Here we describe our experience and results.•Management of DDH associated with JIA has no established guidelines in literature. Here, we share our experience in managing such rare cases.•We believe that medical control of JIA before proceeding for an open reduction of DDH is the key to successful results. Developmental dysplasia of the hip (DDH) is a common hip disorder and its association with other musculoskeletal, genetic, and neurological diseases were well described in the literature. Juvenile idiopathic arthritis (JIA) is a rare rheumatological condition, and its presence in a Developmental dysplasia of the hip (DDH) child makes this a very challenging case.This case report is describing the presentation of 9 months old girl to orthopedic service referred from the pediatric rheumatology clinic after diagnosing her and starting the treatment for Juvenile idiopathic arthritis (JIA). Bilateral neglected Developmental dysplasia of the hip (DDH) - International Hip Dysplasia Institute (IHDI) type 4- was detected during her clinical and radiological assessment, necessitating surgical management after controlling her Juvenile idiopathic arthritis (JIA). The surgical procedure and its clinical and radiological outcomes more than four years after her surgical treatment are described in detail in this report as well.The management of Developmental dysplasia of the hip (DDH) associated with Juvenile idiopathic arthritis (JIA) has no established guidelines in literature. Here, we share our experience in managing such rare cases. We believe that medical control of Juvenile idiopathic arthritis (JIA) before proceeding for open reduction of Developmental dysplasia of the hip (DDH) is the key to successful results.The reported case is uniquely having both Developmental dysplasia of the hip (DDH) and Juvenile idiopathic arthritis (JIA) treated with open reduction, pelvic osteotomy, and femoral shortening resulting in outstanding clinical and radiological outcomes. Medical treatment of the disease is the key and assists alleviating the symptoms and delaying joint destruction. That includes nonsteroidal anti-inflammatory, systemic corticosteroids, methotrexate, sulfasalazine, and biological treatment .Synovectomy of the hip in patients with juvenile idiopathic arthritis is a well-known treatment for the management of refractory cases of hip synovitis that is not responding to conservative management .One of the main objectives of surgically treating neglected Developmental dysplasia of the hip (DDH) patients is to obtain stable mobile and painless hips, which might not be achieved in a joint involved in Juvenile idiopathic arthritis (JIA).The purpose of this study is to report an unusual case of a patient well known to have familial juvenile idiopathic polyarticular arthritis and presented with bilateral developmental dysplasia of the hip. The current case report work has been reported in line with the Surgical Case Report Guidelines SCARE 2018 criteria .2A 7-year-old Saudi girl, diagnosed at the age of nine months with both familial juvenile idiopathic polyarticular arthritis and bilateral developmental dysplasia of the hip (DDH). She is also known to have hypertension, congenital solitary left kidney.Our colleagues from pediatric rheumatology started treating her medically at the age of nine months initially with Indomethacin, Prednisone, and Alfacalcidol drops.The patient was diagnosed with bilateral developmental dysplasia of the hip (DDH) at the age of 9 months. And as the patient had inflamed hips and knees due to active polyarthritis status, we decided to delay treatment of her bilateral developmental dysplasia of the hip (DDH) until pediatric rheumatologist controlled her disease. And At the age of 16 months, she was still having active arthritis involving both wrists, small joints of both hands as well as bilateral knee and hips joints. She was labeled as a refractory disease with partial response to Non-Steroidal Anti-Inflammatory, systemic steroid, and Methotrexate medications. At that time, she had IHDI grade 4, bilateral dislocated developmental dysplasia of the hip [Her juvenile idiopathic arthritis was well controlled medically at the age of two with Methotrexate, Abatacept, and antihypertensive medication. At the age of two years old, surgical reduction was indicated and was operated by an experienced surgeon in Developmental dysplasia of the hip (DDH) surgery operating such cases for more than ten years. Initially, she underwent right hip open reduction, adductor tenotomy, and pelvic osteotomy with bone allograft, femoral shortening osteotomy and plate fixation, and spica cast application for 6 weeks then 4 weeks of broomstick cast for 4 weeks utilizing the technique of Wade et al.  Fig. 2)Fig. 2). The second surgery was postponed 7 months from the first surgery to assure the full recovery of operated hip ROM and allow sufficient period for full weight-bearing walking activity to recover the bone density from the expected disuse osteopenia, which will make the associated bony procedures more efficient and carries lower complications rate.During the open hip reduction for both hips, we faced an unusual intra-articular obstacles in the form of adhesions and an abundant amount of synovitis immediately after opening the hip joint capsule - which is an integral part of open hip reduction in neglected Developmental dysplasia of the hip (DDH) cases-. Synovectomy was done, and tissue was sent for histopathology study confirming severe synovitis.Usually, after surgical treatment of neglected Developmental dysplasia of the hip (DDH) patients, the routine referral to physiotherapy services is not carried out especially if the child is living far from the hospital and most of the children treated for Developmental dysplasia of the hip (DDH) alone had smooth recovery of hip function. In this case, because of the concern about the recovery of hips range of motion (ROM), an early referral to physiotherapy was done immediately after removal of the cast for each side to start gait training, recover ROM, and strengthen the hip and knee muscles.Two years later, the proximal femurs plates and screws - at the shortening osteotomy site - were surgically removed. The patient remained following in the clinic utill the writing of this report. On her last presentation in the clinic, at the 7th year of her age, she had grown well and completely independent in her daily activities. She is free of any joints pain and deformity, has full range of motion and normal gait .Fig. 4PeFinal results were amazingly excellent with non-painful hips, full range of motion, functionally scoring grade A for both hips in the McKay scoring system . Hips x-3Juvenile idiopathic arthritis (JIA) is a rheumatologic disorder characterized by autoimmune inflammation of synovial joints . GloballCollectively, it results in disability and early joint damage . It striMedical treatment had been considered the backbone for managing Juvenile idiopathic arthritis (JIA). Control of the disease is the key, and promotes in the alleviation of symptoms and delaying joint destruction. That includes non-steroidal anti-inflammatory, systemic corticosteroids, methotrexate, sulfasalazine, and biological treatment .Open and arthroscopic synovectomy has been performed in refractory cases that are thought to improve symptoms . Hip joiDevelopmental dysplasia of the hip (DDH) is a spectrum of hip developmental anomaly from simple acetabular dysplasia to full dislocation, happening in utero or neonatally. The disease involves the developmental interruption of acetabulum and femoral head as well .Treatment of Developmental dysplasia of the hip (DDH) in a walking child is different and more challenging than the earlier stage. Soft tissue becomes more rigid, forming intracapsular and extracapsular obstacles to reduction necessitating surgical open hip reduction .Open hip reduction is the treatment of choice for Developmental dysplasia of the hip (DDH) patients who failed closed reduction or exceeded 18 months of age, with a success rate of maintaining a reduction in 99% of cases, and 12% of variable subluxated joints . Open reModified Smith-Peterson anterolateral approach is usually the approach of choice in patients more than 18 months old, and it’s very useful as it allows for a concomitant pelvic osteotomy and capsulorrhaphy . Klisic Pelvic osteotomy should be done for persistent acetabular dysplasia when acetabular coverage is deficient. Recently, there is a tendency to include acetabular procedure at the same time of open reduction to obtain better intra-operative hip stability and maximize the potential for the development of normal acetabulum .Complications after open reduction of Developmental dysplasia of the hip (DDH) include osteonecrosis, re-dislocation, and stiffness. A study by Castaneda et al. discussing complication post-open reduction of late presenting Developmental dysplasia of the hip (DDH) showed 18% risk of residual dysplasia or subluxation, and 5.5% of re-dislocation in patients who had open reduction alone, and 1.9% in patient who had both open reduction and pelvic osteotomy, and both, re-dislocation and subluxation, were associated with increased age at the time of surgery, they also noted that the rate of Avascular Necrosis (AVN) post-open reduction of Developmental dysplasia of the hip (DDH) was 14% . Re-dislThe patient we reported was 2 years old when she had her Juvenile idiopathic arthritis (JIA) medically controlled, and soon she underwent successful bilateral hip surgeries with 7 months interval to allow effective recovery. That included open reduction, adductor tenotomy, and pelvic osteotomy with bone allograft, femoral shortening osteotomy, plate fixation, and spica cast application. The severe synovitis she had manifested in joints pain and swelling, and might be a factor in advancing her Developmental dysplasia of the hip (DDH) stage pre- operatively. The thick synovial tissue that was excised intraoperatively, as part of the procedure, may have improved her post-operative hip status and function. The treatment plan went uneventfully with no apparent complication. Instead, she had great outcomes. She is now enrolled in school and independently performing daily activities of her age group.The results were outstanding clinically and radiologically. We can state that it is not contraindicated to perform Developmental dysplasia of the hip (DDH) open reduction on Juvenile idiopathic arthritis (JIA) diseased patients, and it is safely done in the appropriate time and settings. In our belief, the medical control of Juvenile idiopathic arthritis (JIA) was the key to success in this dilemma, and such exceptional results cannot be reproduced without such successful medical control. We strongly advise the treating surgeon for such a clinical challenge not to rush the surgical treatment until the medical treatment confirms its control on the disease activity. Otherwise, the good outcomes are less likely to be achieved. We also believe that the solid base for optimal management in these cases is the proper communication and coordination between the Pediatric Rheumatologist, Pediatric Orthopedic surgeon, and rehabilitation specialist. We recommend and hope to have future case series and larger sample size studies to obtain a wider view of this unique combination of diseases.4No previous guidelines, to our knowledge, have highlighted the outcomes of surgical treatment in combined Developmental dysplasia of the hip (DDH) and Juvenile idiopathic arthritis (JIA) cases. The reported case is uniquely having both Developmental dysplasia of the hip (DDH) and Juvenile idiopathic arthritis (JIA) treated with open reduction, pelvic osteotomy and femoral shortening resulting in outstanding clinical and radiological outcomes. The key to successful outcome in our belief and recommendation is to control the medical aspect of Juvenile idiopathic arthritis (JIA) before attempting open reduction of Developmental dysplasia of the hip (DDH).None.None.The study was approved by institutional review board by king faisal specialist hospital and research centre.Written informed consent was obtained from the patient’s father for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Thamer S. Alhussainan: Surgeon, Supervisor and editor.Abdullah M. Alghamdi: Reviewed the literature, writer and data collector.Rakan A. Almogbel: Writer, organizer and paper submitter.Not required.Rakan A Almogbel.


Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honey bee-hive propolis. The mentioned compound, a well-known NF-κB inhibitor, has been used in traditional medicine as a potent anti-inflammatory agent. CAPE has a broad spectrum of biological properties including anti-viral, anti-bacterial, anti-cancer, immunomodulatory, and wound-healing activities. This review characterizes published data about CAPE biological properties and potential therapeutic applications, that can be used in various diseases. Th. Th57]. Studies on the treatment of thermal burns in rats conducted with the use of CAPE showed macroscopically 7, 21 and 70 days after the burn of a smaller wound surface and acceleration of contraction leading to the closure of the thermal damage to the skin in groups where CAPE was used compared to groups not supplied with the described compound. The positive effects of CAPE on the regeneration process of damaged skin in this study was also confirmed by biochemical analysis carried out 14 days after the burn. Analysis of myeloperoxidase activity showed a significant decrease in acute phase reagents. The nitric oxide determination showed a similar result. Tissue analysis 70 days after the burn also confirmed the long-term effect of CAPE, as it showed a reduced amount of myofibroblasts and CD68 positive macrophages in the CAPE group, and higher levels of hydroxyproline. These data show that the effect of CAPE on burn healing is still visible even after 70 days (CAPE administration stopped 14 days after the burn) . AttentiE)-2-propenoic acid  ethyl ester (VP961) was the strongest. In addition, VP961 is the first known compound capable of directly activating HO-1 and simultaneously inducing protein expression of this enzyme [CAPE can be useful in many pathological conditions caused by oxidative stress ,64. The s enzyme . Other ss enzyme .Obesity is associated with numerous clinical disorders, such as hypertension, hyperglycemia, insulin resistance, endothelial dysfunction, elevated triglycerides and high cholesterol . AdipocyThe mechanism of CAPE anti-tumor activity is complex and omni-directional. CAPE can express an anti-cancer effect by inhibiting DNA synthesis ,71, inteCancer chemotherapy requires the introduction of new solutions in the treatment regimen due to drug resistance, low effectiveness and many adverse effects of chemotherapeutic agents. Some tumors are internally resistant to many of the potent cytotoxic agents used in cancer therapy. Other cancers, initially sensitive, are not susceptible not only to the initially used therapeutic agents, but also to other drugs not used in the initial stages of therapy ,78. CombThe interaction of anticancer drugs with substances of natural origin such as CAPE may be useful as support for cancer therapy in terms of chemoprevention of non-cancerous cells ,88,89. CAngiogenesis, the formation of new blood vessels, is an essential step in the progression of cancer, which allows the supply of nutrients and oxygen, as well as the removal of side products from cancer-changed tissues. In addition, newly formed blood vessels are the gateway to the expansion of cancer cells and the formation of metastases in other tissues and organs ,91. The Tumor metastases include ECM degradation ,98, whicBoth mRNA and COX-2 protein levels (present in inflamed sites) are strongly upregulated in OSCC  ,106 and The therapeutic efficacy of CAPE was studied in rats with experimental endotoxin-induced periodontitis. Osteoclastic bone resorption is conjugated to an increase in RANKL, which causes destruction of follicular bone in periodontitis. To analyze follicular bone loss, RANKL activation was evaluated. Histological analyzes revealed lower RANKL levels in the CAPE treated group than in the saline group ,111. ThiCAPE demonstrated in dementia research an improvement in memory and prevention of memory impairment by enhancing antioxidant protection as a result of increased GSH (reduced glutathione) levels in rat brains. Reduced glutathione is the basic protection of the brain against oxidative stress and is used as a biomarker of oxidative stress .The global demand for therapeutic alternatives in cancer therapy means that more effective and cheaper chemotherapeutic drugs are still being sought. Therefore, combinations of chemotherapeutic drugs with substances of natural origin with documented anti-cancer effects such as CAPE give hope for optimistic results. The combined use of CAPE together with anti-cancer drugs can be an important element in the design of a comprehensive anti-cancer therapy strategy, covering both the aspect of treating the cancer itself through the use of the synergistic cytotoxic effect of CAPE and anti-cancer drugs, as well as equally important in the chemoprevention of non-cancerous cells exposed to adverse side effects of anti-cancer drugs . Table 1Despite the enormous advantages of CAPE, there are several issues that may cause problems with the actual implementation of this compound in practical medicine. Due to the phenolic nature of CAPE, it exhibits a large spectrum of biological activities that can be used in various disease entities, but it has low solubility, and thus poor bioavailability, which significantly limits its effectiveness and requires the use of high doses . ProblemThe pleiotropic effect of the caffeic acid phenethyl ester gives a wide range of therapeutic possibilities in many disease entities, in which CAPE has not been used so far, e.g., dementia or bone resorption. Therefore, this active compound will remain the subject of much future research. Human research needs to be significantly expanded as most research on CAPE is based on animal and in vitro studies.


About 95% of all testicular cancers are represented by testicular germ cell tumors (TGCTs), which include seminoma and non-seminoma histological types. TGCT is the most common solid tumor among males 15–34 years of age, with an estimated 8,850 new cases and 410 deaths during 2017 in the United States. The highest incidence rates of testicular cancer are in Norway  and the lowest are in India  and Thailand . The annual incidence of Testicular cancer (TC) has doubled over the past 40 years with an increasing trend over time, particularly in Caucasian males .The pathogenesis of TC is poorly known. The identification of pathogenic mechanisms and risk factors involved in testicular carcinogenesis still represent topics of extremely high clinical interest. The origin of TGCT, probably starting at early stages of embryogenesis, seems to be a part of the Testicular Dysgenesis Syndrome (TDS) where some early PGC/gonocytes are blocked in their differentiation, are tightly regulated by epigenetic modification in terms of microRNA expression and DNA methylation, retaining their early marker profile ; others risk factors are personal or family history of testicular cancer, age, ethnicity, and infertility.Garolla et al.). Therefore, the exposition to different environmental agents, such as pesticides and non-steroidal estrogens can increase the risk of developing this neoplasm. The increased exposure to environmental factors, particularly chemical pollutants with endocrine disrupting activity, can alters the major hormonal axis that drives testis development and function from gestational age. The susceptibility to these alterations further depends on genetic factors that justify the strong familiarity of TC . The presence of testicular microlithiasis in patients with such risk factors increases more the risk of cancer. Testicular microlithiasis (TM) represents itself a risk factor for TGCT, because in infertile men the presence of TM is associated to an ~18-fold higher prevalence of testicular cancer as reported in a full meta-analysis of eight carefully selected studies . Longitudinal studies are warranted to elucidate whether this cross-sectional association actually reflects a higher susceptibility of infertile men with TM to develop testicular cancer over time.Moreover, a possible causal relationship between viral infections and TGCTs was firstly evoked almost 40 years ago and is still a subject of debate. Recent efforts in oncological and virological research have brought to light the oncogenic potential of different virus species. Evidences from a systematic review and meta-analysis support an oncogenic effect of HIV and EBV on the human testis, but the evidence was insufficient to establish causality .This special issue, entitled “Testicular Cancer: New Insights on the Origin, Genetics, Treatment, Fertility, General Health, Quality of Life and Sexual Function,” provides an overview of clinical diagnosis and disease management and an approach to explain the molecular development of TC. The limited number of studies and the resulting lack of exact knowledge about development, differentiation, and treatment of TC leaves several clinical problems regarding treatment and follow-up unsolved. The aim of this special issue intends to give an update on the most controversial issues in research areas of TGCT, as well as new results and express the opinions of a selection of specialists who have expanded the field with their recent discoveries. Both clinical and basic researches are reported and many questions are addressed. One of these deals regard the diagnostic strategies which still remain problem to be solved. Diagnosis for TGCTs is greatly based on detecting serum markers such as alpha- fetoprotein, beta-human chorionic gonadotropin, and lactate dehydrogenase but only 60% of all patients show elevations of these markers. For this reason tumor markers alone are not able to detect many recurrences, indeed in about 40% of men with disease recurrence the levels of these markers are usually “normal.” Therefore, the discovery of novel clinical biomarkers of TC would clearly help the early detection and the monitor of the disease. The use of proteomic platforms permit to discover putative prognostic and diagnostic markers of testicular cancer. A panel of proteins for early detection, identified by proteomics technique, might be used for prognostic evaluation and for follow-up of TC. Moreover, the molecular mechanisms revealed by these proteomic studies might represents molecular targets for anticancer treatments . Other molecular findings are also associated with local cancer invasiveness as OCT4, KLF4, and PTTG1 expression in seminoma .With effective treatment, the overall five-year survival rate of TGCT is 97%. Men diagnosed with GCT have excellent survival rates due to advances in the multimodal treatment paradigm of chemotherapy, radiation therapy, and surgery. Despite the good response of these tumors to platinum-based chemotherapy, some patients are refractory to treatment and present poor clinical outcomes. During carcinogenesis and tumor development, cancer cells reprogram energy metabolism toward a hyper-glycolytic phenotype, with over-expression of metabolism related proteins, like glucose and monocarboxylate transporters, pH regulators, and intracellular glycolytic enzymes (Warburg effect). The alterations in the expression of proteins related with the Warburg effect and hyper-glycolytic and acid-resistant phenotype are associated with aggressive clinicopathological parameters .Retroperitoneal Lymph Node Dissection (RPLND) is generally considered as a treatment option for non-seminomas, when lymph nodes are compromised. There are three different RPLND techniques: open, laparoscopic, and robotic. The open approach is as effective as the other two in its oncological efficiency. Recent studies have been pointing out a slight increase of advantages on the robotic approach. Also, it is noteworthy that new technologies are on the rise, improving the laparoscopic approach, requiring further studies after their uses are consolidated .Testicular function usually gets worse after treatment for testicular cancer, so the patients must be carefully followed for signs of hypogonadism and associated comorbidities. Hypogonadism has been often reported in testicular tumor survivors because of the radio- and/or chemo-induced Leydig cell damage. Longitudinal studies have revealed a higher negative impact of chemotherapy on Leydig cell function than radiotherapy or orchiectomy alone, leading to a higher risk for hypogonadism and its related complications, including cardiovascular, metabolic and bone mineralization impairment, and sexual dysfunction in testicular tumor survivors. Compared to orchiectomy alone, combined or high-dose chemotherapy and radiotherapy increase the risk for metabolic syndrome, DM, and cardiovascular events .These cancer survivors will therefore have to live with the long-term physical and psychological consequences of both their treatments  and the diagnosis itself. Invasive and destructive surgery such as retroperitoneal lymph node dissection increases the frequency of such dysfunctions . HoweverSchepisi et al.).Individual health, sexual relationships affect several important aspects of survival and significantly influence the QoL of long-term survivors. Physical, psychological, work-related problems and changing perspectives about work and life in general influenced life and career decisions among testicular cancer survivors .Finally cancer treatment is not an individual experience, but induces deep effects on patients' families, who often have to assume a caregiving role for the duration of and following treatment for cancer. The role of a more integrated system of the patient and his social support, with the purpose of improving QoL not only during active treatment, but also in the follow-up period, and to encourage a less traumatic return to the everyday life (We would like to express our sincere gratitude to all authors and referees for their contribution to this issue. Multidisciplinary and collaborative efforts in recent years have clearly improved our understanding of the pathogenesis of testicular cancer but this disease remains an enigma in many aspects especially the environmental etiology.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


MVK gene on mouse chromosome 5. This transgenic mouse will be useful to explore the pathogenesis of HIDS.Mutation of mevalonate kinase (MVK) is thought to account for most cases of hyperimmunoglobulinemia D syndrome (HIDS) with recurrent fever. However, its mechanism and the relationship between elevated serum immunoglobulin D (IgD) and the clinical features of HIDS are unclear. In this study, we generated by fusion PCR a vector to express high levels of chimeric secretory IgD (csIgD) specifically in the liver. We then generated seven founder lines of transgenic mice by co-microinjection, and verified them using genomic PCR and Southern blotting. We detected the expression of csIgD by reverse transcription PCR, quantitative PCR, western blotting, and enzyme-linked immunosorbent assays. We demonstrated that csIgD could be specifically and stably expressed in the liver. We used flow cytometry to show that overexpression of csIgD in the bone marrow and spleen cells had no effect on B cell development. Morphologic and anatomical observation of the transgenic mice revealed skin damage, hepatosplenomegaly, and nephromegaly in some transgenic mice; in these mice, pathological sections showed high levels of cell necrosis and protein-like sediments in the liver, spleen, and kidney. We demonstrated that the genomic insertion sites of the transgenes did not disrupt the


Squamous cell carcinoma (SCC) accounts for most nonmelanoma skin cancer–related metastatic disease and deaths. Histopathology and correct surgical excision remain the gold standard for the diagnosis and treatment of SCC; however, new diagnostic imaging techniques such as dermoscopy and reflectance confocal microscopy have increased the diagnostic accuracy in terms of early recognition, better differential diagnosis, more precise selection of areas to biopsy, and noninvasive monitoring of treatments. The therapeutic intervention in patients with severe actinic damage and multiple in situ/low-risk SCC, and the development of innovative treatments such as epidermal growth factor receptor inhibitors and immune checkpoint inhibitors for locally advanced and metastatic SCC, are improving considerably the approach to the disease. This review summarizes the up-to-date knowledge in the field of detection, treatment, and monitoring of cutaneous SCC. Squamous cell carcinoma (SCC) is the second most common cutaneous malignancy after basal cell carcinoma, with an increasing incidence worldwide . AlthougSCC accounts for most nonmelanoma skin cancer–related metastatic disease; therefore, recognition and treatment of early SCC is important for the prevention of neoplastic progression. Although histopathology and surgical excision remain the gold standard for the diagnosis and treatment of SCC, new diagnostic imaging techniques such as dermoscopy and reflectance confocal microscopy (RCM) are increasing the diagnostic accuracy of these keratinizing neoplasms, allowing better recognition and a more precise selection of suspicious areas to biopsy, and provide a noninvasive, accurate way to monitor treatments. Moreover, the therapeutic intervention on the cancerization field in patients with severe actinic damage and multiple in situ/low-risk SCC, and the development of innovative treatments such as epidermal growth factor receptor inhibitors and immune checkpoint inhibitors for locally advanced and metastatic SCC, are improving considerably the approach to the disease.A presumptive diagnosis of SCC is based on the physician’s interpretation of clinical information, including appearance and morphology, anatomic location, and patient-reported history. While the most frequent clinical presentation of SCC in situ is an erythematous scaly patch or slightly elevated plaque, which is barely noticed by the patients, invasive SCC is often ulcerated and can be patchy, papulonodular, papillomatous, or exophytic –5.Although histopathology remains the gold standard for the diagnosis of SCC, some noninvasive optical technologies such as dermoscopy and RCM have recently been applied in an attempt to enhance clinical diagnosis accuracy and to obtain an in vivo characterization of the tumor .Dermoscopy is a noninvasive diagnostic technique that allows in vivo evaluation of colors and microstructures of the epidermis, the dermoepidermal junction, and the papillary dermis at 10-fold magnification . AlthougIn situ SCC (Bowen disease) is characterized by yellowish white opaque scales and clusters of 2 types of roundish vascular pattern: small dotted vessels and glomerular or coiled vessels. Both patterns often appear within the same lesion and are distributed in small, densely packed clusters or groups . In pigmWhen in situ SCC progresses to microinvasive SCC, the lesion thickens clinically, and hairpin and/or linear-irregular vessels appear in dermoscopy examination, occasionally giving a red starburst-like image on dermoscopy. In addition to typical vessel morphology, a keratotic center and ulceration might be seen. Invasive SCC presents more polymorphic vessels such as linear irregular, hairpin and grouped glomerular/dotted vessels over a whitish background with a central mass of keratin or ulceration . Such deThe combination of clustered dotted/glomerular vascular patterns and hyperkeratosis, seen as discrete yellow scales, has previously been shown to achieve 98% diagnostic probability for SCC . HoweverRCM is a noninvasive technique for in vivo imaging of the skin with a cellular-level resolution   that useMoreover, early recognition of SCC by RCM is difficult, and clear differentiation between AK and in situ SCC or between in situ and invasive SCC remains a challenge, as keratinocyte atypia is considered in both the most relevant parameter ,12. AKs High-frequency ultrasonography (HFUS) is a fast and accessible, noninvasive, convenient, practical, and safe dermatological diagnostic imaging examination that is now widely used in skin cancer. It allows real-time visual information with high diagnostic value and provides the physician with an extra hand in everyday practice. HFUS uses frequencies of approximately 20 MHz, which are dedicated to depicting the skin and allow scanning of the whole skin . As the ultrasound probe increases in frequency, its resolution increases but penetration decreases. Used in conjunction with clinical and/or dermoscopic examination of suspected skin cancer, HFUS may offer additional diagnostic information compared to other technologies. In fact, Wortsman et al, in a large retrospective study of 4,338 ultrasonographic skin examinations, showed that the addition of HFUS increased the correctness of clinical diagnosis from 73% to 97% .In HFUS, tumor depth is ascertained with B-mode, and Doppler blood flow technologies permit the measurement of tumor neovascularity and the mapping of vascular structures. SCC is usually seen as a hypoechogenic mass in relation to the surrounding tissue, without clear specific features that allow the differential diagnosis from other nonmelanoma skin cancer or other skin lesions. Sometimes the inflammation and the scar tissue beneath or surrounding the lesion can be isoechoic to the tumor and lead to misjudgment of borders. Moreover, the hyperkeratotic scale characteristic of some SCC might also interfere in the image of the tumor. In fact, to study the lesions that have severe crusting or keratinization such as some SCC, it is recommended to remove the scale or crust, since they cause attenuation of the sound beam, reducing the accuracy of the test. Accordingly, Marmur et al pointed out that, owing to the SCC characteristic of generally presenting hyperkeratosis and to the higher inflammatory process associated, the tumor area could be overestimated in some cases when evaluated by ultrasound . For thiHowever, HFUS is useful for determining the local aggressiveness of the tumor. SCC is more likely to invade soft tissues, cartilage, and adjacent bone than other nonmelanoma skin cancer, and this can be assessed with ultrasonography. In fact, currently, the main clinical use of HFUS in SCC regards preoperative assessment of the invasion in critical areas such as the face or the scalp, as HFUS gives a clear picture of the size and depth of the tumor, which is particularly important in planning the extent of the surgery.Optical coherence tomography (OCT) is an emerging technology that uses infrared light for performing high-resolution, cross-sectional imaging. OCT is analogous to ultrasound imaging, except that it uses light instead of sound  and it mDiagnosis is routinely confirmed by biopsy, and histological examination will differentiate between in situ and invasive SCC and detect aggressive histopathological growth patterns. However, conventional histopathological examination is also undergoing some changes, as new imaging techniques are emerging and beginning to replace the typical fixation, processing, and staining methods. This is the case of ex vivo fluorescence and RCM, which allows a rapid microscopic examination of freshly excised unfixed tissue directly in the surgery room during Mohs surgery after a few seconds of immersion in a fluorescence media . This opUnder conventional histopathology or ex vivo RCM, features such as the degree of differentiation, aggressive histological subtypes , depth greater than 2 mm (measured from the granular layer of the adjacent intact epidermis), Clark level IV or greater, and presence of perineural and/or angiolymphatic invasion classify the lesion as high risk [Once an invasive/aggressive SCC is diagnosed, it must be staged as the risk for metastasis is reported to be approximately 4% , and eveStaging of the tumor is classically performed according to the TNM  American Joint Committee on Cancer (AJCC) criteria . HoweverIn all the staging scales there are several clinical-pathological markers of high-risk SCC such as tumor size (which can vary depending on the location), Breslow or tumor depth, perineural and lymph/vascular invasion, histological differentiation of the tumor (despite not being included in the latest AJCC classification), and the immune status of the patient (worse prognosis is seen in immunocompromised patients). When the patient fulfills 2 or more high-risk markers, further staging by sentinel lymph node biopsy (SLNB) is recommended, as about 20% of these patients will present positive SLNB. However, the impact on the overall survival or disease-free survival has still not been established ,26.Follow-up of patients must be individualized and determined both by the clinical history of the individual and the subtype of the SCC; however, screening for new primary skin cancers should be performed at least once per year, adjusting frequency on the basis of individual patient risk.The recently published guidelines for SCC  resume tSurgical excision is still the gold standard and includes conventional and Mohs surgery . ConventIf surgical therapy is not feasible or elected, nonsurgical local approaches may be considered . For in Nonsurgical ablative modalities are also accepted in some cases in which surgery is not feasible, contraindicated, or not preferred by the patient. These include laser ablation CO2, erbium), electrocoagulation, and cryosurgery. However, given the lack of histological margin control with these approaches, the recurrence rate of SCC is higher . Primary, erbium,High-risk SCC should always be surgically excised, preferably by Mohs technique; however, adjuvant radiation therapy to the local tumor site following surgical treatment may be considered in primary SCC concerning perineural invasion or at high risk for regional or distant metastasis.Regarding locally advanced and metastatic SCC, treatment is based on the extent of disease. If lymph nodes are involved, dissection must be performed whenever possible, and adjuvant radiation with or without concurrent systemic therapy must be considered . SystemiThe main advances in SCC diagnosis are in the field of noninvasive imaging techniques. While histopathology remains the gold standard, noninvasive imaging techniques such as dermoscopy and RCM have recently been applied not only to enhance clinical diagnostic accuracy, but also to achieve an in vivo microscopic characterization of the tumors and margins previous to biopsy and surgery. The role of Doppler ultrasonography in evaluating the deep invasive components and lymph node involvement is unquestionable. As a result, the staging, management decisions, and treatment monitoring of the SCC is continuously improving thanks to the development of skin imaging techniques. Moreover, the current concept of cancerization field and the development of several nonsurgical treatment modalities  have provided a wider range of therapies for low-risk SCC and actinic keratosis. On the other hand, the new available systemic therapies  for locally advanced and metastatic SCC are improving the management and hopefully the outcome of SCC.


Cardiovascular disease is a serious threat to human health and a leading cause of mortality worldwide. Recent years have witnessed exciting progress in the understanding of heart formation and development, enabling cardiac biologists to make significant advance in the field of therapeutic heart regeneration. Most of our understanding of heart development and regeneration, including the genes and signaling pathways, are driven by pioneering works in non-mammalian model organisms, such as fruit fly, fish, frog, and chicken. Compared to mammalian animal models, non-mammalian model organisms have special advantages in high-throughput applications such as disease modeling, drug discovery, and cardiotoxicity screening. Genetically engineered animals of cardiovascular diseases provide valuable tools to investigate the molecular and cellular mechanisms of pathogenesis and to evaluate therapeutic strategies. A large number of congenital heart diseases (CHDs) non-mammalian models have been established and tested for the genes and signaling pathways involved in the diseases. Here, we reviewed the mechanisms of heart development and regeneration revealed by these models, highlighting the advantages of non-mammalian models as tools for cardiac research. The knowledge from these animal models will facilitate therapeutic discoveries and ultimately serve to accelerate translational medicine. Cardiovascular disease is a common disease that is a serious threat to human health . AccordiOur understanding of human heart development and cardiac diseases is still inadequate. The molecular and genetic networks of heart diseases are complicated, leading to a variety of structural and functional cardiac phenotypes. The molecular mechanisms, prevention and treatment of various forms of cardiovascular diseases have always been hot topics in biomedical research.Both the morphogenesis and the underlying genetic networks of heart development are conserved across species . This coHere, we introduced four popular non-mammalian animal models , focusing on their cardiac development, and recent progress in heart regeneration. A deeper understanding of the magical evolution of the heart, and the underlying molecular regulatory networks, will shed light on the essential factors involved in heart development and regeneration, and treatment of cardiac diseases.Heart development is a delicately regulated process and is highly conserved across species. During embryonic development, the heart undergoes a dynamic and complex process starting with the convergence of the myocardial and endocardial precursors to the midline, and culminating in the morphogenesis of these differentiated cells into a complex organ both morphologically and functionally . The devThe genetic networks regulating vertebrate heart development are highly conserved . This coThe heart development in animal models can be effectively studied at the genetic level to reveal genes that control the fate of cardiac cells and determine the response of cardiac cells to signals from neighboring micro-environment. In recent years, with the rapid development of genome editing technology, high-throughput sequencing and single cell sequencing technology, combined with the numerous genetic data of inherited diseases obtained by Genome-Wide Association Studies (GWAS) , researcIn most vertebrate, the heart development can be artificially divided into the following stages: (1) induction of cardiogenic cells from the embryonic mesoderm; (2) coalescing of these cells into a linear heart tube; (3) cardiac looping and asymmetric development; and (4) chamber specialization and growth. These processes are highly similar in most vertebrates, which indicates the evolutionary conservation of the heart building plan.Due to the evolutionary conservation of development, observations in non-mammalian models have contributed basic insights into the heart developmental mechanisms and allow us to extrapolate to human. Despite the differences in final form and physiology, there are many important discoveries in human heart development guided by studies of non-mammalian models. A well-known example is the identification of the contribution of neural crest cells (NCCs) to outflow tract (OFT) remodeling, which was first identified by the classic fate mapping experiments using chimeric embryos of quail donor and chicken host . The invDrosophila is the only invertebrate, and has the most distant from human in evolutionary status. Due to evolutionary conservation, from the research works of Drosophila, we can understand the most basic building blocks of cardiac development  is a simple tubular structure under the surface of dorsal midline, mainly composed of two kinds of cells, cardiomyocytes inside of the contractile cardiac tube and pericardial cells outside the cardiac tube without contractility , the cardiac progenitor cells appear in the lateral marginal zone of the blastula. These progenitors migrate toward the midline of the embryo during gastrulation. At about 15 hpf, the cardiac progenitor cells fuse into the cardiac disk with endocardial cells in the center lined by ventricular and atrial myocytes. At 22 hpf, the heart begins regular contraction. From 24 to 28 hpf, the cardiac disk elongates into a linear heart tube and begins leftward migration. The cardiac valve and the two chambered heart has formed by 48 hpf .Unique characteristics of zebrafish make them particularly attractive for cardiovascular research. Its advantages include external fertilization, small size, early optical transparency, easy genetic manipulation, and the ability to survive without a functional cardiovascular system at early stages of development . It’s eaXenopus has a three-chamber heart that consists of two atria and one ventricle. The right side of the heart receives deoxygenated blood from the body, and the left side receives freshly oxygenated blood from the lungs. The two streams of blood mix together in the ventricle, emitting a concoction that is not completely oxygenated to the rest of the body  (pannier (GATA4) (neuromancer (Tbx20) (The n humans . The ide(Nkx2.5) , pannier (GATA4) , neuroma (Tbx20) , 2008, a (Tbx20) .Xenopus, and chicken models, which contribute to advance the discovery of heart development mechanisms. For example, faust (fautm236a) is an ENU-induced, embryonic lethal recessive mutation in zebrafish that selectively disrupts formation of the definitive heart tube  transcription factor Mesp1 (Mesoderm Posterior 1) is considered to be one of the earliest markers of cardiac precursors . As a maThe different anatomical structures of the heart come from two groups of cardiac progenitor cells with distinct molecular characteristics, referred to as the first heart field (FHF) and the second heart field (SHF). The cells in the FHF mainly differentiate to form the left ventricle and parts of the atria. Adjacent to the FHF, the SHF contributes predominantly to the right ventricle, atria, inflow and outflow tracts. Compared to FHF, SHF has stronger cell proliferation ability with slower differentiation. SHF cells are multi-potent that can be differentiated into various cardiac cell types, such as cardiomyocytes, smooth muscle cells, endothelial cells, and fibroblast cells, while FHF cells mostly generate cardiomyocytes. FHF cells express Tbx5, HCN4, and Nkx2.5. SHF cells specifically express transcription factors Islet1, Tbx1, Six2 and growth factors Fgf8/10 . The expDuring embryonic development of all vertebrates, the looping of heart tube leads to the conversion of its anterior-posterior polarity into left-right polarity. The direction of heart looping depends on the left-right asymmetry established through the asymmetric expression of the genes Nodal, Lefty and Pitx2 on the left side of the body , which iAs a new class of regulators of cardiomyogenesis and heart diseases, microRNAs have been proved to be essential for cardiac development and indispensable for maintaining the homeostasis and function of the heart. The overall disturbance of the cardiac miRNAome by the deletion of the microRNA processing enzyme Dicer leads to dilated cardiomyopathy . The expIn humans, myocardial infarction is a common cause of cardiac injury. Unfortunately, the human cardiac cells show very limited ability for regeneration to replace the lost cardiomyocytes. The necrotic cardiomyocytes are gradually replaced with fibrotic tissue through a re-modeling process, which can eventually lead to heart failure . RegenerResearch of cardiac regeneration focuses on the development of a wide spectrum of model organisms to decipher the mechanisms and factors involved in heart repair. For decades, animal models of cardiomyocyte regeneration have been restricted to non-mammalian organism models , such asZebrafish possess highly efficient cardiac regenerative capacity throughout their lifetime, providing novel insights into the understanding of human cardiac regeneration . The zebXenopus is regarded as a leading model of regeneration research. A new study using Xenopus laevis as a model of heart regeneration showed that the tadpole hearts can regenerate until the larvae reach metamorphosis. Excessive or reduced thyroid hormones reduce the cardiac regenerative capacity, suggesting that fine-tuning the availability of thyroid hormones may be necessary for heart regeneration (neration .Oryzias latipies) heart can be scarred after injury without regeneration (Xenopus tropicalis can regenerate heart tissue after ventricular resection, while mature adults of the closely related species Xenopus laevis are not capable of cardiac regeneration (Interestingly, even animal species with close evolutionary kinship may have very different heart regeneration capabilities. In cyprinids, while the hearts of zebrafish and goldfish  have strneration . Young aneration , 2018. EOver the past few decades, there is a growing understanding of heart development and regeneration in the non-mammalian model organisms, which has provided a valuable reference for related research in mammalians. A deep understanding of the formation and development of the heart has allowed cardiac biologists to significantly intervene in the challenge of therapeutic heart regeneration. In non-mammalian animal models, various platforms can be established quickly, including forward and reverse genetic manipulations and high-throughput omics studies. The latest gene editing tools, including CRISPR/Cas9 and high-precision base editors, are continuously being optimized for the use in non-mammalian animals. Massive genetic data brought by the rapid development of big data era, in combination with new genetic tools, deep sequencing, as well as further advances in microscopy imaging becoming available, there is no doubt that non-mammalian animal models will continue to reveal novel insights into cardiac development and contribute to cardiac repair. Deciphering the cellular and molecular mechanisms that regulate cardiac development and regeneration will promote the development of therapeutic strategies to cure heart diseases, impacting millions of people worldwide.JX wrote the initial draft of the manuscript. ZM and HR wrote the manuscript. YX and WY contributed to design, writing, and final approval of the manuscript. TZ contributed to conception and design, financial support, administrative support, writing, and final approval of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Iodine is a microelement that is naturally present in some foods, added to others, and available as a dietary supplement. Iodine from the diet is converted into the iodide ion before it is absorbed throughout the gastrointestinal tract ,2. When Thyroid function is primarily regulated by the thyroid-stimulating hormone (TSH), secreted by the pituitary gland, which increases thyroidal uptake of iodine and stimulates the synthesis and release of T3 and T4. In the presence of inadequate iodine intake, TSH levels remain elevated, leading to goiter, an enlargement of the thyroid gland that reflects the body’s attempt to trap more iodine from the circulation and produce thyroid hormones.Iodine deficiency impairs thyroid hormone production and has many adverse effects during the course of the life, collectively termed the iodine deficiency disorders (IDDs), which depend on its severity and the age of the affected subjects. Although goiter is the classic sign of iodine deficiency, and can take place at any age, the most serious adverse effect of iodine deficiency is damage to the fetus during pregnancy, since the absence or inadequate level of thyroid hormones cause significant clinical manifestations such as increased risk of stillbirths, abortions, perinatal mortality, congenital abnormalities, cretinism, impaired growth ,16. NowaOver the last few decades, intensive efforts have been made by the governments of IDD-affected countries to implement and control salt iodization program, since the most cost-effective strategy for IDD is universal salt iodization with the recommended iodine concentration of 20–40 mg iodine per kg salt . DespiteIn this issue, we provide an update on the iodine status of the general population in different countries of the world, including Moldovia , Korea , the Uni


In vitro systems are ideal setups to investigate the basic principles of biochemical reactions and subsequently the bricks of life. Cell-free protein synthesis (CFPS) systems mimic the transcription and translation processes of whole cells in a controlled environment and allow the detailed study of single components and reaction networks. In silico studies of CFPS systems help us to understand interactions and to identify limitations and bottlenecks in those systems. Black-box models laid the foundation for understanding the production and degradation dynamics of macromolecule components such as mRNA, ribosomes, and proteins. Subsequently, more sophisticated models revealed shortages in steps such as translation initiation and tRNA supply and helped to partially overcome these limitations. Currently, the scope of CFPS modeling has broadened to various applications, ranging from the screening of kinetic parameters to the stochastic analysis of liposome-encapsulated CFPS systems and the assessment of energy supply properties in combination with flux balance analysis (FBA). These are based either on synthetic transcription–translation systems with a well-defined composition or on crude cell extracts that contain a more complex component assembly. While the product titer and production volume of such systems have increased from a few microliters to hundreds of liters, several limitations of the system remain. To date, and even within the best commercial systems, the protein titer with CFPS systems is orders of magnitude lower than that of in vivo whole-cell production due to resource expense and reduced longevity (Cell-free protein synthesis (CFPS) technology has a long history in life sciences, which started with fundamental research on deducing the genetic code . Over seongevity . Here, pin silico and in vitro  and algebraic equations to dynamically describe model states. In a structured model, equations incorporate affinity constants and other parameters. To reduce complexity, models can be formulated following an unstructured black-box approach, considering only apparent kinetics . The difin vitro expression of GFP is to consider the macromolecular components, DNA, mRNA, and proteins in a black-box model  for the TX-TL system. Key kinetic parameters of the xylose-repressor system were approximated from DNA titration experiments. Simulations were performed using parameters identified by Bayesian parameter inference. Extending the model to describe the concurrent expression of two targets, plasmids carrying GFP and mCherry derivatives revealed competition for translational resources. In general, the reported translation elongation rates (between 0.10 and 0.02 aa s–1) were slower than those reported for CFPS systems. The inefficient use of available energy accounted for the low performance. Another model approach for investigating resource competition in CFPS was formulated by The use of E. coli CFPS extract was presented by Varner and colleagues , translation, and elongation (kTL) are experimental readouts. However, the range of these parameters is broad , models that consider the joint burden on resources will come into focus (Currently, CFPS models can identify bottlenecks in the transcriptional and translational processes as well as infer kinetic parameters from model data. The consensus of most model predictions is the identification of the translational rather than the transcriptional process as one of the key targets for further developments in CFPS systems. Potential starting points are translation initiation, tRNA supply, and recycling. In most approaches, the modeled mechanisms of the translational process seem to be oversimplified. Inspiring approaches for to focus . A feedbto focus . This siJM reviewed the literature, designed the concept, wrote the manuscript, and prepared the figures. MS-H and RT co-edited and supervised the manuscript. All authors approved the manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes. The mitogen-activated protein kinase (MAPK) superfamily is a cell-mediated signaling pathway which connects inputs to the cell, with modifications in gene expressions leading to changes in the cellular phenotype. To mediate its function, the MAPK signaling pathway is composed of three kinds of kinases, with each of them consisting of multiple members, i.e., the extracellular regulated kinases (ERKs), the Jun amino-terminal kinases/stress-activated kinases (JNKs/SAPKs), and the p38 kinase.The MAPK/ERK signaling pathway in the central nervous system works at two different stages: throughout development and in adulthood. Throughout development, the pathway is sensitive to driving signals from the environment, promoting differentiation migration guidance to the final fate and developing the final cellular phenotype . Once coThroughout development, the type of system that may induce the MAPK signaling pathway and the target of activated ERK may differ in organ and cellular type, so the configuration of the cellular mechanisms that may induce ERK activation and the putative targets of the activated ERK may be specific for a particular organ in a particular moment and give the system a particular rule. In addition, during pathological conditions, the ERK pathway may subserve mechanisms leading to the misfunction of cellular mechanisms associated with this disease.Therefore, keeping in mind the double role of ERK throughout development and in adulthood, this review is centered on the mechanisms of ERK activation/inhibition which modulates and drives the central core of social and emotional behaviors, i.e., the amygdala and amygdala-related areas. We will analyze the specific function of ERK in the configuration of the emotional-related anatomical areas and in the processing of emotional and social information. Finally, we will consider the pathologies associated with ERK alterations.In the nervous system, as a general rule, the MAP-ERK pathway can be activated by two types of extracellular signals which operate through two types of receptors, i.e., G-protein coupled receptors (GCPR) and the receptor tyrosine kinase (RTK). Additionally, as a general rule, signaling systems operating through RTK are triggered by neurotrophins responsible for neurodevelopment, while neurotransmitters trigger GPCR which convey plastic and operative machineries in adult neural cells. Each MAPK is the end point of a module of three consecutive kinases that act as a cascade. The first step is the phosphorylation of an MAPK kinase kinase (MKKK), followed by the phosphorylation of an MEK kinase , which in turn activates an MAPK, such as ERKs, JNK, or p38 kinases . It is wThere are two isoforms of ERK in this pathway: The 44kDa ERK1 and the 42 kDa ERK2. These two isoforms share up to an 84% sequence identity of the amino acid backbone. There has been a lot of controversy on whether there is functional compensation between both isoforms. ERK1 knockout mutants do not show relevant impairment in emotional and cognitive tests, including fear conditioning and passive avoidance . AdditioA deep analysis of transgenic mice reported several additional specific features for each isoform. Therefore, knocking ERK1 results in no changes in the hippocampal and amygdala plasticity, probably due to compensatory mechanisms, but results in the enhancement of LTP facilitation in the nucleus accumbens, which results in the enhancement of striatal-dependent long-term memory . FurtherOnce activated, ERK may remain in the cytoplasm and activate cytosolic pathways or translocate to the nucleus to activate different genes. Additionally, throughout this process, p-ERK may dimerize, which adds new aspects to be considered. Most of the research on targets of activated ERK has been studied in tumorigenic cell lines, but the findings of such a fundamental process in cell biology are still relevant to neuronal systems.Several proteins that anchor ERK to the cytoplasmic compartment have been described. One of these elements is MAP kinase phosphatase 3 (MKP3). The overexpression of a catalytic inactive form of MKP3 results in anchoring pERK to the cytoplasm b, which does not alter its capacity to phosphorylate cytoplasmic substrates, but is unable to activate Elk-1-dependent gene transcription, initiating DNA replication in response to growth factors . FurtherCytoplasmic targets of pERK are involved in apoptosis and neurogenesis. It has been found that the growth factor induction of ERK activation during development maintains proliferation differentiation and the survival of neural cells, while the withdrawal of growth factors activates p38 and JNK pathways that lead to apoptosis mechanisms ,32,44. TpERK has a small size and is able to move into the nucleus through diffusion along nuclear pores, and this nuclear translocation is a highly dynamic process . NuclearOnce in the nucleus, pERK is able to activate different transcription factors, which leads to the expression of different genes. The types of gene that can be activated by pERK will depend on the type of cell and the moment of development. In addition, the activation of a particular gene may depend on the level of pERK reached in the nucleus, for example, transient ERK activation results in c-fos transcription, but its product cannot be accumulated and become unstable. Only sustained ERK activation is able to phosphorylate c-fos, which reciprocally maintains ERK activation and can accumulate and drive additional signaling . SeveralGiven the fact that many IEGs may be targeted by activated ERK, it raises the question of which of these IEGs may be activated in a particular moment and place. This question has not been fully addressed by the literature, but several aspects can be considered. First, the promotor region of most of these IEGs contains several which are controlled by different kinases, including ERK. Therefore, the expression of a particular IEG may depend on the combined activity of multiple signaling pathways. As an example, ERK activation is required for CREB transcription, but additional factors are necessary to trigger relevant CREB transcription . TherefoAdditionally, in the particular case of the central nervous system, it needs to be considered that the topographic occurrence of events is highly relevant for cellular activity. Neurons are highly polarized cells which have been shown to locally translate proteins at dendrites in a stimuli-dependent manner independently from the somatic input . Local tTherefore, ERK activation is a central pathway that may drive its action at a local level by activating the local translation of mRNA, promote the trafficking of synaptic components to facilitate plasticity, or induce IEG activity in the nucleus. The availability of the transcription factors that can be activated by ERK depends on the cell type, brain region, and life stage.There is much evidence that links ERK malfunction to neurological syndromes associated with autism spectrum disorders . This evERK participates in two stages of brain development that can be conceptualized as embryonic and early postnatal development. In the embryonic period, FGF8 signaling along ERK participates in proliferation, migration, and the final fate of neural cells, which results in the configuration of the main brain subdivisions ,28,29,30Mutations affecting MAPK/ERK signaling pathways result in a wide range of alterations, including skin pigmentation, heart and lung alterations, skull malformations, and alterations in the configuration of the encephalic vesicle. These kinds of alterations come from the pattern of ERK expression in early development, which includes the neural crest cells whose derivatives migrate to the skull, skin (melanocytes), heart , and bronchopulmonary system  . In the The patterning of the brain depends, to a great extent, on direct FGF8-ERK signaling. FGF8 is a morphogen in the sense that it is produced in specific regions of the developing encephalic vesicle and generates a gradient over the surrounding areas. Then, the activation of tyrosine kinase receptors (TKR) in the targeted areas generates a cascade of signaling that finally results in ERK phosphorylation, which, in turn, initiates mechanisms of cell proliferation, differentiation, and migration to the final fate. FGF8 is highly expressed in two secondary organizers, i.e., the isthmus (Is) in the boundary between the midbrain and rhomboencephalon and the anterior neural ridge (ANR), which is the edge of the anterior part of the neural plate located between the roof and the floor plates primordia during and after neural tube closure. On the other hand, ERK is highly phosphorylated at both sides of the isthmus and in the area just caudal to the rostral tip of the telencephalon . TherefoThere are up to three tyrosine kinase receptors that can bind FGF8, i.e., FGFR1-3 . The FGFThe FGF8-ERK signaling system directs the processes of the regional configuration of telencephalic areas, and once developed, the general patterning and morphogenesis of the main forebrain and midbrain divisions. FGF8 signaling on radial glial cells of the developing thalamus induces ERK1/2 activation in the radial fibers which guide the proliferation and migration of neural progenitors from the thalamic mantle layer to the final fate, in order to generate the thalamic map. Reduced FGF8 production results in a decreased number of thalamic cells and deficient thalamocortical innervation, and this process is parallel to a reduction in ERK phosphorylation in the developing thalamus .Another aspect that is disrupted when the MAPK/ERK signaling pathway is altered is the organization of the cerebral cortex. The genesis of the mammalian cerebral cortex consists of at least two basic processes : On one The cerebral cortex originates from neural progenitor cells (NPCs) within the ventricular zone (VZ). In the first phase, the NPCs of the VZ produce neurons and later on, glial cells. During the first neurogenesis phase, the self-renewing multipotent NPCs divide in two ways, i.e., symmetric and asymmetric divisions. Symmetric divisions produce two cells that differentiate towards neurons. Asymmetric divisions produce a cell-renewing progenitor and a daughter cell, which may differentiate towards a neuron or stay as an intermediate progenitor cell (IPC). In turn, the IPCs may undergo another asymmetric or symmetric division to continue the process ,70.Newly born neurons secrete stimuli that induce gliogenesis from undifferentiated NPCs in later phases of embryogenesis . During Control of the cell cycle is one of the key elements in controlling the final number of cortical neurons. Several experiments have shed light on this aspect using murine models of 16p11.2 deletion. This model mimics the human syndrome of this deletion in humans that accounts for the 1% of cases of autism spectrum disorders . The 16pIn addition to the in situ development of the cortex, MAPK/ERK signaling also contributes to the generation and final fate of cortical interneurons by regulating the generation of progenitors in the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) . In thesOnce configured, the main components involved in emotional and social processing need to maturate to produce the final architecture subserving those functions. The maturation process consists of several biochemical and morphological changes that result in the extension of extrinsic and intrinsic connections, developing the dendritic trees and spines and apoptotic mechanisms to produce the final number of neurons in a given center. These processes are highly regulated by several pathways of intracellular signals in which ERK is also involved. In fact, a dynamic regulation of MAPK phosphorylation pathways throughout postnatal development has been found in the hippocampus . SpecifiAlterations of the normal maturation process may come from a stressful condition, such as maternal separation. In this paradigm, a reduction of brain-derived neurotrophic factor (BDNF) synthesis which results in a reduction of MAPK/ERK signaling through the TrkB pathway has been described. As a final result of this manipulation, a reduction of spines in hippocampal neurons has been found .327. In these cases, a blockade of the ERK pathway at PN6 resulted in an increase of forebrain apoptosis and long-lasting deleterious effects of normal behavior in adulthood, including social recognition, impaired memory, and reduced LTP. No such deficits were observed when the blockade was performed at or over PN14 [The relevance of ERK phosphorylation in early postnatal development and its consequences for adult behavior were also tested by an intraperitoneal injection of the MEK inhibitor SLver PN14 . Neural ver PN14 .One important aspect of the final configuration of neuronal typology is the dendritic branching. BTBR T+tf/J (BTBR) is an inbred strain of mice that has been extensively used as a model of autism as these animals display several autistic-like behavioral features, including deficits in social communications and interaction and repetitive stereotyped behaviors . In thesA role of ERK phosphorylation has also been postulated in the synaptogenesis occurring during postnatal development. A high period of synaptogenesis around PN15 has been found . During The ubiquity of ERK expression in the CNS rises the possibility of participation of this pathway in multiple cognitive processes . The actThe first experiment which studied ERK kinases and LTP together was carried out in the hippocampus, one of the most relevant regions which integrates and stores memory after being encoded at other areas. Many have divided the hippocampus, based on its role in information processing, into the dorsal and ventral hippocampus. While the dorsal hippocampus obtained inputs from the medial septal area, known as the entorhinal cortex, the ventral hippocampus is the only one receiving projections from the amygdala. Inputs to both these subareas point out a primordial role in spatial memory of the dorsal division of the hippocampus, while the ventral hippocampus processes social memory ,97.The extensive work on “place cells” mostly focused on the CA1-CA3 fields of the hippocampus is a good and illustrative example of how critical the pivotal role of the ERK pathway in LTP generation in the dorsal hippocampus and spatial memory formation is ,86. To tThis distinct activation of the MAPK/ERK pathway between the dorsal and ventral hippocampus further supports the idea of them having distinct roles in memory formation and processing. These different roles come from multiple organizational differences. The main input to the dorsal and ventral hippocampus comes from two functionally different areas of the entorhinal cortex . MoreoveOn the other hand, infusion into the dorsal hippocampus of specific ERK inhibitors (PD098059) impairs consolidation, but not acquisition, of spatial memory. Inhibition of the consolidation of memory then leads to an impairment of long-term memory. The inhibition of long-term memory is caused by ERK inhibition, which leads to decreased local protein synthesis rates. The reduction in local protein rates then leads to the non-reinforcement of specific synaptic systems . The inhB receptor at DG, CA1, CA2, and CA3 fields, inhibiting pyramidal and granular neurons, respectively, but increasing the activation of ERK1/2 [In the dentate gyrus (DG), BDNF-induced LTP increases the activation of BDNF receptor TrkB and ERK when comparing young and aged animals ,106. Howf ERK1/2 ,108. Likf ERK1/2 . Cholinef ERK1/2 .Altogether, ERK’s role does not seem to exclusively be as a spatial memory generator, but more as a signal transduction modulator. Good examples of this are the promotion and reinforcement at place cells at CA1, inhibition through the activation of GABAergic interneurons at the hippocampus, and the inhibition of cholinergic neurons at the medial septum. This is why the ERK1/2 pathway appears to play a role as an integrator of signals which ensures the correct convergence and reinforcement of memories, being both a generator and inhibitor of such memories.If ERK activation plays a role in which stimuli are reinforced and which plastic changes take place in spatial memory, this is also the case in social behaviors. This memory is stored and processed in the ventral hippocampus, amygdala, hypothalamus, and bed nucleus of the stria terminalis (ST). As in the case of spatial memory, the nature of this reinforcement largely depends on the context, meaning the type of neuron, receiving stimuli, and the surrounding context which integrates these stimuli .During social behavior, the MAPK/ERK pathway is mostly activated when encoding social-related memories. However, some cases exist when only testing social interaction in rodents, which does not necessarily involve memory. These experiments show a decrease in social interaction measured by olfactory exploration times after the inoculation of SL327 (an MEK1/2 inhibitor) in olfactory bulbs. The greatest impact of the MAPK/ERK pathway on social behavior has been seen in social recognition memory. Social recognition memory is the process of social behavior which allows a subject to remember an already acquainted conspecific. Protein synthesis is required when information regarding social stimuli is integrated and stored in long-term memory. The specific details of the experimental set up may lead to different outcomes. For example, social recognition memory requires two stages of protein synthesis at olfactory bulbs, medial amygdala, and the pyriform cortex when introducing juveniles as novel social stimuli . In thesComplementary studies on the medial amygdala show that only in the case of long-term (24 h) social recognition memory is protein synthesis required for the consolidation of memory . NonetheOn the other hand, ERK is activated in different variants of social behavior, such as aggressive behaviors, social anxiety, and social defeat ,112,113.As for the case of spatial memory, in social behavior, ERK activation seems to stimulate neuronal plasticity reinforcement on specific synapses. The nature of this reinforcement seems to be dependent on stimuli convergence. In the case of social behavior, considering its overlap with other systems, such as anxiety, stress, and aggression, this convergence might be even more complex. For example, the oxytocin and relaxin-3 pathway lead to opposite effects on social recognition memory; while oxytocin promotes it , RLN3 imThere is abundant literature on the role of MAPK signaling in plasticity mechanisms related to fear conditioning. Pioneer studies showed MAPK cascade involvement in NMDA-dependent LTP . AlthougERK activation takes place in a specific manner, which relates to areas regulating the learning process. The involvement of ERK in the retrieval of fear memories has been demonstrated in the inhibitory avoidance paradigm, where an increase of pERK has been shown in areas such as the hippocampus, entorhinal, and anterior cingulate cortex . MoreoveMAPK/ERK signaling also plays a relevant role during the reconsolidation process. Throughout this process, fear memories need to be consolidated again after being activated . InterfeConsolidation and reconsolidation processes depend on de novo protein synthesis that, in part, is triggered by MAPK/ERK signaling systems . HoweverAs we have previously described, MAPK signaling pathways intervene and control cellular functions, resulting in a direct function of memory and emotional processes. Therefore, alterations or modulations of these pathways can lead to different processes implicated in various human diseases. Throughout this and the next section, we will analyze the state-of-the-art of MAPK signaling pathways in human disease, with a special focus on neurodegenerative disorders  and autiThe role of the MAPK/ERK pathway in neurodegenerative diseases is mainly related to glial cell function and the inflammatory response. The activation of resident immune cells of the brain, glial cells (microglia and astroglia), triggers the pro-inflammatory state with the production of nitric oxide (NO), cytokines, and chemokines and the implication of inflammatory-related pathways ,125,126.Parkinson’s disease (PD) is an age-associated disease mostly identified by an extrapyramidal alteration of movement. From a pathological point of view, PD is characterized by the selective and progressive loss of dopaminergic-melanized neurons located in caudoventral regions of the substantia nigra, reactive gliosis, and intracytoplasmic inclusions of α-synuclein known as the Lewy bodies . In thisLeucine-rich repeat kinase 2 (LRRK2), also known as dardarin, is a 2527 amino acid (~280 kDa) protein that, in humans, is encoded by the PARK8 human gene and constituted by several functional domains, including leucine-rich repeats, an Ras-related GTPase domain, an MAP3K domain, and multiple potential protein interaction domains . SeveralThe impact of ERK in PD-associated neurodegeneration has also been analyzed using the most relevant animal models of parkinsonism, both neurotoxins 6- OHDA and 1-Methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP), suggesting that ERK may contribute to the pathogenesis of neurodegeneration.6-OHDA remains the most widely used tool to induce a selective nigrostriatal lesion in murine models and dopaminergic cell lines. In this regard, B65 6-OHDA-induced cell death depends on chronic ERK activation, and this dopaminergic death can be mostly attenuated using an MEK blocker . ConversMPTP is a compound that, having passed through the blood–brain barrier, is catabolized by astrocytes to its neurotoxic form MPP+ and causes permanent symptoms of parkinsonism selectively affecting dopaminergic neurons in the substantia nigra. The addition of MPP+ to neuroblastoma cell lines increases α-synuclein, induces the activation of ERK, and triggers cell death that can be reverted using the MEK-P inhibitor U0126 . As the Finally, the implication of the ERK pathway in PD is beyond animal models. The substantia nigra of PD patients presents phosphorylated-ERK associated with fibrillar bundles inside coarse discrete cytoplasmic granular accumulations surrounding Lewy bodies, suggesting a potential interaction between the mitochondrial function and the MAPK/ERK signaling pathway in dopaminergic neurodegeneration .Alzheimer’s disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disease . AD is aMAPK pathways differentially activate during AD. All three MAP-kinases are implicated in mild and severe cases (Braak stages III–VI), both ERK and JNK/SAPK are implicated in Braak stages I and II and in non-demented cases without pathology hallmarks (Braak stage 0), and either ERK alone or JNK/SAPK alone can be activated . This diAmyloid β, the principal component of amyloid plaques, constitutes the main link with ERK pathway activation. In this sense, it has been established in both in vivo and in vitro studies that chronically elevated levels of Aβ induce the dysregulation of hippocampal ERK MAPK ,139. AddInteracting with both AD-associated proteins, the α7 nicotinic acetylcholine receptor (α7nAChR) binds to soluble amyloid-beta, resulting in tau phosphorylation and the formation of neurofibrillary tangles. Moreover, α7nAChR mediates the activation of p38 MAPK and ERK1/2 signaling pathways, suggesting an essential role of both α7nAChR and MAPK signaling pathways in the uptake and accumulation of β-amyloid .Furthermore, during the last decade, it has been suggested that mitochondrial dysfunction is an early pathological feature of AD related to oxidative stress and Ca2+ homeostasis that triggers Aβ-induced synaptic dysfunction . It has However, the role of ERK in AD is not clear, since an increase of total ERK, specifically within synaptosomes, is associated with a deficient memory task performance in AD transgenic mice . In thisAmyotrophic lateral sclerosis (ALS), a term proposed by Charcot in 1874 , is a deHuntington’s disease (HD) is one of nine autosomal dominant neurological diseases caused by an expansion mutation of CAG triplets encoding polyglutamine (polyQ) sequences in N-terminal domains. It affects 3–7 cases per 100,000 of the Western Europe population, and its symptoms include motor disorders , cognitive disorders , and psychological disorders (such as irritability and depression), which end with the death of patients. While the wild-type huntingtin (Htt) protein modulates intracellular vesicular trafficking and neuronal development, mutant Htt, with an elongated polyQ domain, generates toxic N-terminal fragments after undergoing proteolytic processing .Mutant Htt presents kinase downstream ERK deficiency involved in transcriptional dysregulation and by triggering striatal degeneration, it also decreases the response to cortico-striatal BDNF signaling and downregulates ERK-dependent glutamate transporter expression, increasing cells susceptible to glutamatergic excitotoxicity ,149.A prion is the altered form of a 23-kDa constitutive protein  that has lost its normal function, but has acquired the property of transforming the standard form into a pathological form. This protein has a regular conformation called PrPc, encoded by a gene (PRNP) localized to human chromosome 20. In prion pathologies or prionopathies, an altered isoform originating as a result of the incomplete proteolysis of PrPc, called PrPsc, tends to form amyloid aggregates in the form of plaques in the brain. Prionopathies are disorders of the conformation of proteins, which manifest themselves as spongiform encephalopathy in animals, such as scrapie, and as neurodegenerative diseases in humans. The accumulation of PrPsc causes the involvement of the gray matter with neuronal death, gliosis, and spongiform changes. Activated microglia is a classic hallmark of neuroinflammation associated with prions, as these cells phagocytize and eliminate amyloid plaques ,178. As Scrapie-infected hamster’s brains present an up-regulation of both pJNK and pERK . ERK is As we have previously described, MAPK signaling pathways intervene and control cellular functions resulting in a direct function of memory and emotional processes. Therefore, alterations or modulations of these pathways can lead to different processes implicated in various human diseases. Throughout this and the next section, we will analyze the state-of-the-art of MAPK signaling pathways in human disease, with a special focus on autism and neurodegenerative disorders.From the classical definition proposed by Kanner in 1943 , and by Recent studies support the critical role of MAPK/ERK signaling in metabolism, where this pathway intervenes in the regulation of cell metabolism, since alterations in MAPK/ERK signaling are associated with metabolic syndrome . In thisOn the other hand, MAPK/ERK is also implicated in the stabilization of dendritic spines, since it participates in encoding adhesion molecules and scaffolding proteins ,189. In Finally, recent studies suggest the existence of a critical window connecting alterations in MAPK/ERK activity and autism, since the blockade of MAPK/ERK signaling at postnatal day 6 in rats induces autistic behavioral phenotypes that are not present at day 14 ,153.The MAPK/ERK signaling pathway in the central nervous system participates at two different stages: Throughout development and in adulthood. During these periods, different transcription factors can be activated by MAPK/ERK, depending on the type of cell and the moment in life.In embryonic and early postnatal phases, signals transmitted through MAPK/ERK in progenitor cells elicit neurogenesis and repress gliogenesis . In thisERK participates in different neuronal processes, such as spatial memory, social behavior, and fear conditioning. While ERK elicits a signal transduction modulator role in spatial memory, activated ERK stimulates neuronal plasticity reinforcement on specific synapses in social behavior. On the other hand, MAPK/ERK signaling systems, which follow different pathways in the hippocampus and amygdala, trigger crucial de novo protein synthesis for consolidation and reconsolidation processes .It was previously believed that in terms of the simplistic term-dependent ERK function, while the early activation of ERK was thought to be typically neuroprotective, delayed and chronic ERK activation were understood to promote neuronal cell death . HoweverIn addition to the chronic activation of ERK, its localization within the cell seems to play a crucial role in initiating neurodegenerative processes .However, it is difficult to directly associate the MAPK/ERK signaling pathway to a specific neurodegenerative disease as this pathway is part of a more extensive network of other intricate signaling pathways. On top of that, ERK also interacts with more than 70 different cytoplasmic and nuclear substrates, modulating many fundamental cellular processes, such as cortical neurogenesis, proliferation, and excitation, which may have a cumulative effect on cognitive and behavioral impairments. Many pathologies of the central nervous system have been associated with disruption of the MAPK/ERK signaling pathway, in agreement with the ubiquity of this enzyme in neurons and glial elements. Some of these syndromes are directly related to ERK gain/loss of function and in other cases, ERK implication is indirectly a consequence of the wide spectrum of MAPK/ERK signaling pathways participating in central nervous system homeostasis.