The Double Burden: Deciphering Chronic Limb-Threatening Ischemia in End-Stage Renal Disease.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) in patients with end-stage renal disease (ESRD) poses significant challenges in clinical management due to its unique pathology and poor treatment outcomes. This review calls for a tailored classification and risk assessment for these patients to guide better revascularization choices with early minor amputation as a first-line strategy in advanced stages. METHODS: This review consolidates key findings from recent literature on CLTI in ESRD, focusing on disease mechanisms, treatment options, and patient outcomes. It evaluates the literature to clarify the decision-making process for managing CLTI in ESRD. RESULTS: CLTI in ESRD patients often results in worse clinical outcomes, such as nonhealing wounds, increased limb loss, and higher mortality rates. While the literature reveals ongoing debates regarding the optimal revascularization method, recent retrospective studies and meta-analyses suggest potential benefits of endovascular treatment (EVT) over open bypass surgery (OB) in reducing mortality and wound complications, with comparable amputation-free survival rates. CONCLUSIONS: The selection of revascularization methods in ESRD patients with CLTI is complex, necessitating individualized strategies. The importance of early detection and timely intervention is critical to decelerate disease progression and improve revascularization outcomes. There is a shift in these treatment strategies toward less invasive endovascular procedures, acknowledging the limitations these patients face with open revascularization surgeries. Considering early minor amputations after revascularization could prevent worse consequences, reflecting a shift in the approach to managing CLTI in ESRD patients.

Right ventricle toxicity in cancer treatment: a focused review on cardiac imaging.

Background: The right ventricle (RV) remains the 'forgotten chamber' in the clinical assessment of cancer therapy-related cardiac dysfunction (CTRCD). Aim: We aimed to review the role that various cardiac imaging modalities play in RV assessment as part of the integrative management of patients undergoing cancer therapy. Discussion: RV assessment remains challenging by traditional 2D echocardiography. In this review we discuss other parameters such as right atrial strain, and other echocardiographic modalities such as 3D and stress echocardiography. We also elaborate on the specific role that cardiac magnetic resonance imaging and equilibrium radionuclide angiocardiography can play in assessing the RV. Conclusion: Biventricular function should be monitored following chemotherapy for early detection of subclinical CTRCD and possible solitary RV changes.

Cancer is among the most common health concerns worldwide. In addition to cancer's effects itself on the body, chemotherapy agents and medication, drug treatments that use powerful chemicals to kill cancer cells, are putting further strain on individuals' bodies impairing their quality of life. Chemotherapy agents are a major risk factor for cardiac injuries by their cardiotoxic effects (the damage they cause to the heart). Previous studies have tried to find the earliest way of noticing cardiac changes in patients who are receiving special chemotherapy drugs. Most of the studies and definitions for this cardiotoxic event are limited to the assessment of left ventricles, one of the chambers of the heart that is involved in providing oxygenated blood to the body. However, there is some evidence that suggests the evaluation of the right ventricle, another chamber of the heart that pumps blood low in oxygen to the lungs, for faster notice. Having this insight can open new targets for cancer therapy-related cardiac dysfunction (CTRCD) prevention and therapy.

Emerging role of mesenchymal stem/stromal cells (MSCs) and MSCs-derived exosomes in bone- and joint-associated musculoskeletal disorders: a new frontier.

Exosomes are membranous vesicles with a 30 to 150 nm diameter secreted by mesenchymal stem/stromal cells (MSCs) and other cells, such as immune cells and cancer cells. Exosomes convey proteins, bioactive lipids, and genetic components to recipient cells, such as microRNAs (miRNAs). Consequently, they have been implicated in regulating intercellular communication mediators under physiological and pathological circumstances. Exosomes therapy as a cell-free approach bypasses many concerns regarding the therapeutic application of stem/stromal cells, including undesirable proliferation, heterogeneity, and immunogenic effects. Indeed, exosomes have become a promising strategy to treat human diseases, particularly bone- and joint-associated musculoskeletal disorders, because of their characteristics, such as potentiated stability in circulation, biocompatibility, low immunogenicity, and toxicity. In this light, a diversity of studies have indicated that inhibiting inflammation, inducing angiogenesis, provoking osteoblast and chondrocyte proliferation and migration, and negative regulation of matrix-degrading enzymes result in bone and cartilage recovery upon administration of MSCs-derived exosomes. Notwithstanding, insufficient quantity of isolated exosomes, lack of reliable potency test, and exosomes heterogeneity hurdle their application in clinics. Herein, we will deliver an outline respecting the advantages of MSCs-derived exosomes-based therapy in common bone- and joint-associated musculoskeletal disorders. Moreover, we will have a glimpse the underlying mechanism behind the MSCs-elicited therapeutic merits in these conditions.

Recent progress in cancer immunotherapy: Overview of current status and challenges.

Cancer treatment is presently one of the most important challenges in medical science. Surgery, chemotherapy, radiotherapy, or combining these methods is used to eliminate the tumor. Hormone therapy, bone marrow transplantation, stem cell therapy as well as immunotherapy are other well-known therapeutic modalities. Immunotherapy, as the most important complementary method, uses the immune system for treating cancer followed by surgery, chemotherapy, and radiotherapy. This method is systematically used to prevent malignancies development mainly via potentiating antitumor immune cells activation and conversely compromising their exhaustion with the lowest negative effects on healthy cells. Active immunotherapy can be employed for cancer immunotherapy by directly using the ingredients of the immune system and activating immune responses. On the other hand, inactive immunotherapy is utilized by indirect induction and using immune cell-based products consisting of monoclonal antibodies. It has strongly been proved that combination therapy with immunotherapies and other therapeutic means, such as anti-angiogenic agents, could be a rational plan to treat cancer. Herein, we have focused on recent findings concerning the therapeutic merits of cancer therapy using immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and cancer vaccine alone or in combination with other approaches. Also, we offer a glimpse into the current challenges in this context.

Glycemic profile variability: An independent risk factor for diabetic neuropathy in patients with type 2 diabetes.

BACKGROUND: Impaired glycemic control is a potential predictor for macro- and microvascular complications of diabetes, which could be recognized by glycemic variability. The aim of this 10-year prospective cohort study presented here is to gain a better understanding of the correlation between GV and diabetic peripheral neuropathy (DPN) as one of the most common complications of T2DM. METHODS: Since February 2010, 1152 adult patients with T2DM have been followed-up. Baseline features, anthropometric measurements, and laboratory findings were collected and documented during ten years. The association between DPN incidence and glycemic profile variability was evaluated using cox regression analysis. The coefficient of variation of glycemic indices within subjects was calculated and compared using an independent sample t-test. RESULTS: Individuals who developed neuropathy had significantly higher mean levels of glycemic indices (HbA1c, FBS, and 2hpp), urinary albumin excretion, mean creatinine levels, and a longer duration of diabetes. A significant positive correlation between incidence of DPN and glycemic profile variability (cv-FBS10 %, cv-FBS20 %, cv-2hpp20 %, cv-HbA1c5 % and cv-HbA1c10 %) was revealed. Results also showed that higher variability of FBS was associated with the higher risk of neuropathy incidence (HR: 12.29, p-value: 0.045), which indicates that glycemic profile variability is an independent risk factor for DPN in patients with T2DM. CONCLUSION: Variability of glycemic profiles from a visit to visit, regardless of sustained hyperglycemia, was indeed a significant risk factor for DPN in diabetic type 2 patients. CV-FBS was the most critical glycemic variability indices for DPN development.

Aortic remodeling, distal stent-graft induced new entry and endoleak following frozen elephant trunk: A systematic review and meta-analysis.

BACKGROUND: The introduction of the frozen elephant trunk (FET) technique for total arch replacement (TAR) has revolutionized the field of aortovascular surgery. However, although FET yields excellent results, the risk of certain complications requiring secondary intervention remains present, negating its one-step hybrid advantage over conventional techniques. This systematic review and meta-analysis sought to evaluate controversies regarding the incidence of FET-related complications, with a focus on aortic remodeling, distal stent-graft induced new entry (dSINE) and endoleak, in patients with type A aortic dissection (TAAD) and/or thoracic aortic aneurysm. MATERIALS AND METHODS: A comprehensive literature search was conducted using multiple electronic databases including EMBASE, Scopus, and PubMed/MEDLINE to identify evidence on TAR with FET in patients with TAAD and/or aneurysm. Studies published up until January 2022 were included, and after applying exclusion criteria, a total of 43 studies were extracted. RESULTS: A total of 5068 patients who underwent FET procedure were included. The pooled estimates of dSINE and endoleak were 2% (95% confidence interval [CI] 0.01-0.06, I2 = 78%) and 3% (95% CI 0.01-0.11, I2 = 89%), respectively. The pooled rate of secondary thoracic endovascular aortic repair (TEVAR) post-FET was 7% (95% CI 0.05-0.12, I2 = 89%) while the pooled rate of false lumen thrombosis at the level of stent-graft was 91% (95% CI 0.75-0.97, I2 = 92%). After subgroup analysis, heterogeneity for distal stent-graft induced new entry (dSINE) and endoleak resolved among European patients, where Thoraflex Hybrid (THP) and E-Vita stent-grafts were used (both I2 = 0%). In addition, heterogeneity for secondary TEVAR after FET resolved among Asians receiving Cronus (I2 = 15.1%) and Frozenix stent-grafts (I2 = 1%). CONCLUSION: Our results showed that the FET procedure in patients with TAAD and/or aneurysm is associated with excellent results, with a particularly low incidence of dSINE and endoleak as well as highly favorable aortic remodeling. However the type of stent-graft and the study location were sources of heterogeneity, emphasizing the need for multicenter studies directly comparing FET grafts. Finally, THP can be considered the primary FET device choice due to its superior results.

Atherogenic index of plasma is an independent predictor of metabolic-associated fatty liver disease in patients with type 2 diabetes.

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease, is the leading cause of liver disease that can ultimately lead to cirrhosis. Identifying a screening marker for early diagnosis of MAFLD in patients with type 2 diabetes (T2D) can reduce the risk of morbidity and mortality. This study investigated the association between the atherogenic index of plasma (AIP) and MAFLD in patients with T2D. METHOD: A retrospective case-control study was conducted and medical records of patients with T2D were assessed. The baseline characteristics, anthropometric indices, laboratory measurements including liver functions tests, fasting blood sugar, HbA1C, lipid profile were documented. RESULTS: Out of 2547 patients with T2D, 824 (32.4%) had MAFLD. The multivariate logistic regression analysis showed a significant difference in female-to-male ratio (1.11 vs. 1.33, OR = 0.347, P-value < 0.001), ALT (42.5 ± 28.1 vs. 22.4 ± 11.1, OR = 1.057, P-value < 0.001), and AIP (0.6 ± 0.3 vs. 0.5 ± 0.3, OR = 5.057, P-value < 0.001) between MAFLD and non-MAFLD groups, respectively. According to the AIP quartile, the prevalence of MAFLD increased significantly in patients with higher AIP quartiles (P-value < 0.001). Also, we found a cut-off of 0.54 for AIP in predicting MAFLD in patients with T2D (sensitivity = 57.8%, specificity = 54.4%). CONCLUSION: In this study, we found that AIP is a good and independent predictor for MAFLD in patients with T2D which could help physicians in early diagnosis and follow-up of patients with T2D.

Metallic Nanoparticles for the Modulation of Tumor Microenvironment; A New Horizon.

Cancer is one of the most critical human challenges which endangers many people's lives every year with enormous direct and indirect costs worldwide. Unfortunately, despite many advanced treatments used in cancer clinics today, the treatments are deficiently encumbered with many side effects often encountered by clinicians while deploying general methods such as chemotherapy, radiotherapy, surgery, or a combination thereof. Due to their low clinical efficacy, numerous side effects, higher economic costs, and relatively poor acceptance by patients, researchers are striving to find better alternatives for treating this life-threatening complication. As a result, Metal nanoparticles (Metal NPs) have been developed for nearly 2 decades due to their important therapeutic properties. Nanoparticles are quite close in size to biological molecules and can easily penetrate into the cell, so one of the goals of nanotechnology is to mount molecules and drugs on nanoparticles and transfer them to the cell. These NPs are effective as multifunctional nanoplatforms for cancer treatment. They have an advantage over routine drugs in delivering anticancer drugs to a specific location. However, targeting cancer sites while performing anti-cancer treatment can be effective in improving the disease and reducing its complications. Among these, the usage of these nanoparticles (NPs) in photodynamic therapy and sonodynamic therapy are notable. Herein, this review is aimed at investigating the effect and appliances of Metal NPs in the modulation tumor microenvironment which bodes well for the utilization of vast and emerging nanomaterial resources.

Zone proximalization in frozen elephant trunk: what is the optimal zone for open intervention? A systematic review and meta-analysis.

INTRODUCTION: The treatment of complex aortic lesions involving the ascending, arch, and proximal descending aorta, remains challenging for surgeons despite the evolution of surgical techniques and aortic prostheses over decades. The frozen elephant trunk (FET) approach offers a one-stage repair of this entity of aortic pathologies. The main scope of this systematic review and meta-analysis is to evaluate the clinical outcomes and effectiveness of FET. EVIDENCE ACQUISITION: In a systematic review, multiple electronic databases including EMBASE, Scopus, and PubMed/MEDLINE were searched from inception to June 2021 to identify relevant studies reporting on outcomes of total arch replacement (TAR) with FET. EVIDENCE SYNTHESIS: Eighty-five studies met inclusion criteria, encompassing 10960 patients. Meta-analysis was conducted using the R-studio (RStudio, Boston, MA, USA) and STATA software (StataCorp LLC, College Station, TX, USA). The pooled in-hospital mortality rate was 7% (95% CI 0.05-0.09; I2=76%) and 12% for renal failure (95% CI 0.09-0.15; I2=88%), while the rates for paraplegia and cerebrovascular accidents were 3% (95% CI 0.02-0.04; I2=0%) and 6% (95% CI 0.05-0.08; I2=73%), respectively. Lower heterogeneity was attained after the stratification by the aortic pathologies, except for the renal failure. The distal anastomosis of the stent in zone 2 was significantly correlated with a lower renal failure development compared to zone 3 (odds ratio 0.52; 95% CI 0.33-0.82; P=0.069; I2=0%). CONCLUSIONS: Our results indicate that the morbidities and mortality following TAR with FET were acceptable. We also associated the distal anastomosis in zone 2 with fewer renal failure development compared to that in zone 3.

Liposomes: Structure, Biomedical Applications, and Stability Parameters With Emphasis on Cholesterol.

Liposomes are essentially a subtype of nanoparticles comprising a hydrophobic tail and a hydrophilic head constituting a phospholipid membrane. The spherical or multilayered spherical structures of liposomes are highly rich in lipid contents with numerous criteria for their classification, including structural features, structural parameters, and size, synthesis methods, preparation, and drug loading. Despite various liposomal applications, such as drug, vaccine/gene delivery, biosensors fabrication, diagnosis, and food products applications, their use encounters many limitations due to physico-chemical instability as their stability is vigorously affected by the constituting ingredients wherein cholesterol performs a vital role in the stability of the liposomal membrane. It has well established that cholesterol exerts its impact by controlling fluidity, permeability, membrane strength, elasticity and stiffness, transition temperature (Tm), drug retention, phospholipid packing, and plasma stability. Although the undetermined optimum amount of cholesterol for preparing a stable and controlled release vehicle has been the downside, but researchers are still focused on cholesterol as a promising material for the stability of liposomes necessitating explanation for the stability promotion of liposomes. Herein, the prior art pertaining to the liposomal appliances, especially for drug delivery in cancer therapy, and their stability emphasizing the roles of cholesterol.

High risk of drug toxicity in social isolation stress due to liver dysfunction: Role of oxidative stress and inflammation.

BACKGROUND: Previous studies have shown that social isolation stress (SIS) could associate with several systemic diseases; however, the role of SIS on liver dysfunction has yet to be established. This study aimed to investigate the effect of SIS on liver function and possible drug toxicity through liver inflammation and oxidative stress. METHODS: Male Naval Medical Research Institute mice in two groups of SIS and control were treated with typical anti-depressant and anxiolytic agents including fluoxetine, norfluoxetine, desipramine, and imipramine in both groups. Then blood concentrations (or their active metabolites) of these drugs were assessed. Liver function test, including aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, and conjugated bilirubin), oxidative activity, inflammatory cytokines, and the gene expression of cytochrome P450 enzymes were assessed. RESULTS: We observed that the liver enzymes including AST and ALT was slightly higher in SIS animals. The blood concentrations of fluoxetine, norfluoxetine, desipramine, and imipramine were significantly higher in SIS animals. The gene expression of CYP1A2, CYP2A6, CYP2C9, CYP2C29, and CYP2D were significantly decreased in SIS animals. Our results showed that SIS animals had significantly higher level of tumor necrosis factor-α, interleukin-1ß, and interleukin-6. SIS could significantly decrease the activity of antioxidant agent (Glutathione). CONCLUSION: We hypothesized that SIS could induce liver dysfunction and decrease the rate of drug clearance through liver inflammation and oxidative stress; therefore, the blood concentration of anti-depressant/anxiolytic agents should closely monitor in SIS due to the high toxicity of these agents.

Adverse reactions in a large cohort of patients with inborn errors of immunity receiving intravenous immunoglobulin.

BACKGROUND: Intravenous immunoglobulins (IVIg) are the major treatment in inborn errors of immunity (IEI) disorders; However, IVIg infusions show some adverse effects. We aimed to assess the adverse reactions of IVIg infusions. METHODS: Data of IVIg infusions in IEI patients were collected from 2011 to 2021. Totally, 363 IEI patients received IVIg regularly in Iran entered the study. The adverse reactions are classified regarding their severity and chronicity. RESULTS: 22,667 IVIg infusions were performed in the study. 157 patients (43.2%) and 1349 (5.9%) infusions were associated with at least one type of adverse reaction. The highest rates of adverse reactions were seen in severe combined immunodeficiency. Myalgia, chills, headache, fever, and hypotension were the most frequent adverse effects of IVIg. CONCLUSION: The reactions affect almost half of the patients mainly in the first infusions which necessitate the close observation of IEI patients receiving IVIg.

A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies.

To date, two chimeric antigen receptors (CAR)-T cell products from autologous T cells have been approved by The United States Food and Drug Administration (FDA). The case-by-case autologous T cell generation setting is largely considered as a pivotal restraining cause for its large-scale clinical use because of the costly and prolonged manufacturing procedure. Further, activated CAR-T cells mainly express immune checkpoint molecules, including CTLA4, PD1, LAG3, abrogating CAR-T anti-tumor activity. In addition, CAR-T cell therapy potently results in some toxicity, such as cytokine releases syndrome (CRS). Therefore, the development of the universal allogeneic T cells with higher anti-tumor effects is of paramount importance. Thus, genome-editing technologies, in particular, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 are currently being used to establish "off-the-shelf" CAR-T cells with robust resistance to immune cell-suppressive molecules. In fact, that simultaneous ablation of PD-1, T cell receptor alpha constant (TRAC or TCR), and also ß-2 microglobulin (B2M) by CRISPR-Cas9 technique can support the manufacture of universal CAR-T cells with robust resistance to PD-L1. . Indeed, the ablation of ß2M or TARC can severely hinder swift elimination of allogeneic T cells those express foreign HLA-I molecules, and thereby enables the generation of CAR-T cells from allogeneic healthy donors T cells with higher persistence in vivo. Herein, we will deliver a brief overview of the CAR-T cell application in the context of tumor immunotherapy. More importantly, we will discuss recent finding concerning the application of genome editing technologies for preparing universal CAR-T cells or cells that can effectively counter tumor escape, with a special focus on CRISPR-Cas9 technology.