The future of cancer therapy: exploring the potential of patient-derived organoids in drug development.

Cancer therapy is on the brink of a significant transformation with the inclusion of patient-derived organoids (PDOs) in drug development. These three-dimensional cell cultures, directly derived from a patient's tumor, accurately replicate the complex structure and genetic makeup of the original cancer. This makes them a promising tool for advancing oncology. In this review, we explore the practical applications of PDOs in clinical drug screening and pharmacognostic assessment, as well as their role in refining therapeutic strategies. We provide insights into the latest advancements in PDO technology and its implications for predicting treatment responses and facilitating novel drug discoveries. Additionally, we address the operational challenges associated with incorporating PDOs into the drug development process, such as scaling up organoid cultures, ensuring consistent results, and addressing the ethical use of patient-derived materials. Aimed at researchers, clinicians, and key stakeholders in oncology, this article aims to succinctly present both the extraordinary potential and the obstacles to integrating PDOs, thereby shedding light on their prospective impact on the future of cancer treatment.

Advances and challenges in gene therapy strategies for pediatric cancer: a comprehensive update.

Pediatric cancers represent a tragic but also promising area for gene therapy. Although conventional treatments have improved survival rates, there is still a need for targeted and less toxic interventions. This article critically analyzes recent advances in gene therapy for pediatric malignancies and discusses the challenges that remain. We explore the innovative vectors and delivery systems that have emerged, such as adeno-associated viruses and non-viral platforms, which show promise in addressing the unique pathophysiology of pediatric tumors. Specifically, we examine the field of chimeric antigen receptor (CAR) T-cell therapies and their adaptation for solid tumors, which historically have been more challenging to treat than hematologic malignancies. We also discuss the genetic and epigenetic complexities inherent to pediatric cancers, such as tumor heterogeneity and the dynamic tumor microenvironment, which pose significant hurdles for gene therapy. Ethical considerations specific to pediatric populations, including consent and long-term follow-up, are also analyzed. Additionally, we scrutinize the translation of research from preclinical models that often fail to mimic pediatric cancer biology to the regulatory landscapes that can either support or hinder innovation. In summary, this article provides an up-to-date overview of gene therapy in pediatric oncology, highlighting both the rapid scientific progress and the substantial obstacles that need to be addressed. Through this lens, we propose a roadmap for future research that prioritizes the safety, efficacy, and complex ethical considerations involved in treating pediatric patients. Our ultimate goal is to move from incremental advancements to transformative therapies.

Exploring the intricate relationship between miRNA dysregulation and breast cancer development: insights into the impact of environmental chemicals.

Breast cancer stands as the most prevalent form of cancer among women globally, influenced by a combination of genetic and environmental factors. Recent studies have investigated changes in microRNAs (miRNAs) during breast cancer progression and the potential impact of environmental chemicals on miRNA expression. This review aims to provide an updated overview of miRNA alterations in breast cancer and to explore their potential association with environmental chemicals. We will discuss the current knowledge on dysregulated miRNAs in breast cancer, including both upregulated and downregulated miRNAs. Additionally, we will review the influence of environmental chemicals, such as endocrine-disrupting compounds, heavy metals, and air pollutants, on miRNA expression and their potential contribution to breast cancer development. This review aims to advance our understanding of the complex molecular mechanisms underlying miRNA dysregulation in breast cancer by comprehensively examining miRNA alterations and their association with environmental chemicals. This knowledge is crucial for the development of targeted therapies and preventive measures. Furthermore, identifying specific miRNAs affected by environmental chemicals may allow the prediction of individual susceptibility to breast cancer and the design of personalized intervention strategies.

Biochemical implications of robotic surgery: a new frontier in the operating room.

Robotic surgery represents a milestone in surgical procedures, offering advantages such as less invasive methods, elimination of tremors, scaled motion, and 3D visualization. This in-depth analysis explores the complex biochemical effects of robotic methods. The use of pneumoperitoneum and steep Trendelenburg positioning can decrease pulmonary compliance and splanchnic perfusion while increasing hypercarbia. However, robotic surgery reduces surgical stress and inflammation by minimizing tissue trauma. This contributes to faster recovery but may limit immune function. Robotic procedures also limit ischemia-reperfusion injury and oxidative damage compared to open surgery. They also help preserve native antioxidant defenses and coagulation. In a clinical setting, robotic procedures reduce blood loss, pain, complications, and length of stay compared to traditional procedures. However, risks remain, including device failure, the need for conversion to open surgery and increased costs. On the oncology side, there is still debate about margins, recurrence, and long-term survival. The advent of advanced technologies, such as intraoperative biosensors, localized drug delivery systems, and the incorporation of artificial intelligence, may further improve the efficiency of robotic surgery. However, ethical dilemmas regarding patient consent, privacy, access, and regulation of this disruptive innovation need to be addressed. Overall, this review sheds light on the complex biochemical implications of robotic surgery and highlights areas that require additional mechanistic investigation. It presents a comprehensive approach to responsibly maximize the potential of robotic surgery to improve patient outcomes, integrating technical skill with careful consideration of physiological and ethical issues.

Kynurenine and Beta-Alanine Serum Levels are Associated with the Expression of Wnt Pathway Genes in Patients with Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Despite its worldwide prevalence, there is currently no clear explanation for the mechanism of this disease. In addition, the lack of reliable and accurate biomarkers makes the early detection of PD difficult. Therefore, we examined serum beta-alanine and kynurenine levels and expression of Wnt pathway genes in leukocytes from patients with PD. METHODS: Ninety patients, 45 with PD and 45 healthy subjects, were enrolled in this study. Ten milliliters of blood were drawn from all participants. Serum levels of beta-alanine and kynurenine were measured by ELISA, and the expression of Wnt pathway genes in leukocytes was determined by real-time PCR. RESULTS: Serum levels of kynurenine and beta-alanine were higher in PD patients than in the control group. Data analysis also showed that the expression of some Wnt pathway genes was decreased in leukocytes. CONCLUSIONS: The correlation between serum levels of beta-alanine and kynurenine and the expression of the gene that encodes the Wnt signaling pathway in leukocytes was found in patients with PD. As a result, these biomarkers can be utilized for the early detection, monitoring, and treatment of patients with PD.

Proteostasis and neurodegeneration: a closer look at autophagy in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the accumulation of misfolded amyloid-beta and tau proteins. Autophagy acts as a proteostasis process to remove protein clumps, although it progressively weakens with aging and AD, thus facilitating the accumulation of toxic proteins and causing neurodegeneration. This review examines the impact of impaired autophagy on the progression of AD disease pathology. Under normal circumstances, autophagy removes abnormal proteins and damaged organelles, but any dysfunction in this process can lead to the exacerbation of amyloid and tau pathology, particularly in AD. There is increasing attention to therapeutic tactics to revitalize autophagy, including reduced caloric intake, autophagy-stimulating drugs, and genetic therapy. However, the translation of these strategies into clinical practice faces several hurdles. In summary, this review integrates the understanding of the intricate role of autophagy dysfunction in Alzheimer's disease progression and reinforces the promising prospects of autophagy as a beneficial target for treatments to modify the course of Alzheimer's disease.

MicroRNAs as Targets for Cancer Diagnosis: Interests and Limitations.

MicroRNAs are small RNAs with ability to attach to the large number of RNA that regulate gene expression on post-transcriptional level via inhibition or degradation of specific mRNAs. MiRNAs in cells are the primary regulators of functions such as cell growth, differentiation, and apoptosis and considerably influence cell function. The expression levels of microRNAs change in human diseases, including cancer. These changes highlight their essential role in cancer pathogenesis. Ubiquitous irregular expression profiles of miRNAs have been detected in various human cancers using genome-wide identification techniques, which are emerging as novel diagnostic and prognostic cancer biomarkers of high specificity and sensitivity. The measurable miRNAs with enhanced stability in blood, tissues, and other body fluids provide a comprehensive source of miRNA-dependent biomarkers for human cancers. The leading role of miRNAs as potential biomarkers in human cancers is discussed in this article. In addition, the interests and difficulties of miRNAs as biomarkers have been explored.

Melatonin: a promising neuroprotective agent for cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion (CIR) injury is initiated by the generation of reactive oxygen species (ROS), which leads to the oxidation of cellular proteins, DNA, and lipids as an initial event. The reperfusion process impairs critical cascades that support cell survival, including mitochondrial biogenesis and antioxidant enzyme activity. Failure to activate prosurvival signals may result in increased neuronal cell death and exacerbation of CIR damage. Melatonin, a hormone produced naturally in the body, has high concentrations in both the cerebrospinal fluid and the brain. However, melatonin production declines significantly with age, which may contribute to the development of age-related neurological disorders due to reduced levels. By activating various signaling pathways, melatonin can affect multiple aspects of human health due to its diverse range of activities. Therefore, understanding the underlying intracellular and molecular mechanisms is crucial before investigating the neuroprotective effects of melatonin in cerebral ischemia-reperfusion injury.

Relationship between miRNA-21, miRNA-155, and miRNA-182 expression and inflammatory factors in cerebrospinal fluid from patients with multiple sclerosis.

BACKGROUND: The impact of microRNAs (miRNAs) on the differentiation and function of inflammatory cells is well-established. MiRNAs play a crucial role in modulating the expression of pro-inflammatory genes in neuronal cells as well. With this knowledge in mind, our study aimed to explore the relationship between the expression of miRNAs and inflammatory markers in the cerebrospinal fluid (CSF) of patients diagnosed with multiple sclerosis (MS). By investigating this relationship, we aimed to gain insights into the potential involvement of miRNAs in the regulation of inflammation in the context of MS. MATERIALS AND METHODS: The expression levels of miRNA-21, miRNA-155, and miRNA-182 in cerebrospinal fluid (CSF) samples from multiple sclerosis (MS) patients and controls were determined by RT-PCR. CSF levels of the inflammatory cytokines IL-1ß, IL-6, and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). In addition, high-sensitivity C-reactive protein (hs-CRP) levels were measured by quantitative turbidimetry. RESULTS: The expression levels of microRNAs and inflammatory factors were found to be significantly higher in the CSF of MS patients compared to controls (P < 0.05). Receiver operating characteristics (ROC) analysis revealed that miRNA-21, miRNA-182, and miRNA-155 had a high area under the curve (AUC) in discriminating MS patients, with AUC values of 0.97 (P < 0.0001) for miRNA-21, 0.97 (P < 0.0001) for miRNA-182, and 0.96 (P < 0.0001) for miRNA-155. Notably, CSF miRNA-155 showed the highest accuracy in correctly diagnosing MS. Furthermore, a statistically significant relationship was observed between inflammatory cytokines and miRNA-21, miRNA-155 and miRNA-182. CONCLUSION: Our results demonstrated that cerebrospinal fluid (CSF) levels of IL-1ß, IL-6, TNF-α, hs-CRP and specific miRNAs serve as biomarkers for assessing central nervous system (CNS) inflammation and neurodegenerative processes in patients with multiple sclerosis (MS).

The Role of Mitochondrial Biogenesis in Ischemic Stroke.

Ischaemic stroke is a sudden neurological disorder caused by localised cerebral ischaemia and persistent cerebral infarction. Occlusion of large arteries due to atherothrombosis, cerebral embolism (i.e., embolic infarction), no thrombotic occlusion in small, deep cerebral arteries (i.e., lacunar infarction), and stenosis of proximal arteries due to hypotension leading to decreased cerebral blood flow in arterial supply zones are the most common causes of ischemic stroke (i.e., hemodynamic stroke). It is now known that organelles play an important role in various signaling events and cellular functions. The molecular mechanisms of mitochondria are involved in cerebral ischemia by generating and scavenging reactive oxygen species, apoptosis, biogenesis, mitochondrial dynamics, and inflammation are all examples of electron transport chain dysfunction. More knowledge about the involvement of mitochondria in ischemia-induced neuronal death and neuronal protection will contribute to the development of better treatment programs for stroke syndromes such as ischemic stroke.

Intranasal delivery of stem cells labeled by nanoparticles in neurodegenerative disorders: Challenges and opportunities.

Neurodegenerative disorders occur through progressive loss of function or structure of neurons, with loss of sensation and cognition values. The lack of successful therapeutic approaches to solve neurologic disorders causes physical disability and paralysis and has a significant socioeconomic impact on patients. In recent years, nanocarriers and stem cells have attracted tremendous attention as a reliable approach to treating neurodegenerative disorders. In this regard, nanoparticle-based labeling combined with imaging technologies has enabled researchers to survey transplanted stem cells and fully understand their fate by monitoring their survival, migration, and differentiation. For the practical implementation of stem cell therapies in the clinical setting, it is necessary to accurately label and follow stem cells after administration. Several approaches to labeling and tracking stem cells using nanotechnology have been proposed as potential treatment strategies for neurological diseases. Considering the limitations of intravenous or direct stem cell administration, intranasal delivery of nanoparticle-labeled stem cells in neurological disorders is a new method of delivering stem cells to the central nervous system (CNS). This review describes the challenges and limitations of stem cell-based nanotechnology methods for labeling/tracking, intranasal delivery of cells, and cell fate regulation as theragnostic labeling. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

MicroRNA targeting: A novel therapeutic intervention for ovarian cancer.

Ovarian cancer, a perilous form of cancer affecting the female reproductive system, exhibits intricate communication networks that contribute to its progression. This study aims to identify crucial molecular abnormalities linked to the disease to enhance diagnostic and therapeutic strategies. In particular, we investigate the role of microRNAs (miRNAs) as diagnostic biomarkers and explore their potential in treating ovarian cancer. By targeting miRNAs, which can influence multiple pathways and genes, substantial therapeutic benefits can be attained. In this review we want to shed light on the promising application of miRNA-based interventions and provide insights into the specific miRNAs implicated in ovarian cancer pathogenesis.

Evaluation of dihydrotestosterone and dihydroprogesterone levels and gene expression of genes involved in neurosteroidogenesis in the SH-SY5Y Alzheimer disease cell model.

Introduction: Alzheimer's disease (AD) is the most common form of dementia worldwide. This study investigated the effects of lipopolysaccharide on neurosteroidogenesis and its relationship to growth and differentiation using SH-SY5Y cells. Methods: In this study, we used the MTT assay to assess the impact of LPS on SH-SY5Y cell viability. We also evaluated apoptotic effects using FITC Annexin V staining to detect phosphatidylserine in the cell membrane. To identify gene expression related to human neurogenesis, we utilized the RT2 Profiler TM PCR array human neurogenesis PAHS-404Z. Results: Our study found that LPS had an IC50 level of 0.25 µg/mL on the SH-SY5Y cell line after 48 h. We observed Aß deposition in SH-SY5Y cells treated with LPS, and a decrease in DHT and DHP levels in the cells. Our analysis showed that the total rate of apoptosis varied with LPS dilution: 4.6% at 0.1 µg/mL, 10.5% at 10 µg/mL, and 44.1% at 50 µg/mL. We also observed an increase in the expression of several genes involved in human neurogenesis, including ASCL1, BCL2, BDNF, CDK5R1, CDK5RAP2, CREB1, DRD2, HES1, HEYL, NOTCH1, STAT3, and TGFB1, after treatment with LPS at 10 µg/mL and 50 µg/mL. LPS at 50 µg/mL increased the expression of FLNA and NEUROG2, as well as the other genes mentioned. Conclusion: Our study showed that LPS treatment altered the expression of human neurogenesis genes and decreased DHT and DHP levels in SH-SY5Y cells. These findings suggest that targeting LPS, DHT, and DHP could be potential therapeutic strategies to treat AD or improve its symptoms.

Diagnostic Value of ATG5, Apo-Lipoprotein B-48, Thyroid Hormones, and Homocysteine in Patients with Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. In this study, serum levels of autophagy-related 5 (ATG5), apolipoprotein B-48, thyroid hormones, and homocysteine were examined in patients with AD to determine their diagnostic and predictive value for early diagnosis and prevention of AD. MATERIALS: For this study, fifty serum samples were obtained from patients with AD and fifty serum samples from healthy controls. Serum levels of ATG 5, apo B48, thyroid hormones, homocysteine, vitamin B12, and folic acid were determined by ELISA. Spectrophotometry was used to determine serum lipid concentrations. RESULTS: The mean age of the case group was 69 ± 6.4 years and that of the control group was 67 ± 4.2 years. There were differences between the control and case groups in serum levels of homocysteine, apo B48, ATG5, hsCRP, LDL, HDL, cholesterol, and VitB12 (p < 0.05). According to the results of the ROC curve, measurements of serum levels of ATG5, homocysteine, and apo B48 have excellent performance in distinguishing patients with Alzheimer's disease from patients without AD. CONCLUSIONS: This study suggests that the measurement of serum levels of ATG5, homocysteine, and apo B48, along with other available biomarkers, can be helpful in the diagnosis and management of patients with AD in the early stages of their disease.

Gene polymorphism of leptin and risk for heart disease, obesity, and high BMI: a systematic review and pooled analysis in adult obese subjects.

OBJECTIVES: Leptin polymorphism (LEP) has been associated with coronary heart disease (CAD), obesity, and high body mass index (BMI). However, we performed a systematic review and meta-analysis to discover the association because previous studies reached different conclusions. METHODS: Review Manager, version 5.3.5, and Stata, version 15.0, were used for statistical analysis. We calculated the effect size of the studies using the OR with the corresponding 95% CI, and two-sided (bilateral) p-values of 0.05 were considered significant. To determine heterogeneity among the selected studies, the Q test and I2 statistics were used. Meta-regression was used to examine the disease (heart disease, obesity, and high BMI) and heterogeneity between these subgroups. RESULTS: Eleven studies with 18,984 subjects were included in this study. The G-2548A (rs12112075), rs7799039, and A19G (rs2167270) polymorphisms of the leptin gene (but not the Lys656Asn (rs1805094) polymorphism) are associated with an increased risk of cardiovascular disease. Our pooled analysis revealed an association between the G-2548A (rs12112075) polymorphism and heart disease, high BMI, and obesity. This indicates that individuals carrying the AA allele are at an increased risk for heart disease, high BMI, and obesity. People with heart failure and coronary artery disease did not have the rs7799039 polymorphism or its alleles linked to them. CONCLUSIONS: Combined analysis of data from current and published research suggests that the leptin gene polymorphisms G-2548A (rs12112075), rs7799039, and A19G (rs2167270) (but not the Lys656Asn (rs1805094) polymorphism) are associated with an increased risk of cardiovascular disease. Further research is needed to understand this association.

MicroRNAs as a New Target for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease associated with advanced age. It is characterized by cognitive decline and memory loss and accounts for most cases of dementia in older people. AD can be rooted in genetic, epigenetic, or environmental causes. No drugs or other therapeutic agents prevent or delay AD progression. MicroRNAs (miRNAs) are short and uncoded RNAs that can bind to 200 RNAs approximately. By inhibiting or destroying specific messenger RNAs (mRNAs), they control gene expression and broadly affect cellular functions. MiRNAs play important roles in regulating neuronal growth, neuronal differentiation, dendritic spine morphology, and synaptic flexibility in the nervous system. The expression levels of miRNAs are changed in neurological diseases, including AD, suggesting that they play an essential role in the pathogenesis of the disease. Therefore, targeting disrupted miRNAs may be a novel therapeutic approach against AD and offers multiple solutions, including harnessing the beneficial effects of beta-amyloid, reducing tau protein, reducing neuronal cell death, and protecting synapses in AD.

CAR T Cells: Cancer Cell Surface Receptors Are the Target for Cancer Therapy.

Immunotherapy has become a prominent strategy for the treatment of cancer. A method that improves the immune system's ability to attack a tumor (Enhances antigen binding). Targeted killing of malignant cells by adoptive transfer of chimeric antigen receptor (CAR) T cells is a promising immunotherapy technique in the treatment of cancers. For this purpose, the patient's immune cells, with genetic engineering aid, are loaded with chimeric receptors that have particular antigen binding and activate cytotoxic T lymphocytes. That increases the effectiveness of immune cells and destroying cancer cells. This review discusses the basic structure and function of CAR-T cells and how antigenic targets are identified to treat different cancers and address the disadvantages of this treatment for cancer.

Diagnostic Potential of Autophagy-5 Protein, Apolipoprotein B-48, and Oxidative Stress Markers in Serum of Patients with Early-Stage Ischemic Stroke.

OBJECTIVE: Strokes are among the leading causes of death worldwide and have different characteristics. Different physiopathological mechanisms characterize the numerous subtypes of ischemic stroke (IS). In this study, we investigated the relationship between serum levels of autophagy-5 protein, apolipoprotein B-48, and oxidative stress markers in patients with ischemic stroke. METHODS: For this study, 100 participants were recruited, of which 50 were patients with IS and 50 were healthy individuals. We conducted a case-control study at Imam Reza Hospital from March 2019 to April 2020. Serum levels of ATG5, apo B-48, and oxidative stress markers were determined in both groups. Our Receiver Operating Characteristic Analysis evaluated the additional diagnostic value of these factors in both groups. RESULTS: Diabetes, smoking, age, sex, alcohol consumption, weight, and height did not differ significantly between the 2 groups (P > 0.05). However, the 2 groups had significant differences in hypertension and body mass index (P < 0.05). Fifty-four percent (27 patients) of patients with IS had an ischemic stroke in large vessels, while 46% (23 patients) had an ischemic stroke in small vessels. Serum levels of ATG5, apo B-48, and oxidative stress markers were higher in the case group than in the control group (P < 0.0001). CONCLUSIONS: In patients with IS, serum levels of ATG5, apoB-48, malonaldehyde, total oxidative stress, and total antioxidant capacity can be used as novel biomarkers to predict or treat the disease.

Application of exosomes for the alleviation of COVID-19-related pathologies.

The pandemic of COVID-19 caused worldwide concern. Due to the lack of appropriate medications and the inefficiency of commercially available vaccines, lots of efforts are being made to develop de novo therapeutic modalities. Besides this, the possibility of several genetic mutations in the viral genome has led to the generation of resistant strains such as Omicron against neutralizing antibodies and vaccines, leading to worsening public health status. Exosomes (Exo), nanosized vesicles, possess several therapeutic properties that participate in intercellular communication. The discovery and application of Exo in regenerative medicine have paved the way for the alleviation of several pathologies. These nanosized particles act as natural bioshuttles and transfer several biomolecules and anti-inflammatory cytokines. To date, several approaches are available for the administration of Exo into the targeted site inside the body, although the establishment of standard administration routes remains unclear. As severe acute respiratory syndrome coronavirus 2 primarily affects the respiratory system, we here tried to highlight the transplantation of Exo in the alleviation of COVID-19 pathologies.