Various methods are available for cancer screening, and the methods are performed depending on the origin site of cancer. Among these methods, biopsy followed by medical imaging is the most common. After cancer progression is determined, an optimal treatment—such as surgery, chemotherapy, and/or radiation therapy—is selected. A new assay has been developed that detects circulating tumor cells (CTCs). Tracking changes in CTCs may reveal important tumoral sensitivity information or resistance patterns to specific regimens and prompt changes in therapy on a personalized basis. Characterization of CTCs at the DNA, RNA, and protein levels is important for gaining insight for clinical applications. A small number of CTCs can be analyzed to obtain genome information such as the progression of cancer including metastasis, even in a single cluster. Although many clinical studies, particularly CTC enumeration and detection of specific oncogene expression, have increased the success rate of diagnosis and predicting prognosis, there is no consensus regarding the technical approaches and various aspects of the methodology, making it difficult to standardize optimal methods for CTC analysis. However, ongoing technological advances are currently being achieved and large-scale clinical studies are being conducted. Applying CTC analysis in the clinic would be very useful for advancing diagnosis, prognosis prediction, and therapeutics. A mammogram is a low-dose X-ray that detects changes in breast tissue. Another imaging method for screening and diagnosis of breast cancer is magnetic resonance imaging (MRI), which is a non-invasive imaging technology that produces three-dimensional detailed anatomical images [® has been established as a noninvasive screening test for colorectal cancer that analyzes stool DNA [Cancer screening aims to detect cancer in order to achieve diagnosis before cancer progression. Well-known methods for screening include blood, urine, biopsy, or medical imaging tests. If cancer-related signs are detected, more conclusive and invasive methods are performed to confirm the diagnosis. Therefore, different methods for cancer screening are performed depending on the site. Screening involves evaluating the origin site before signs or symptoms of the cancer appear. According to the guidelines of the United States Preventive Services Task Force (USPSTF), regular mammograms can lower the risk of breast cancer-related death -secreting cells were successfully detected in cancer patients. Elevated levels of cathepsin D indicate the recurrence of breast cancer. Overexpression of cathepsin D is also associated with tumorigenesis of colorectal cancer (CRC) and lung adenocarcinoma and with aggressive forms in prostate cancer [MUC1 is a transmembrane mucin that acts as a tumor-associated antigen in various carcinomas including metastatic progression [Viable CTCs can be analyzed by detecting secreted proteins such as specific antigens or cytokeratins by the epithelial immunospot assay ,38. The e cancer . MUC1 isgression ,40. Furtgression ,41. Thergression .Alterations in glycosylation structures in CTCs could serve as important diagnostic markers . MalignaIsolation of viable CTCs is technically challenging because most methods yield low numbers of partially purified CTCs that are damaged during the cell purification process . The limHER)-2-negative tumor patients to HER-2 gene amplification on CTCs followed by administration of trastuzumab [HER-2-negative (tissue in primary site) and cytokeratin-19 (CK19) mRNA-positive CTCs were randomly assigned and administered trastuzumab [HER-2-negative patients following treatment with trastuzumab [There is a clear need for improved cancer biomarkers in the clinic, and CTCs have been proposed as a very effective solution. This is because CTCs have numerous very desirable characteristics as cancer biomarkers. CTCs are have been detected in the peripheral blood of the most common solid tumors, suggesting that CTCs can be universally applied in cancer screening ,27,39. Cstuzumab . In thisstuzumab . A decrestuzumab . This clstuzumab ,52. NeveAs described above, despite the numerous clinical studies related to CTC analysis in cancer patients, these analyses are not routinely used as cancer therapy by physicians. This may be because of the large number of methods for detecting CTCs by physicians and biologists, making it difficult to choose the optimal method . There iRecently, CTCs have been widely analyzed as an alternative for diagnosis, predicting prognosis, and establishing treatment strategies. However, a very complicated process is required to detect and analyze CTCs; therefore, actual clinical applications are limited. Challenges such as standardizing biomarkers that can be applied to each solid cancer or distinguishing resistance even in the same type of cancer must be overcome. However, technological advances are currently being accomplished and large-scale clinical studies are being attempted. Because the unique information that can be acquired by CTC analysis has great potential to understand the peculiar environments of solid tumors, future applications of CTC analysis in the clinic would be a very useful technology.


Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed. Armand Trousseau first reported on the relationship between thrombosis and cancer in 1865. Since then, numerous studies have established that thrombosis is a common complication for cancer patients, contributing to the second-leading cause of mortality in cancer patients . ThromboVenous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). The development of VTE is often initiated in the valve sinus where a number of features surrounding these valves make the site prone to thrombosis. These include abnormal and reduced blood flow, reduced shear stress, and hypoxia leading to an intact but dysfunctional endothelium . In addiAlthough there are fewer data available on arterial thrombosis in cancer compared with on VTE, it is nonetheless observed in cancer. There have been multiple case reports suggesting acute arterial thrombosis in the setting of a new malignancy . Navi etThe pathogenesis of arterial thrombosis differs substantially from venous thrombosis as it typically occurs with endothelial damage. An atherosclerotic plaque is prone to thrombosis when it presents as a lipid-rich core with a thin fibrous cap. A thrombus can form over a ruptured plaque or an intact plaque that has superficial endothelial erosion . PlateleMany chemotherapeutic agents are known to be prothrombotic and there are multiple case reports documenting an association between chemotherapy and arterial thrombosis. Platinum-based agents (cisplatin), vascular endothelial growth factor (VEGF) inhibitors (bevacizumab), and VEGF tyrosine kinase receptor inhibitors (sorafenib/sunitinib/pazopanib) have been associated with increased rates of arterial thrombosis . Other mThrombotic complications observed in cancer are not limited to VTE or arterial thrombosis, with other more severe manifestations of the procoagulant state such as disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) ,22,23. DDIC is often difficult to distinguish from thrombotic microangiopathy (TMA), which manifests as thrombotic purpura and haemolytic uremic syndrome . TMA shaCancer is a well-known and established risk factor for thromboembolic events; however, there are several other risk factors known to increase a cancer patient’s risk of developing thrombosis. In cancer patients, arterial and venous thrombosis are considered clinical manifestations of a multifactorial systemic disease and result from a number of risk factors which can be divided into the individual patient and cancer-associated risks . Such riIn the general population, incidence rates for VTE increase exponentially with age ,31. A laFew studies have looked at the overall effect of sex in a cancer cohort and the risk of developing VTE. Retrospective studies show that females are at greater risk for VTE , while mIn a large retrospective study by Khorana et al. , the ratMultiple studies have identified an association between medical comorbidities and an increased risk of cancer-associated thrombosis. Comorbid conditions such as renal failure, respiratory disease, heart disease, obesity, and acute infection have been found to be associated with an increased risk of developing VTE in cancer patients, with infection identified as one of the most strongly associated risk factors for VTE ,32.Immobility plays a role in predisposing cancer patients to VTE. Mobility in cancer patients is clinically assessed by performance status, and higher rates of VTE were observed in cancer patients with poor performance status ,39. In aA previous episode of VTE is a major risk factor for developing VTE. Cancer patients with a history of VTE have a 6- to 7-fold increased risk of VTE recurrence when compared with cancer patients with no history of VTE ,42.The rates of cancer-associated thrombosis (CAT) can be impacted by a number of cancer-related risk factors including cancer site, stage, histological subtype, and time since diagnosis. It is important to note that comparison of VTE rates amongst different patients in the literature is often difficult due to varying differences in study design, patient populations, methods for data collection, and follow-up periods .The primary site of the cancer is frequently identified as a risk factor for VTE, with cancers of the pancreas, uterus, lung, stomach, and kidney, and primary brain tumours associated with an increased risk of VTE . A recenPatients with advanced-stage cancer appear to be at a greater risk of developing VTE . In a DaHistological subtypes of some types of cancer have been linked to an increased risk of VTE. For example, histological subtypes of lung and ovarian cancer show varying degrees of increased risk for VTE, while other histopathological subtypes of colon and breast cancer are nonpredictive for cancer-associated VTE incidence . StudiesAhlbrecht et al. published results from the Vienna Cancer and Thrombosis study and reported that tumour grade was associated with an increased risk of VTE in a cohort of patients’ variety of solid tumours . PatientThe immediate period following a cancer diagnosis is when the risk of developing VTE is highest . This coThe prothrombotic state of malignancy is often provoked by cancer therapies and treatments, including surgery. Historically, the observed incidence of VTE has been greatest in cancer patients admitted to the hospital, either for surgery or acute medical illness . VTE is Chemotherapy is an important risk factor for VTE amongst cancer patients and may explain its increasing incidence over the past few decades . Cancer The importance of angiogenesis in tumour growth, invasion, and metastasis has led to the use of inhibitors that target blood vessel formation. Bevacizumab is a monoclonal antibody targeting circulating vascular endothelial growth factor (VEGF), which can be released from cancer cells and activates the endothelium. The effect of bevacizumab appears to have a greater impact on increasing the risk of arterial rather than venous thromboembolic events. While it is unclear if this drug increases the risk of VTE , severalCentral venous catheters (CVC) are vital for a number of aspects of cancer therapy, including delivery of intravenous drugs and collecting blood samples ,66. TheiThe molecular mechanisms leading to the predisposition of cancer patients to thromboembolic events are poorly understood. However, several mechanisms that can promote a hypercoagulable state are seen in cancer patients, thereby increasing the risk of thromboembolic events. This section will focus on both direct  and indiTissue factor (TF) is the best characterised tumour-derived procoagulant protein. It is a 47 kDa transmembrane protein that primarily initiates the extrinsic pathway of the coagulation cascade, resulting in thrombin generation which activates platelets and initiates blood clotting . TF is aMP released from cancer cells can serve as direct and indirect contributors to the prothrombotic mechanism in cancer. MP are small (0.1–1 µm diameter) membrane vesicles that are released from apoptotic or activated normal cells, or resting malignant cells. Early studies showed that breast and hepatocarcinoma cell lines showed procoagulant activity both in vivo and in vitro, which was associated with tumour-shed vesicles . More reCancer-associated fibroblasts express podoplanin ,82, a prPAI-1 is a key inhibitor of fibrinolysis which has been shown to be highly expressed in pancreatic cancer cells . IncreasCP is a cysteine protease that was firstly isolated from rabbit malignant tissue and reported to induce direct coagulation activation by directly activating factor X, without a requirement for coagulation factor VII . It was Adenosine diphosphate (ADP) and thrombin are well-known platelet aggregation agonists. Cancer cells are known to secrete ADP which causes platelet activation and aggregation via the P2Y1 and P2Y12 receptors . ThrombiBoth cancer-derived factors and associated mechanisms that can activate or facilitate interactions with host cells can subsequently promote thromboembolic events. The host cells that have main roles in promoting thrombosis in cancer include platelets, leukocytes, and endothelial cells. A summary of indirect mechanisms that can promote thrombosis in cancer is depicted in As described above, TF-positive MP observed in cancer patients are derived from cancer cells. In addition, they can also be released from activated endothelial cells and monocytes in response to cancer. Inflammatory cytokine release from cancer cells can cause activation of endothelial cells and monocytes and stimulate the release of TF-positive MP; however, the relative contribution of tumour cells and host cells to the total amount of TF-positive MP observed in cancer patients is unknown.Tumour cells synthesise and secrete various inflammatory cytokines which are generally thrombogenic, capable of promoting a procoagulant phenotype in host endothelial cells . In addiProangiogenic and growth factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and granulocyte colony stimulating factor (G-CSF) also play a role in regulating the procoagulant phenotype of host cells. VEGF is secreted by various tumour cells and can induce TF expression on macrophages . G-CSF hCancer cells have the capacity to express specific adhesion molecules allowing for attachment to blood vessel walls and interactions with blood cells, as well as the activation of the procoagulant properties of host cells, primarily the endothelial cells, leukocytes, and platelets. The attachment of tumour cells to endothelial cells is significant in localising the initiation of clotting near the blood vessel wall and the subsequent formation of a thrombus. Several adhesion molecules have been described for the adhesion of different types of tumour cells to endothelial cells. For example, under flow conditions, HT-29M colon carcinoma cells used E-selectin to roll and adhere on activated endothelial cells. Vascular cell adhesion molecule-1 was required for the adhesion of A375M cells 29M . These sThe release of neutrophil extracellular traps (NETs) in response to pancreatic-cancer-derived factors has recently been reported in vitro . NETs arSeveral types of cancers are a mucin-producing carcinoma with aberrant expression and altered glycosylation of several mucins ,120. TheTumours provide a highly hypoxic microenvironment ,126, a cDAMPs are released by dying tumour cells or through cell stress pathways that do not necessarily lead to cell death. Their role has just started to become understood in cancer . They reDespite a large body of evidence suggesting that cisplatin-based chemotherapy predisposes patients to thromboembolic events, the mechanism of cisplatin-associated thrombosis is not fully understood. Lechner et al. reported that cisplatin treatment of two human endothelial cell lines resulted in endothelial cell apoptosis, with the progressive release of procoagulant endothelial microparticles that generated thrombin independently of TF . ChemothIn a study observing thrombophilic genes in gastrointestinal cancers, Pihusch and colleagues found an increased presence of the factor V Leiden and prothrombin gene G20210A mutation in those who subsequently developed thromboembolic disease .An early study investigating the haemostatic balance in pancreatic cancer found that the coagulation inhibitors antithrombin III, heparin cofactor II, protein C, free protein S, and thrombomodulin were significantly decreased during the progression of pancreatic cancer after diagnosis .Cancer patients have a significantly higher risk of developing VTE as compared to non-cancer patients. This is due to a combination of cancer-related, treatment-related, and patient-related factors. The pathophysiology of cancer-associated thrombosis is multifactorial and poorly understood. Patients with cancer-associated thrombosis have significantly shorter overall survival than cancer patients without thrombosis. All cancer patients should be periodically assessed for VTE risk. The risks of cancer-associated thrombosis increase with hospitalisation, infection, chemotherapy, blood transfusions, erythropoiesis-stimulating agents, the presence of medical comorbidities, and the presence of central venous catheters. Cancer patients undergoing major abdominal or pelvic surgery should be offered postoperative VTE prophylaxis for up to 4 weeks. Healthcare professionals should educate patients about the signs and symptoms of VTE. A high index of suspicion is required for the early diagnosis of cancer-associated thrombosis, and early initiation of treatment can improve survival.A detailed discussion concerning therapeutic management of cancer-associated thrombosis is beyond the scope of this review. The reader is referred to several exhaustive reviews on this topic, which cover the use and appropriateness of thromboprophylaxis in cancer patients undergoing surgery and in the ambulatory patient setting, as well as clinical strategies for acute and extended treatment (>6 months) and treatment issues within special populations  ,143. LowIn recent years there have been significant advances in our understanding of the molecular mechanisms associated with the increased risk of VTE in cancer, although there remain significant gaps in our knowledge of the causes of and best approaches for thromboprophylaxis in cancer-associated thrombosis. More research in this field should lead to a better understanding of the pathophysiology and optimal therapeutic approaches for the prevention of cancer-related thrombosis.


The main goal and promise of comparative genomics has been to create a comprehensive catalog of genomic information and function across the phenomenal diversity of living systems. A recent study has demonstrated the evolutionary insights possible by generating high-quality whole-genome assemblies from multiple species of a clade. Drosophila). Happily, advances in technologies for DNA sequencing and computational analysis have made it practical to generate new high-quality genome assemblies at an accelerating pace. Excellent genomic resources are now publicly available for hundreds of plant, invertebrate, and vertebrate species, to say nothing of the remarkable databases of microbial diversity.The first whole-genome reference assemblies were available for only the highest priority species  from a major clade for thorough analysis. This leaves investigators who are working on other closely related species to ‘borrow’ information from the selected keystone representative of a given taxonomic group. Fortunately, the continuing reductions in sequencing costs, and the development of new tools that generate more robust assemblies, are progressively removing this barrier. It is increasingly feasible to generate high-quality, highly contiguous whole-genome assemblies not only for individual representatives of clades but also in parallel for multiple species within a group. This increasing granularity of comparative genomic information provides new opportunities for evolutionary analysis. The increased resolution of information facilitates the ability of investigators to estimate the timing of genomic innovations and to measure variation in rates of genomic evolution through time and across lineages. This is not possible on a sparsely annotated phylogenetic tree. These improved assemblies (with fewer gaps) can reveal patterns of evolutionary change that previously could not be discerned. For example, recent efforts have added the dimensions of segmental duplications, structural variants, and even haplotype phasing to the traditional genomic data sets of single, unphased nucleotide differences and small insertion/deletions .Mus caroli and Mus pahari. They chose these two relatives of the well-studied laboratory mouse (Mus musculus) because previous work had shown that M. caroli and M. pahari shared a common ancestor with M. musculus approximately 3 million years ago and 6 million years ago, respectively. Together with the rat (Rattus norvegicus), this constitutes a clade of four rodents with high-quality genome sequences that Thybert et al. explicitly present as a parallel to the hominid clade of humans, chimpanzees, gorillas, and orangutans. Using the newly included murid genomes, Thybert et al. have addressed various questions regarding patterns of genomic change in these two mammalian groups. When all we had available were the human, chimpanzee, and mouse genomes, one could ask questions regarding differences in gene content or genomic organization between representative primates and a representative rodent. But with clades of genomes within each lineage, Thybert and colleagues have compared patterns of evolutionary change at a much higher resolution and have begun addressing the temporal dynamics of specific aspects of genome evolution that have not been previously investigated in these lineages.A valuable and informative example of this trend toward finer-scale phylogenetic resolution has recently been published by Thybert and colleagues . In thisMus. In one case, new LINE elements specific to murid rodents accumulated within the androgen-binding protein gene cluster, apparently contributing to gene copy number increases in murids, particularly M. musculus. This gene family has been associated with behavioral mate choice and the dynamics of a hybrid zone between two mouse subspecies [It has long been known that rodents exhibit a higher rate of large (multi-megabase) chromosomal rearrangements than do primates. New intra-family comparisons show that there have been periods of rapid rearrangement interspersed with periods of much slower change during murid evolution. New assemblies also show that other features of the murid genome evolve more rapidly than they do in primates, including single nucleotide changes , SINE elements, CTCF-binding motifs, and, particularly, LINE elements. The evidence suggests that the expansion of LINE elements led to various changes in genome function in the genus bspecies . New anaMus species, only M. caroli displays a novel CTCF-binding site within the B2 element. Consequently, only M. caroli has increased CTCF-binding site numbers due to SINE element proliferation. Given the potential functional impact of increased CTCF-binding sites, this has considerable implications for understanding the evolution of gene regulation across rodent lineages. Overall, Thybert et al. observed that murid genomes exhibit faster evolution than do primates across multiple domains , but that episodes of accelerated change can occur independently in different murid lineages and that some of these rates fluctuate over evolutionary timescales within a given lineage.Another example of the value of more extensive sampling of genomes within and across clades is the novel finding by Thybert and colleagues that, although the B2 SINE element has increased in number in all three This analysis by Thybert et al. provides a welcome example of the insights to be gained by comparing multiple genomes across several major lineages . A 2014 analysis of 48 bird genomes was another clear illustration of the value of this approach , 6.Several projects are now underway that promise to dramatically increase the number of species for which high-quality genome assemblies are available. Additional assemblies for a wider range of primates are in progress or have recently been published . This isThe continuing advances in genome analysis technology, involving methods for both data generation and computational analysis, are making truly revolutionary sequencing projects feasible. One can foresee a not-too-distant future in which almost gapless high-accuracy whole-genome assemblies are publicly available for tens of thousands of plant, invertebrate, and vertebrate species. Goals that were inconceivable even a few years ago are now under serious discussion . A golde


Pseudorabies  is a viral disease caused by pseudorabies virus (PRV). First isolated in 1902, classical PRV has circulated globally since the 1980s, especially in locations with large pig populations. PRV is extremely infectious and infected pigs shed large quantities of virus in bodily secretions and excretions. PRV is mainly spread via direct contact, but may also transmit by air, water and contaminated fomites. Outbreaks of PRV in pigs are difficult to control, causing catastrophic economic losses in the swine industry. Immunization of pigs with the Bartha-K61 vaccine, a live-attenuated PRV strain . The BarPhylogenetic analysis of publicly available genome sequences for classical and variant PRVs based on whole genome sequences  or 106.1 TCID50 (subcutaneous) of PRV did not result in any symptoms [Whether humans are susceptible to PRV infection has been a subject of controversy. A past serosurvey of 455 volunteers with either suspected PRV infection or high-risk of occupational exposure were shown to be negative for PRV-specific neutralizing antibodies, and self-inoculation with 10symptoms .Conversely, suspected human infections with classical PRV were reported as early as 1914, in which two laboratory technicians exposed to contaminated materials developed weakness, restlessness, sore throat, and itching . All thrRecently, one case of endophthalmitis (an inflammation of the interior of the eye) was reported . A 46-yeAnother Chinese study  investigDespite vaccination efforts, classical PRV is still prevalent in wild feral pigs and variant PRV in many Chinese pigs. High levels of exposure between humans and swine  means that if PRV can infect humans, it is surprising that relatively few cases has been reported thus far. It could be speculated that due to species differences (i.e. immune responses), PRV may be less virulent, or asymptomatic, in most humans as opposed to other animals. Additionally, the likely possibility that current clinical diagnostic protocols for unexplained fevers and encephalitis do not always include the specific detection of PRV would contribute to an underreporting of cases. Advances in detection (i.e. NGS) techniques will help with identifying unknown causative pathogens from the cerebrospinal fluids of patients with meningoencephalitis  and may The evidence so far suggests that PRV infection may be an occupational risk and may cause disease in humans, but live virus has not yet been isolated from patients. Live PRV has not yet been shown to cause disease in humans after infection, and obviously no re-isolation experiments are possible without live PRV from humans. Thus, not all of Koch's Postulates have been fulfilled, and despite circumstantial observations, there is still no conclusive evidence for PRV-induced disease in humans. Interestingly, past studies in experimental PRV infection of rhesus macaques showed inconsistent results . A 1930


Periostin is a matricellular protein that is expressed in bone and joint tissues. To determine the expression of periostin in primary bone tumours and to assess whether it plays a role in tumour progression, we carried out immunohistochemistry and ELISA for periostin in a range of neoplastic and non-neoplastic bone and joint lesions.140 formalin-fixed paraffin-embedded sections of bone tumours and tumour-like lesions were stained by an indirect immunoperoxidase technique with a polyclonal anti-periostin antibody. Periostin expression was also assessed in rheumatoid arthritis (RA) and non-inflammatory osteoarthritis (OA) synovium and synovial fluid immunohistochemistry and ELISA respectively.Periostin was most strongly expressed in osteoid/woven bone of neoplastic and non-neoplastic bone-forming lesions, including osteoblastoma, osteosarcoma, fibrous dysplasia, osteofibrous dysplasia, fracture callus and myositis ossificans, and mineralised chondroid matrix/woven bone in chondroblastoma and clear cell chondrosarcoma. Reactive host bone at the edge of growing tumours, particularly in areas of increased vascularity and fibrosis, also stained strongly for periostin. Vascular elements in RA synovium strongly expressed periostin, and synovial fluid levels of periostin were higher in RA than OA.In keeping with its known role in modulating the synthesis of collagen and other extracellular matrix proteins in bone, strong periostin expression was noted in benign and malignant lesions forming an osteoid or osteoid-like matrix. Periostin was also noted in other bone tumours and was found in areas of reactive bone and increased vascularity at the edge of growing tumours, consistent with its involvement in tissue remodelling and angiogenesis associated with tumour progression. Periostin, a secreted extracellular matrix protein that belongs to the fasciclin family, was originally characterised in osteoblasts and first termed osteoblast-specific factor 2 , 2. PeriPeriostin is expressed at sites of injury/repair and inflammation , 6, 7. IIn this study we investigated immunophenotypic expression of periostin in a wide range of primary tumours and tumour-like lesions of bone as well as in bone secondaries and metastatic osteosarcomas. Our aims were two-fold: first, to determine whether periostin expression is increased in specific bone tumour types; and second, to examine whether periostin plays a role in tumour progression.Tissue samples from 140 biopsies or surgical resections of bone tumours and tumour-like lesions, were retrieved from the files of the Nuffield Orthopaedic Centre, Histopathology Department, Oxford  using a polyclonal rabbit antiserum against human periostin raised by using peptide DNLDSDIRRGLESNVN (representing aminoacids 143–158 of human periostin) as an immunogen , 17. As A quantitative measure of the level of periostin in knee joint RA and OA synovial fluid was determined by ELISA (enzyme-linked immunosorbent assay). The periostin concentration was assessed using a Human periostin/OSF-2 ELISA kit . Statistical evaluation was performed using the Mann–Whitney U test with p values less than 0.05 considered as statistically significant.In normal bone there was strong expression of periostin in collagenous fibrous tissue of the periosteum. At points of tendon or ligament insertion into bone, strong periostin staining was also seen within collagenous tissue. There was no staining for periostin in normal lamellar cortical and cancellous bone, and osteocytes, bone lining cells, osteoblasts and osteoclasts did not express periostin. Fatty and hematopoietic marrow was generally negative for periostin but, in some specimens, staining for periostin was noted in small sinusoidal vascular channels within the marrow. In normal joints, the synovium and hyaline articular cartilage did not stain for periostin.Strong staining for periostin was seen in the osteoid matrix formed by osteoblastic cells in neoplastic and non-neoplastic bone-forming lesions. Periostin staining was noted in the osteoid matrix covering organized reactive bone in fracture callus and myositis ossificans. In osteoblastoma, newly formed osteoid stained strongly for periostin Fig. a; stainiThere was no specific staining of the chondroid matrix or cartilage cells for periostin in enchondroma, osteochondroma, or low/high-grade conventional chondrosarcoma. The dense fibrous perichondrium covering osteochondromas (which is continuous with the periosteum) stained strongly for periostin Fig. a. At theIn aneurysmal bone cyst (ABC) and simple bone cyst, the fibrous stroma and reactive bone within the cyst wall was positive for periostin Fig. a. In giaStaining for periostin was noted in non-neoplastic bone at the edge of growing benign and malignant primary bone tumours Fig. a; this wImmunohistochemistry showed no staining for periostin of synovial lining cells in OA or RA synovium. Strong staining for periostin was noted in RA in the superficial subintima where there was staining of the fibrous tissue matrix and the smooth muscle wall of small blood vessels in areas of increased vascularity Fig. a; in conIn this study, we have characterised periostin expression in neoplastic and non-neoplastic lesions of bone and joint. In keeping with its role in bone matrix formation, periostin was found to be strongly expressed in osteoid/bone-forming lesions; it was also noted in the mineralised chondroid/osteoid matrix of chondroblastomas and clear cell chondrosarcomas and in the connective tissue matrix of other primary bone tumours. Periostin expression was also prominent in areas of reactive host bone around infiltrating primary and secondary bone tumours, suggesting a role for this matricellular protein in tumour progression.Periostin is a 90-kDa secreted protein which binds to type I collagen and other ECM proteins including fibronectin, Notch1, tenascin-C and BMP-1 –6, 18–20Periostin was originally called osteoblast specific factor-2 and in this study we have shown that periostin is highly expressed in reparative lesions associated with osteoid/woven bone formation, such as fracture callus and myositis ossificans as well as in benign and malignant bone-forming tumours. Expression of periostin in osteosarcoma has previously been reported with high expression being correlated with tumour angiogenesis and poor prognosis , 15. We Periostin was strongly expressed in the perichondrium covering osteochondromas and in areas of endochondral ossification at the base of growing osteochondromas but there was no staining in cells or matrix of the cartilage cap. Periostin expression was absent in other cartilage tumours including enchondroma and low/high-grade conventional chondrosarcoma. Our findings contrast with those of Lai and Chen , who ideWe consistently noted increased expression of periostin in non-lesional bone at the edge of growing benign and malignant bone tumours. It has been shown that periostin plays a role in the progression of inflammatory and neoplastic lesions , 12, 23.There were similarities in the pattern of periostin expression in inflamed RA synovium and growing bone tumours. Periostin is known to be involved in the migration of synovial fibroblasts associated with RA pannus formation and joint destruction , 10. We In keeping with its known role in modulating the synthesis of collagen and other extracellular matrix proteins in bone, strong periostin expression was noted in benign and malignant lesions forming an osteoid or osteoid-like matrix. Periostin was also noted in other bone tumours and was found in areas of reactive bone and increased vascularity at the edge of growing tumours, consistent with its involvement in tissue remodelling and angiogenesis associated with tumour progression.


Nowadays, bone diseases and defects as a result of trauma, cancers, infections and degenerative and inflammatory conditions are increasing. Consequently, bone repair and replacement have been developed with improvement of orthopedic technologies and biomaterials of superior properties. This review paper is intended to sum up and discuss the most relevant studies performed in the field of bone biology and bone regeneration approaches. Therefore, the bone tissue regeneration was investigated by synthetic substitutes, scaffolds incorporating active molecules, nanomedicine, cell-based products, biomimetic fibrous and nonfibrous substitutes, biomaterial-based three-dimensional (3D) cell-printing substitutes, bioactive porous polymer/inorganic composites, magnetic field and nano-scaffolds with stem cells and bone–biomaterials interface studies. Bone presents numerous performs including principal backing structure designed formation, the binding place for muscles, ligaments and tendons, mechanical support and shield of most important tissues  cell-printing substitutes, bioactive porous polymer/inorganic composite and magnetic field and nano-scaffolds with stem cells, bone biomaterial interface studies. The interactions between bone cells and biomaterials, as they play a crucial role in bone repair.Bone is not homogeneously solid, but it is arranged of living bone cells set in a biomineral medium. Actually, bone is designed by the toughening of this medium nearby entangled cells. Bone itself involves chiefly of collagen fibers and an inorganic bone mineral in the form of small crystals 6(OH)2 3− , synthetic functions (synthesis of blood cells) and metabolic functions . The four most important cells including: osteogenic, osteoblasts, osteocytes, and osteoclasts (together recognized as the basic multicellular unit (BMU)) contained in bone regeneration and structure are shown in Fig. Osteoblasts are derived from osteoprogenitor cells of mesenchymal origin in bone marrow and other connective tissues. They are differentiated and proliferated to osteoblasts before bone formation, stimulated through bone morphogenetic proteins (BMPs). These cells are responsible for growing or remodeling of bone  films were used to repair 1-cm trauma in the radius bone of mature rabbits, and histologic results indicated that the cortical bone was redeveloped over the defect  ceramic and its composites (with HA) showed good in vitro bioactivity, biocompatibility, and antibacterial properties for bone tissue engineering application  was produced with osteoconductive and osteoinductive properties  application of recombinant growth factors and a combination of growth factors associated with a natural medium or calcium phosphate substantial carrier, (b) application of proteins to target cellular receptors, and (c) application of small molecules that target the signaling pathway  synthetic polypeptide applied to augment spinal fusion  scaffolds have emerged as polymeric promising biomaterials with excellent potential for bone tissue engineering applications because of their good biodegradability, biocompatibility and vascularization, and unique physiochemical properties. They induced cell adhesion and growth on their porous structure for bone regeneration  may attack intracellular sites contained by osteoblasts, result in complications in microbial eradication and amplified vulnerability to osteomyelitis subsequent contamination  and nano-sized carriers for antibiotic delivery have been confirmed to be applicable in curing infectious diseases, containing antibiotic-resistant ones, in vitro and in vivo. For instance, several NPs are able to join to the membrane of microorganisms by electrostatic interface and destruct the unity of the microorganism membrane  NPs. Their extensive antibacterial performance is proved. They are extensively applied to remove various bacteria containing Staphylococcus epidermidis, methicillin-resistant S. epidermidis (MRSE), and methicillin-resistant S. aureus (MRSA), while PMMA bone cement contained 2% of gentamicin sulfate avoided only the propagation of S. epidermidis -based bone cement, consisting of Ag NPs (about 50 nm), completely prevented the propagation of 2 and molar ratio of P to Ca = 1/5) fabricated by the foam replica technique. The results indicated that this scaffold has antibacterial activity  NPs were employed to coat a bioactive glass-based structure  transplanted onto fibronectin-coated polylactic acid scaffold  stromal cells can operate as a healing substitute for focal cartilage damages and have capability to differentiate to osteogenesis. Stimulatingly in a current research, SMSCs from knee joints presented greater osteogenic and adipogenic potential than SMSCs of hip joints  scaffold confirmed effective ECM mineralization of osteoblast  have lately being discovered for bone tissue engineering. DPSCs present the low percentages of morbidity, widespread differentiation capacity into chondrogenic, and osteogenic cell lines, and expression of bone markers in vitro and in vivo /HA scaffold showed substantial in vivo bone construction in immunodeficient mice through subcutaneously seeding  are obtained from human blastocysts. Effective differentiation of hESCs into the osteogenic lineage has been confirmed in frequent reports mutually in vitro and in vivo. Actually, following osteogenic stimulation, hESCs demonstrated to retain molecular and fundamental characteristics similar to bone cells by means of the creation of mineralized bone in vitro. Osteogenic cells derived from ESCs seeded on poly(Induced pluripotent stem cells (iPSCs) have been originated from adult somatic cells such as skin fibroblast  technique were fabricated. The high surface area of the nanofibrous permits further the HA to be exposed, which is appropriate for bone tissue regeneration . For the duration of the precipitation reaction, the Ca/P proportion was reserved to 1.67 to guarantee stoichiometric apatite fabrication. Just the lowest concentration of gelatin-apatite leads to a growth in normal strength  scans, using a calculating software, to fabricate a bone graft substitutes (BGS) structure that matches to a bony defect (Burleson and DiPaola -derived stem cell (hAFSC)-laden hydrogel, a mixture of PCL and tricalcium phosphate (TCP), and pluronic F127  copolymers  and poly glycolic acid (PGA), as well as polylactic-PPF (polypropylene fumarate) has been used as an injectable bone substitute scaffold for conducted tissue regeneration. It was similarly utilized as a substrate for osteoblast cultures. The growth of composite substrates adjoining polypropylene fumarate and mineral elements, such as HA or bioglasses, in contrast with the broad investigation works devoted to PLGA and PLA composites , biocompatible and thermoprocessable  and magnetic fields to improve bone repair efficiency containing osteogenic improvements by means of magnetic fields, MNPs and magnetic approaches to develop the cells, scaffolds and growth factor conveyances including cell tagging, targeting, designing, and gene modifications  due to electrodynamic interactions and magneto mechanical interactions -doped HA (FeHA) nanoparticles in cultures with osteoblast-like cells in the absence, or presence, of an SMF were investigated. Application of external magnetic field to FeHA lead to a substantial cell growth, proliferation and more osteoblastic activity as a result of the tremendous biological impacts of HA and the partial iron content. Consequently, the variations in the biological characteristic and endocytosis of the cells, created by the MNPs using external magnetic field, may pointedly improve the cell performance and bone renewal abilities  scaffolds was fabricated using a 3D printing method. The results indicate that cell growth on the Fe3O4/MBG/PCL scaffolds was greater than non-magnetized control sample (Zhang et al. In another study, nanofibrous γ-FeFor the effective integration of implants or scaffolds for tissue regeneration, cell adhesion to biomaterials is a vital necessity. Adjusting cells–scaffolds communications seems of most important to affect succeeding cell biological progressions for instance attachment, proliferation and differentiation Tormos . Numerou2 and CH3 groups to assess the consequence of surface chemistry and hydrophilicity on protein adsorption and cell performance such as the attachment strength of MC3T3-E1 preosteoblasts and the medium mineralization. The results show mineralization by cells on OH and NH2 surfaces is associated with improved alpha 5 beta 1 integrin adhesion and FAK stimulation (Keselowsky et al. The cell activities are regulated by biodegradable polymers with properties such as chemical structure, polymer ratio of PLA or PGA for example, molecular weight and crystallinity. Polymer degradation products for instance catalysts, additives, byproducts and residual monomers that led to an inflammatory reaction and influence the cell attachment, cell survival and proliferation (Puppi et al. This review investigated the bone physiology, different strategies for bone repair and interface studies. The published results provide insightful information for development of new biomaterial-based products. However, there is a vital necessity to investigate the results of all clinical trials. There are several bone repair strategies including bone graft replacements, implantable materials and scaffolds, optimized 3D structure and favored surface properties. Bioactive constituents are necessitated while the bone defects become larger. For this goal, signaling factors, polypeptides and small biomolecules are presently being assessed at the pre-clinical phase. The incorporation of bioactive molecules with novel carriers may result in a developed conveyance of the active molecules at a reliable and useful amount. Besides, cell-based approaches can be utilized for big and complicated bone defects. The efficient clinical treatment demands more controlling phases for future developments.


Although carcinoid syndrome is regarded as a rare entity, carcinoid patients with evidence of cardiac involvement show a markedly reduced survival time. Patients with advanced signs of right-sided heart failure represent a subgroup at particularly high risk. Echocardiography remains the gold standard to diagnose or confirm structural cardiac involvement in patients with underlying carcinoid disease. This is the notion that propelled us to report on cases of carcinoid syndrome with cardiac involvement. We also review carcinoid syndrome and carcinoid heart disease, and challenges regarding the diagnosis and management of carcinoid heart disease. Carcinoid heart disease (CHD) has previously been reported as a rare form of valvular heart disease, mostly associated with metastatic carcinoid tumour. Most systemic manifestations of carcinoid tumours are related to the release of vasoactive substances from the tumour, including serotonin and other circulating humoral substances. Although CHD is presumed to be rare, we use this opportunity to report on a collection of interesting patients with CHD, who presented differently and posed challenges in their short- and long-term management.Seven patients with carcinoid and cardiac involvement are summarised in Patient 1: The first patient was a 78-year-old African male who first presented to his local hospital with constitutional symptoms and abdominal distension, which progressed over a four-month period. He was later referred to us for further management. This was his first-ever consultation and admission to any medical facility. There was no past surgical or medical history of note and no history of illicit drug use. However he was an occasional drinker and a smoker with a three-pack year history. He had no family history of note.Physical examination revealed skin hyperpigmentation, lower abdominal mass and features of severe tricuspid regurgitation with right heart failure. The rest of his clinical examination was unremarkable. Carcinoid syndrome with CHD was suspected during routine transthoracic echocardiographic assessment, and his images are shown in His biochemical laboratory results revealed a markedly elevated serum 5-hydroxyindoleacetic acid (HIAA), which was more than 10 times the upper limit of normal. An octreotide scan was positive for the primary lesion localised around the periprostatic area. Additional blood results revealed normal renal and hepatic function. His full blood count revealed features in keeping with anaemia of chronic diseases. The prostate-specific antigen level was mildly elevated. Chest radiography revealed a mildly increased cardiothoracic ratio and hyperinflated lungs. Unfortunately, the patient refused further hospital management, including surgery, and died a year later.Patient 2: The second patient was a 32-year-old male of Indian descent who presented with a two-month history of abdominal pain, weight loss and diarrhoea. He had no significant past medical, surgical, family or occupational history. Patient 2: The second patient was a 32-year-old male of Indian descent who presented with a two-month history of abdominal pain, weight loss and diarrhoea. He had no significant past medical, surgical, family or occupational history.His clinical examination revealed features of right heart failure with severe tricuspid and moderate pulmonary valve regurgitation. The rest of his examination was unremarkable. Chest radiography revealed a mildly increased cardiothoracic ratio and an electrocardiogram revealed sinus rhythm. Blood results revealed mild pre-renal dysfunction, anaemia of chronic disease, normal liver function test and normal comprehensive metabolic panel. Further biochemical results revealed an elevated 5-HIAA level and prior to referral, his private practitioner had already commenced medical therapy, which included octreotide.Two weeks later the patient was referred for a specialist’s opinion and further management. His echocardiographic and computed tomographic images are presented in Prevalence of carcinoid syndrome and CHDReports have indicated that at least 50% of patients with clinical manifestations of carcinoid syndrome present with echocardiographic evidence of cardiac or cardiovascular involvement.Previous reports have indicated that the incidence of carcinoid tumours occurs at a rate of 1.2 to 2.1 in 100 000 of the general population.9Although it is usually believed that carcinoid tumours that have hepatic involvement are highly associated with pathological cardiovascular damage, particularly right-sided cardiac involvement related to the large amount of metabolic products reaching the heart, a small proportion of patients, around five to 10%, present with significant left-sided disease due to direct blood flow from the right to the left side of the heart, or in some cases related to the presence of a primary lung tumour. In addition, cardiac manifestations of carcinoid syndrome could also be related to the paraneoplastic effects of vasoactive substances released by malignant cells rather than any direct metastatic involvement of the heart. Most importantly, patients with progressive cardiac disease tend to have higher levels of these vasoactive substances compared to those without cardiac disease.Cardiac and cardiovascular structural changes in CHDTypical pathological features of CHD are plaque-like deposits of fibrous tissue deposited on the endocardium of the valvular cusps and leaflets, atria and ventricles, sometimes involving the downstream aspects of the tricuspid and pulmonary valves, endocardium of the cardiac chambers, intima of the vanae cavae, pulmonary artery and coronary sinus , 2.Although the fibrous tissue may result in distortion of the valves, the morphology of the valve leaflets is classically not disrupted. However, the endocardial thickening may lead to valve retraction and fixation , 2.The tricuspid valve is most commonly involved, with typical tricuspid valvular regurgitation and rarely stenosis. The pulmonary valve is the second most commonly affected, presenting as mixed pulmonary valve disease. Pulmonary stenosis is more frequently noted, compared with tricuspid stenosis, due to the smaller orifice of the pulmonary valve and also due to plaque deposition on the pulmonary valve, within the pulmonary annulus and sinuses, results in narrowing of the pulmonary roof.In rare situations, primary ovarian carcinoid disease may lead to CHD without evidence of hepatic metastases because the ovarian vein drainage bypasses the portal circulation. This pathognomic mechanism was previously reported in four patients from the Mayo Clinic.11The Mayo Clinic previously reported 132 carcinoid syndrome patients, where a total of 74 (56%) patients had echocardiographic evidence suggestive of CHD. A total of 62 (90%) of the 74 patients had moderate to severe tricuspid valve regurgitation and 36 (49%) developed thickened, retracted, immobile pulmonary leaflets.Natural history and controversies of CHDCardiac involvement in carcinoid syndrome heralds a decline in clinical outcome with poor survival rate without treatment. The previous three-year mortality rate data on CHD patients had indicated only a 31% survival rate, compared with approximately twice the survival rate for patients without cardiac involvement.4Previously, a small study evaluated and reported on a total of 71 patients with carcinoid syndrome, who had serial echocardiograms performed a year apart, and retrospectively assessed factors that were associated with progression of cardiac disease.9In addition, Denney et al.16Diagnosis of CHDClinical presentations: usually a high index of clinical suspicion is needed to diagnose CHD. The time interval from the onset of carcinoid symptoms to the diagnosis of CHD is usually approximately two years, however it may take as long as five years.5The physical examination will usually reveal features of regurgitant lesions and most commonly a pansystolic murmur of tricuspid regurgitation along the left sternal border. In some cases, there may be a concomitant murmur of pulmonary stenosis or regurgitation or both. A careful interpretation of the jugular venous pressure is crucial when assessing patients with suspected CHD. The classical large V wave may be the first finding on physical examination, suggestive of significant tricuspid regurgitation.Biochemical screening: clinical suspicion of carcinoid syndrome or CHD usually leads to further evaluation, including biochemical screening, with the measurement of urinary 5-HIAA excretion. The biochemical measurement of 24-hour urinary 5-HIAA excretion has shown a sensitivity and specificity of 75 and 100%, respectively, for the diagnosis of carcinoid syndrome.Chest radiography: a chest radiograph and electrocardiogram have limited value in diagnosing CHD. A chest X-ray is usually normal in at least 50% of patients and in the remainder it may be non-specific. Other radiographic features in carcinoid patients with CHD include cardiac enlargement and pleural effusions or nodules.Electrocardiography:Transthoracic echocardiography 2D-TTE): this remains the gold standard during the initial diagnostic evaluation of any patients suspected of CHD. Classical 2D-TTE findings will include thickened and shortened tricuspid valve (TV) leaflets. Similar to our two cases, the TV leaflets may become severely retracted, with reduced leaflet mobility. In most instances, the septal and anterior TV leaflets are predominantly affected , 2. In aD-TTE: thSimilar to the tricuspid valve, pulmonary valvular cusps usually appear thickened, with retraction and reduced leaflet mobility, and it may be difficult to visualise them during routine echocardiographic evaluation. Doppler echocardiographic assessment of the pulmonary valve may be helpful as there are challenges related to difficulties in demonstrating anatomical changes. The right atrium and ventricle may become increasingly dilated over time , 2. A daManagement strategies for CHDThe principal management strategies in CHD patients should strictly focus on primary treatment of right heart failure, therapy to reduce secretion of tumour product, and valve surgery.Medical management: medical treatment modalities for right heart failure in patients with CHD include standard heart-failure therapy. However these strategic approaches have not been proven effective in most patients with CHD.Somatostatin analogue, particularly octreotide, has a direct effect on reducing the vasoactive peptides and has demonstrated direct clinical benefit and biochemical improvement. Alternatively, lanreotide, which has the advantage of less frequent administration compared with octreotide, may be a good option. Reports have indicated that somatostatin analogue has demonstrated symptomatic relief and a decrease in measurable urinary 5-HIAA excretion and serum serotonin concentration.10Newer treatment options include the leukocyte interferonalpha, which may be used in conjunction with somatostatin antagonist. However data on this treatment option are limited.Cardiac surgery: asymptomatic patients or those who exhibit minimal symptoms usually need closer follow up with regular transthoracic echocardiography and exercise testing to assess their functional status. Patients who develop severe cardiovascular symptoms related to CHD should be evaluated for valve-replacement surgery. For suitable candidates, valve surgery is the only definitive curative treatment modality for severe heart failure. Although reports have implicated balloon valvoplasty as an alternative and it has produced symptomatic improvement in some patients with stenotic valve lesions related to CHD, data on its application in CHD patients are limited.17Indications for surgery: right heart-failure symptoms, severely impaired exercise capacity, progressive right ventricular enlargement or decline in right ventricular systolic function are some of the indications for surgical intervention in CHD patients. However, some patients with severe CHD may require cardiac valve surgery despite minimal cardiac symptoms.Although tricuspid mechanical valve prostheses may be considered adequately durable and relatively unaffected by vasoactive substances, bioprosthetic valves may be preferable since anticoagulants can be avoided.Pulmonary valvectomy or valve replacement is preferred for those with pulmonary valve disease secondary to carcinoid disease. Although pulmonary valve replacement may reduce the risk of right heart dilatation postoperatively, larger studies with more convincing results are warranted.Successful surgical intervention has been associated with an improvement in survival rate and quality of life in those patients who were successfully treated surgically. Despite this premise, older patients (over the age of 60 years) remain a high surgical risk group, with an associated high death rate, which is even higher in those with significant co-morbidities.Peri-operative management: the surgical approach for CHD patients requires a highly skilled multidisciplinary team with broad experience, as anaesthesia can trigger carcinoid crisis and subsequent death in patients going for surgery.Prognosis of CHDPrevious studies have reported outcome differences between carcinoid syndrome patients with versus those without CHD, and demonstrated markedly shortened life expectancy in patients with underlying cardiac involvement.9Levels of 5-HIAA should be closely monitored, as this is an independent predictor for the development or progression of CHD while on or even after medical management. Although, it was believed that optimal control of serotonin release may prevent or delay development of early cardiac lesions, reports have indicated that somatostatin analogues, chemotherapy and hepatic de-arterialisation may not sufficiently counteract the pathophysiological mechanisms involved in the causation and progression of valvular heart lesions.9Surgical valve replacement reduces heart-failure symptoms and is associated with improvement in a patient’s functional state. However, a significantly high 30-day mortality rate, which is attributed to bleeding complications, intractable heart failure and other concomitant co-morbidities, has been a major drawback. According to the Duke carcinoid database, supported by other databases, older age, particularly over 60 years of age, is an important independent risk factor for high peri-operative complications and is also associated with high mortality rates.59At least half of the patients with carcinoid syndrome present with structural heart disease, usually evidenced during routine transthoracic echocardiographic examination. Although carcinoid heart disease is undoubtedly regarded as a rare form of structural heart disease, a strong suspicion should be raised in patients with classical or florid carcinoid syndrome. Although echocardiography remains the gold standard for diagnostic and confirmatory purposes, biochemical screening and imaging for primary carcinoid tumour should form an integral part of the diagnostic algorithm.Valve replacement is associated with significant improvement in heart-failure symptoms and improves patients’ functional capacity. However, stringent peri-operative management is vital to avoid carcinoid crisis and impending death. Although there are no definite stringent criteria for the choice of an artificial valve, mechanical valve prostheses are considered durable as they are not affected by vasoactive substances. However bioprosthetic valves should be preferred to avoid long-term anticoagulation. Early detection and valve surgery should be considered to avoid the development of right heart failure, as advanced heart failure represents a high-risk subgroup. In patients with advanced heart failure and possible advanced myocardial dysfunction, transplantation could be an option.


Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target. Cardiac hypertrophy and remodeling occur to compensate for internal or external stress before the onset of heart failure. Although this change is initially an adaptive response to maintain cardiac function, sustained hypertrophic stimulation becomes maladaptive, and eventually develops into heart failure . CardiomIt is traditionally believed that the progression of pathological cardiac hypertrophy is irreversible; once it develops into severe heart failure, there are no other effective treatments besides heart transplantation . It has Cyclophilin A (CyPA) is a highly conserved and ubiquitous protein that was first discovered as a receptor for cyclosporin A (CsA) in cells . InitialCyclophilins (CyPs) belong to a group of a protein family that has peptidyl-prolyl cis–trans isomerase (PPIase) activity and is widely distributed in eukaryotes and prokaryotes . CyPA waCyPA has several functions including PPIase activity, protein folding, protein assembly and protein trafficking in cells  and apoptosis-inducing factor (AIF)) , and inv−/− (knockout) mice and in wild-type (WT) mice, Bsg−/− mice showed reduced oxidative stress and MMPs activity in the left ventricle, less cardiac hypertrophy and cardiac interstitial fibrosis, as well as significantly improved long-term survival. Angiotensin II (AngII) or mechanical stretch induced cardiac fibroblasts express EMMPRIN. Up-regulation of EMMPRIN stimulated proliferation of cardiac fibroblasts by activating Akt and mitogen-activated protein kinases (MAPK) signaling pathways [Yurchenko et al. first identified extracellular matrix metalloproteinase inducer , which is encoded by basigin (Bsg), as a receptor for extracellular CyPA . CyPA-inpathways . These dPathological cardiac hypertrophy is often secondary to a variety of heart diseases, including hypertension, valvular heart disease, cardiomyopathy, and myocardial infarction. It is generally believed that the excessive production of ROS is an important mechanism for cardiac hypertrophy and remodeling . ROS areIn vitro and in vivo experiments have confirmed that CyPA can cause cardiac hypertrophy, and ventricular remodeling, and promote pathological cardiac hypertrophy [CyPA is a pathogenic protein that mediates oxidative stress-induced cardiovascular dysfunction, such as atherosclerosis , aortic ertrophy . The mai−/− (CyPA knockout) and WT mice; however, there were no significant differences in the degree of cardiac hypertrophy between Ppia−/- and WT mice [−/−) mice have been shown to exhibit increased ROS production; moreover, CyPA is highly expressed in atherosclerotic plaques of ApoE−/- mice, which has a pro-inflammatory effect on endothelial cells, leading to plaque progression [−/− mice and ApoE−/−Ppia−/− mice with Ang II infusion, four weeks later they found that the cardiac weight, interventricular septum thickness, and cardiac myocyte size of ApoE−/−Ppia−/− mice were significantly improved compared with ApoE−/− mice. In addition, the cells that proliferate and migrate to the perivascular area are significantly reduced in ApoE−/−Ppia−/− mice, as well as collagen content and fibrosis in the perivascular area. The production of ROS in the hearts and blood vessels of ApoE−/−Ppia−/− mice was significantly reduced [−/− mice. Nigro et al. confirmed that CyPA is involved in the development of atherosclerosis by promoting oxidative stress and inflammation. Researchers simultaneously fed ApoE−/− mice and ApoE−/−Ppia−/− mice a high-fat diet. After 16 weeks, they found that the ApoE−/−Ppia−/− mice developed significantly reduced atherosclerosis compared with ApoE−/− mice, and CyPA deficiency was associated with decreased vascular cell adhesion molecule 1 (VCAM-1) expression, ROS, inflammation, ECs activation and apoptosis [Studies have shown that the concentration of CyPA and oxidative stress in plasma of patients with heart failure caused by various factors is significantly increased ,55,56, s WT mice . Satoh hgression . When re reduced . These dpoptosis . In a mopoptosis . These fThe recruitment and transportation of leukocytes are important aspects of the inflammatory process . AlthougIn vitro cell experiments have shown that culture medium prepared from AngII-stimulated cardiac fibroblasts, which were isolated from ApoE−/− mice, were used to culture cardiomyocytes, and resulted in an increased myocardial hypertrophy index, such as cardiomyocyte protein synthesis and embryonic gene expression. Further experiments confirmed that cardiac fibroblasts isolated from ApoE−/− mice secreted a large amount of CyPA in response to Ang II, stimulated the proliferation and migration of cardiac fibroblasts by enhancing ROS production, and the migration increased in a concentration-dependent manner. Researchers also tried to study whether cardiomyocytes secrete CyPA under the stimulation of Ang II. However, the required serum-free medium caused a large number of cardiomyocytes to die. Direct stimulation of cardiomyocytes with recombinant CyPA can lead to cardiomyocyte hypertrophy [ertrophy . The obsertrophy ; Su et aertrophy . This suertrophy , suggestROS is essential for acetylation of CyPA and its secretion , while aIn addition to cardiomyocytes and cardiac fibroblasts, mammalian myocardial tissues also include ECs and VSMCs . ActivatEC dysfunction is a key event in the development and progression of vascular disease . Jin et Abnormal VSMC growth contributes to the pathogenesis of blood vessels . CyPA waCardiac fibroblasts are the main source of the ECM. Activated cardiac fibroblasts secrete a large amount of ECM, which promotes collagen accumulation in the myocardial interstitium , changes the passive stiffness properties of the myocardium, and affects ventricular compliance . There aThe expression of CyPA and EMMPRIN in plasma of patients with acute myocardial infarction (AMI) increases. The change in CyPA concentration affects ventricular remodeling and cardiac function after AMI, which may be related to CyPA-mediated MMP-2 and MMP-9 activation ,86. In a−/- mice, while MMP-2 expression was not significantly different between the two groups [Based on the up-regulation of CyPA and EMMPRIN in myocardial tissue of patients with inflammatory cardiomyopathy , Seizer o groups . A studyo groups . MMP-9 iIn VSMCs, CyPA binds to EMMPRIN to promote MMP-2 expression and mediate migration and proliferation of VSMCs . The expClinical studies have found that CyPA is significantly elevated in the plasma of patients with ventricular remodeling and heart failure caused by various diseases such as hypertension, AMI, and myocarditis ,55,56. A2+-calmodulin (CaM)-calcineurin (CN)-nuclear factor of activated T cell (NFAT) signaling pathway plays a crucial role in the development of cardiac hypertrophy [Early studies have shown that the Caertrophy . CsA, whertrophy . The useertrophy , but simertrophy , suggestertrophy . NIM811,ertrophy , and mayStatins such as simvastatin can inhibit oxidative stress-induced CyPA secretion in a dose-dependent manner in VSMCs likely via decreased isoprenylation of small GTPases . StatinsThe renin–angiotensin–aldosterone system (RAAS) plays an important role in the progression of left ventricular remodeling and heart failure after myocardial infarction. A large amount of clinical evidence indicates drugs that inhibit RAAS, such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), can slow left ventricular remodeling and improve the prognosis of patients with heart failure . StudiesThis article describes the main mechanisms by which CyPA promotes cardiac hypertrophy and remodeling, including the promotion of oxidative stress and inflammation and the role of CyPA in the main cells  in myocardial tissue, and summarizes the effects of several drugs for the treatment of heart failure on CyPA. We suggest that CyPA and its receptor EMMPRIN can be used as new therapeutic targets for preventing and improving pathological cardiac hypertrophy. However, specific signaling pathways by which the CyPA/EMMPRIN axis regulates oxidative stress and inflammation, thereby inducing cardiac hypertrophy and remodeling, are not yet known. In pathological cardiac hypertrophy caused by various factors, CyPA may activate different types of MMPs to mediate myocardial fibrosis and remodeling. At present, most of the viewpoints suggest that CyPA plays a role of promoting inflammation and oxidative stress in the development of pathological cardiac hypertrophy, but the pro-angiogenic effect of low concentration of CyPA in ECs suggests that it may have an advantage in promoting the regression of pathological cardiac hypertrophy. Further basic science and clinical trials are required to elucidate the specific mechanisms by which CyPA/EMMPRIN promotes pathological cardiac hypertrophy under different pathophysiological conditions, which will be of great significance for the development of new treatments that prevent or reverse cardiac remodeling.


JAK2, CALR, or MPL genes and characterized by myeloid proliferation and increased blood cell counts. They encompass three closely related conditions, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Elevated levels of cytokines released by clonal and non-clonal cells generate a chronic proinflammatory state that contributes to disease pathogenesis. Thrombosis represents the most common cause of morbidity and mortality in MPN, although paradoxically, patients may also present with a bleeding diathesis. The mechanisms leading to thrombosis are complex and multiple and include increased blood cells together with qualitative abnormalities of red cells, leukocytes, and platelets that favor a prothrombotic activated phenotype. The functional interplay between blood cells, the clotting cascade, and dysfunctional endothelium contributes to hypercoagulability and this process is perpetuated by the effect of inflammatory cytokines. In addition to their well-known function in hemostasis, platelets contribute to innate immunity and inflammation and play a key role in MPN thromboinflammatory state. In vivo platelet activation leads to platelet aggregate formation and exposure of adhesion molecules which favor their interaction with activated neutrophils and monocytes leading to circulating platelet-leukocyte heterotypic aggregates. Platelets are recruited to the activated endothelium further enhancing the reciprocal activation of both cell types. Crosstalk between activated cells drives cytokine production, further fuelling the self-reinforcing thromboinflammatory loop. In addition, MPN platelets provide a procoagulant scaffold which triggers the coagulation cascade and platelet-derived microparticles amplify this response. Markers of platelet, leukocyte, endothelial and coagulation activation are increased in MPN patients although prospective studies are required to determine the potential value of these parameters for identifying patients at increased thrombotic risk. Thrombosis remains the main complication of MPN patients, with a high risk of recurrence despite adequate cytoreductive and antithrombotic treatment. Deeper insight into the mechanism favoring thrombosis development in this setting may lead to novel therapeutic approaches for MPN thrombosis. Considering the critical role of inflammation in the vascular risk, concomitant targeting of inflammatory pathways could potentially impact on primary or secondary prevention strategies.Chronic myeloproliferative neoplasms (MPN) are stem cell disorders driven by mutations in  JAK2, CALR, and MPL. The JAK2V617F mutation is the most frequent molecular abnormality and may be found in over 95% of patients with PV and 50–60% of those with ET and PMF (CALR) represent the second most frequent abnormality, which can be detected in 20–30% of ET and PMF patients (MPL mutations can be found in a low proportion (1–10%) of ET and PMF patients and generate constitutive receptor activation. None of the above-mentioned mutations are detected in 10–25% of ET and PMF cases, so-called triple-negative patients (Philadelphia-negative chronic myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders characterized by excessive production of myeloid progenitors and mature blood cells. They comprise three closely related disorders, including essential thrombocythemia (ET), which is characterized by megakaryocyte proliferation and thrombocytosis, polycythemia vera (PV), which is defined by predominant erythroid expansion and increased red blood cells, frequently associated with high leukocyte and platelet counts, and primary myelofibrosis (PMF), featured by increased numbers of dysplastic megakaryocytes and granulocyte progenitors together with variable degrees of bone marrow fibrosis . HyperacThrombosis is the main cause of morbidity and mortality in MPN and develops in around 20–35% of patients with PV, 15–30% in ET, and 10–15% in PMF , 5. ArteJAK2V617F mutation, has been proposed to better predict the thrombotic outcome in ET  is associated with increased bleeding rather than thrombosis. Indeed, ET patients with extreme thrombocytosis, in the absence of leucocytosis, carry a lower thrombotic risk  to platelet GPIbα leading to loss of large vWF multimers and acquired von Willebrand disease contributes to the bleeding diathesis , both of which engage CD11b/CD18 (Mac-1). In accordance to elevated P-selectin, increased levels of platelet-neutrophil and platelet-monocyte aggregates have been shown in circulation in ET , 28, PV ex vivo  are at higher risk of bleeding under aspirin, mainly attributed to acquired von Willebrand disease. Screening for ristocetin cofactor activity and withholding aspirin therapy if <30% is suggested in this scenario (JAK2-mutated ET patients who have no contraindications for antiplatelet therapy (CALR-positive low-risk ET patients does not reduce thrombosis and may actually increase bleeding, it is not routinely recommended for primary prophylaxis in this subgroup (The efficacy of low-dose aspirin for the prevention of thrombotic complications in MPN highlights the key role of platelets in this setting . Patientscenario . Current therapy . On the subgroup . Aspirinsubgroup . Howeversubgroup , highligsubgroup . On thissubgroup .Statins have been shown to decrease the risk of both atherothrombotic events and venous thromboembolism. Among their pleiotropic actions, statins exert potent anti-inflammatory effects on the vascular wall and suppress platelet, endothelial and leukocyte activation . Due to Thrombosis remains the main complication of MPN patients, with a high risk of recurrence despite adequate cytoreductive and antithrombotic treatment . MultiplCM contributed to the writing of the article and prepared the figures. PH wrote the article. Both authors contributed to manuscript editing and final approval.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.


One of the outstanding problems in understanding the behavior of intermediate-to-silicic magmatic systems is the mechanism(s) by which large volumes of crystal-poor rhyolite can be extracted from crystal-rich mushy storage zones in the mid-deep crust. The mechanisms commonly invoked are hindered settling, micro-settling, and compaction. The concept of micro-settling involves extraction of grains from a crystal framework during Ostwald ripening and has been shown to be non-viable in the metallic systems for which it was originally proposed. Micro-settling is also likely to be insignificant in silicic mushes, because ripening rates are slow for quartz and plagioclase, contact areas between grains in a crystal mush are likely to be large, and abundant low-angle grain boundaries promote grain coalescence rather than ripening. Published calculations of melt segregation rates by hindered settling  neglect all but fluid dynamical interactions between particles. Because tabular silicate minerals are likely to form open, mechanically coherent, frameworks at porosities as high as ~ 75%, settling of single crystals is only likely in very melt-rich systems. Gravitationally-driven viscous compaction requires deformation of crystals by either dissolution–reprecipitation or dislocation creep. There is, as yet, no reported microstructural evidence of extensive, syn-magmatic, internally-generated, viscous deformation in fully solidified silicic plutonic rocks. If subsequent directed searches do not reveal clear evidence for internally-generated buoyancy-driven melt segregation processes, it is likely that other factors, such as rejuvenation by magma replenishment, gas filter-pressing, or externally-imposed stress during regional deformation, are required to segregate large volumes of crystal-poor rhyolitic liquids from crustal mushy zones. One of the outstanding problems in understanding the behavior of intermediate-to-silicic magmatic systems is the processes(s) by which voluminous eruptions of crystal-poor evolved liquid can be generated  in magmatic rocks demonstrate a deficit at small grain sizes, and this is generally attributed to Ostwald ripening  shape can be maintained will have shapes controlled predominantly by the kinetics of interfacial attachment and the relative growth rates of the different faces. Materials for which interfacial attachment is easy tend to grow as rounded grains, whereas those which grow by mechanisms involving the nucleation and spread of new layers grow as strongly facetted grains , the grains will be rounded  dissolving grains and (large) growing grains. In a system in which interfacial attachment kinetics is important, we would thus expect to see a round shape for all grains of radius smaller than the critical radius, while grains larger than the critical radius will have some facets. In a system in which rates of ripening are controlled by either mass transport by diffusion through the bulk matrix , or interfacial attachment/detachment kinetics, the critical radius is the number-average radius  and growth shapes  , is not significant for grains larger than a few tens of microns . Higher packings occur in systems in which the solid particles are relatively dense  comprises 56–54 vol.% solids  to enable creep by diffusion-controlled processes involving dissolution–reprecipitation [or melt-assisted diffusion creep , whereas the segregation of evolved interstitial liquid from a crystal mush occurs during a decrease in temperature , essentially encapsulating the dichotomy concerning rhyolites as either sourced directly from melting source rocks or as evolved interstitial liquids expelled from a crystal mush.The grain-scale distribution of liquid in melting and solidifying systems is not the same, and this difference introduces poorly-understood discrepancies in the behavior of the two types of system. For example, Sawyer  pointed If it is, indeed, the case that an externally-imposed stress field is required to generate large volumes of crystal-poor rhyolite, such eruptions should be concentrated in tectonically active regions. The Taupo Volcanic Zone of New Zealand fits the bill, with Allan et al. , 2017 arIn this contribution, I have argued that we need to reconsider the commonly postulated mechanisms, all essentially driven by internally-generated buoyancy forces, by which large volumes of crystal-poor rhyolitic magma can be extracted from their tonalitic mushy nurseries. Micro-settling is not viable as a process in either metals or silicate mushes, and hindered settling as generally modelled in the melt segregation literature is only applicable for crystal-poor systems. No microstructural evidence has yet been reported that supports widespread gravitationally-driven viscous compaction of crystal mushes by either dislocation creep or creep facilitated by diffusion: clearly, we should concentrate efforts on searching for the sort of supporting evidence outlined above to demonstrate that compaction is, indeed, an important mechanism operating in silicic mushes.A complete understanding of the rates and mechanisms by which interstitial melt might segregate from a solidifying crystal mush essentially requires a better understanding of how crystal mushes behave. Future experimental work should be directed at studying the timing and rates of clustering during settling, the porosity of the resultant framework, and the rates and extent to which it collapses, particularly under shear. The time-scales of segregation in mushes undergoing deformation should be investigated to determine whether regional tectonic stresses are sufficient to create melt drainage networks on appropriate time-scales (e.g., Schoene et al.


Drosophila melanogaster as a model for TBI study. The relatively small brain size , conserved neurotransmitter signaling mechanisms and sophisticated genetics of Drosophila allows for cell biological, molecular and genetic analyses that are impractical in mammalian models of TBI.Traumatic brain injury (TBI), caused by a sudden blow or jolt to the brain that disrupts normal function, is an emerging health epidemic with ∼2.5 million cases occurring annually in the United States that are severe enough to cause hospitalization or death. Most common causes of TBI include contact sports, vehicle crashes and domestic violence or war injuries. Injury to the central nervous system is one of the most consistent candidates for initiating the molecular and cellular cascades that result in Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Not every TBI event is alike with effects varying from person to person. The majority of people recover from mild TBI within a short period of time, but repeated incidents can have deleterious long-lasting effects which depend on factors such as the number of TBIs sustained, time till medical attention, age, gender and genetics of the individual. Despite extensive research, many questions still remain regarding diagnosis, treatment, and prevention of long-term effects from TBI as well as recovery of brain function. In this review, we present an overview of TBI pathology, discuss mammalian models for TBI and focus on current methods using  TBI represents a major health problem affecting about 10 million people worldwide each year . Althoug2+ and Na+ channels  deposits, a hallmark of AD, have been detected histologically in young TBI patients  and in 3Patients recovering from TBI are prone to sleep-wake cycle disturbances  which isAlthough mechanisms that lead to cell death after TBI have been analyzed extensively, little is known about how surrounding cells might mediate this cell death. The complex nature of TBI pathology, both in terms of the severity and distribution of injury to the brain and the brain’s response to injury, make the task of developing therapies a big challenge. Therefore, small animal models including rodents, flies and zebrafish can be very useful for initial characterization and identification of potential therapeutic targets which can then be interrogated in larger models for a more successful translation to human research.In view of the heterogeneous nature of brain injury pathology, several large and small animal TBI models have been developed. One of the earliest TBI models, the freeze lesion model, was used in cats, dogs and macaque monkeys . Larger For these reasons, rodents have become popular as models for TBI research. Rodents also share great similarity with human brains and are easier to purchase and maintain than larger animals. TBI models like FPI , corticaThe most common TBI model, FPI has been successfully applied in several animal models including rabbit, cat, rat, mouse and pig . The injThe CCI model uses an electromagnetic impactor device to produce a mechanical deformation of the cortex  which caIn the weight drop model, injury is caused by a free-falling, guided weight  impactinBlast-related brain injuries are among the most commonly sustained injuries by soldiers and veterans who have served at war sites. Various test methods such as open-field blasts, blast tubes and shock tubes have been designed over the years to model explosive blast injuries suffered by humans. Of these, blast-tubes  are wideDrosophila melanogaster offers several advantages like short lifespan, cost and ease of maintenance  each catering to different modeling functions  is a collection of 205 inbred strains that present a favorable scenario for performing genome-wide association (GWA) mapping analyses to identify candidate causal genes, polymorphisms associated with them and pathways affecting quantitative traits  device  exhibiteataxia, indicating that the HIT device delivers primary injuries to the brain  device (To induce head-specific TBI to ) device . The dCH) device .Flies inflicted with trauma using the HIT device exhibit reduced lifespan, activation of innate immune response and death within 24 h (if the extent of injury exceeds a certain threshold) . Katzenb1118 flies injured using the HIT device had intestinal barrier dysfunction within 24 h, which directly correlates with 25% mortality , Toll and JAK-STAT pathways, which combat fungal and bacterial infections , moody (blood brain barrier), wunen-2 , reversed polarity , and gli  was seen 24 h after TBI in this study. In addition, they have also observed increased mortality and impaired negative geotaxis response, increased apoptotic cell death, impaired motor control, reduced lifespan, reduced and fragmented sleep and upregulation of stress response genes after TBI. Overall, dCHI is a good model for closed head injury in Drosophila especially since the trauma is restricted to the head only and is also highly reproducible. However, with dCHI, each replicate will have to be treated separately since the device can only handle one fly at a time, but the trauma is consistent between replicates.The Allada lab used glial targeted translating ribosome affinity purification in combination with RNA sequencing (TRAP-seq) and identified glial immune pathways as mediators of TBI effects in flies injured using dCHI . The Drofections . An upreDrosophila has garnered attention as an attractive model for the study of neurodegenerative diseases. Lately, genome-wide sequencing to identify changes in gene expression induced by brain injury has also become a focus of study among researchers. RNA-seq datasets for studies on rat, mice and flies have identified several genes and gene ontology terms that are enriched in response to TBI.Mice and rat are the two most commonly used mammalian models for studying TBI. However, due to the short life-span, sophisticated genetics and ease of maintenance , DrosophRattus norvegicus (Rn) study (GSE64986) (In the SE64986) , adult mSE64986) . OriginaMus musculus (Mm) study (GSE79441) (In the SE79441) , male C5D. melanogaster (Dm) study (GSE85821)  , w1118 mT device  with 5-mter 24 h . RNA-seqter 24 h .Reanalysis of select RNA-seq datasets from each species  revealedDrosophila, there is a significant upregulation of Sid, a nuclease gene induced in response to oxidative stress  terms that significantly overlap between the species   .A large portion of gene expression changes commonly seen in human TBI studies are also observed in these animal models. Proteomic analysis of post-mortem human TBI brains show alterations in immune response, synaptic and mitochondrial function . Gene exThese findings demonstrate that several responses related to TBI are conserved among model systems but there are also species-specific processes that are affected post-injury.p-value < 0.05) using DAVID   and tabulated across gene regions . Differescovery] ,b. Fly aA variety of animal models have been developed that mimic the different injury mechanisms associated with human TBI. In spite of all these advancements, therapeutic strategies for treatment of TBI are limited since current diagnosis relies on identifying symptoms and monitoring trauma patients. The Brain trauma foundation recommends decompressive craniotomy, hypothermia, hyperosmolar therapy, cerebrospinal fluid drainage and ventilation therapies for management of severe TBI . AchieviDrosophila has proven to be a useful model to study not only neurodegenerative diseases but also disorders associated with other systems. Single-cell sequencing done on adult Drosophila brain has been able to present a brain atlas that covers all cells in normal brain and how it changes over the lifespan of a fly  were analyzed in this study and can be found at www.ncbi.nlm.nih.gov/geo.DR is the principal investigator and conceived the project. ES and KG conceptualized the content. ES performed the data analysis and wrote the manuscript. KG edited the manuscript and assisted with data analysis.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.


We present a case of traumatic rupture of the spleen in a man with cleidocranial dysplasia. The computed tomography imaging showed multiple low-grade lacerations of the spleen which initially led to conservative patient management. However, with clinical deterioration, the patient underwent an emergent splenectomy. Post-operative histology revealed splenic peliosis with multiple lacerations. The radiological and surgical management of post-traumatic splenic peliosis may differ from those with an otherwise normal spleen. While peliosis may occur in any organ belonging to the mononuclear phagocytic system , isolated splenic peliosis remains rare1. There have been no published cases of patients with splenic peliosis associated with cleidocranial dysplasia. To our knowledge, only 21 cases of isolated splenic peliosis have been reported in the literature2. Radiological imaging can be non-specific in splenic peliosis, and the most common differential diagnoses include lymphoma, vascular tumours or infective pathology3.Splenic peliosis is an extremely rare benign condition characterised by the presence of blood-filled cysts varying in size from one millimetre to several centimeters4.Cleidocranial dysplasia, also known as cleidocranial dysostosis, is a congenital disorder caused by a genetic mutation. It is a rare generalized skeletal dysplasia with a bone developmental abnormality. The condition is characterised by widened sutures, multiple wormian bones, hypoplasia or aplasia of the clavicles, abnormal teeth, vertebral and pubic symphysis abnormalitiesA 35-year-old gentleman presented to the emergency department (ED) following a motor-bicycle accident (MBA). He was known to have congenital cleidocranial dysplasia, but an otherwise unremarkable history. On clinical assessment, the patient was haemodynamically stable with significant tenderness over the left lateral chest wall and left hip. Trauma computed tomography (CT) revealed multiple posterior rib fractures on the left side with a small haemopneumothorax, multiple splenic lacerations with a subcapsular haematoma  and a coHistopathology noted subcapsular haemorrhage and, on sectioning, the specimen showed multiple haemorrhagic cyst-like lesions of up to 35 mm in diameter and traumatic haemorrhage . These c5. The etiology of splenic peliosis is often unclear, however, causal links between chronic alcoholism, corticosteroids, AIDS and the oral contraceptive pill are thought to be linked 2. In some cases, no predisposing link can be found3. There is a view in the literature that these represent congenital or acquired vascular malformations which manifests into cystic dilation under raised local intravascular pressure6. Interestingly, our case had congenital cleidocranial dysplasia. Although there has been no reported associative link in the literature between peliosis and cleidocranial dysplasia, it is plausible that these patients may be predisposed to congenital vascular malformations and hence possibly a higher incidence of peliosis.Splenic peliosis is a rare condition and often clinically silent, until found incidentally on routine scans. Splenic rupture, either spontaneous or traumatic, may result in acute presentation1. If the cysts rupture, either spontaneously or secondary to trauma, subcapsular haematoma, splenic laceration, and intra-abdominal haemorrhage will be evident. The radiological diagnosis of peliosis, or any other incidental pathology, can be very challenging in the setting of abdominal trauma, as the findings might be obscured by co-existent splenic lacerations. CT imaging interpretation may upgrade the splenic injury due to the presence of congenital haemorrhagic cysts mimicking the appearance of multiple splenic lacerations. The main CT imaging findings of peliosis are multiple well-defined or ill-defined low-density lesions, high density in presence of haemorrhage, with a variable pattern of enhancement post contrast7. Magnetic resonance imaging can also aid in the diagnosis of peliosis, although CT imaging is routine in trauma1.The diagnosis of splenic peliosis relies on the radiological findings of multiple small hypo-attenuating cyst-like lesions with fluid levels mostly located around the para-follicular region of the spleen6. In the presence of trauma, surgical intervention and splenectomy is effective management, although where patients are haemodynamically stable, and resources permit, interventional radiology to perform splenic artery embolization can also be effective8.The surgical management in splenic laceration with peliosis may differ from those with a normal spleen with a lower threshold for splenectomy. This is to prevent organ rupture and reduce the risk of life-threatening morbidity and mortality. Prophylactic splenectomy has been recommended in those individuals with an incidental diagnosis of splenic peliosisIsolated splenic peliosis is a rare entity, which could predispose patients to life-threatening bleeding with or without significant trauma. CT imaging plays an important role in the diagnosis and patient management, and surgical intervention is the definitive management to prevent life-threatening morbidity and mortality.