Evaluation of potential alterations related to ADHD in the effective connectivity between the default mode network and cerebellum, hippocampus, thalamus, and primary visual cortex.

Hyperactivity in children with attention-deficit/hyperactivity disorder (ADHD) leads to restlessness and impulse-control impairments. Nevertheless, the relation between ADHD symptoms and brain regions interactions remains unclear. We focused on dynamic causal modeling to study the effective connectivity in a fully connected network comprised of four regions of the default mode network (DMN) (linked to response control behaviors) and four other regions with previously-reported structural alterations due to ADHD. Then, via the parametric empirical Bayes analysis, the most significant connections, with the highest correlation to the covariates ADHD/control, age, and sex were extracted. Our results demonstrated a positive correlation between ADHD and effective connectivity between the right cerebellum and three DMN nodes (intrinsically inhibitory connections). Therefore, an increase in the effective connectivity leads to more inhibition imposition from the right cerebellum to DMN that reduces this network activation. The lower DMN activity makes leaving the resting-state easier, which may be involved in the restlessness symptom. Furthermore, our results indicated a negative correlation between age and these connections. We showed that the difference between the average of effective connectivities of ADHD and control groups in the age-range of 7-11 years disappeared after 14 years-old. Therefore, aging tends to alleviate ADHD-specific symptoms.

Mediterranean diet enriched with olive oil shows no consistent benefits on cardiometabolic and anthropometric parameters: a systematic review with meta-analysis of randomized controlled trials.

PURPOSE: Cardiovascular disease (CVD) is the primary cause of death worldwide but there is a variation in its burden across some nations that seems to be related to dietary habits. Mediterranean populations have lower rates of morbidity and mortality from CVD. Thus, this systematic review and meta-analysis aimed to assess the impacts of the Mediterranean diet (MedDiet) enriched with olive oil on blood lipids, glycemic indices, blood pressure, and anthropometric indices. METHODS: A comprehensive search of the Web of Science, PubMed (MEDLINE), Scopus, Cochrane Library, Google Scholar, Embase, and CINAHL databases until March 2024 was conducted to identify clinical trials studying the effects of MedDiet enriched with olive oil on the aforementioned parameters. RESULTS: In total, 3303 records were retrieved. A total of 18 clinical trials met the inclusion criteria after records were screened for eligibility. According to the pooled analysis from the random-effects model, the MedDiet enriched with olive oil significantly reduced triglycerides (TG) compared with the control group (WMD = -2.40 mg/dl; 95%CI, -4.533 to -0.262; P = 0.027). Strong heterogeneity was observed. Sensitivity analysis did not change our results and no significant effect of any trial on the overall effect sizes of all variables were found. There was a concern about the reporting bias for some studies which reported some main outcomes. CONCLUSION: MedDiet enriched with olive oil showed no consistent effects on any of the reported markers of cardiovascular health except on TG. SYSTEMATIC REVIEW REGISTRATION: CRD42023424641.

The association between dietary inflammatory index with some cardio-metabolic risk indices among the patients with type 2 diabetes from Hoveyzeh cohort study: a cross-sectional study.

BACKGROUND: The dietary inflammatory index (DII) serves as a tool to assess the inflammatory impact of an individual's diet. This study aimed to investigate the association between DII and some cardio-metabolic risk indices among patients with T2DM. METHODS: Data from the Hoveyzeh Cohort Study, encompassing 2045 adults with T2DM, were analyzed. DII scores were calculated based on food frequency questionnaires. Anthropometric measurements and biochemical tests were performed to assess cardio-metabolic risk factors. RESULTS: Higher DII scores were positively associated with elevated triglyceride levels, triglyceride-glucose (TyG) index, lipid accumulation product (LAP), anthropometric indices including a body shape index (ABSI), body roundness index (BRI), body mass index (BMI), hip, waist circumferences (WC), and waist-to-height ratio (all Ptrend < 0.05). Notably, no significant association was observed between DII and fasting blood sugar (FBS) levels (Ptrend > 0.05). Additionally, dietary intake analysis revealed a negative correlation between DII scores and intake of fiber, fruits, vegetables, legumes, fish, seafood, dairy products, magnesium, and vitamins A, C, D, and E (all Ptrend < 0.05). Conversely, higher DII scores were associated with increased consumption of red meat, processed meat, refined cereals, potatoes, and soft drinks (all Ptrend < 0.05). CONCLUSION: This study underscores the critical link between dietary inflammation, assessed by the DII score, and a multitude of cardio-metabolic risk factors in patients with T2DM. Notably, while the study did not find a significant association between DII and fasting blood sugar levels, it identified robust associations with novel anthropometric and biochemical indices indicative of cardio-metabolic risk. These findings highlight the potential of dietary interventions as a cornerstone strategy for managing T2DM and mitigating its associated complications.

Receptor tyrosine kinase inhibitors in cancer.

Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) some of which have entered clinical application. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy or immunotherapy agents with one RTKI or multiple RTKIs) especially for drug resistant cancers.

Diagnostic Accuracy of the Desmopressin Stimulation Test in the Comprehensive Assessment of ACTH-Dependent Cushing's Syndrome: A Comparative Analysis with BIPSS and TSS.

BACKGROUND: Cushing's syndrome (CS) poses diagnostic challenges, particularly in distinguishing pituitary-dependent Cushing's syndrome, Cushing's disease (CD), from the ectopic ACTH syndrome (EAS). This study evaluated the diagnostic value of the desmopressin stimulation test (DST) in patients with ACTH-dependent CS in helping this discrimination. METHODS: Twenty-three ACTH-dependent CS patients underwent sequential DST, bilateral inferior petrosal sinus sampling (BIPSS), and transsphenoidal surgery (TSS). Two definitions of a positive DST results were applied. Diagnostic performance was assessed using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios. To avoid bias from predetermined criteria, we generated univariate receiver-operating characteristic (ROC) curves, plotting sensitivity against 1-specificity at various percentage cortisol and ACTH response levels. RESULTS: Against BIPSS, DST demonstrated robust sensitivity (Definition 1: 90.0%, Definition 2: 76.2%) and overall accuracy (Definition 1: 87.0%, Definition 2: 73.9%). PPV was high (Definition 1: 95.0%, Definition 2: 94.1%), but NPV indicated potential false negatives. Compared to TSS, DST showed good sensitivity (Definition 1: 90.9-77.3%) and PPV (100.0%) but limited NPV (16.7%). The likelihood ratios emphasized the diagnostic value of the test. Notably, against TSS, DST showed perfect discriminatory power (AUC 1.000 for percent ACTH, 0.983 for percent cortisol). CONCLUSION: The desmopressin test shows promise in accurately identifying the underlying cause of ACTH-dependent CS, potentially reducing the reliance on invasive procedures and providing a practical solution for managing complex cases. Further research with larger cohorts is required to validate the utility of the DST in routine clinical practice.

The role of endoplasmic reticulum stress in the regulation of long noncoding RNAs in cancer.

Cancer cells must overcome a variety of external and internal stresses to survive and proliferate. These unfavorable conditions include the accumulation of mutations, nutrient deficiency, oxidative stress, and hypoxia. These stresses can cause aggregation of misfolded proteins inside the endoplasmic reticulum. Under these conditions, the cell undergoes endoplasmic reticulum stress (ER-stress), and consequently initiates the unfolded protein response (UPR). Activation of the UPR triggers transcription factors and regulatory factors, including long noncoding RNAs (lncRNAs), which control the gene expression profile to maintain cellular stability and hemostasis. Recent investigations have shown that cancer cells can ensure their survival under adverse conditions by the UPR affecting the expression of lncRNAs. Therefore, understanding the relationship between lncRNA expression and ER stress could open new avenues, and suggest potential therapies to treat various types of cancer.

Diagnostic accuracy of bilateral inferior petrosal sinus sampling using desmopressin or corticotropic- releasing hormone in ACTH-dependent Cushing's syndrome: A systematic review and meta-analysis.

The current gold standard diagnostic method for Cushing disease (CD) is bilateral inferior petrosal sinus sampling (BIPSS) after corticotropin-releasing hormone (CRH) stimulation. Due to shortages of CRH, BIPSS has been performed with desmopressin (DDAVP) instead. The objective of this systematic review and meta-analysis was to estimate the diagnostic accuracy of BIPSS using DDAVP or CRH for the differential diagnosis of Cushing's syndrome (CS). A literature review was done in PubMed, Scopus, EMBASE, and google scholar databases to derive summary estimates of the overall diagnostic sensitivity and accuracy of BIPSS using DDAVP or CRH in Cushing's syndrome. Pooled sensitivity, specificity, diagnostic odds ratio and summary receiver operating characteristic curves (SROC) for differential diagnosis of Cushing's syndrome in the random-effects models, were computed. Overall, 11 different studies with a total of 612 participants, were eligible for the analysis. Five articles with data on BIPSS using DDAVP, 5 papers on BIPSS using CRH, and another one evaluated the results of stimulation using DDAVP, with or without CRH, for differential diagnosis of Cushing's syndrome. The pooled (95% CI) sensitivity and specificity of BIPSS using DDAVP, were 96% (91-98%) and 1.00 (0.00-1.00), respectively. The area under the SROC curve was 0.95. The pooled (95% CI) sensitivity and specificity of BIPSS using CRH, were 98% (92-99%) and 1.00 (0.00-1.00), respectively, and the area under the SROC curve was 0.98. The I2 index (95% CI) was 0% (0-100%) for both BIPSS using DDAVP and using CRH. As a result, DDAVP stimulation is a safe, effective, less expensive, valuable and available alternative to CRH in the setting of BIPSS for all age groups of patients with CS. Registration code in PROSPERO: CRD42021292531.

Crosstalk between non-coding RNAs expression profile, drug resistance and immune response in breast cancer.

Drug resistance is one of the most critical challenges facing researchers in treating breast cancer. Despite numerous treatments for breast cancer, including conventional chemical drugs, monoclonal antibodies, and immunotherapeutic drugs known as immune checkpoint inhibitors (ICI), many patients resist various approaches. In recent years, the relationship between gene expression profiles and drug resistance phenotypes has attracted much attention. Non-coding RNAs (ncRNAs) are regulatory molecules that have been shown to regulate gene expression and cell transcriptome. Two categories, microRNAs and long non-coding RNAs have been more considered and studied among these ncRNAs. Studying the role of different ncRNAs in chemical drug resistance and ICI resistance together can be beneficial in selecting more effective treatments for breast cancer. Changing the expression and action mechanism of these regulatory molecules on drug resistance phenotypes is the main topic of this review article.

Exploring the role of polyphenols in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory and autoimmune disorder which is mainly characterized by inflammation in joints, bone erosions and cartilaginous destruction that leads to joint dysfunction, deformation, and/or permanent functional impairment. The prevalence of RA is increasing, incurring a considerable burden on healthcare systems globally. The exact etiology of RA is unknown, with various pathways implicated in its pathophysiology. Non-steroidal anti-inflammatory drugs (NSAIDs) including celecoxib, diclofenac and ibuprofen, disease-modifying anti-rheumatic drugs (DMARD) including azathioprine, methotrexate and cyclosporine, biological agents including anakinra, infliximab, and rituximab and immunosuppressants are used for symptomatic relief in patients with RA, but these medications have severe adverse effects such as gastric ulcers, hypertension, hepatotoxicity and renal abnormalities which restrict their use in the treatment of RA; new RA treatments with minimal side-effects are urgently required. There is accumulating evidence that dietary polyphenols may show therapeutic efficacy in RA through their antioxidant, anti-inflammatory, apoptotic, and immunosuppressant activities and modulation of the tumor necrosis factor-α (TNF-α), interleukin (IL)-6, mitogen-activated protein kinase (MAPK), IL-1ß, c-Jun N-terminal kinase (JNK), and nuclear factor κ light-chain-enhancer of activated B cell (NF-κB) pathways. While resveratrol, genistein, carnosol, epigallocatechin gallate, curcumin, kaempferol, and hydroxytyrosol have also been studied for the treatment of RA, the majority of data are derived from animal models. Here, we review the various pathways involved in the development of RA and the preclinical and clinical data supporting polyphenols as potential therapeutic agents in RA patients. Our review highlights that high-quality clinical studies are required to decisively establish the anti-rheumatic efficacy of polyphenolic compounds.

The effect of COVID-19 pandemic on the shrimp industry of Iran.

The first case of COVID-19 was reported in December 2019, and then the virus has spread throughout the world, which led to lockdown in different countries, including Iran. Restrictions on transportation and travel of personnel caused some shortages in aquaculture, particularly in shrimp farms. This study aims to evaluate the impact of the COVID-19 outbreak on the shrimp farming industry in Iran. An online questionnaire was designed to collect information from shrimp farmers, material suppliers, food preparing factories, managers of shrimp hatchery centers, and shrimp exporters. Our results showed that the COVID-19 outbreak has significantly decreased the shrimp annual sales, export, and price in Iran. Also, the production of larvae was affected by COVID-19. Shrimp farming industries are still subject to impacts of the pandemic by reducing hatchery production, shrimp demand, and increasing production and transportation costs.

Chemoprotective and chemosensitizing effects of apigenin on cancer therapy.

BACKGROUND: Therapeutic resistance to radiation and chemotherapy is one of the major obstacles in cancer treatment. Although synthetic radiosensitizers are pragmatic solution to enhance tumor sensitivity, they pose concerns of toxicity and non-specificity. In the last decades, scientists scrutinized novel plant-derived radiosensitizers and chemosensitizers, such as flavones, owing to their substantial physiological effects like low toxicity and non-mutagenic properties on the human cells. The combination therapy with apigenin is potential candidate in cancer therapeutics. This review explicates the combinatorial strategies involving apigenin to overcome drug resistance and boost the anti-cancer properties. METHODS: We selected full-text English papers on international databases like PubMed, Web of Science, Google Scholar, Scopus, and ScienceDirect from 1972 up to 2020. The keywords included in the search were: Apigenin, Chemoprotective, Chemosensitizing, Side Effects, and Molecular Mechanisms. RESULTS: In this review, we focused on combination therapy, particularly with apigenin augmenting the anti-cancer effects of chemo drugs on tumor cells, reduce their side effects, subdue drug resistance, and protect healthy cells. The reviewed research data implies that these co-therapies exhibited a synergistic effect on various cancer cells, where apigenin sensitized the chemo drug through different pathways including a significant reduction in overexpressed genes, AKT phosphorylation, NFκB, inhibition of Nrf2, overexpression of caspases, up-regulation of p53 and MAPK, compared to the monotherapies. Meanwhile, contrary to the chemo drugs alone, combined treatments significantly induced apoptosis in the treated cells. CONCLUSION: Briefly, our analysis proposed that the combination therapies with apigenin could suppress the unwanted toxicity of chemotherapeutic agents. It is believed that these expedient results may pave the path for the development of drugs with a high therapeutic index. Nevertheless, human clinical trials are a prerequisite to consider the potential use of apigenin in the prevention and treatment of various cancers. Conclusively, the clinical trials to comprehend the role of apigenin as a chemoprotective agent are still in infancy.

Naringin and naringenin as anticancer agents and adjuvants in cancer combination therapy: Efficacy and molecular mechanisms of action, a comprehensive narrative review.

Although the rates of many cancers are controlled in Western countries, those of some cancers, such as lung, breast, and colorectal cancer are currently increasing in many low- and middle-income countries due to increases in risk factors caused by development and societal problems. Additionally, endogenous factors, such as inherited mutations, steroid hormones, insulin, and insulin-like growth factor systems, inflammation, oxidative stress, and exogenous factors (including tobacco, alcohol, infectious agents, and radiation), are believed to compromise cell functions and lead to carcinogenesis. Chemotherapy, surgery, radiation therapy, hormone therapy, and targeted therapies are some examples of the approaches used for cancer treatment. However, various short- and long-term side effects can also considerably impact patient prognosis based on clinical factors associated with treatments. Recently, increasing numbers of studies have been conducted to identify novel therapeutic agents from natural products, among which plant-derived bioactive compounds have been increasingly studied. Naringin (NG) and its aglycone naringenin (NGE) are abundantly present in citrus fruits, such as grapefruits and oranges. Their anti-carcinogenic activities have been shown to be exerted through several cell signal transduction pathways. Recently, different pharmacological strategies based on combination therapy, involving NG and NGE with the current anti-cancer agents have shown prodigious synergistic effects when compared to monotherapy. Besides, NG and NGE have been reported to overcome multidrug resistance, resulting from different defensive mechanisms in cancer, which is one of the major obstacles of clinical treatment. Thus, we comprehensively reviewed the inhibitory effects of NG and NGE on several types of cancers through different signal transduction pathways, the roles on sensitizing with the current anticancer medicines, and the efficacy of the cancer combination therapy.

Data-Driven Model-Free Adaptive Control of Z-Source Inverters.

The universal paradigm shift towards green energy has accelerated the development of modern algorithms and technologies, among them converters such as Z-Source Inverters (ZSI) are playing an important role. ZSIs are single-stage inverters which are capable of performing both buck and boost operations through an impedance network that enables the shoot-through state. Despite all advantages, these inverters are associated with the non-minimum phase feature imposing heavy restrictions on their closed-loop response. Moreover, uncertainties such as parameter perturbation, unmodeled dynamics, and load disturbances may degrade their performance or even lead to instability, especially when model-based controllers are applied. To tackle these issues, a data-driven model-free adaptive controller is proposed in this paper which guarantees stability and the desired performance of the inverter in the presence of uncertainties. It performs the control action in two steps: First, a model of the system is updated using the current input and output signals of the system. Based on this updated model, the control action is re-tuned to achieve the desired performance. The convergence and stability of the proposed control system are proved in the Lyapunov sense. Experiments corroborate the effectiveness and superiority of the presented method over model-based controllers including PI, state feedback, and optimal robust linear quadratic integral controllers in terms of various metrics.

Toxicological profile of lipid-based nanostructures: are they considered as completely safe nanocarriers?

Nanoparticles are ubiquitous in the environment and are widely used in medical science (e.g. bioimaging, diagnosis, and drug therapy delivery). Due to unique physicochemical properties, they are able to cross many barriers, which is not possible for traditional drugs. Nevertheless, exposure to NPs and their following interactions with organelles and macromolecules can result in negative effects on cells, especially, they can induce cytotoxicity, epigenicity, genotoxicity, and cell death. Lipid-based nanomaterials (LNPs) are one of the most important achievements in drug delivery mainly due to their superior physicochemical and biological characteristics, particularly its safety. Although they are considered as the completely safe nanocarriers in biomedicine, the lipid composition, the surfactant, emulsifier, and stabilizer used in the LNP preparation, and surface electrical charge are important factors that might influence the toxicity of LNPs. According to the author's opinion, their toxicity profile should be evaluated case-by-case regarding the intended applications. Since there is a lack of all-inclusive review on the various aspects of LNPs with an emphasis on toxicological profiles including cyto-genotoxiciy, this comprehensive and critical review is outlined.

Transforming growth factor-ß signaling: Tumorigenesis and targeting for cancer therapy.

Transforming growth factor (TGF)-ß is a multitasking cytokine such that its aberrant expression is related to cancer progression and metastasis. TGF-ß is produced by a variety of cells within the tumor microenvironment (TME), and it is responsible for regulation of the activity of cells within this milieu. TGF-ß is a main inducer of epithelial-mesenchymal transition (EMT), immune evasion, and metastasis during cancer progression. TGF-ß exerts most of its functions by acting on TßRI and TßRII receptors in canonical (Smad-dependent) or noncanonical (Smad-independent) pathways. Members of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and nuclear factor κß are involved in the non-Smad TGF-ß pathway. TGF-ß acts by complex signaling, and deletion in one of the effectors in this pathway may influence the outcome in a diverse way by taking even an antitumor role. The stage and the type of tumor (contextual cues from cancer cells and/or the TME) and the concentration of TGF-ß are other important factors determining the fate of cancer (progression or repression). There are a number of ways for targeting TGF-ß signaling in cancer, among them the special focus is on TßRII suppression.

NF-κB targeting for overcoming tumor resistance and normal tissues toxicity.

Radiotherapy and chemotherapy are two famous modalities in tumor-targeted therapy that lead to systemic and local toxicities for normal tissues. Moreover, several studies have confirmed that exposure of the tumor to radiation or chemotherapy drugs stimulate some signaling pathways in the tumor microenvironment (TME), leading to resistance of cancer cells to apoptosis, as well as promoting angiogenesis and tumor growth. Nuclear factor kappa B (NF-κB) plays a central role in the regulation of inflammatory responses in both normal tissues and tumors via the release of several cytokines, regulation of prostaglandins, reduction/oxidation (redox) reactions, angiogenesis, and cell death. Upregulation of NF-κB in normal tissues causes an appearance of inflammatory reactions and oxidative stress, whereas it regulates angiogenesis and suppresses apoptosis, leading to resistance to subsequent doses of radiation or chemotherapy. Selective inhibition of NF-κB in experimental studies has shown promising results for tumor sensitization via apoptosis induction, inhibition of angiogenesis, and increasing delay of tumor growth. The use of some agents for NF-κB inhibition has been shown to alleviate radiation/chemotherapy toxicities in normal cells/ tissues. In this current review, we explained the pivotal role of NF-κB in both normal tissue toxicity and tumor resistance. We also discussed the promising strategies for overcoming these problems with regard to chemotherapy and radiotherapy.

Selenium as an adjuvant for modification of radiation response.

Ionizing radiation plays a central role in several medical and industrial purposes. In spite of the beneficial effects of ionizing radiation, there are some concerns related to accidental exposure that could pose a threat to the lives of exposed people. This issue is also very critical for triage of injured people in a possible terror event or nuclear disaster. The most common side effects of ionizing radiation are experienced in cancer patients who had undergone radiotherapy. For complete eradication of tumors, there is a need for high doses of ionizing radiation. However, these high doses lead to severe toxicities in adjacent organs. Management of normal tissue toxicity may be achieved via modulation of radiation responses in both normal and malignant cells. It has been suggested that treatment of patients with some adjuvant agents may be useful for amelioration of radiation toxicity or sensitization of tumor cells. However, there are always some concerns for possible severe toxicities and protection of tumor cells, which in turn affect radiotherapy outcomes. Selenium is a trace element in the body that has shown potent antioxidant and radioprotective effects for many years. Selenium can potently stimulate antioxidant defense of cells, especially via upregulation of glutathione (GSH) level and glutathione peroxidase activity. Some studies in recent years have shown that selenium is able to mitigate radiation toxicity when administered after exposure. These studies suggest that selenium may be a useful radiomitigator for an accidental radiation event. Molecular and cellular studies have revealed that selenium protects different normal cells against radiation, while it may sensitize tumor cells. These differential effects of selenium have also been revealed in some clinical studies. In the present study, we aimed to review the radiomitigative and radioprotective effects of selenium on normal cells/tissues, as well as its radiosensitive effect on cancer cells.

Thyroid function following breast cancer chemotherapy: A systematic review.

BACKGROUND: Chemotherapy, as a systemic therapy, is one of the most effective modalities for cancer treatment. However, the use of chemotherapeutic drugs in patients with breast cancer can lead to thyroid dysfunction. This systematic review summarizes the available data on thyroid function following breast cancer chemotherapy. METHODS: To illuminate the thyroid toxicities induced by different chemotherapy regimens in patients with breast cancer, a systematic search was done in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline in Scopus, Embase, PubMed and Web of Science electronic databases up to December 2018. On the basis of a set of prespecified inclusion and exclusion criteria, eight eligible articles providing data on thyroid function following chemotherapy in patients with breast cancer were included in the study. RESULTS: According to the obtained results, it was found that for most cases, the levels of triiodothyronine (T3), free T3 (FT3), thyroxin (T4) and free T4 (FT4) hormones decrease following breast cancer chemotherapy regimens used in these eligible studies. However, alteration of thyroid-stimulating hormone (TSH) level after breast cancer chemotherapy was not clear. CONCLUSION: The findings showed that thyroid function and TSH hormone level can change in patients with breast cancer receiving different chemotherapy regimens.

Extracellular-signal-regulated kinase/mitogen-activated protein kinase signaling as a target for cancer therapy: an updated review.

Mitogen-activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal-epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular-signal-regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross-talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase-2, transforming growth factor-ß, NOTCH and (in particular) with phosphatidylinositol 3-kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK-targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre-evaluation of cancer-type-specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.

Genomic Instability and Carcinogenesis of Heavy Charged Particles Radiation: Clinical and Environmental Implications.

One of the uses of ionizing radiation is in cancer treatment. The use of heavy charged particles for treatment has been introduced in recent decades because of their priority for deposition of radiation energy in the tumor, via the Bragg peak phenomenon. In addition to medical implications, exposure to heavy charged particles is a crucial issue for environmental and space radiobiology. Ionizing radiation is one of the most powerful clastogenic and carcinogenic agents. Studies have shown that although both low and high linear energy transfer (LET) radiations are carcinogenic, their risks are different. Molecular studies have also shown that although heavy charged particles mainly induce DNA damage directly, they may be more potent inducer of endogenous generation of free radicals compared to the low LET gamma or X-rays. It seems that the severity of genotoxicity for non-irradiated bystander cells is potentiated as the quality of radiation increases. However, this is not true in all situations. Evidence suggests the involvement of some mechanisms such as upregulation of pro-oxidant enzymes and change in the methylation of DNA in the development of genomic instability and carcinogenesis. This review aimed to report important issues for genotoxicity of carcinogenic effects of heavy charged particles. Furthermore, we tried to explain some mechanisms that may be involved in cancer development following exposure to heavy charged particles.