Liquid biopsy in ovarian cancer: advantages and limitations for prognosis and diagnosis.

Ovarian cancer (OC) is a highly fatal gynecologic malignancy, often diagnosed at an advanced stage which presents significant challenges for disease management. The clinical application of conventional tissue biopsy methods and serological biomarkers has limitations for the diagnosis and prognosis of OC patients. Liquid biopsy is a novel sampling method that involves analyzing distinctive tumor elements secreted into the peripheral blood. Growing evidence suggests that liquid biopsy methods such as circulating tumor cells, cell-free RNA, circulating tumor DNA, exosomes, and tumor-educated platelets may improve early prognosis and diagnosis of OC, leading to enhanced therapeutic management of the disease. This study reviewed the evidence demonstrating the utility of liquid biopsy components in OC prognosis and diagnosis, and evaluated the current advantages and limitations of these methods. Additionally, the existing obstacles and crucial topics for future studies utilizing liquid biopsy in OC patients were discussed.

Short-term beneficial effects of human dental pulp stem cells and their secretome in a rat model of mild ischemic stroke.

Although cell therapy has been applied in regenerative medicine for decades, recent years have seen greatly increased attention being given to the use of stem cell-based derivatives such as cell-free secretome. Dental pulp stem cells (DPSCs) are widely available, easily accessible, and have high neuroprotective and angiogenic properties. In addition, DPSC-derived secretome contains a rich mixture of trophic factors. The current investigation evaluated the short-term therapeutic effects of human DPSCs and their secretome in a rat model of mild ischemic stroke. Mild ischemic stroke was induced by 30 min middle cerebral artery occlusion, and hDPSCs or their secretome was administered intra-arterially and intranasally. Neurological function, infarct size, spatial working memory, and relative expression of seven target genes in two categories of neurotrophic and angiogenic factors were assessed three days after stroke. In the short-term, all treatments reduced the severity of neurological and histological deficits caused by ischemic stroke. Moreover, transient middle cerebral artery occlusion led to the striatal and cortical over-expression of BDNF, NT-3, and angiogenin, while NGF and VEGF expression was reduced. Almost all interventions were able to modulate the expression of target genes after stroke. The obtained data revealed that single intra-arterial administration of hDPSCs or their secretome, single intranasal transplantation of hDPSCs, or repeated intranasal administration of hDPSC-derived secretome was able to ameliorate the devastating effects of a mild stroke, at least in the short-term.

Pathological Mechanisms Induced by TRPM2 Ion Channels Activation in Renal Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion (IR) injury triggers a cascade of signaling reactions involving an increase in Ca2 + charge and reactive oxygen species (ROS) levels resulting in necrosis, inflammation, apoptosis, and subsequently acute kidney injury (AKI).Transient receptor potential (TRP) channels include an essential class of Ca2+ permeable cation channels, which are segregated into six main channels: the canonical channel (TRPC), the vanilloid-related channel (TRPV), the melastatin-related channel (TRPM), the ankyrin-related channel (TRPA), the mucolipin-related channel (TRPML) and polycystin-related channel (TRPP) or polycystic kidney disease protein (PKD2). TRP channels are involved in adjusting vascular tone, vascular permeability, cell volume, proliferation, secretion, angiogenesis and apoptosis.TRPM channels include eight isoforms (TRPM1-TRPM8) and TRPM2 is the second member of this subfamily that has been expressed in various tissues and organs such as the brain, heart, kidney and lung. Renal TRPM2 channels have an important role in renal IR damage. So that TRPM2 deficient mice are resistant to renal IR injury. TRPM2 channels are triggered by several chemicals including hydrogen peroxide, Ca2+, and cyclic adenosine diphosphate (ADP) ribose (cADPR) that are generated during AKI caused by IR injury, as well as being implicated in cell death caused by oxidative stress, inflammation, and apoptosis.

Early and mid-term outcomes of carotid angioplasty and stent placement in 579 patients.

BACKGROUND AND PURPOSE: Carotid angioplasty and stenting (CAS) could be considered for preventing stroke in patients with carotid artery stenosis. This study aimed to determine the incidence and the risk factors of the early and mid-term complications associated with CAS. METHODS: This is a retrospective cohort study conducted at Shiraz University of Medical Sciences from March 2011 to March 2019. Patients at high risk and standard risk for carotid endarterectomy were included. The primary composite outcome was defined as stroke, myocardial infarction (MI), and death in the first 30 days after CAS. All-cause mortality, vascular mortality, and stroke were investigated during mid-term follow-up. RESULTS: A total of 579 patients (618 CAS) were recruited (mean age: 71.52 years). Overall, 394 (68.40%), 211 (36.63%), 179 (31.07%), and 96 (16.72%) patients had hypertension, dyslipidemia, diabetes mellitus, or were cigarette smokers, respectively. Primary composite outcomes were observed in 2.59% of patients (1.55% stroke, 0.69% MI, and 1.72% death). Atrial fibrillation was a predictor of primary composite outcome in multivariate logistic regression (p = .048). The presence of total occlusion in the contralateral carotid artery was significantly associated with the risk of stroke in univariate logistic regression (p = .041). The patients were followed for a period ranging from 1 to 83 months. The overall survival rate for all-cause mortality was 93.48% at 1 year, 77.24% at 5 years, and 52.92% at 8 years. All-cause mortality was significantly higher among patients with symptomatic carotid stenosis (p = .014). CONCLUSION: CAS provides acceptable short-term and mid-term outcomes in a unique population of high- and standard-surgical-risk, symptomatic and asymptomatic, octogenarian, and nonoctogenarian patients.

Therapeutic potential of hair follicle-derived stem cell intranasal transplantation in a rat model of ischemic stroke.

BACKGROUND: Stem cell-based therapy has received considerable attention as a potential candidate in the treatment of ischemic stroke; however, employing an appropriate type of stem cells and an effective delivery route are still challenging. In the present study, we investigated the therapeutic effect of safe, noninvasive, and brain-targeted intranasal administration of hair follicle-derived stem cells (HFSCs) in a rat model of ischemic stroke. METHODS: Stem cells were obtained from the adult rat hair follicles. In experiment 1, stroke was induced by 30 min middle cerebral artery occlusion (MCAO) and stem cells were intranasally transplanted immediately after ischemia. In experiment 2, stroke was induced by 120 min MCAO and stem cells were administered 24 h after cerebral ischemia. In all experimental groups, neurological performance, short-term spatial working memory and infarct volume were assessed. Moreover, relative expression of major trophic factors in the striatum and cortex was evaluated by the quantitative PCR technique. The end point of experiment 1 was day 3 and the end point of experiment 2 was day 15. RESULTS: In both experiments, intranasal administration of HFSCs improved functional performance and decreased infarct volume compared to the MCAO rats. Furthermore, NeuN and VEGF expression were higher in the transplanted group and stem cell therapy partially prevented BDNF and neurotrophin-3 over-expression induced by cerebral ischemia. CONCLUSIONS: These findings highlight the curative potential of HFSCs following intranasal transplantation in a rat model of ischemic stroke.

The Hospitalization Rate of Cerebral Venous Sinus Thrombosis before and during COVID-19 Pandemic Era: A Single-Center Retrospective Cohort Study.

OBJECTIVES: There are several reports of the association between SARS-CoV-2 infection (COVID-19) and cerebral venous sinus thrombosis (CVST). In this study, we aimed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic (before vaccination program). MATERIALS AND METHODS: In this retrospective cohort study, the hospitalization rate of adult CVST patients in Namazi hospital, a tertiary referral center in the south of Iran, was compared in two periods of time. We defined March 2018 to March 2019 as the pre-COVID-19 period and March 2020 to March 2021 as the COVID-19 period. RESULTS: 50 and 77 adult CVST patients were hospitalized in the pre-COVID-19 and COVID-19 periods, respectively. The crude CVST hospitalization rate increased from 14.33 in the pre-COVID-19 period to 21.7 per million in the COVID-19 era (P = 0.021). However, after age and sex adjustment, the incremental trend in hospitalization rate was not significant (95% CrI: -2.2, 5.14). Patients > 50-year-old were more often hospitalized in the COVID-19 period (P = 0.042). SARS-CoV-2 PCR test was done in 49.3% out of all COVID-19 period patients, which were positive in 6.5%. Modified Rankin Scale (mRS) score ≥3 at three-month follow-up was associated with age (P = 0.015) and malignancy (P = 0.014) in pre-COVID period; and was associated with age (P = 0.025), altered mental status on admission time (P<0.001), malignancy (P = 0.041) and COVID-19 infection (P = 0.008) in COVID-19 period. CONCLUSION: Since there was a more dismal outcome in COVID-19 associated CVST, a high index of suspicion for CVST among COVID-19 positive is recommended.

The Beneficial Potential of Genetically Modified Stem Cells in the Treatment of Stroke: a Review.

The last two decades have witnessed a surge in investigations proposing stem cells as a promising strategy to treat stroke. Since growth factor release is considered as one of the most important aspects of cell-based therapy, stem cells over-expressing growth factors are hypothesized to yield higher levels of therapeutic efficiency. In pre-clinical studies of the last 15 years that were investigating the efficiency of stem cell therapy for stroke, a variety of stem cell types were genetically modified to over-express various factors. In this review we summarize the current knowledge on the therapeutic efficiency of stem cell-derived growth factors, encompassing techniques employed and time points to evaluate. In addition, we discuss several types of stem cells, including the recently developed model of epidermal neural crest stem cells, and genetically modified stem cells over-expressing specific factors, which could elevate the restorative potential of naive stem cells. The restorative potential is based on enhanced survival/differentiation potential of transplanted cells, apoptosis inhibition, infarct volume reduction, neovascularization or functional improvement. Since the majority of studies have focused on the short-term curative effects of genetically engineered stem cells, we emphasize the need to address their long-term impact.

Aspirin impacts on stem cells: Implications for therapeutic targets.

Despite the regenerative potential of stem cell therapy in pre-clinical investigations, clinical translation of cell-based therapy has not been completely clarified. In recent years, the importance of lifestyle, patient comorbidities, and prescribed medication has attracted more attention in the efficacy of cell therapy. As a nonsteroidal anti-inflammatory drug, aspirin is one of the most prevalent prescribed medications in the clinic for various disorders. Hence, aspirin treatment might affect the efficacy of stem cell therapy. In this regard, the current review focused on the impacts of aspirin on the viability, proliferation, differentiation, and immunomodulatory properties of stem cells in vitro as well as in experimental animal models.

Dysregulated Expression of MiR-19b, MiR-25, MiR-17, WT1, and CEBPA in Patients with Acute Myeloid Leukemia and Association with Graft versus Host Disease after Hematopoietic Stem Cell Transplantation.

Elham JamaliObjectives Acute myeloid leukemia (AML) is a blood malignancy characterized by the proliferation of aberrant cells in the bone marrow and blood that interfere with normal blood cells. We have investigated whether changes in the level of micro-ribonucleic acid (miR)-19b, miR-17, and miR-25, Wilms' tumor (WT1), and CCAAT enhancer-binding protein α (CEBPA) genes expression affect disease prognosis and clinical outcome in AML patients. Materials and Methods The expression level of miR-19-b, miR-17, and miR-25, as well as WT1 and CEBPA genes in a group of patients and controls as well as different risk groups (high, intermediate, and favorite risk), M3 versus non-M3, and graft-versus-host disease (GvHD) versus non-GvHD patients were assessed using a quantitative SYBR Green real-time polymerase chain reaction method. Results When compared with the baseline level at the period of diagnosis before chemotherapy, the expression of miR-19b and miR-17 in AML patients increased significantly after chemotherapy. The level of miR-19b and miR-25 expression in AML patients with M3 and non-M3 French-American-British subgroups differ significantly. MiR-19b and miR-25 expression was elevated in GvHD patients, while miR-19b and miR-25 expression was somewhat decreased in GvHD patients compared with non-GvHD patients, albeit the difference was not statistically significant. Also, patients with different cytogenetic aberrations had similar levels of miR-19-b and miR-25 expression. Conclusion MiR-19b, miR-17, and miR-25 are aberrantly expressed in AML patients' peripheral blood leukocytes, which may play a role in the development of acute GvHD following hematopoietic stem cell transplantation.

Therapeutic Effects of Dimethyl Fumarate on the Rat Model of Brain Ischemia

Abstract Blood-brain barrier (BBB) disruption, inflammation, and cell death are major pathogenic mechanisms in ischemic stroke. Dimethyl fumarate (DMF) has anti-inflammatory and immune-modulatory effects. So, this study aimed to elucidate the effects of DMF on brain ischemia in the middle cerebral artery occlusion (MCAO) model. 69 Sprague-Dawley male rats were allocated into a sham group that was just subjected to surgery stress; vehicle and DMF groups, after MCAO, received vehicle or 30 mg/kg DMF for three days. Neurological scores were evaluated every day. BBB disruption was evaluated by the extravasation of Evans blue. In addition to the measurement of brain water content, the total and infarct volume, numerical density, and the total number of neurons, non-neurons, and dead neurons in the right cortex were estimated by stereological methods. RT-PCR was done to analyze the expression levels of NF-κB and Nrf2. Although brain ischemia treatment with DMF did not have a significant effect on the infarction size, it improved neurobehavioral function, BBB disruption, cerebral edema, increased number of neurons, and expression of Nrf2. It also decreased the number of dead neurons and the expression of NF-κB. DMF beneficial effects on stroke may be mediated through both increase of the Nrf2 and decrease of NF-κB expression

MiR-181a and -b expression in acute lymphoblastic leukemia and its correlation with acute graft-versus-host disease after hematopoietic stem cell transplantation, COVID-19 and torque teno viruses.

Acute lymphoblastic leukemia (ALL), a malignant transformation and proliferation of the lymphoid line of blood cells, is characterized by chromosomal abnormalities and genetic changes. The purpose of this research was the evaluation of expression level of miR-181a and -b in patients with ALL compared to the control group. Furthermore, we examined their expression level in hematopoietic stem-cell transplantation (HSCT) patients who developed acute graft-versus-host disease (aGVHD) in comparison with those without aGVHD and explore the relationship between their expression level and cytogenetic abnormalities. In this cross-sectional study, 76 newly diagnosed adult De novo ALL patients were enrolled who were admitted to our referral hospital. All patients received standard chemotherapy, consisting of daunorubicin. A total of 37 patients underwent HSCT from the related human leukocyte antigen-matched donors. ALL patients have been diagnosed with the coronavirus disease 2019 (COVID-19) and Torque teno viruses (TTVs). We assessed the expression levels of miR-181a and -b in the peripheral blood sample of ALL patients at the time of diagnosis prior to chemotherapy, and healthy matched individuals by RT-PCR. TTVs and COVID-19 load were also determined via RT-PCR. In conclusion, the expression level of miR-181a and -b were significantly higher in ALL patients than healthy controls and also increased in patients who developed aGVHD in comparison with those without aGVHD. MiR-181a and -b can be a useful biomarker in ALL and a useful indicator of aGVHD. The expression level of miR-181a in ALL patients with COVID-19 is significantly up-regulated, while it is reduced in these patients with TTV.

Expression Levels of Il-6 and Il-18 in Acute Myeloid Leukemia and Its Relation with Response to Therapy and Acute GvHD After Bone Marrow Transplantation.

Cytokines seem to play a crucial role in physiological and pathological conditions of acute myeloid leukemia (AML). The aim of this study was to evaluate the expression levels of interleukins-6 (IL-6) and IL-18 in patients with AML and its correlation with response to therapy and graft versus host disease (GvHD) after bone marrow transplantation. The expression levels of IL-6 and IL-18 genes were done in all patients and compared with matched control. Complete remission (CR) was used for evaluation of the effects of these cytokines on response to treatment in patients group. The expression level of these cytokines was also evaluated in patients who underwent bone marrow transplantation and experienced acute GvHD in compare with patients without aGvHD. Il-6 gene expression level was significantly higher in these patients in comparison with control but Il-18 gene expression level was not statistically significant compared to control group. Il-6 and also Il-18 expression levels were significantly higher in patients without a response to treatment according to CR compared to patient's whit response to treatment as well as patients experienced aGvHD after bone marrow transplantation. IL-6 and Il-18 are important markers in the progression of the disease and could be considered as a prognostic marker in acute leukemia. It is recommended that more studies with larger study groups and more involved cytokines are needed for more evaluation of the cytokine roles in pathophysiology and progression of acute leukemia.

Effect of nicorandil on the spatial arrangement of primary motor cortical neurons in the sub-acute phase of stroke in a rat model.

INTRODUCTION: Ischemic stroke remains a major cause of disability and death worldwide. The density and the spatial distribution of the primary motor (M1) cortical neurons are important in signal transmission and control the movement-related functions. Recently, the neuroprotective effect of nicorandil in cerebral ischemia was described through its anti-apoptosis, antioxidant and anti-inflammatory properties. This study aimed to determine the effects of nicorandil on the neurobehavioral outcome, infarct size, and density, and spatial distribution of M1 cortical neurons after cerebral ischemia. METHODS: Thirty Sprague-Dawley rats were randomly divided into three groups. Sham underwent surgery without middle cerebral artery occlusion (MCAO) and drug. The MCAO and treatment groups after MCAO received saline or nicorandil 2, 24, 48, and 72 h after the induction of brain ischemia. Neurobehavioral tests were performed, brains removed, sectioned, and stained by 2,3,5-triphenyltetrazolium chloride (TTC) to estimate the size of the infarction and Nissl staining to evaluate the numerical density, mean area, and the distribution pattern of M1 cortical neurons, using Voronoi spatial tessellation. RESULTS: Although nicorandil treatment significantly decreased the neurological deficits and density of neuronal neighbors, it could not preserve the normal regular spatial distributions of M1 cortical neurons after MCAO. It also could not significantly improve motor function or reduce ischemic lesion size. CONCLUSIONS: Treatment using the present dose of nicorandil during sub-acute ischemic stroke could not increase neuronal density or preserve the normal regular spatial distributions after MCAO. However, it had beneficial effects on neurobehavioral and motor function and somewhat reduced ischemic lesion size.

Effect of Dimethyl Fumarate on the Motor Function and Spatial Arrangement of Primary Motor Cortical Neurons in the Sub-Acute Phase of Stroke in a Rat Model.

BACKGROUND: The therapeutic effects of dimethyl fumarate (DMF) in patients with multiple sclerosis and animal models of neurologic disease were reported. The density and the distribution pattern of motor neurons are important in transmitting the signal and controlling the movement-related functions. The present study evaluated the effects of DMF treatment on the neurological functions, infarct volume, and spatial distribution of the neurons in the primary motor cortex after cerebral ischemia. METHODS: Thirty-three Sprague-Dawley rats were randomly divided into three groups: The sham group underwent surgery without middle cerebral artery occlusion (MCAO) and drug. The vehicle and treatment groups after MCAO received a vehicle or DMF for three consecutive days. Post-stroke neurological and motor functions were assessed. At the end of the third day, the brains were removed, and the cerebral infarct volume was evaluated. We used cresyl violet staining to analyze the density and the spatial arrangement of motor cortical neurons using Voronoi tessellation. RESULTS: Treatment of the brain ischemia for three days with DMF could not significantly reduce the neurological and motor function deficits and infarct volume. However, it reduced the neuronal area and death and preserved their spatial distribution in the normal regular pattern. CONCLUSION: Cerebral ischemia decreased the neuronal density of the primary motor cortex and changed their distributions to a random pattern. DMF treatment during sub-acute ischemic stroke did not significantly improve the neurological deficit scores. However, it could prevent neuronal swelling and death and preserved the spatial distribution of the cortical neurons in their normal pattern.

Hookah Smoking: A Potentially Risk Factor for First-Ever Ischemic Stroke.

OBJECTIVE: Hookah consumption, as a common non-cigarette tobacco product, is wrongly considered as less harmful. Moreover, little is known about hookah consumption and risk of ischemic stroke. The current study aimed to assess the association between hookah consumption and first-ever ischemic stroke (FEIS). METHODS: This case-control study was performed on individuals admitted at a tertiary referral center in Shiraz, Southern Iran between October 1, 2018 and September 20, 2019. We compared FEIS patients with randomly selected stroke-free individuals as a control group. Using a multiple logistic regression analysis, we assessed the association between hookah consumption and FEIS. RESULTS: A total of 208 FEIS patients (mean age 65.2 ± 15.9 years) and 212 age and sex-matched controls (mean age 63.2 ± 14.4) were recruited. The prevalence of vascular risk factors and comorbidities including ischemic heart disease, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, cigarette smoking, and sleep apnea was higher in patients with FEIS than their control counterparts. After adjusting for a wide range of confounders, including socioeconomic factors, hookah consumption was still an independent risk factor for FEIS (odds ratio: 3.2, 95% CI: 1.7-6.1). CONCLUSION: Hookah consumption is associated strongly with FEIS. Public awareness about risk of hookah consumption should be raised.