IL-17 in type II diabetes mellitus (T2DM) immunopathogenesis and complications; molecular approaches.

Chronic inflammation has long been considered the characteristic feature of type II diabetes mellitus (T2DM) Immunopathogenesis. Pro-inflammatory cytokines are considered the central drivers of the inflammatory cascade leading to ß-cell dysfunction and insulin resistance (IR), two major pathologic events contributing to T2DM. Analyzing the cytokine profile of T2DM patients has also introduced interleukin-17 (IL-17) as an upstream regulator of inflammation, regarding its role in inducing the nuclear factor-kappa B (NF-κB) pathway. In diabetic tissues, IL-17 induces the expression of inflammatory cytokines and chemokines. Hence, IL-17 can deteriorate insulin signaling and ß-cell function by activating the JNK pathway and inducing infiltration of neutrophils into pancreatic islets, respectively. Additionally, higher levels of IL-17 expression in patients with diabetic complications compared to non-complicated individuals have also proposed a role for IL-17 in T2DM complications. Here, we highlight the role of IL-17 in the Immunopathogenesis of T2DM and corresponding pathways, recent advances in preclinical and clinical studies targeting IL-17 in T2DM, and corresponding challenges and possible solutions.

Outcome after Neuro-interventional Treatment of Intracranial Aneurysm (as a First Treatment Modality).

Endovascular treatment is widely applied as the first-line treatment for intracranial aneurysms and includes simple coiling (SC), stent-assisted coiling (SAC), flow diversion stent, and flow disruption stent. The present study is a retrospective cohort study performed in Imam Khomeini Hospital, Department of Neurovascular Intervention, between March 2016 and March 2021. A total number of 229 patients with intracranial aneurysms who underwent therapeutic intravascular interventions were enrolled, of which 89 were treated with SC, 111 with SAC, 25 with flow diversion stent, and 4 with flow disruption stent. The mean age of the subjects was 51.8±12.6 years, and 51.1% were male. Modified Raymond-Roy classification (MRRC) was used to define the occlusion outcome. The success rate, considered as Class I and Class II of MRRC at treatment time was 89% (94.4% in SC, and 84.7% in SAC), which was increased to 90.9% (94% in SC, 93% in SAC, 69.6% in flow diversion stenting, 100% in flow disruption) at 6-month follow-up, and 84.6% (80.8% in SC, 87.8% in SAC, 78.3% in flow diversion stenting, and 100% in flow disruption) at 12-month follow-up. The mean modified Rankin Scale (mRS) before the procedure was 0.05±0.26 which was increased to 0.22±0.76 after the procedure, 0.22±0.76 at 6 months, and 0.30±0.95 at 12 months (P<0.001). Similar to previous studies, the present study demonstrates that neurovascular intervention can treat ruptured aneurysms as the first therapeutic modality with favourable outcomes. A double-blind, randomized clinical trial is needed to eliminate the confounding factors and better demonstrate the outcome.

Current progress of chimeric antigen receptor (CAR) T versus CAR NK cell for immunotherapy of solid tumors.

Equipping cancer-fighting immune cells with chimeric antigen receptor (CAR) has gained immense attention for cancer treatment. CAR-engineered T cells (CAR T cells) are the first immune-engineered cells that have achieved brilliant results in anti-cancer therapy. Despite promising anti-cancer features, CAR T cells could also cause fatal side effects and have shown inadequate efficacy in some studies. This has led to the introduction of other candidates for CAR transduction, e.g., Natural killer cells (NK cells). Regarding the better safety profile and anti-cancer properties, CAR-armored NK cells (CAR NK cells) could be a beneficial and suitable alternative to CAR T cells. Since introducing these two cells as anti-cancer structures, several studies have investigated their efficacy and safety, and most of them have focused on hematological malignancies. Solid tumors have unique properties that make them more resistant and less curable cancers than hematological malignancies. In this review article, we conduct a comprehensive review of the structure and properties of CAR NK and CAR T cells, compare the recent experience of immunotherapy with CAR T and CAR NK cells in various solid cancers, and overview current challenges and future solutions to battle solid cancers using CARNK cells.

Chimeric Antigen Receptor (CAR)-Based Cell Therapy for Type 1 Diabetes Mellitus (T1DM); Current Progress and Future Approaches.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that destroys insulin-producing pancreatic ß-cells. Insulin replacement therapy is currently the mainstay of treatment for T1DM; however, treatment with insulin does not ameliorate disease progression, as dysregulated immune response and inflammation continue to cause further pancreatic ß-cell degradation. Therefore, shifting therapeutic strategies toward immunomodulating approaches could be effective to prevent and reverse disease progression. Different immune-modulatory therapies could be used, e.g., monoclonal-based immunotherapy, mesenchymal stem cell, and immune cell therapy. Since immune-modulatory approaches could have a systemic effect on the immune system and cause toxicity, more specific treatment options should target the immune response against pancreatic ß-cells. In this regard, chimeric antigen receptor (CAR)-based immunotherapy could be a promising candidate for modulation of dysregulated immune function in T1DM. CAR-based therapy has previously been approved for a number of hematologic malignancies. Nevertheless, there is renewed interest in CAR T cells' " off-the-shelf " treatment for T1DM. Several pre-clinical studies demonstrated that redirecting antigen-specific CAR T cells, especially regulatory CAR T cells (CAR Tregs), toward the pancreatic ß-cells, could prevent diabetes onset and progression in diabetic mice models. Here, we aim to review the current progress of CAR-based immune-cell therapy for T1DM and the corresponding challenges, with a special focus on designing CAR-based immunomodulatory strategies to improve its efficacy in the treatment of T1DM.

The role of heat shock proteins (HSPs) in type 2 diabetes mellitus pathophysiology.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by sustained hyperglycemia caused by impaired insulin signaling and secretion. Metabolic stress, caused by an inappropriate diet, is one of the major hallmarks provoking inflammation, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Heat shock proteins (HSPs) are a group of highly conserved proteins that have a crucial role in chaperoning damaged and misfolded proteins to avoid disruption of cellular homeostasis under stress conditions. To do this, HSPs interact with diverse intra-and extracellular pathways among which are the insulin signaling, insulin secretion, and apoptosis pathways. Therefore, HSP dysfunction, e.g. HSP70, may lead to disruption of the pathways responsible for insulin secretion and uptake. Consistently, the altered expression of other HSPs and genetic polymorphisms in HSP-producing genes in diabetic subjects has made HSPs hot research in T2DM. This paper provides a comprehensive overview of the role of different HSPs in T2DM pathogenesis, affected cellular pathways, and the potential therapeutic strategies targeting HSPs in T2DM.

Targeting the cGAS-STING pathway as an inflammatory crossroad in coronavirus disease 2019 (COVID-19).

CONTEXT AND OBJECTIVE: The emerging pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has imposed significant mortality and morbidity on the world. An appropriate immune response is necessary to inhibit SARS-CoV-2 spread throughout the body. RESULTS: During the early stages of infection, the pathway of stimulators of interferon genes (STING), known as the cGAS-STING pathway, has a significant role in the induction of the antiviral immune response by regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Interferon regulatory factor 3 (IRF3), two key pathways responsible for proinflammatory cytokines and type I IFN secretion, respectively. DISCUSSION: During the late stages of COVID-19, the uncontrolled inflammatory responses, also known as cytokine storm, lead to the progression of the disease and poor prognosis. Hyperactivity of STING, leading to elevated titers of proinflammatory cytokines, including Interleukin-I (IL-1), IL-4, IL-6, IL-18, and tissue necrosis factor-α (TNF-α), is considered one of the primary mechanisms contributing to the cytokine storm in COVID-19. CONCLUSION: Exploring the underlying molecular processes involved in dysregulated inflammation can bring up novel anti-COVID-19 therapeutic options. In this article, we aim to discuss the role and current studies targeting the cGAS/STING signaling pathway in both early and late stages of COVID-19 and COVID-19-related complications and the therapeutic potential of STING agonists/antagonists. Furthermore, STING agonists have been discussed as a vaccine adjuvant to induce a potent and persistent immune response.

Transforming growth factor ß (TGF-ß) pathway in the immunopathogenesis of multiple sclerosis (MS); molecular approaches.

INTRODUCTION: Multiple sclerosis (MS) is an acute demyelinating disease with an autoimmune nature, followed by gradual neurodegeneration and enervating scar formation. Dysregulated immune response is a crucial dilemma contributing to the pathogenesis of MS. The role of chemokines and cytokines, such as transforming growth factor-ß (TGF-ß), have been recently highlighted regarding their altered expressions in MS. TGF-ß has three isoforms, TGF-ß1, TGF-ß2, and TGF-ß3, that are structurally similar; however, they can show different functions. RESULTS: All three isoforms are known to induce immune tolerance by modifying Foxp3+ regulatory T cells. Nevertheless, there are controversial reports concerning the role of TGF-ß1 and 2 in the progression of scar formation in MS. At the same time, these proteins also improve oligodendrocyte differentiation and have shown neuroprotective behavior, two cellular processes that suppress the pathogenesis of MS. TGF-ß3 shares the same properties but is less likely contributes to scar formation, and its direct role in MS remains elusive. DISCUSSION: To develop novel neuroimmunological treatment strategies for MS, the optimal strategy could be the one that causes immune modulation, induces neurogenesis, stimulates remyelination, and prevents excessive scar formation. Therefore, regarding its immunological properties, TGF-ß could be an appropriate candidate; however, contradictory results of previous studies have questioned its role and therapeutic potential in MS. In this review article, we provide an overview of the role of TGF-ß in immunopathogenesis of MS, related clinical and animal studies, and the treatment potential of TGF-ß in MS, emphasizing the role of different TGF-ß isoforms.

Immune evasion of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); molecular approaches.

In December 2019, a new betacoronavirus, known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused an outbreak at the Wuhan seafood market in China. The disease was further named coronavirus disease 2019 (COVID-19). In March 2020, the World Health Organization (WHO) announced the disease to be a pandemic, as more cases were reported globally. SARS-CoV-2, like many other viruses, employs diverse strategies to elude the host immune response and/or counter immune responses. The infection outcome mainly depends on interactions between the virus and the host immune system. Inhibiting IFN production, blocking IFN signaling, enhancing IFN resistance, and hijacking the host's translation machinery to expedite the production of viral proteins are among the main immune evasion mechanisms of SARS-CoV-2. SARS-CoV-2 also downregulates the expression of MHC-I on infected cells, which is an additional immune-evasion mechanism of this virus. Moreover, antigenic modifications to the spike (S) protein, such as deletions, insertions, and also substitutions are essential for resistance to SARS-CoV-2 neutralizing antibodies. This review assesses the interaction between SARS-CoV-2 and host immune response and cellular and molecular approaches used by SARS-CoV-2 for immune evasion. Understanding the mechanisms of SARS-CoV-2 immune evasion is essential since it can improve the development of novel antiviral treatment options as well as vaccination methods.

Major severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccine-associated adverse effects; benefits outweigh the risks.

INTRODUCTION: Since its emergence, there have been huge efforts to design vaccines against coronavirus disease 2019 (COVID-19) to inhibit its interpersonal spread. Global vaccine development is the most promising cost-effective method for overcoming the epidemic. However, following reports of post-vaccination thromboembolic adverse effects, there have been raising concerns about the safety profile of the COVID-19 vaccine. AREAS COVERED: We aimed to review the recent Food and Drug Administration (FDA)-approved vaccines and identify the organ-based major complications of COVID-19 vaccines based on reliable published studies. To find high-quality and large-scale observational, clinical trial, and cohort studies, PubMED, Scholar, Embase, and Web of Science were searched using keywords: COVID-19, SARS-CoV-2, vaccine, Pfizer (BNT162b2), Johnson and Johnson (Ad26.COV2), Moderna (mRNA-1273), Oxford AstraZeneca (ChAdOx1nCoV19), Coronavac (Sinovac), BBIBP-CorV (Sinopharm), adverse effect, and complication. To include all relevant articles, backward searching was also done on similar article citations. Case reports, studies including less than 10 participants, and biased articles were excluded. EXPERT OPINION: Based on data from high-quality and population-based studies, major adverse effects are divided into four major organ-specific groups, including cardiovascular, neurologic, hematologic, and immune-allergic side effects. The incidence of most of these side effects is not different between vaccinated and normal populations, and currently, the benefits of vaccination against COVID-19 are greater than the mortality and morbidity risks of COVID-19 infection. However, further studies, specifically systematic review and meta-analysis, are still indicated to investigate further unknown side effects of these vaccines and the existence of causality between the vaccine and reported adverse events.

Endocrine and metabolic complications of COVID-19: lessons learned and future prospects.

Coronavirus disease 2019 (COVID-19) is well known for its respiratory complications; however, it can also cause extrapulmonary manifestations, including cardiovascular, thrombotic, renal, gastrointestinal, neurologic, and endocrinological symptoms. Endocrinological complications of COVID-19 are rare but can considerably impact the outcome of the patients. Moreover, preexisting endocrinologic disorders can affect the severity of COVID-19. Thyroid, pancreas, adrenal, neuroendocrine, gonadal, and parathyroid glands are the main endocrinologic organs that can be targeted by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Endocrinological complications of COVID-19 are rare but can significantly deteriorate the patients' prognosis. Understanding the interaction between COVID-19 and the endocrine system can provide a potential treatment option to improve the outcome of COVID-19. In this article, we aim to review the short-term and long-term organ-based endocrinological complications of COVID-19, the pathophysiology, the influence of each complication on COVID-19 prognosis, and potential therapeutic interventions based on current published data. Moreover, current clinical trials of potential endocrinological interventions to develop therapeutic strategies for COVID-19 have been discussed.

OMICRON: Virology, immunopathogenesis, and laboratory diagnosis.

Since its emersion, coronavirus disease 2019 (COVID-19) has been a significant global dilemma. Several mutations in the severe acute respiratory virus (SARS-Co-2) genome has given rise to different variants with various levels of transmissibility, severity and mortality. Up until November 2021, the variants of concern declared by the World Health Organization were Alpha, Beta, Delta and Gamma. Since then, a novel variant named Omicron (B.1.1.529) has been developed. BA.1, BA.1.1, BA.2 and BA.3 are four known subvariants of Omicron. The Omicron variant involves new mutations in its spike protein, most of which are in its receptor binding site, and increase its transmissibility and decrease its antibody and vaccine response. Understanding the virology and mutations of Omicron is necessary for developing diagnostic and therapeutic methods. Moreover, important issues, such as the risk of re-infection, the response to different kinds of vaccines, the need for a booster vaccine dose and the increased risk of Omicron infection in pediatrics, need to be addressed. In this article, we provide an overview of the biological and immunopathological properties of Omicron and its subvariants, its clinical signs and symptoms, Omicron and pediatrics, vaccines against Omicron, re-infection with Omicron, diagnostic approaches and specific challenges of Omicron in the successful control and management of the rapid global spread of this variant.

An updated overview of recent advances, challenges, and clinical considerations of IL-6 signaling blockade in severe coronavirus disease 2019 (COVID-19).

Since 2019, COVID-19 has become the most important health dilemma around the world. The dysregulated immune response which results in ARDS and cytokine storm has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through induction of pro-inflammatory chemokines and cytokines, is the pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, IL-6 pathway blockade is considered an emerging approach with high efficacy to reduce lung damage in COVID-19. This article aims to review the pleiotropic roles of the IL-6 pathway in lung damage and ARDS in severe COVID-19, and the rationale for IL-6 signaling blockade at different levels, including IL-6 soluble and membrane receptor pathways, IL-6 downstream signaling (such as JAK-STAT) inhibition, and non-specific anti-inflammatory therapeutic approaches. Recent clinical data of each method, with specific concentration on tocilizumab, along with other new drugs, such as sarilumab and siltuximab, have been discussed. Challenges of IL-6 signaling inhibition, such as the risk of superinfection and hepatic injury, and possible solutions have also been explained. Moreover, to achieve the highest efficacy, ongoing clinical trials and special clinical considerations of using different IL-6 inhibitors have been discussed in detail. Special considerations, including the appropriate timing and dosage, monotherapy or combination therapy, and proper side effect managment must be noticed regarding the clinical administration of these drugs. Future studies are still necessary to improve the productivity and unknown aspects of IL-6 signaling blockade for personalized treatment of severe COVID-19.

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects.

Natural Killer (NK) cells are critical members of the innate immunity lymphocytes and have a critical role in host defense against malignant cells. Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) redirects the specificity of the immune cell against a target-specific antigen. ACT has recently created an outstanding opportunity for cancer treatment. Unlike CAR-armored T cells which hadnsome shortcomings as the CAR-receiving construct, Major histocompatibility complex (MHC)-independency, shorter lifespan, the potential to produce an off-the-shelf immune product, and potent anti-tumor properties of the NK cells has introduced NK cells as a potent alternative target for expression of CAR. Here, we aim to provide an updated overview on the current improvements in CAR NK design and immunobiology and describe the potential of CAR-modified NK cells as an alternative "off-the-shelf" carrier of CAR. We also provide lists for the sources of NK cells in the process of CAR NK cell production, different methods for transduction of the CAR genetic sequence to NK cells, the differences between CAR T and CAR NK, and CAR NK-targeted tumor antigens in current studies. Additionally, we provide data on recently published preclinical and clinical studies of CAR NK therapy and a list of finished and ongoing clinical trials. For achieving CAR NK products with higher efficacy and safety, we discuss current challenges in transduction and expansion of CAR NK cells, CAR NK therapy side effects, and challenges that limit the optimal efficacy of CAR NK cells and recommend possible solutions to enhance the persistence, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.

IL-38 as an early predictor of the ischemic stroke prognosis.

BACKGROUND: Ischemic stroke is caused by a sudden neurological defect following a vascular occlusion and elicits a local and systemic inflammation in brain tissue. Interleukin-38 is an anti-inflammatory cytokine associated with ischemic and inflammatory diseases. This study was designed to analyze the effect of tPA therapy on interleukin-38 serum level changes and the serum level of IL-38 in the prognosis of ischemic stroke patients in the next three months. METHODS: We enrolled 29 ischemic stroke patients confirmed by a neurologist based on radiologic and clinical manifestation between 2019 September to 2020 February. The patients who had NIHSS more than 6 with no underlying inflammatory diseases were selected for tPA therapy. On admission and 24 h after tPA therapy, the IL-38 serum level was measured by ELISA kit. RESULTS: The results showed that serum levels of IL-38 were significantly increased after tPA therapy (P < 0.001). A remarkable relationship was observed between the modified Rankin Score (mRS) and IL-38 serum changes in response to tPA therapy (P < 0.001). Besides, IL-38 serum changes following tPA were dramatically related to NIHSS at hospitalization (P = 0.007). Also, our analysis posed a positive relation between NIHSS at hospitalization and mRs criteria (P = 0.023). No notable relation has been observed between IL-38 serum levels before and after tPA and mRs (P = 0.601 and P = 0.074, respectively). Furthermore, there was no evidence for the relation between NIHSS at hospitalization and IL-38 levels before and after tPA (P = 0.457 and P = 0.105, respectively). CONCLUSION: The results indicate that tPA could meaningfully increase the IL-38 serum level. Also, a negative correlation has been found between IL-38 serum changes in response to tPA and mRS. Since the lower changes in IL-38 serum level result in a poorer prognosis, we conclude that IL-38 serum changes might be a novel early predictor factor for ischemic stroke prognosis.

Immune-Based Therapy for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel zoonotic virus identified as the cause of coronavirus disease 2019 (COVID-19) that has crossed species and infected humans. In order to develop new insights on the immune-based treatments against this disease, it is vital to understand the immunopathology of the COVID-19, implications of the immune response to SARS-CoV-2, and immune dysfunction in response to SARS-CoV-2. There is no approved drug for the treatment of COVID-19. It is, thus, promising to design immune-based treatments that inhibit the infectious mechanism of the virus, improve the inadequate immune response, or regulate the hyperactivated immune response in severely ill patients. According to the antiviral immune response against the virus, antibody-based immunotherapies of COVID-19 include injection of convalescent plasma from recovered patients, high-dose intravenous immunoglobulins (IVIG), monoclonal antibodies, and polyclonal antibodies. Also, cell-based treatment, vaccine-based approaches, cytokine-based immunotherapy, immune checkpoint inhibitors, JAK inhibitors, decoy receptors, and immunosuppressive drugs are discussed in this chapter.

Immunobiology and immunotherapy of COVID-19: A clinically updated overview.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new member of the coronavirus family that can cause coronavirus disease 2019 (COVID-19). COVID-9 has become a global pandemic with severe health issues around the world. Identifying the accurate immunopathogenesis of the COVID-19 and the immune response against SARS-CoV-2 is necessary for the development of therapeutic approaches and rational drug design. This paper aims to overview the updated clinical data on the immunopathogenesis of the COVID-19 and review the innate and adaptive immune response to SARS-CoV-2. Also, challenges of the immune response to SARS-CoV-2 leading to dysfunctional immune response and their contribution to the progression of the disease have been discussed. To achieve a more efficient immune response, multiple methods could be applied, including regulation of the immune response, augmentation of the immune system against the virus, inhibition of the dysfunctional immune checkpoints, and inhibition of the viral replication/infection. Based on the immune response against SARS-CoV-2 and its dysfunction, we introduce potential immunotherapies as well as reviewing recruiting/completed clinical trials of COVID-19.

Clinical Applications of Interleukin-37: A Key Player in the Immunopathogenesis of Immune Disorders.

Recently, the era of medicine has been encountered with the exponential growth of special seroimmunobiomarkers in clinical trials. Lately, Interleukin-37 (IL-37) has attracted a wide range of basic medical scientists' attention due to its controversial functions in physiologic or pathologic microenvironments. In this research, an updated overview of immunobiological functions and clinical applications of IL-37 in a wide range of diseases, are discussed in order to highlight the role of recent laboratory-based results of IL-37. Data of this systematic review article were collected from initial 237 articles in Google Scholar search engine, Science Direct, PubMed, Scopus, and Embase databases. Eventually, 134 total articles were considered from March 2000 to June 2019 time interval, by using 5 keywords. Relevant English articles, abstracts and conference papers all were included. No restrictions of methods and type of the article were imposed. As one of the newly immunotherapeutic based approaches, clinical applications of cytokines are promisingly taken into account for diagnosis and treatment of multiple diseases. Various evidence suggests that IL-37 has notable roles in the regulation of acute and chronic inflammatory responses. Also, IL-37 has been studied in pregnancy, obesity, infectious, cardiovascular, neurologic, autoimmune, and metabolic diseases. Also, the protective functions of IL-37 against multiple cancers, are disputably related to the type and stage of cancer as well as the IL-37 variant. The broad spectrum of IL-37 and its receptors in diseases, seem to be a potential candidate with pivotal effects for immunomodulation and immune gene therapy of various pathologic states.

Solid Tumors Challenges and New Insights of CAR T Cell Engineering.

Adoptive cell therapy using CAR T cells has emerged as a novel treatment strategy with promising results against B cell malignancies; however, CAR T cells have not shown much success against solid malignancies. There are several obstacles which diminish the efficacy of CAR T cells, but the immunosuppressive tumor microenvironment (TME) of the tumor stands out as the most important factor. TME includes Tumor-Associated Stroma, Immunosuppressive cells and cytokines, tumor hypoxia and metabolism, and Immune Inhibitory Checkpoints which affect the CAR T cell efficacy and activity in solid tumors. A precise understanding of the TME could pave the way to engineer novel modifications of CAR T cells which can overcome the immunosuppressive TME. In this review, we will describe different sections of the TME and introduce novel approaches to improve the CAR T cells potential against solid tumors based on recent clinical and preclinical data. Also, we will provide new suggestions on how to modify CARs to augment of CAR T cells efficacy. Since there are also some challenges beyond the TME that are important for CAR function, we will also discuss and provide data about the improvement of CAR T cells trafficking and delivery to the tumor site and how to solve the problem of tumor antigen heterogeneity.

Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells.

T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. In this review, we discuss the structure of the CAR, current clinical advantages from finished and ongoing trials, adverse effects, challenges and controversies, new engineering methods of CAR, and clinical considerations that are associated with CAR T cell therapy both in hematological malignancies and solid tumors. Also, we provide a comprehensive description of recently introduced modifications for designing smarter models of CAR T cells. Specific hurdles and problems that limit the optimal function of CAR T cells, especially on solid tumors, and possible solutions according to new modifications and generations of CAR T cells have been introduced here. We also provide information of the future directions on how to enhance engineering the next smarter generations of CAR T cells in order to decrease the adverse effects and increase the potency and efficacy of CAR T cells against cancer.

Bile cast nephropathy due to cholestatic jaundice after using stanozolol in 2 amateur bodybuilders.

Elevated level of bile can cause bile cast nephropathy, which can be seen in patients with severe cholestatic liver disease. Stanozolol is a C17α-alkylation steroid derived from dihydrotestosterone and its major adverse effect is cholestatic jaundice. We report 2 bodybuilders who received stanozolol for 6 weeks and developed icterus. Serum total bilirubin was around 50 mg/dL. Liver biopsy showed intrahepatic cholestasis. In spite of fluid and albumin therapy, serum creatinine increased and the patients experienced oliguria. Urine sediment showed granular cast and normal erythrocyte count. Protein excretion in 24-hour urine was less than 1000 mg in both patients. Hemodialysis was started on and renal biopsy revealed acute tubular epithelial cell damage along with bile pigment (cast) deposition, compatible with bile cast-related nephropathy. Serum bilirubin decreased gradually and urine output increased. Serum creatinine was around 1.5 mg/dL in both of the patients 2 months after discharge.