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Clinica Chimica Acta; International... Jun 2024Breast cancer (BC) remains the most prevalent cancer among women worldwide, despite significant advancements in its prevention and treatment. The escalating incidence of...
Breast cancer (BC) remains the most prevalent cancer among women worldwide, despite significant advancements in its prevention and treatment. The escalating incidence of BC globally necessitates continued research into novel diagnostic and therapeutic strategies. Metabolomics, a burgeoning field, offers a comprehensive analysis of all metabolites within a cell, tissue, system, or organism, providing crucial insights into the dynamic changes occurring during cancer development and progression. This review focuses on the metabolic alterations associated with BC, highlighting the potential of metabolomics in identifying biomarkers for early detection, diagnosis, treatment and prognosis. Metabolomics studies have revealed distinct metabolic signatures in BC, including alterations in lipid metabolism, amino acid metabolism, and energy metabolism. These metabolic changes not only support the rapid proliferation of cancer cells but also influence the tumour microenvironment and therapeutic response. Furthermore, metabolomics holds great promise in personalized medicine, facilitating the development of tailored treatment strategies based on an individual's metabolic profile. By providing a holistic view of the metabolic changes in BC, metabolomics has the potential to revolutionize our understanding of the disease and improve patient outcomes.
PubMed: 38944408
DOI: 10.1016/j.cca.2024.119836 -
Mitochondrion Jun 2024Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein... (Review)
Review
Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.
PubMed: 38944367
DOI: 10.1016/j.mito.2024.101926 -
Clinical Immunology (Orlando, Fla.) Jun 2024Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of...
OBJECTIVE
Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1.
METHODS
Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs.
RESULTS
Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6.
CONCLUSION
LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.
PubMed: 38944365
DOI: 10.1016/j.clim.2024.110290 -
Clinical Immunology (Orlando, Fla.) Jun 2024Septic cardiomyopathy (SCM) is characterized by an abnormal inflammatory response and increased mortality. The role of efferocytosis in SCM is not well understood. We...
Integrated multi-omics analysis and machine learning developed diagnostic markers and prognostic model based on Efferocytosis-associated signatures for septic cardiomyopathy.
Septic cardiomyopathy (SCM) is characterized by an abnormal inflammatory response and increased mortality. The role of efferocytosis in SCM is not well understood. We used integrated multi-omics analysis to explore the clinical and genetic roles of efferocytosis in SCM. We identified six module genes (ATP11C, CD36, CEBPB, MAPK3, MAPKAPK2, PECAM1) strongly associated with SCM, leading to an accurate predictive model. Subgroups defined by EFFscore exhibited distinct clinical features and immune infiltration levels. Survival analysis showed that the C1 subtype with a lower EFFscore had better survival outcomes. scRNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from sepsis patients identified four genes (CEBPB, CD36, PECAM1, MAPKAPK2) associated with high EFFscores, highlighting their role in SCM. Molecular docking confirmed interactions between diagnostic genes and tamibarotene. Experimental validation supported our computational results. In conclusion, our study identifies a novel efferocytosis-related SCM subtype and diagnostic biomarkers, offering new insights for clinical diagnosis and therapy.
PubMed: 38944364
DOI: 10.1016/j.clim.2024.110301 -
Radiotherapy and Oncology : Journal of... Jun 2024Sacrococcygeal chordomas have high recurrence rates and are challenging to treat.
INTRODUCTION
Sacrococcygeal chordomas have high recurrence rates and are challenging to treat.
METHODS
In this phase II prospective, randomized, stratified trial, the safety and feasibility of hypofractionated ion radiation therapy were investigated. The primary focus was monitored through the incidence of Grade 3-5 NCI-CTC-AE toxicity. Secondary endpoints included local progression-free (LPFS) and overall survival (OS).
RESULTS
The study enrolled 82 patients with primary (87 %) and recurrent (13 %) inoperable or incompletely resected sacral chordomas from January 2013 to July 2022, divided equally into proton therapy (Arm A) and carbon ion beam therapy (Arm B) groups, each receiving a total dose of 64 Gy (RBE) in 16 fractions, 5-6 fractions per week. Overall 74 % of patients received no previous surgery and 66 % of tumors were confirmed by a brachyury staining. The mean and median Gross Tumor Volume at the time of treatment (GTV) was 407 ml and 185 ml, respectively. The median follow-up of the surviving patients was 44.7 months, and the 2-year and 4-year OS rates were 96 % and 81 %, respectively. Factors such as smaller GTV and younger age trended towards better OS. The LPFS after 2-year and 4-year was 84 % and 70 %, respectively. Male gender emerged as a significant predictor of LPFS. There was no significant difference between the treatment groups. We observed five grade IV wound healing disorders (6 %).
CONCLUSION
The initial response rates were promising; however local control was not sustained. More comparative research on fractionation schemes is essential to refine treatment approaches for inoperable sacral chordoma.
PubMed: 38944346
DOI: 10.1016/j.radonc.2024.110418 -
Experimental Neurology Jun 2024Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable...
Moderate intensity aerobic exercise alleviates motor deficits in 6-OHDA lesioned rats and reduces serum levels of biomarkers of Parkinson's disease severity without recovery of striatal dopamine or tyrosine hydroxylase.
Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable by therapeutic approaches. However, evidence for AE-related recovery of striatal dopamine (DA) signaling or tyrosine hydroxylase (TH) loss has been inconsistent in rodent studies. This ambiguity may be related to the timing of AE intervention in relation to the status of nigrostriatal neuron loss. Here, we replicated human PD at diagnosis by establishing motor impairment with >80% striatal DA and TH loss prior to initiating AE, and assessed its potential to alleviate motor decline and restore DA and TH loss. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), biomarkers of human PD severity, changed in response to AE. 6-hydroxydopamine (6-OHDA) was infused unilaterally into rat medial forebrain bundle to induce progressive nigrostriatal neuron loss over 28 days. Moderate intensity AE (3× per week, 40 min/session), began 8-10 days post-lesion following establishment of impaired forelimb use. Striatal tissue DA, TH protein and mRNA, and serum levels of NfL/GFAP were determined 3-wks after AE began. Despite severe striatal DA depletion at AE initiation, forelimb use deficits and hypokinesia onset were alleviated by AE, without recovery of striatal DA or TH protein loss, but reduced NfL and GFAP serum levels. This proof-of-concept study shows AE alleviates motor impairment when initiated with >80% striatal DA loss without obligate recovery of striatal DA or TH protein. Moreover, the AE-related reduction of NfL and GFAP serum levels may serve as objective blood-based biomarkers of AE efficacy.
PubMed: 38944332
DOI: 10.1016/j.expneurol.2024.114875 -
Journal of Affective Disorders Jun 2024There is an imbalance between goal-directed and habitual-learning system in patients with obsessive-compulsive disorder (OCD). At present, the relationship between...
BACKGROUND
There is an imbalance between goal-directed and habitual-learning system in patients with obsessive-compulsive disorder (OCD). At present, the relationship between cognitive behavior therapy (CBT) as a first-line therapy and goal-directed and habitual-learning disorder is still unclear. We attempted to discuss the effect of CBT treatment in patients with OCD, using abnormalities in goal-directed and habitual-learning-related brain regions at baseline as predictive factors.
METHODS
A total of 71 subjects, including 35 OCD patients and 36 healthy controls, were recruited. The OCD patients underwent 8 weeks of cognitive-behavioral therapy (CBT). These patients were divided into two groups based on treatment response (N = 18, N = 17). Further subgroup analysis was conducted based on disease duration (N = 17, N = 18) and age of onset (N = 14, N = 21). We collected resting-state ROI-ROI functional connectivity data and apply repeated-measures linear mixed-effects models to investigate the differences of different subgroups.
RESULTS
CBT led to symptom improvement in OCD patients, with varying degrees of effectiveness across subgroups. The orbitofrontal cortex (OFC) and insula, key regions for goal-directed behavior and habitual-learning, respectively, showed significant impacts on CBT efficacy in subgroups with different disease durations and ages of onset.
CONCLUSION
The findings suggest that the goal-directed system may influence the efficacy of CBT through goal selection, maintenance, and emotion regulation. Furthermore, we found that disease duration and age of onset may affect treatment outcomes by modulating functional connectivity between goal-directed and habitual-learning brain regions.
PubMed: 38944296
DOI: 10.1016/j.jad.2024.06.110 -
Fish & Shellfish Immunology Jun 2024The immune system of bony fish closely resembles that of mammals, comprising both specific (adaptive) and non-specific (innate) components. Notably, the...
The immune system of bony fish closely resembles that of mammals, comprising both specific (adaptive) and non-specific (innate) components. Notably, the mucosa-associated lymphoid tissue (MALT) serves as the first line of defense within the non-specific immune system, playing a critical role in protecting these aquatic organisms against invading pathogens. MALT encompasses a network of immune cells strategically distributed throughout the gills and intestines, forming an integral part of the mucosal barrier that interfaces directly with the surrounding aquatic environment. Spring Viremia of Carp Virus(SVCV), a highly pathogenic agent causing substantial harm to common carp populations, has been designated as a Class 2 animal disease by the Ministry of Agriculture and Rural Affairs of China. Utilizing a comprehensive array of research techniques, including Hematoxylin and Eosin (HE)、Alcian Blue Periodic Acid-Schiff (AB-PAS)、transcriptome analysis for global gene expression profiling and Reverse Transcription-Polymerase Chain Reaction (RT-qPCR), this study uncovered several key findings: SVCV is capable of compromising the mucosal architecture in the gill and intestinal tissues of carp, and stimulate the proliferation of mucous cells both in gill and intestinal tissues. Critically, the study revealed that SVCV's invasion elicits a robust response from the carp's mucosal immune system, demonstrating the organism's capacity to resist SVCV invasion despite the challenges posed by the pathogen.
PubMed: 38944254
DOI: 10.1016/j.fsi.2024.109726 -
Microbial Pathogenesis Jun 2024Cervical cancer (CC) is the fourth most common cancer among female patients. The primary cause of all types of cervical cancer is human papillomavirus (HPV), which was...
Cervical cancer (CC) is the fourth most common cancer among female patients. The primary cause of all types of cervical cancer is human papillomavirus (HPV), which was projected to account for 5,70,000 reported cases in 2018. Two HPV strains (16 and 18) account for 70% of cervical abnormalities and precancerous cervical cancers. CC is one of the main causes of the 17% cancer-related death rate among Indian women between the ages of 30 and 69 is CC. The side effects of the currently approved treatments for cervical cancer could endanger the lives of women affected by the illness. Thus, probiotics may be extremely important in the management of CC. Numerous studies on probiotics and their potential for use in cancer diagnosis, prevention, and treatment have been conducted. This review describes the enhancement of the immune system, promotion of a balanced vaginal microbiome, and decreased risk of secondary infections, which have anti-inflammatory effects on the body. Probiotics have the potential to reduce inflammation, thereby adversely affecting cancer cell growth and metastasis. During the course of antibiotic therapy, they support a balanced vaginal microbiome. Oncogenic virus inactivation is possible with probiotic strains. In postmenopausal women, the use of vaginal probiotics helps lessen menopausal symptoms caused by Genitourinary Syndrome of Menopause (GSM). The antitumor effects of other medications can be enhanced by them as potential agents, because they can both promote the growth of beneficial bacteria and reduce the quantity of potentially harmful bacteria. The development of tumors and the proliferation of cancer cells may be indirectly affected by the restoration of the microbial balance. Probiotics may be able to prevent and treat cervical cancer, as they seem to have anticancer properties. To identify probiotics with anticancer qualities that can supplement and possibly even replace traditional cancer treatments, further investigation is required, including carefully planned clinical trials.
PubMed: 38944216
DOI: 10.1016/j.micpath.2024.106764 -
Free Radical Biology & Medicine Jun 2024Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity....
Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity. Although many mitochondrial transporters are associated with metabolic diseases, how they regulate mitochondrial function and their metabolic contributions at the cellular level are largely unknown. Here, we show that mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 is required for mitochondrial respiration. SLC25A19 deficiency leads to reduced cell viability, increased integrated stress response (ISR), enhanced glycolysis and elevated cell sensitivity to 2-deoxyglucose (2-DG) treatment. Through a series of biochemical assays, we found that the depletion of mitochondrial NADH is the primary cause of the impaired mitochondrial respiration in SLC25A19 deficient cells. We also showed involvement of SLC25A19 in regulating the enzymatic activities of complexes I and III, the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle and amino acid metabolism. Consistently, addition of idebenone, an analog of coenzyme Q10, restores mitochondrial respiration and cell viability in SLC25A19 deficient cells. Together, our findings provide new insight into the functions of SLC25A19 in mitochondrial and cellular physiology, and suggest that restoring mitochondrial respiration could be a novel strategy for treating SLC25A19-associated disorders.
PubMed: 38944213
DOI: 10.1016/j.freeradbiomed.2024.06.019