountered in six eyes (six patients). After a 120-month median follow-up period, 24 patients (5%) died of second neoplasms ( = 3) or metastases ( = 21). Significant predictive factors for metastasis and death included advanced IIRC tumor stage ( < 0.0001), the presence of high-risk pathological features in the enucleated eyes ( = 0.013), parental refusal of the recommended primary treatment plan ( < 0.0001), and extraocular extension ( < 0.0001).
CONCLUSION
The 5-year survival rates of Rb patients in Jordan are as high as those in high-income countries. However, 5% are still dying from metastatic disease, prompting the need for awareness campaigns to educate the public about the high cure rates and to prevent treatment abandonment.
PubMed: 37731722
DOI: 10.3389/fmed.2023.1244308 -
Developmental Cell Nov 2023The retinoblastoma (RB) and Hippo pathways interact to regulate cell proliferation and differentiation. However, the mechanism of interaction is not fully understood....
The retinoblastoma (RB) and Hippo pathways interact to regulate cell proliferation and differentiation. However, the mechanism of interaction is not fully understood. Drosophila photoreceptors with inactivated RB and Hippo pathways specify normally but fail to maintain their neuronal identity and dedifferentiate. We performed single-cell RNA sequencing to elucidate the cause of dedifferentiation and to determine the fate of these cells. We find that dedifferentiated cells adopt a progenitor-like fate due to inappropriate activation of the retinal differentiation suppressor homothorax (hth) by Yki/Sd. This results in the activation of a distinct Yki/Hth transcriptional program, driving photoreceptor dedifferentiation. We show that Rbf physically interacts with Yki and, together with the GAGA factor, inhibits the hth expression. Thus, RB and Hippo pathways cooperate to maintain photoreceptor differentiation by preventing inappropriate expression of hth in differentiating photoreceptors. Our work highlights the importance of both RB and Hippo pathway activities for maintaining the state of terminal differentiation.
Topics: Animals; Drosophila; Drosophila melanogaster; Drosophila Proteins; Nuclear Proteins; Retinal Neoplasms; Retinoblastoma; Retinoblastoma Protein; Signal Transduction; Stem Cells; Trans-Activators; Transcription Factors
PubMed: 37848027
DOI: 10.1016/j.devcel.2023.09.003 -
Biomedicine & Pharmacotherapy =... Sep 2023Cordycepin (with a molecular formula of CHNO), a natural adenosine isolated from Cordyceps militaris, has an important regulatory effect on skeletal muscle remodelling...
Cordycepin (with a molecular formula of CHNO), a natural adenosine isolated from Cordyceps militaris, has an important regulatory effect on skeletal muscle remodelling and quality maintenance. The aim of this study was to investigate the effect of cordycepin on myoblast differentiation and explore the underlying molecular mechanisms of this effect. Our results showed that cordycepin inhibited myogenesis by downregulating myogenic differentiation (MyoD) and myogenin (MyoG), preserved undifferentiated reserve cell pools by upregulating myogenic factor 5 (Myf5) and retinoblastoma-like protein p130 (p130), and enhanced energy reserves by decreasing intracellular reactive oxygen species (ROS) and enhancing mitochondrial membrane potential, mitochondrial mass, and ATP content. The effect of cordycepin on myogenesis was associated with increased phosphorylation of extracellular signal-regulated kinase 1/2 (p-ERK1/2). PD98059 (a specific inhibitor of p-ERK1/2) attenuated the inhibitory effect of cordycepin on C2C12 differentiation. The present study reveals that cordycepin inhibits myogenesis through ERK1/2 MAPK signalling activation accompanied by an increase in skeletal muscle energy reserves and improving skeletal muscle oxidative stress, which may have implications for its further application for the prevention and treatment of degenerative muscle diseases caused by the depletion of depleted muscle stem cells.
Topics: MAP Kinase Signaling System; Cell Differentiation; Deoxyadenosines; Muscle Development
PubMed: 37453196
DOI: 10.1016/j.biopha.2023.115163 -
Cancer Reports (Hoboken, N.J.) Sep 2023Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The incidence of HCC is affected by genetic and non-genetic factors. Genetically,... (Review)
Review
BACKGROUND
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The incidence of HCC is affected by genetic and non-genetic factors. Genetically, mutations in the genes, tumor protein P53 (TP53), catenin beta 1 (CTNNB1), AT-rich interaction domain 1A (ARIC1A), cyclin dependent kinase inhibitor 2A (CDKN2A), mannose 6-phosphate (M6P), smooth muscle action against decapentaplegic (SMAD2), retinoblastoma gene (RB1), cyclin D, antigen presenting cells (APC), AXIN1, and E-cadherin, have been shown to contribute to the occurrence of HCC. Non-genetic factors, including alcohol consumption, exposure to aflatoxin, age, gender, presence of hepatitis B (HBV), hepatitis C (HCV), and non-alcoholic fatty liver disease (NAFLD), increase the risk of HCC.
RECENT FINDINGS
The severity of the disease and its occurrence vary based on geographical location. Furthermore, men and minorities have been shown to be disproportionately affected by HCC, compared with women and non-minorities. Ethnicity has been reported to significantly affect tumorigenesis and clinical outcomes in patients diagnosed with HCC. Generally, differences in gene expression and/or the presence of comorbid medical diseases affect or influence the progression of HCC. Non-Caucasian HCC patients are significantly more likely to have poorer survival outcomes, compared to their Caucasian counterparts. Finally, there are a number of factors that contribute to the success rate of treatments for HCC.
CONCLUSION
Assessment and treatment of HCC must be consistent using evidence-based guidelines and standardized outcomes, as well as international clinical practice guidelines for global consensus. Standardizing the assessment approach and method will enable comparison and improvement of liver cancer research through collaboration between researchers, healthcare providers, and advocacy groups. In this review, we will focus on discussing epidemiological factors that result in deviations and changes in treatment approaches for HCC.
Topics: Male; Humans; Female; Carcinoma, Hepatocellular; Liver Neoplasms; Prevalence; Hepatitis B; Hepatitis C; Treatment Outcome
PubMed: 37344125
DOI: 10.1002/cnr2.1821 -
Progress in Retinal and Eye Research May 2024Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools,... (Review)
Review
Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and retinal prostheses offer hope for vision restoration, these high-cost therapies will benefit few patients. Understanding retinal diseases is therefore key to advance effective treatments, requiring in vitro models replicating pathology and allowing quantitative assessments for drug discovery. Pluripotent stem cells (PSCs) provide a unique solution given their limitless supply and ability to differentiate into light-responsive retinal tissues encompassing all cell types. This review focuses on the history and current state of photoreceptor and retinal pigment epithelium (RPE) cell generation from PSCs. We explore the applications of this technology in disease modelling, experimental therapy testing, biomarker identification, and toxicity studies. We consider challenges in scalability, standardisation, and reproducibility, and stress the importance of incorporating vasculature and immune cells into retinal organoids. We advocate for high-throughput automation in data acquisition and analyses and underscore the value of advanced micro-physiological systems that fully capture the interactions between the neural retina, RPE, and choriocapillaris.
Topics: Animals; Humans; Cell Differentiation; Pluripotent Stem Cells; Retinal Diseases; Retinal Pigment Epithelium
PubMed: 38369182
DOI: 10.1016/j.preteyeres.2024.101248 -
Aging and Disease Feb 2024Diabetic wounds represent a formidable challenge in the clinical management of diabetes mellitus, markedly diminishing the patient's quality of life. These wounds arise... (Review)
Review
Diabetic wounds represent a formidable challenge in the clinical management of diabetes mellitus, markedly diminishing the patient's quality of life. These wounds arise from a multifaceted etiology, with the pathophysiological underpinnings remaining elusive and complex. Diabetes precipitates neuropathies and vasculopathies in the lower extremities, culminating in infections, ulcerations, and extensive tissue damage. The hallmarks of non-healing diabetic wounds include senescence, persistent inflammation, heightened apoptosis, and attenuated cellular proliferation. The TP53 gene, a pivotal tumor suppressor frequently silenced in human malignancies, orchestrates cellular proliferation, senescence, DNA repair, and apoptosis. While p53 is integral in cell cycle regulation, its role in initial tissue repair appears to be deleterious. In typical cutaneous wounds, p53 levels transiently dip, swiftly reverting to baseline. Yet in diabetic wounds, protracted p53 activation impedes healing via two distinct pathways: i) activating the p53-p21-Retinoblastoma (RB) axis, which halts the cell cycle, and ii) upregulating the cGAS-STING and nuclear factor-kappaB (NF-κB) cascades, instigating ferroptosis and pyroptosis. Furthermore, p53 intersects with various metabolic pathways, including glycolysis, gluconeogenesis, oxidative phosphorylation, and autophagy. In diabetic wounds, p53 may drive metabolic reprogramming, thus potentially derailing macrophage polarization. This review synthesizes case studies investigating the therapeutic modulation of p53 in diabetic wounds care. In summation, p53 modulates chronic inflammation and cellular aging within diabetic cutaneous wounds and is implicated in a novel cell death modality, encompassing ferroptosis and pyroptosis, which hinders the reparative process.
PubMed: 38377027
DOI: 10.14336/AD.2024.0212