The aim of this study was to compare the external apical root resorption (EARR) in patients receiving fixed orthodontic treatment with self-ligating or conventional brackets.Studies comparing the EARR between orthodontic patients using self-ligating or conventional brackets were identified through electronic search in databases including CENTRAL, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and SIGLE, and manual search in relevant journals and reference lists of the included studies until Apr 2016. The extraction of data and risk of bias evaluation were conducted by two investigators independently. The original outcome underwent statistical pooling by using Review Manager 5.Seven studies were included in the systematic review, out of which, five studies were statistically pooled in meta-analysis. The value of EARR of maxillary central incisors in the self-ligating bracket group was significantly lower than that in the conventional bracket group . No significant differences in other incisors were observed between self−ligating and conventional brackets.Current evidences suggest self-ligating brackets do not outperform conventional brackets in reducing the EARR in maxillary lateral incisors, mandible central incisors and mandible lateral incisors. However, self-ligating brackets appear to have an advantage in protecting maxillary central incisor from EARR, which still needs to be confirmed by more high-quality studies. Currently, orthodontic treatment requires an average duration of 2–3 years. The lengthy treatment poses higher risks of numerous side effects to patients, among which external apical root resorption (EARR) has been frequently reported .EARR could be defined as the blunting and shortening of root apex caused by the pathologic loss of the cementum and dentine. It is widely accepted that the elimination of hyalinization zone is critical for the physiological tooth movement . HoweverThe EARR induced by orthodontic treatment, most of which were graded as minor or moderate, generally resulted in no significantly clinical symptoms . NeverthAlthough EARR in orthodontics has been considered as an iatrogenic problem, the relationship between orthodontic treatment-related factors and EARR has never been fully answered. Previous study suggested the occurrence of EARR appears to be closely associated with mechanical factors during orthodontic treatment . The treIn current orthodontic clinics, self-ligating (SL) brackets have been widely used due to the free of ligature by additional rubber elastics or steel ligatures, and the resulting reduction of the chair time and the frictional resistance between archwire and brackets . FurtherThis systematic review and meta-analysis was performed referring to Cochrane Handbook for systematic Reviews of Interventions and Perferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist . Two revAn extensive electronic search was conducted through databases including Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and SIGLE. The search strategy combined MeSH heading words with free text words without context. The adopted MeSH terms were ‘root resorption’ and ‘orthodontic appliances’. The free text words included root shortening, root alternation, self-ligating and ligating. The search strategies for databases were established based on that for PubMed. The electronic search was conducted on Apr 10, 2016. In addition, manual search was undertaken among issues of relevant journals and the reference lists of retrieved articles by reviewing the titles and abstracts. No language restriction was applied during the literature search.The inclusion criteria were as follows: (1) Types of studies: randomized controlled trials (RCTs), controlled clinical trials (CCTs) and cohort studies are eligible; (2) Types of participants: subjects should be healthy patients who required fixed orthodontic treatment; (3) Types of Intervention: patients received fixed orthodontic treatment using SL or non-SL brackets; (4) Outcomes: the reduction of root length (in millimeters and in percentage).The exclusion criteria were as follows: (1) Review articles, descriptive studies, opinion articles, case reports or abstracts; (2) Animal studies; (3) Studies involving subjects with systemic diseases or diagnosed as root absorption before orthodontic treatment.A customized data extraction form was developed. Relevant information regarding study designs, participant information, interventions, outcomes  and treatment duration were extracted.The risk of bias assessment form recommended by Saltaji et al.  and Wu e2 statistic. The random-effect model would be adopted for the meta-analysis if the heterogeneity was assessed as high (I2 > 50%); Otherwise, the fixed-effect model was employed. The statistical significance of the hypothesis test was set as p < 0.05 (2-tailed Z test). Subgroup analysis was performed on the basis of treatment durations. Sensitivity analysis was performed to test the stability of overall results in the meta-analysis by omitting study separately. Descriptive analysis was adopted when the statistical synthesis of data failed. The funnel plot and Beggs’ rank correlation test were used to determine the publication bias if the number of recruited studies exceeded 10 [Review Manager  was used for the meta-analysis of quantitative data. For continuous data, the standardized mean difference (SMD) and its 95% confidence interval (CI) were adopted as the treatment effects and pooled for analysis. The heterogeneity of recruited studies was explored by Ieeded 10 .A total of 449 articles were retrieved through the electronic and manual searching. Of these, 439 irrelevant citations were excluded and ten studies were considered potentially eligible after evaluating titles and abstracts. The full-texts of the reserved ten studies were retrieved and assessed referring to the inclusion and exclusion criteria. Finally, seven studies –23 fulfiA total of 553 participants were included. All the participants were systemically healthy and received fixed orthodontic treatment. Among the seven recruited studies, one was categorized as RCT, two were CCTs and the other four studies were cohort studies Table . One of The detailed information regarding the risk of bias evaluation was summarized in Table Five studies reported the values of EARR with teeth grouped as maxillary central incisors, maxillary lateral incisors, mandibular central incisors and mandibular lateral incisors during fixed orthodontic treatment. The feasible data was statistically pooled to compare the values of EARR between two types of brackets. The meta-analysis results showed that the patients using SL brackets suffered less EARR of maxillary central incisor compared to those using non-SL brackets  Fig. , while nOut of the five included studies in meta-analysis, three studies –20 had fp =0.06). Jacobs et al. [p > 0.05).The other two studies , 23 wereLeite et al.  evaluateThis systematic review was performed to provide data on the EARR during orthodontic treatment using SL or non-SL brackets. After a comprehensive literature search and evaluation, seven articles were recruited in this systematic review, among which, five studies were statistically pooled for the quantitative analysis. The meta-analysis results suggest that SL bracket is superior to non-SL bracket in protecting maxillary central incisors from EARR Fig. . While nThe sensitivity analysis omitting Leite et al. and Scott et al. , 21 brouThe exact mechanism of the EARR development is still unclear, but it is generally accepted the root resorption is positively associated with force magnitudes and apical movement distance , 24. RecThe treatment duration has been suggested as a risk factor to the development of root resorption . Among tPrevious studies demonstrated the association between EARR occurrence and numerous mechanical factors including force magnitude, amount of tooth movement, force type and treatment appliance , 7. The The diagnosis of EARR has been mainly through radiographs. Out of the seven included studies, four studies adopted periapical radiographs, two used panoramic radiographs, and the other one employed CBCT Table . Though Firstly, though extensive literature search was conducted, only five studies were included in the meta-analysis, leading to the deficient statistical power. Secondly, out of the five studies in meta-analysis, one study evaluated the percentage of root reduction while the other four reported the absolute values of root resorption. Though SMD was computed in the quantitative analysis, the outcomes should be interpreted with caution in clinical settings. Thirdly, though subgroup and sensitivity analysis was performed, the source of heterogeneity might not be thoroughly investigated since no information regarding several risk factors of EARR, like tooth movement distance and force magnitude, was reported in primary studies. Fourthly, funnel plots for publication bias assessment has not been conducted because only five studies were included in the meta-analysis. Therefore, further high-quality original studies are needed to arrive at a more stable conclusion.Based on present limited evidence, SL brackets appear to have a long-term protective effect to maxillary central incisors from root resorption compared to non-SL brackets. No different influences on other incisors were detected. The results of this study could suggest the priority of SL brackets to patients with more susceptible maxillary central incisor roots or unfavorable crown-root ratio in fixed orthodontic treatment. However, methodologically sound clinical trials are required to provide more reliable evidences regarding this issue.


Maintenance or restoration of a good range of motion of the knee is one of the most important outcomes following knee surgery. According to previous studies, opening wedge high tibial osteotomy enables better recovery of range of motion in knee flexion than that achievable after total knee arthroplasty or unicompartmental knee arthroplasty. However, few reports provide a detailed description of the postoperative recovery of knee extension range of motion after opening wedge high tibial osteotomy. We describe our experience with a knee extension training program using a single-joint hybrid assistive limb device  during the acute recovery phase after opening wedge high tibial osteotomy. The HAL-SJ is a wearable robotic device that facilitates voluntary control of knee joint motion.A 67-year-old Japanese woman who underwent opening wedge high tibial osteotomy for spontaneous osteonecrosis of the left medial femoral condyle received HAL-SJ-based knee extension training postoperatively. Our experience with this patient revealed that knee extension training with the HAL-SJ during the acute phase following opening wedge high tibial osteotomy is feasible. Furthermore, the patient’s knee extension range of motion improved to values similar to those seen during the preoperative stage, and her flexion range of motion was improved at 3 months after the surgery.HAL-SJ-based knee extension training could be used as a novel post-opening wedge high tibial osteotomy rehabilitation modality. Further exploration of individualized optimal settings of the HAL-SJ is required to improve its safety and efficacy. OWHTO is performed to treat osteoarthritis of the knee and spontaneous osteonecrosis of the knee (SPONK) localized to the medial compartment, in order to correct varus deformity of the knee joint and lower limb alignment . Currentet al.  reportedet al. . In thiset al. . The HALet al. . The HALet al. –12. Alth2. She reported feeling pain in the medial joint space of the knee during walking, as well as during climbing or descending stairs. At the time of the first admission, her systolic/diastolic blood pressure was 165/97 mmHg. Table 6/μl, hemoglobin 14.4 g/dl, hematocrit 43.6%, and platelets 263 × 103/μl.A 67-year-old Japanese woman underwent OWHTO to treat SPONK that had occurred in the left medial femoral condyle Fig. . The patThe HAL-SJ treatment program was divided into five phases . Phase 1et al. [Phase 2 involved surgery (day of surgery). The patient underwent OWHTO Figs.  and 2a uPhase 3 consisted of postoperative observation from day 1 to day 7 postoperatively. For postoperative rehabilitation, partial weight bearing was allowed after a non-weight-bearing period of 2 weeks, and full weight bearing began at 4 weeks postoperatively. The patient received rehabilitation training under the guidance of a physical therapist (ROM exercises and muscle-strengthening training) for 20–40 minutes each day, 5 days per week, from the first postoperative day until discharge. For ROM exercises, continuous passive motion training began on the first postoperative day for 1 hour per day and continued every day until discharge. On postoperative day 7, we attached electrodes to the quadriceps muscle to detect the bioelectric potential along the long axis of the rectus femoris muscle belly Fig. . Then, tPhase 4 consisted of HAL-SJ therapy from postoperative day 8 to discharge. The CVC mode of HAL-SJ serves to support the patient’s voluntary motion on the basis of voluntary muscle activity and the assistive torque provided to the knee joint . In thisPhase 5 consisted of post-HAL-SJ therapy observation from discharge until 3 months after the end of HAL-SJ therapy, during which the following indicators were assessed: EL, assessed as the difference between the maximum knee joint extension angle during passive exercise and that during active exercise; knee pain rated on the visual analogue scale (VAS); isometric knee extension muscle strength (IKEMS); active ROM before surgery, before and after HAL-SJ training, and at 1 and 3 months after the end of training; and the Japanese Orthopaedic Association (JOA) score  before sThe case described in the present report illustrates two important clinical suggestions. First, knee extension training using the HAL-SJ during the acute phase after OWHTO is clinically feasible. Second, although we did not find an improvement in the EL or a consistent tendency toward improvement in knee pain, extension ROM recovered to near-preoperative values, and flexion ROM improved at 3 months after the surgery.We previously reported the case of a patient who underwent three sessions of knee extension training using the HAL-SJ as part of the inpatient acute rehabilitation program after TKA, and we also found in that case that HAL-SJ-assisted training was safe and feasible . In the et al. [In our patient, there was no consistent improvement in EL or decrease in knee joint pain after knee extension training using the HAL-SJ, although knee extension ROM recovered to a level similar to that before surgery, and knee flexion ROM increased 3 months after the surgery. Takeuchi et al.  describeet al. , suggestet al. , was notet al.  reportedThe basic differences between TKA and OWHTO are related to the fact that TKA is a surgical procedure in which the internal structures of the joint are entirely replaced with an artificial joint, whereas OWHTO is a surgical procedure in which only the alignment of the load axis is corrected, and the correction is performed extraarticularly, while the degenerated joint’s internal structure is preserved. Even in patients with limited knee extension preoperatively, the amount of bone cut during TKA and the technique used for the detachment of soft tissues allow for improvement in knee extension. Meanwhile, because OWHTO involves alignment correction through extraarticular osteotomy, any limitation of joint extension already present before surgery is difficult to improve through OWHTO. During HAL-SJ training, the assistance provided by the robotic device helps improve the range of active extension to approximately the range of passive extension, minimizing EL. In other words, because OWHTO is less likely to bring an improvement in the range of passive extension, it may be difficult to demonstrate the beneficial effect of post-OWHTO training using the HAL-SJ. In Japan, improvement in knee flexion ROM is of particular importance because certain aspects of the Japanese lifestyle involve activities such as sitting on the floor with the knees in full flexion and the buttocks resting on the heels. Detailed investigations regarding this topic have been performed , 16, butThe observations in our patient indicated that knee extension training using the HAL-SJ is feasible during the acute phase after OWHTO. Unlike TKA, which involves replacement of the degenerated and deformed intraarticular structure with a compatible artificial component, OWHTO is a surgical procedure whose aim is to adjust lower limb alignment while preserving the joint via osteotomy. Therefore, complete knee extension cannot be obtained through OWHTO. Further exploration regarding individualized optimal settings of the HAL-SJ is required to improve the safety and efficacy of HAL-SJ training in the acute phase after knee joint surgery.


Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that develops from Barrett's esophagus (BE), an intestinal metaplasia of the distal esophagus. microRNAs (miRNAs), short non-coding regulatory RNAs, are frequently dysregulated in BE and are thought to play key roles in the onset of BE and its progression to EAC. miRNAs thus have potential diagnostic and prognostic value and are increasingly being used as cancer biomarkers. This review summarizes the current literature related to miRNAs that are dysregulated in BE within the context of Hedgehog, Notch, MAPK, NF kappa-B, Wnt and epithelial-mesenchymal transition (EMT) signaling which are thought to drive BE onset and progression. This comprehensive analysis of miRNAs and their associated signaling in the regulation of BE provides an overview of vital discoveries in this field and highlights gaps in our understanding of BE pathophysiology that warrant further investigation. MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs of approximately 18-25 nucleotides in length which regulate gene expression by binding to the 3’-untranslated region (3’-UTR) of target mRNAs to inhibit their translation or facilitate their degradation , 8624, 8Several other miRNAs differentially regulated in BE appear to regulate cell cycle progression through modulation of downstream validated Wnt targets Tables  and 2. mAlthough not normally expressed in squamous esophageal epithelium, NF-κB signaling is elevated in a variety of cancers, inflammatory diseases, and is increased in GERD, BE, and EAC tissue relative to adjacent normal squamous epithelium . NF-κB iB-Cell CLL/Lymphoma 2 (BCL2) and Cytochrome C Oxidase II (COX2), both downstream NF-κB effectors, are upregulated and associated with apoptotic resistance in BE , 104. SeIn the transition from BE to invasive EAC, the Epithelial-Mesenchymal transition (EMT) is a prerequisite for tumor invasion Figure . EMT, a While a number of the key regulators underlying BE pathophysiology and its progression to EAC have been identified, effective protein and miRNA biomarkers for BE remain poorly defined. As regulators of a third of all human genes, miRNAs have potential beyond clinical biomarkers and may be used to elucidate the interactions among signaling pathways in BE pathogenesis, as well as other human diseases. This review strived to provide mechanistic context by correlating the key regulatory proteins involved in BE with miRNAs that are differentially expressed in BE. Using IPA, we were able to correlate miRNAs dysregulated in BE to the intestinalization of esophageal tissue through upregulation of Hedgehog signaling, and in the maintenance of epithelial stemness in BE through upregulation of BMP4 signaling. We further elaborated on the potential mechanisms by which dysregulated miRNAs downregulate NOTCH and ERK signaling while upregulating JNK and p38 signaling to induce mucin expression and maintain intestinal identity. We identified miRNAs which potentially play a role in regulating proliferation and tumorigenicity by suppressing WNT signaling in BE and enhancing WNT signaling during the dysplastic progression to EAC. We illustrate how miRNAs which are dysregulated in GERD, BE and EAC support increased NFkB signaling and expression of pro-inflammatory mediators and apoptotic resistance. Finally, identification of several miRNAs which affect EMT signaling were correlated to the metastatic progression to EAC.Few studies have compared miRNA signatures from tissue and serum, so it is difficult to predict whether circulating miRNA levels accurately reflect those from esophageal biopsies . Of the Transduction of human cancer cells with lentiviral vectors encoding for antisense oligos to selected miRNAs has been shown to reduce pancreatic tumor burden in SCID mice . AccordiWhile this review focused on the downstream targets of miRNAs known to be dysregulated in BE, it should also be noted that these same miRNAs may be used to predict potential upstream master regulators which mediate BE lesion formation. At least 12 of the 98 BE-related miRNAs are direct targets of p53, suggesting that p53 may be causal in some fashion. Specifically, miR-143, miR-145, miR-191, miR-192, miR-22, miR-25, miR-661 and let-7 are upregulated in BE and validated targets of p53. miR-149, miR-210, miR-32 and miR-378 are downregulated by p53. A role for p53 in BE has not been clearly defined, but elevated p53 expression (>5%) is associated with progression to advanced neoplasia .Identification of clinically reliable early miRNA biomarkers of BE will require extensive validation and a deeper understanding of the cellular signaling events which drive BE development. Of the miRNAs discussed in this review, it remains unclear which miRNAs have the potential to serve as biomarkers specific to BE and which are broad spectrum cancer biomarkers. Further studies into the mechanisms by which circulating miRNAs become differentially expressed are needed to identify those miRNAs of real clinical importance. A number of technical challenges remain which have hindered current efforts at identifying miRNA biomarkers including low miRNA yield from serum samples, lack of suitable endogenous miRNA controls, and a lack of strategies to deal with normal variation in circulating miRNA levels. Improved early detection of BE and other cancers will only occur by overcoming these technical challenges and by obtaining a more detailed understanding of miRNA signaling networks.


Bone metastases represent an important complication of malignant tumours. Despite improvement in surgical techniques and advances in systemic therapies, management of patients with bone metastatic disease remains a powerful cornerstone for the radiation oncologist. The primary goal of radiation therapy is to provide pain relief, preserving patients quality of life. Solid tumors frequently metastasize to bone. The exact incidence of bone metastases is difficult to extrapolate, but it has been estimated that approximately 35.000 people per year in Italy will develop bone metastases . Dependiversus 6 months) [Bone metastasis are usually associated with a poor prognosis with median survival rates limited to several months. However, year after year, significant progress in systemic and supportive therapies have increased patients’ life expectancy. Therefore, patients with metastatic disease represent a heterogeneous patient group and overall survival depend on both primary tumor site and concomitant presence/absence of visceral metastases. Nowadays, patients who develop oligometastases from prostate and breast cancer have a longer median survival compared to those with bone-only metastatic lung cancer (36 months  months) –3.Independently of clinical outcomes, the vast majority of patients with bone metastases requires an active treatment, due to pain, difficulty with ambulation, pathologic fractures, spinal cord compression, hypercalcemia and neurologic deficits.Skeletal metastases are the most common localization, occurring principally in lumbar and thoracic spine, pelvis, ribs and long bones of the upper and lower extremity. Certain skeletal sites are pathognomonic of specific primary tumor. For instance, involvement of the scapular is more common with renal primaries, whereas skull metastases develop more frequently from primary breast cancer.Several variables, including life expectancy, predicted outcomes, disease characteristics and patient preferences must be considered to tailor the best cancer therapy for the individual patient. Radiation therapy (RT) can represent an effective palliative intervention in metastatic disease to maintain and improve patient's quality of life (QoL). The majority of patients will experience pain during their disease course and pain management can significantly improve their QoL. This review provides highlights in effects, clinical efficacy and tolerability of RT delivered by linear accelerators in the management of patients with bone metastases.The important role of RT in the palliation of bone metastases is well recognized. RT is performed primarily to relieve pain, definitely control a bone affected from metastases and prevent pathologic fractures as well as spinal cord compression. Radioisotopes can be administered for more diffuse bone pain that is not eligible for palliative RT, whereas bisphosphonates are usually considered in case of multiple unpainful skeletal metastases.The goals of RT are to improve QoL, reduce analgesic requirements and maintain or ameliorate skeletal function. Beneficial effects on pain may necessitate several days to a few weeks, so analgesic medication must be optimized during that interval .The initial patient evaluation should be adequate and accurate, using validated instruments specific for cancer patients in palliative care. It is important to report patient symptom experience, using a pain scale of 0 - 10, in which 0 represents no pain and 10 represents maximum pain . The EurBriefly, first-line palliative RT is indicated for symptomatic bone metastases, after the appearance of new painful site or after failure or insufficient effect subsequent to a first irradiation.Due to the persistence of red bone marrow, the axial skeleton is seeded more than the appendicular skeleton. Bone metastases are mainly associated to an overstimulation of osteoclasts or osteoblasts causing a lytic or blastic lesion, respectively. Both lytic and blastic lesions can cause bone pain. Osteoclast activation contributes to painful osteolytic metastases due to higher rate of pathologic fractures. Bone cancer pain principally depends on three mechanisms , 7. FirsThe optimal fractionation schedule is still an unresolved issue. In clinical practice, the selection of the fractionation schemes is often influenced by patient characteristics , tumor-related factors  and logistic issues . A summary of the main clinical circumstances is provided in Table Single fraction RT schedule, prescribed to the appropriate target volume, is recommended as the standard of care for the treatment of symptomatic and uncomplicated bone metastases .versus 8%, p < 0.00001). Single fraction treatment optimized patient and caregiver convenience and was related with lower acute toxicity, including nausea and vomiting, fatigue, diarrhoea and skin reactions. Single fraction was also associated with a higher pathological fracture and spinal cord compression rates compared to multiple fraction treatment, but this result did not reach statistical significance . However, the limitation of this analysis is mostly related to the primary end-points heterogeneity of the RCTs included.During the past two decades, multiple randomized controlled trials (RCTs) have demonstrated pain relief equivalency between a single 8 Gray (Gy) fraction and multiple fraction regimens, including 30 Gy in 10 fractions, 24 Gy in 6 fractions and 20 Gy in 5 fractions . RecentlDespite its proven clinical effectiveness and its cost efficiency, worldwide the single fraction regimen is underused into daily practice for palliative RT for painful bone metastases . The reaIn case of spinal metastases, percutaneous vertebroplasty combined with adjuvant RT seems to be better that RT alone to relief pain, maintain vertebral body stability and improve patients’ QoL .Although data are limited, a multiple fractionated treatment, including 20 Gy in 5 fractions and 30 Gy in 10 fractions, could be considered appropriate in those patients at risk of pathologic fractures, in order to guarantee a tumor down-staging prior to surgical approach. On the other hand, where the treatment objective is tumor shrinkage and pain control in presence of a bone lesion associated with large soft tissue mass, no dose-fractionation recommendation can be define .versus multiple fractions. Both regimens were effective with no significant difference in back pain relief (56% versus 59%), motor capacity (68% versus 71%) and good bladder function (90% versus 89%). Authors suggested single fraction RT has been recommended as regimen of choice in clinical practice for patients with spinal cord compression and short expected survival [Metastatic spinal cord compression represents a medical emergency. An immediate, aggressive treatment approach is essential to preserve neurologic function and to improve patient's QoL. RT, surgery or combined modality constitutes the management for spinal cord compression. Although, in the past, RT was considered the standard of care, nowadays, due to improvements in neurosurgical techniques, new evidence suggested that direct decompressive surgery plus postoperative RT seems to be superior to RT alone for spinal cord compression caused by metastatic tumor . The typsurvival .versus radiation oncologist-based - among trials, the International Bone Metastases Consensus Working Party on palliative radiotherapy defines and recommends the following response categories [In order to reduce the variation in the measurement of pain - self-reporting pain tegories : 1) CompConsidering that single fraction RT is equally effective to multiple fractions for most patients, the overall response percentages is presented. There is no consistent dose-response relationship for pain relief, suggesting that response is mainly mediated by a change in the local bone environment . GloballQoL plays a progressively more important role in the evaluation of overall treatment efficacy. Due to short life expectancy of the vast majority of metastatic patients, acute toxicity is much more clinically relevant than late complications. However, with improvement in systemic therapies, some patients, especially those with oligometastases, have a better prognosis and, thus, are potentially at risk of developing late toxicity.Toxicity depends mostly on the total dose delivered to the normal tissues adjacent to the target volume. It is predictable and generally self-limiting. No major differences in gastrointestinal disturbances , itching, skin reactions and tiredness were reported between single fraction or multiple fractions regimens .Side effects are manageable with conservative measures. For instance, for treatment over the abdomen or with large target volumes in the pelvis, it is reasonable to use a prophylactic antiemetic to reduce acute nausea and vomiting.Pain flare is described as a temporary increase in bone pain at the treated metastatic site, during or shortly after RT completion . Its phyto arise from the release of biochemical mediators of inflammation or the edema compressing nerves in the area of treatment . Pain flThree-dimensional conformal radiation therapy (3-DCRT) is now firmly considered the standard of practice to treat bone metastases. 3-DCRT allows to conform dose distribution to the target volume, reducing dose to the surrounding normal tissues. Before treatment, a computed tomography (CT) scan of the affected anatomic site is obtained. Patient should be positioned in a comfortable and reproducible position. Using a three-dimensional CT planning, the most conformal treatment plan is prepared. The goal is to deliver the maximum dose to the target volume and spare the normal tissues. Figure Stereotactic body radiation (SBRT) is a modern treatment modality that delivers high doses to metastatic bone with a great accuracy, minimizing the dose to the adjacent critical structures, primarily spinal cord and cauda equine, but also lung, esophagus, kidney, bowel and contiguous vertebral bodies. Considering the heterogeneity of prognosis for patients with bone metastases, there is a consistent interest to identify a subset of patients with oligometastatic disease - up to three metastatic lesions - who may achieve more durable pain control with SBRT , 30.SBRT is performed on vertebral body lesions, without extension to the posterior cortical, allowing for distance between target volume and spinal cord and thus limiting neural structures to threshold below the dose of radiculopathy and myelopathy. SBRT treatment field encompass only the tumor lesion. This equates to the anterior portion of the involved vertebral body, with the inclusion of posterior wall and pedicles in more posterior bone metastases site. A typical target volume definition is shown in Figure Indications for SBRT include solitary or up to three vertebral metastases. Lesions should be smaller than 5 cm in diameter. Symptomatic spinal cord compression can represent a contraindication to SBRT treatment . EffectiRe-irradiation to the same bone site should be considered after initial palliative RT in the following scenario: 1) no response in previously irradiated area; 2) partial response and the hope of additional benefit from repeat treatment; 3) pain relapse after initial satisfactory response.versus initial multiple fractions schedule, may be due to the limits of radiation tolerance [Patients requiring re-irradiation represent a substantial group, considering that up to 40% of patients do not obtain any pain relief after initial RT and pain relapse occurs in approximately 50% of initial responders within one year after RT . Globallolerance , 34. Mosversus 24 Gy in multiple fractions. The choice to re-irradiate was left to the radiation oncologist's discretion. Mean time to re-treatment was 13 weeks in single fraction patients and 21 weeks in multiple fractions patients. For the different primary tumors, mean time to re-treatment was 22 weeks for prostate cancer, 14 weeks for breast cancer, 11 weeks for lung cancer and 13 weeks for other primary tumors. Apparently, a longer waiting period to start re-irradiation was observed in patients with prostate cancer compared with the other primary tumors. However only 19% of progressive prostate patients responded again. Thus it seems appropriate to no postpone re-irradiation for too long. Regarding the effectiveness of re-treatment, response was recorded in 66% initial 8 Gy patients and 46% initial multi fractions patients (p = 0.12), with longer mean duration of remission in initial single fraction patients (16 weeks versus 8 weeks).Despite the huge number of patients undergoing re-irradiation, the paucity of data limits definitive guidelines. The International Bone Metastases Consensus Working Party published a consensus on palliative RT in an attempt to promote appropriate set of end-points, including re-irradiation criteria . In the versus 20 Gy in multiple fractions - in patients with bone metastases requiring re-treatment [At present no definitive recommendation can be given regarding dose and fractions in re-irradiation. Single 8 Gy treatment should be considered a valid option. This suggestion is based on the results of the RCT that compared the pain-relieving efficacy of two dose fractionation schedules - single 8 Gy fraction reatment . This waIn case of localized RT-refractory painful bone metastases, SBRT could be considered a treatment option. In previously irradiated bone metastases, several phase I/II trials tested different doses, including 24 Gy in 3 fractions and 10-30 Gy in 1-5 fractions –38. HoweCurrently, new emergent targeted therapies blocking key agents for the development and progression of bone metastases have been tested, especially in prostate cancer field . Based oRecently, the combination of RT and ablative approaches, including radiofrequency ablation (RFA), high intensity focused ultrasound (HIFU) and cryoablation has been proposed as therapeutic option to control painful bone metastases –42. But RT is a well-accepted local treatment modality for patients with painful bone metastases. Effective use of RT requires a well consolidate multidisciplinary approach and a close cooperation between surgical, radiation and clinical oncology, as well as nursing personal is paramount.Single fraction treatment is efficacious and cost-effective for the relief of painful bone metastases.Additional data are required to define the correct fractionation in spinal cord compression and pathological fractures. SBRT has emerged as a modern high precision technique able to improve pain control with durable effect, especially in retreatment setting or oligometastatic patients. However, further data are paramount to better define its role in this scenario.


Recent epidemiological findings suggest that high levels of dietary acid load can affect insulin sensitivity and glucose metabolism. Consumption of high protein diets results in the over-production of metabolic acids which has been associated with the development of chronic metabolic disturbances. Mild metabolic acidosis has been shown to impair peripheral insulin action and several epidemiological findings suggest that metabolic acid load markers are associated with insulin resistance and impaired glycemic control through an interference intracellular insulin signaling pathways and translocation. In addition, higher incidence of diabetes, insulin resistance, or impaired glucose control have been found in subjects with elevated metabolic acid load markers. Hence, lowering dietary acid load may be relevant for improving glucose homeostasis and prevention of type 2 diabetes development on a long-term basis. However, limitations related to patient acid load estimation, nutritional determinants, and metabolic status considerably flaws available findings, and the lack of solid data on the background physiopathology contributes to the questionability of results. Furthermore, evidence from interventional studies is very limited and the trials carried out report no beneficial results following alkali supplementation. Available literature suggests that poor acid load control may contribute to impaired insulin sensitivity and glucose homeostasis, but it is not sufficiently supportive to fully elucidate the issue and additional well-designed studies are clearly needed. Insulin resistance plays a pivotal role in the pathogenesis of multiple metabolic diseases, and it is considered the strongest predictor of diabetes development . Vegetab2, which are excreted via renal system) represents the resultant of and all biochemical reactions occurring in the body and it is mostly constituted by the end-products of amino acids catabolism  − [HCO3−] 24-h urine [§ NAE (mEq/day) = [titratable acids* + NH-h urine .* The potential renal acid load (PRAL) accounts for the intestinal absorption rates of protein, potassium, calcium and magnesium and the dissociation of phosphate reflecting a greater “acid-forming potential” .3 infusion increases adipocyte insulin binding, whereas the infusion of ammonium chloride decreases medium pH and insulin binding to adipocytes due to a change in receptor concentration [3 in healthy individuals [Although there is no conclusive evidence, several pathophysiological mechanisms exist to explain the association between metabolic acidosis and insulin resistance. Systemic infusion of lactate in rats was found to reduce insulin-stimulated glucose transport in muscle during a hyper-insulinemic euglycemic clamp . Animal ntration . In cultntration ,21. Morentration . Other pntration ,33. Intentration ,34,35. Cntration ,37. In tntration , althougntration . Of notentration : screeniividuals . Of noteividuals , an insuividuals  and servividuals .3 in patients affected by renal-induced acidosis resulted in significant increase of serum leptin levels [Leptin is a peptidic hormone involved in the regulation of glycaemic homeostasis being partly responsible for insulin peripheral effects ,45. Leptn levels , results3 availability to promote hydrogen-ions disposal via kidneys [3 (60–120 mmol/day) for 18 days in 14 healthy postmenopausal women reduced urinary total nitrogen levels  [3 was sufficient to reduce nitrogen excretion in middle-aged or older subjects [Preservation of skeletal muscle mass and functionality is critical for glucose homeostasis ,50 as it kidneys . In addi kidneys ,58,59. I kidneys ,61,62. M kidneys . A prosp kidneys . Three i< 0.001) . Similarsubjects  (see Tabsubjects .2) than in overweight/obese women. Kiefte-de Jong et al. [Cross-sectional studies on large groups of individuals are likely to indicate a direct relationship between markers of acid load  and insulin sensitivity or glycemic control. This is in accordance with the observation that consuming higher quantities of fruit and vegetables (low amount dietary acid load) reduces the risk of developing insulin resistance and diabetes ,3. Increg et al.  pooled rg et al. . A furthg et al. . Xu et ag et al.  tracked Acid load was estimated by using both PRAL and NEAP based on a seven-day dietary diary. The study found no correlation between acid load and insulin resistance or β-cell dysfunction. However, the long period of follow up (which can bias the dietary data collected), the relative smallness of the sample size, and the specific age-group of participants enrolled (elderly) are significant confounding factors which can have affected the results achieved, accounting for the lack of consistency with other findings.3 bolus ingestion in 30 individuals with no reported metabolic disturbances in insulin sensitivity or plasma glucose. The authors found that bicarbonate ingestion offset the after-meal-pH lowering observed in the placebo group independent of glucose or insulin concentrations, thereby excluding any preventive effect on postprandial glycemia elicited by alkali supplementation [3 or NaHCO3 was administered for three months. No change in fasting glucose, serum insulin level, or HOMA-IR, was recorded in the bicarbonate-supplemented groups compared with controls (placebo/KCl supplemented).Bicarbonate supplementation was shown to be effective in offsetting acidosis in patients with end-stage kidney failure . Evidencentation . Anotherentation  was condThe data reviewed here strongly suggests an association between glucose metabolism and acid load biochemical markers. Findings which propose an active role of diet-induced acidosis in the regulation of insulin sensitivity are in accordance with experimental data showing that in models of metabolic acidosis, such as end-stage kidney failure, insulin sensitivity can be restored via alkali supplementation ,53. DietOn the other hand, the mechanisms driving the impairment of insulin function following augmented acid load outlined here are speculative and the findings reviewed here prohibit us from discerning the causes of metabolic acid load. Several other underlying metabolic conditions independent of diet composition can influence acid load, and other biochemical mechanisms regulating pH may underlie the consumption of specific diets. In this respect, Mandel et al.  found thSeveral other limitations affecting the studies reviewed can be highlighted, which can also help the interpretation of results as well as lay the basis for further investigations.The degree of insulin sensitivity is often quantified through HOMA-IR determination , which iCalculated NEAP is an indirect measure adopted across the studies reviewed her, although the standard method to quantify acid load is NAE as elsewhere reported . AdoptinSince metabolic acid disposal is regulated by kidneys, renal clearance impacts acid–base balance ,77, and Focus on single determinants can be challenging due to extraneous factors including the presence of nutritional and metabolic confounders and lifestyle habits such that data can be misleading, especially in the case of large epidemiological studies. For instance, the presence of diabetes (pre-diabetes or undiagnosed diabetes) constitutes a factor promoting the increase of acid load as noted above. Population groups at risk for metabolic disturbances are often homogeneous in the context of certain variables and exhibit intrinsic confounders: individuals positive for diabetes are likely to have higher prevalence of metabolic syndrome, poor exercise habits, lower daily fiber intake, and higher intake of trans fats and high-glycemic index foods .BMI and overall energy intake can act as confounders by influencing insulin sensitivity and glucose homeostasis. In addition, differential adipose tissue deposition  can be pivotal to sustain the development of such metabolic disturbances . For insOne of the major concerns of vegetable-based diets is the role of dietary fiber. As noted above, vegetable-based diets are low acid producing diets, and high fiber consumption constitutes a dietetic strategy to control body weight and help prevent the onset of diabetes and insulin resistance ,3,4,5,97Several of the cohort studies discussed above ,15,67,69Finally, there is a significant shortfall of interventional studies on this topic as to substantiate observational evidence. The only two available studies have recorded no significant metabolic effect following supplementation. Of note, the only reported study on prolonged supplementation  was not The control of metabolic acid load appears to be relevant for global metabolic health and may be one of the variables promoting insulin sensitivity and glucose homeostasis impairment in the case of sub-optimal nutritional habits. Furthermore, it could be promising in the light of potential therapy based on alkaline supplementation to enhance glycemic control in diabetic or insulin-resistant patients.Results from epidemiological studies are suggestive but not conclusive due to multiple experimental confounds. The shortfall of interventional studies and the poor knowledge of the underlying mechanism contribute to weakening existing evidence. Taken together, the limitations discussed above underscore the extreme difficulty of achieving clear data. At present, all results suggest that the poor control of dietary acid load can be an additive mechanism underlying glucose metabolism impairment. Therefore, it might be speculated that the beneficial effects gained from vegetable-based diets consumption are partly due to the restraint of dietary acid load.Future investigations are needed to support existing evidence as well as to better elucidate the issue. Experimental analysis should be specifically designed to rule out any potential confounding factors as well as minimize the impact of all the extra variables which negatively affect current studies.


Virtual-assisted lung mapping is a novel bronchoscopic lung marking technique that uses virtual images to perform multiple concurrent dye marking of barely palpable pulmonary tumors. Subsequent chest computed tomography is required to confirm the locations marked. We here report a patient in whom computed tomography after virtual-assisted lung mapping unexpectedly revealed additional tiny pulmonary nodules.A 64-year-old woman with a history of renal cell carcinoma presented with two pulmonary nodules suspicious of metastases from renal cell carcinoma. Because we anticipated that the nodules would be difficult to palpate intraoperatively, we performed virtual-assisted lung mapping prior to attempting to resect them. Computed tomography after mapping unexpectedly detected two additional nodules. Although the existing markings did not relate to the newly found nodules, we used imaginary auxiliary lines and anatomical landmarks to extend the lung map to incorporate the unexpected nodules. The additional nodules were successfully resected by thoracoscopic wedge resection. Pathologic examination identified all nodules as metastases from renal cell carcinoma, and the surgical margins were negative.Imaginary auxiliary lines and anatomical landmarks extended the existing lung map of virtual-assisted lung mapping, enabling resection of unexpected pulmonary nodules found in post-mapping computed tomography images. Small pulmonary nodules can be found in computed tomography (CT) images taken just before surgery, posing a challenge for surgeons. Virtual-assisted lung mapping (VAL-MAP), a novel lung marking technique for facilitating resection of barely palpable pulmonary tumors , is a prPart of the procedure required for successful use of VAL-MAP is performing chest computed tomography (CT) 2–3 h after VAL-MAP to confirm the locations of the markings and construct three-dimensional images of the markings and tumors to plan surgery [A 64-year-old woman was diagnosed as having pulmonary metastases from renal cell carcinoma. She had undergone surgical resections of bilateral renal cell carcinomas 4 years and 1 year previously. A chest CT revealed two nodules in the left lung suspicious of metastases (Fig. However, this CT unexpectedly revealed two additional suspicious tiny nodules in the left lower lobe that had presumably been hidden by the effect of gravity in pre-VAL-MAP CT, which was taken 3 weeks before the VAL-MAP procedure Fig. b. A threTo address this challenge, imaginary auxiliary lines and anatomical landmarks were constructed to extend the lung map to include the unexpected nodules located in S6 and S10 Fig. . ParticuTo enable location of the additional nodules in S10, an auxiliary line was drawn in complete deflation state, horizontally from point g in Fig. Even though additional lesions were barely palpable, they were successfully located and thoracoscopically resected by wedge resections with the aid of the imaginary auxiliary lines and anatomical landmarks Fig. c, d in aWe successfully resected pulmonary nodules discovered unexpectedly just after VAL-MAP. Such newly found nodules may well be encountered in post-VAL-MAP CT images, some because they became large enough to detect during the interval between pre- and post-VAL-MAP CTs, particularly in the case of metastatic lung tumors, and others, more likely, being tiny nodules that remained undetected in the pre-VAL-MAP CT because of positional differences. To better visualize dorsally placed markings, post-VAL-MAP CTs are routinely performed with the patient in a decubitus position . In our Management of such unexpected tiny pulmonary nodules poses the following two problems: whether surgical intervention is still appropriate and, if so, how best to locate the newly found nodules intraoperatively. Surgical resection of pulmonary metastasis is indicated provided the primary lesion is completely controlled, metastases have only been detected in the lungs, and the patient can tolerate surgery . We deciThen next question was whether to take the patient back to the bronchoscopy suite to add more dye markings for the newly found lesions. However, we considered we would be able to resect the nodules if we extended the existing lung map by adding anatomical landmarks and imaginary auxiliary lines on three-dimensional images rather than adding dye markings, as reported previously . AnatomiImportantly, effective use of auxiliary lines requires consideration of the impact of intraoperative deflation of the lung. Because the distances between lesions and landmarks change when the lung is collapsed, ratios calculated from points on multiple imaginary auxiliary lines are useful. In this case, for example, the distance from a marking to the interlobar fissure was almost the same as that from the nodule in S6 to that fissure Fig. b. IndeedIn summary, we successfully achieved complete resection of unexpected pulmonary nodules found after VAL-MAP marking with the aid of imaginary auxiliary lines and anatomical landmarks.


Mammalian cells have developed different mechanisms to recognize invading pathogens lication . To evadlication , is the lication . Arenavilication . The mailication .Besides arenaviruses, coronaviruses are the only other family of viruses known to encode the DEDDh exoribonuclease in the N-terminal domain of the non-structural protein 14 (nsp14) . CoronavBecares and colleagues have recently investigated whether coronaviral nsp14 exoribonuclease can also inhibit type I IFN . RecombiThe enzymatic function of the viral DEDDh exoribonucleases plays important immune suppressive role in divergent virus families of arenaviruses and coronaviruses. New data suggest that in both cases these viral enzymatic proteins are involved in the destruction of immune stimulatory dsRNA, which normally triggers the type I IFN production. Interestingly, both nsp14 and NP do not only play important roles as type I IFN-antagonists but are also intimately involved in the viral genome replicative process. For example, nsp14 contributes to the high-fidelity replication of the relatively large genome of coronaviruses and possesses a secondary function with the viral genomic 5’ cap-modifying methyltransferase activity encoded in the protein’s C-terminal domain. While NP is a required component of the arenaviral replicase, its exact role during viral genome replication and transcription is not fully understood. Because the unique exoribonucleases of these diverse virus families play equally important roles during viral genome replication and transcription, and especially in mediating immune suppression, future research efforts can exploit this conserved DEDDh structural motif and its enzymatic function as a potential molecular target for the development of broad-spectrum antivirals against these deadly human viral pathogens.


The decorrelation signal intensity of hyperreflective foci in the HFL was associated with logMAR VA  and central subfield thickness  but not with DR severity. These data suggest that reflectance-decorrelated foci on OCTA images are clinically relevant as well as shed lights on the properties in diabetic hyperreflective foci.Diabetic hyperreflective foci in the outer retinal layers are a clinically relevant finding on optical coherence tomography (OCT) images, although their characteristics remain to be elucidated. Here we investigated the decorrelation signal around hyperreflective foci on OCT angiography (OCTA) images in diabetic retinopathy (DR). We retrospectively reviewed sufficient quality OCTA images from 102 eyes of 66 patients that were obtained using split-spectrum amplitude-decorrelation angiography algorithm. Most confluent hyperreflective foci were randomly deposited or appeared in a radiating array on the en-face structural OCT images in the inner nuclear layer (INL) or Henle’s fiber layer (HFL), respectively. Within the INL, hyperreflective foci were not accompanied by decorrelation signals and attached to capillaries on OCTA images. Decorrelation signals were sometimes delineated in hyperreflective foci in the HFL and other times appeared to be pseudopod-like or wrapping around hyperreflective foci, referred to as  Vascular hyperpermeability promotes retinal thickening and the deposition of hard exudates, which result in visual impairment in DR. The central subfield (CSF) thickness is modestly related to the reduction of visual acuity (VA), and the subfoveal hard exudates lead to severe visual impairment in diabetic macular edema (DME)5.Diabetic retinopathy (DR) often causes severe visual loss mediated via angiogenesis and the breakdown of the blood-retinal barrier (BRB)8. Hard exudates appear as confluent hyperreflective foci with various sizes, shapes, and reflectivity levels on spectral-domain optical coherence tomography (SD-OCT) images9. In vivo, high-resolution images obtained with adaptive optics scanning laser ophthalmoscopy (AO-SLO) have revealed round or irregular lesions within hard exudates, which had individual turnover rates10. Although these findings suggest heterogeneous components in hard exudates, it is unclear which in vivo imaging finding corresponds to cellular components and which finding corresponds to extravasated materials.According to pathohistological reports, hard exudates are the precipitates of extravasated components and contain hyaline, lipoproteins, or fat-filled phagocytes13. Differences in the reflectivity levels between sequential B-scan images can be enhanced by several image processing algorithms. The movement of erythrocytes with high reflectance allows for the delineation of physiological and pathological vasculature in the retina22. Other highly reflective components, e.g., the nerve fiber layer, retinal pigment epithelium, ellipsoid zone of photoreceptors, and hyperreflective foci, are delineated on structural OCT images, although it remains to be elucidated whether decorrelation signals are derived from such components23.Recent advances in optical coherence tomography angiography (OCTA) have enabled noninvasive evaluation of retinal vasculatureIn the current study, we characterized the decorrelation signals of hyperreflective foci within the inner nuclear layer (INL) and Henle’s fiber layer (HFL) and evaluated the relationship between clinical parameters and quantified decorrelation signal levels within the HFL in DR.9. Confluent hyperreflective foci correspond to hard exudates in fundus findings and are mainly deposited from the INL to the HFL. Three-dimensional OCT imaging demonstrated that hyperreflective foci were randomly deposited in the INL . Multivariate analysis revealed that both the decorrelation signal intensity and the presence of EZ disruption but not CSF thickness were associated with logMAR VA in all 102 eyes .In some eyes, most hyperreflective foci were accompanied by nce Fig. . The prence Fig. . There wnce Fig. , which ance Fig. . Furthernce Fig. . Thirty-The decorrelation signal intensity of hyperreflective foci in the HFL did not differ between individual grades of DR severity in all 102 eyes or 60 eyes without center-involved DME Fig. . In 40 eeflectance-decorrelated foci as a novel OCTA finding. It suggests that hyperreflective foci or hard exudates are heterogeneous in shapes, positions, and optical properties. Intriguingly, statistical analysis demonstrated that the decorrelation signal intensity of the hyperreflective foci in the HFL was clinically relevant in DR. Further investigation should elucidate the effects of reflectance-decorrelated foci on neuroglial dysfunction in diabetic retinas.In the current study, we comparatively studied the structural OCT and OCTA findings of hyperreflective foci in DR. En-face images of the INL revealed randomly deposited hyperreflective foci that rarely had a decorrelation signal on OCTA images. By contrast, hyperreflective foci in the HFL were arrayed in a radiating fashion and were often accompanied by well-circumscribed lesions with a decorrelation signal, which were referred to as r4, suggesting that factors other than the magnitude of edematous changes influence visual impairment. Since there was the correlation between CSF thickness and the decorrelation signal intensity in this study, we considered that vascular hyperpermeability regulates both reflectance-decorrelated foci and retinal edema and that reflectance-decorrelated foci are a novel factor affecting visual dysfunction. In addition, the decorrelation signal intensity was associated with morphological damage in foveal photoreceptors. These data might allow us to hypothesize that hyperreflective foci with decorrelation signals, which would correspond to parts of lipid-laden macrophages or deposited lipoproteins, contribute to foveal photoreceptor damage as well as other unknown neuroglial impairment. Further analyses regarding the local associations between the decorrelation signals and structural OCT would lead to better understanding of the pathogenesis in DR.Multivariate analysis revealed that visual impairment was associated with both foveal photoreceptor damage and the decorrelation signal intensity of hyperreflective foci in the HFL, rather than CSF thickness in DR. Generally, CSF thickness is modestly correlated with VA reduction in DME28. Hyperreflective foci in subretinal fluids can predict the development of subfoveal hard exudates and concomitant poor visual prognosis after intervention for DME27. In a cross-sectional study, hyperreflective foci in the outer retinal layer were associated with both photoreceptor damage and visual impairment in DME26. These publications are consistent with the association between visual reduction and the reflectance-decorrelated foci in the HFL in the current study. Hard exudates or hyperreflective foci represent either the dynamic extravasation or static deposition of blood components. It may allow us to hypothesize that the dynamic optical properties in reflectance-decorrelated foci represent the extravasation and concomitant neuroglial dysfunction rather than the deposited components.Several publications suggest the clinical relevance of hyperreflective foci in DR29. Intraretinal hyperreflective foci also increase in number and size during anti-VEGF treatment for DME, indicating the dynamic rearrangement of hyperreflective foci30. These publications suggest that these types of hyperreflective foci contain dynamic and hyperreflective materials at least in part and might correspond to lipid-laden macrophages migrating in intraretinal or subretinal spaces. It might agree with the dynamic optical properties in reflectance-decorrelated foci in the HFL. Compared with the flow of erythrocytes in blood vessels, the migration speed of phagocytes is generally slow in retinas31. Decorrelation signals might be dependent on morphological changes in microglia/macrophages at the same position or the intracellular rapid trafficking of organelles, e.g., endosomes and lysosomes, containing highly reflective materials33. Reflectance-decorrelated foci often appeared to be pseudopod-like or wrapping around dot-like hyperreflective foci and were not completely matched to hyperreflective foci. Hard exudates contain small reflective particles, e.g., lipoproteins, from which scattering fluctuation can be derived34. The future study has to explain the dynamic optical properties in parts of hyperreflective foci in DR.We could not conclude the origin of decorrelation signals in hyperreflective foci; the movement of highly reflective materials or scattering fluctuation of reflective small particles, e.g., high-density, low-density lipoproteins, or microvesicles. A clinical publication documented that subretinal hyperreflective foci migrate toward the fovea during the absorption of subretinal fluids35. In other words, as smaller molecules, e.g., water and ions, can be absorbed, macromolecules might be concentrated and statically deposited around capillaries. Another potential explanation is that static lipid-laden macrophages are attached to the vascular basement membrane mediated via adhesion molecules. Therefore, lipid-laden macrophages might reside around capillaries, similar to foam cells beneath the endothelial cells in atherosclerosis36.Hyperreflective foci were attached to capillaries in the INL, and the decorrelation signals were not derived from themselves. Since hard exudates are often observed at the boundary of retinal edema, they might be deposited during the absorption of extracellular fluids37. We could not completely exclude the possibility of a ‘false positive’ decorrelation signal, which is generally considered to be delineated around hyperreflective material. Since the optical axial resolution is 5 µm in this device, the thin slab images in the INL and HFL were approximately but not exactly created by the manufacturer’s software. Further advances in imaging acquisition and processing would improve the analyses and interpretation. We evaluated hyperreflective foci on en-face images using the manufacturer’s software, although three-dimensional analyses would provide a better understanding of such lesions. The current study documented hyperreflective foci in DR in a Japanese population in a single center. Further prospective studies should determine whether the data are generalizable to other chorioretinal diseases in multiple centers using other OCTA devices or other segmentation methods for hyperreflective foci.This retrospective study has several limitations. We saw the segmentation errors in several cases, which might have influences on quantification of the decorrelation signal intensity and CSF thickness. The decorrelation signals were affected by projection artifacts, although we excluded areas with such artifacts in the quantitative analyses. Edematous changes or hyperreflective lesions, that is, shadow artifacts, in inner retinal layers reduce the reflective signals beneath themreflectance-decorrelated foci, as a novel OCTA finding, and would promote the understanding of clinically relevant hyperreflective foci in diabetic retinas.In conclusion, for the first time, we documented the decorrelation signal derived from parts of hyperreflective foci within the HFL, referred to as 38.In this retrospective study, we reviewed 102 consecutive eyes of 66 patients with DR who visited the Department of Ophthalmology of Kyoto University Hospital from February 2015 to January 2017. DR eyes with sufficient quality OCTA images, which were acquired using an Optovue RTVue XR Avanti , were consecutively included. An additional inclusion criterion was the presence of hyperreflective foci in both the INL slab (between 38 μm to 47 μm beneath the inner plexiform layer [IPL]/INL boundary) and HFL slab (between 91 μm to 100 μm above Bruch’s membrane) of structural OCT images within a central 3 × 3 mm square. The exclusion criteria were the presence of other chorioretinal diseases, glaucoma or ocular hypertension; an axial length shorter than 22.0 mm or longer than 26.0 mm; preretinal hemorrhages within a central 3 × 3 mm square on color fundus photography; a history of any intervention for macular lesions; intraocular surgery other than cataract extraction; cataract surgery within 6 months of study enrollment; and a signal strength index (SSI) score of 60 or less determined by the default setting of this instrument. Forty-two eyes had center-involved DME according to the manufacturer’s softwareAll research and measurements adhered to the tenets of the Declaration of Helsinki. The Kyoto University Graduate School and Faculty of Medicine Ethics Committee approved the study protocol. All participants provided written informed consent before inclusion in the study.We performed a comprehensive ophthalmic examination, and best-corrected decimal VA was converted to logMAR VA. Axial length was measured using partial coherence interferometry . OCTA images in the 3 × 3 mm square centered on the fovea were obtained using an Optovue RTVue XR Avanti Fig. . Given t39. Foveal photoreceptor status was also evaluated and classified into two categories; intact or not; on the retinal sectional images dissecting the fovea according to the previous reports40.We measured the mean retinal thickness within 1 mm circle at the fovea as CSF thickness according to the manufacturer’s softwareConfluent hyperreflective foci were mainly delineated in the INL and HFL, and two retinal specialists determined the presence or absence of hyperreflective foci in these layers ; when these specialists disagreed, a third specialist participated. The optical or digital axial resolution is 5 or 3 µm in this device, respectively. Segmentation processes in the manufacturer’s software allowed us to create approximate en-face images in the superficial layer . We further prepared 10 µm-thick slab images at the center of the INL (from the inner boundary 38 μm beneath the IPL to the outer boundary 47 μm beneath the IPL) and HFL  using the default setting of the segmentation and following the manual setting of the thickness. We evaluated the qualitative relationship between hyperreflective foci on en-face structural OCT images and decorrelation signals on en-face OCTA images in the INL and HFL.Specifically, we quantified the decorrelation signal intensity of hyperreflective foci in the HFL according to the following three steps; 1. to determine the areas of hyperreflective foci in the HFL Fig. . We firshttp://www.uhnresearch.ca/facilities/wcif/imagej/) was applied to these images to determine the pixels of hyperreflective foci in the areas without the projection artifacts . The agreement of qualitative or quantitative evaluation of hyperreflective foci was confirmed using the kappa coefficient or intraclass correlation coefficient, respectively. The data were analyzed using analysis of variance (ANOVA) with Bonferroni correction to evaluate differences among groups. Pearson’s correlation coefficient was calculated to test the statistical correlation. We applied forced-entry multiple regression analysis  to adjust for a confounding factor.


Despite recent efforts on the development of finite element (FE) head models of infants, a model capable of capturing head responses under various impact scenarios has not been reported. This is hypothesized partially attributed to the use of simplified linear elastic models for soft tissues of suture, scalp and dura. Orthotropic elastic constants are yet to be determined to incorporate the direction-specific material properties of infant cranial bone due to grain fibres radiating from the ossification centres. We report here on our efforts in advancing the above-mentioned aspects in material modelling in infant head and further incorporate them into subject-specific FE head models of a newborn, 5- and 9-month-old infant. Each model is subjected to five impact tests  and two compression tests. The predicted global head impact responses of the acceleration–time impact curves and the force–deflection compression curves for different age groups agree well with the experimental data reported in the literature. In particular, the newly developed Ogden hyperelastic model for suture, together with the nonlinear modelling of scalp and dura mater, enables the models to achieve more realistic impact performance compared with linear elastic models. The proposed approach for obtaining age-dependent skull bone orthotropic material constants counts both an increase in stiffness and decrease in anisotropy in the skull bone—two essential biological growth parameters during early infancy. The profound deformation of infant head causes a large stretch at the interfaces between the skull bones and the suture, suggesting that infant skull fractures are likely to initiate from the interfaces; the impact angle has a profound influence on global head impact responses and the skull injury metrics for certain impact locations, especially true for a parietal impact.The online version of this article (doi:10.1007/s10237-016-0855-5) contains supplementary material, which is available to authorized users. Skull fractures, especially multiple fractures, bilateral fractures, and fractures with complex configuration, are often suspicious for child abuse  and 9-month-olds (9 M) are developed incorporating the nonlinear elastic models for suture, scalp and dura mater, as well as orthotropic skull bone. The models are subjected to extensive drop tests with the same impact angle as in the experiments, as well as compression tests. The influence of impact angle is then studied, followed by a parametric study using linear elastic models for the soft tissues, and with the sutures removed.The FE meshes are generated based on the geometrical reconstructions of computerized tomography (CT) images from Uppsala University Hospital, which were subjected to postmortal forensic investigations at the National Board of Forensic medicine, Uppsala, for various reasons that are not related to the present study. The use of these anonymized CT images was approved by the local ethical committee. No structural abnormalities are observed in the CT images. The resolution for all the CT images was mentclass2pt{minimSoft connective tissues behave nonlinearly in response to external forces, including the suture, scalp and dura mater  and right–left (RL) directions Fig. : the heaN-phase), amplitude (N-amp) and shape (N-shape). The technical details have been published previously, see, e.g. Kimpara et al.  to assess the agreement between the model prediction and the measured acceleration–time impact curves in terms of phase , and the same head mass is ensured by selecting a certain amount of scalp elements (see Methods). However, inherent morphological differences between the cadavers and the FE models can still exist, such as skull shape, thickness and material properties, even at the same age. In particular, fontanelle and suture sizes can vary widely in infants Faix . We notiFor the newborns, the material properties and suture/fontanelle sizes depend heavily on the gestational ages. The newborn model is generated from CT image of foetus at 39-week gestation, while the cadaver head in the experiment that the developed model is compared with is at 34-week gestation Loyd . Thus, tSupplementary material 1 (wmv 470 KB)Supplementary material 2 (wmv 533 KB)Supplementary material 3 (wmv 603 KB)Supplementary material 4 (wmv 752 KB)Supplementary material 5 (wmv 900 KB)Supplementary material 6 (wmv 869 KB)Supplementary material 7 (wmv 791 KB)Supplementary material 8 (wmv 713 KB)Below is the link to the electronic supplementary material.


Developing targeted cancer therapies typically starts with the identification of oncoproteins that are mutated or over-activated in tumors, followed by the development of small molecules that target the oncoproteins. A paradigm example is the development of Gleevec targeting the BCR-ABL oncoprotein in chronic myeloid leukemia. Many other targeted therapies follow this logic, such as compounds that target RAS mutants or overexpressed Myc (reviewed in ). We recThe Achilles heel of cancer is not necessarily the driver of cancer (oncoproteins can be targeted indirectly). When developing anticancer therapeutics, it is natural to think of targeting oncoproteins that cause tumors. Myc is one oncoprotein that is highly pursued as a cancer target. Despite intensive studies, directly targeting Myc remains challenging. However, several bromodomain inhibitors show promising anticancer activity and decrease Myc transcription [cription . MEK/ERKcription . Our stuPhenotype of genetic knockout mice may not predict the effect of small molecule inhibitors. SIRT2 belongs to the sirtuin family of protein lysine deacylases, which play important roles in many biological pathways. There is sustained interest in exploring whether sirtuins can be therapeutic targets for human cancers. However, a previous study showed that Sirt2 knokcout mice tend to develop tumors earlier than wildtype mice [ype mice . So we wFundamental understanding of the underlying biomolecules is important for developing new therapeutic leads. TM, with the best combination of potency and selectivity among known SIRT2 inhibitors, was developed through fundamental understandings of the enzymatic activity of sirtuins. Sirtuins were originally thought to only remove the two-carbon acetyl groups from protein lysine residues. Recent studies reveal that several sirtuins with weak deacetylase activities can efficiently remove other acyl groups. For example, SIRT5 is an efficient desuccinylase and SIRT6 efficiently removes long chain fatty acyl groups. More surprisingly, even the sirtuins with strong deacetylase activity, SIRT1-3, can remove long chain fatty acyl groups efficiently in vitro , deacetylate APC/C (a complex that is important for cell cycle), destabilize Myc, and activate LDH-A  (reviewed in [iewed in  to correOur finding that SIRT2-specific inhibitors are promising therapeutic candidates against Myc-driven cancers also raised many questions. For instance, it is unclear how SIRT2 regulates the expression of E3 ligases of Myc. Also, SIRT2 possesses both deacetylase and defatty-acylase activities. It will be interesting to differentiate the contribution of SIRT2's defatty-acylase activity in cancers from that of the deacetylase activity. Despite these questions, the above lessons we have learned from this project can be useful to other researchers interested in developing anticancer therapeutics.


Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment. Squamous cell carcinoma represents one of the most common cancers worldwide. It is a malignancy that arises from uncontrolled growth of epithelial cells , and norIn recent times, molecular targets that are involved in the regulation of cell death or viability pathways in cancer cell took a center stage in molecular cancer therapy research . Other tSurvivin is a unique member of the IAP family that is expressed in most human tumors, but is barely detected in normal adult tissues , 14. It Drosophila melanogaster fruit flies show similarity with survivin anthracene (DMBA)-induced hamster buccal-pouch squamous-cell carcinomas. They also found demethylation of survivin allele in DMBS-induced OSCC, suggested gene expression may be modulated by an epigenetic mechanism . As survESCC is one of the most malignant tumors. Survivin is overexpressed in most of the esophageal cancer . MalignaNon-small cell lung carcinoma (NSCLC) is a major class of lung cancer. Most of the NSCLC 80-90%) shows overexpression of survivin % shows o. StudiesSquamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma are three major type of skin cancers. BCC and SCC are sometime called non-melanoma cancer . SurviviMany studies have found survivin overexpression in cervical SCC as compared to the normal tissues –112, andCommonly used techniques, such as ELISA and immunohistochemistry are able to measure survivin in tumor samples. In fact, many pharmaceutical companies, such as Cell Signaling (Cat. 7169), Novus Biologicals Cat. BEK-2121-2P) have come up with commercial kits for survivin detection in biological samples. This may be a quick test for poor prognosis and identifying patients with high risk of tumor recurrence, and could be useful in decision making by clinicians on whether such these patients should be subjected aggressive alternative protocols. Several clinical trials are being conducted to establish survivin detection assays for cancer diagnosis  or short-hairpin RNA (shRNA) techniques or antagonizing survivin function by dominant-negative survivin or by small molecules. Therapeutic uses of survivin have been evaluated in several preclinical and clinical studies.Antisense technologies are proving a useful tool for cancer therapeutics. These include uses of antisense oligos, siRNA and shRNA techniques, which specifically suppressed expression of target genes Fig. . AntisenAs in SCCs, inhibition of survivin showed anti-proliferative effects in many other malignancies. An antisense oligo that targets 232 to 251 nucleotide sequence of survivin showed a significant killing of mesothelioma cancer cells and also sensitized them to chemo-radiotherapy . Growth In this technique, a nonfunctional protein is formed due to the replacement of an essential amino acid by another amino acid. Due to having the same targets, these nonfunctional proteins compete with normal protein and dilute its function. Quite few dominant negative mutants have been designed and tested for the inhibition of survivin, out of which T34A mutant is well studied, in which threonine is replaced with alanine at amino acid 34  was constructed by replacement of cystein residue at amino acid 84 with alanine. In gastric cancer cell lines, transfection with plasmid expressing C84A mutant decreased cell growth and induced spontaneous apoptosis . In prosInterestingly combined therapy using survivin negative dominant mutants and chemo-radiotherapies showed better anti-tumor effects. Mostly the effects of survivin mutants combined with other drugs were reported to be synergistic (more than additive). For instance, combined treatment of NSCLC cells with T34A and radiation induced more cell death than single drug treatments, and this effect was more than additive, suggesting that the inhibition of survivin by T34A mutant could sensitize NSCLC cells to radiation treatment . In anotRibozyme (ribonucleic acid enzyme) is a new approach to degrade RNA in cells for therapeutic purposes . SeveralSeveral ribozymes have developed to inhibit survivin in cancer cells. Choi et al.  have desEnhancing immune response against cancer cells represents a fascinating approach to cancer treatment. Tumor cell specific antigens can be recognized by host immune system as short peptides bind with MHC (major histocompatibility complex) molecules . As an e+ CTL [HLA-I restricted T-cell epitopes of survivin were also found in cancer patients that induced CTL response , 166. Su+ CTL . On the + CTL . Another+ CTL . HoweverSurvivin-specific antibodies have been found in the blood samples of cancer patients  and alsoSmall molecules targeting cancer signaling pathways offer an attractive strategy for controlling tumor growth. A range of small molecules and peptides has been identified that control tumor cell proliferation by targeting survivin Fig. . IncreasHistone acetylation/deacetylation plays an important role in epigenetic regulation of transcription in eukaryotic cells . HistoneHDAC proteins have become pervasive cancer treatment targets due to their involvement in multiple signaling pathways that provide a survival advantage for tumor cells . Many smWAF1/CIP1, which in turn activates survivin degradation mediated by suberoylanilide hydroxamic acid (SAHA)-dependent up-regulation of TGFβ [It is known that TGFβ signaling decreases survivin expression in cancer cells in response to stress . A repor of TGFβ . A recen of TGFβ . In pros of TGFβ . A cliniNF-kB contributes significantly to tumorigenesis by activating anti-apoptotic signaling pathways , leadingHsp90 is an important molecular chaperone for the accurate folding and stabilization of various proteins including survivin. It plays central role during cellular stress conditions. It has been discovered that interaction takes place between BIR domain of survivin and ATPase domain of Hsp90 . DisruptShepherdin is a first antagonist derived from survivin sequence Lys79–Leu87 to inhibit Hsp90-survivin complex formation. It is a cell-permeable peptidomimetic, which attenuates formation of Hsp90-survivin complex by competing with survivin to bind at the same site on Hsp90 . InteresPhosphorylation of survivin on Thr34 during mitosis is a key to its functional activation . Tumor cSeveral other molecules have been developed to target survivin for clinical applications. Terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid) drug has shown to inhibit transcription of specific protein 1 (Sp1) regulated genes, such as survivin and cdc2 , which snrb [YM155 is an imidazolium-based small molecule, which selectively inhibits survivin in many different cancer cell lines, such as OSCC, ESCC, HNSCC, NSCLC, colon and cervical carcinoma –217. Stunrb . Specifinrb . Recentlnrb  demonstrnrb . Geneticnrb . In HNSCnrb . Severalnrb  and phasnrb  clinicalnrb . A phasenrb . Also, aSurvivin is one of the top five tumor markers, exclusively overexpressed in most cancers, making it an ideal target for cancer therapeutics. High level of survivin help in the promotion of cancer development through contributing via a wide range of cellular mechanisms including growth and apoptotic pathways. In cancer patients, an elevated level of survivin is often associated with poor prognosis and therapy resistance, and it also promotes metastasis in cancer cells. Several gene silencing studies have clearly demonstrated a crucial role of survivin in cancer development. Currently, most of the cancer treatment protocols are an involved combination of surgery, chemotherapy and radiotherapy, but even after substantial growth in this direction, patient survival rates have not changed much. Therefore, lots of studies are being conducted to explore the possibility of using molecular targeting therapies along with conventional therapies to tackle the menace of cancer. An increasing number of clinical trials are taking place with the selected patients based on validated biomarker-enrichment Table . Survivi


Acipenser ruthenus) chromosome-specific libraries by microdissection and revealed that they painted two or four pairs of whole sterlet chromosomes, as well as additional chromosomal regions, depending on rediploidization status and chromosomal rearrangements after genome duplication. In this study, we employed next generation sequencing to estimate the content of libraries derived from different paralogous chromosomes of sterlet. For this purpose, we aligned the obtained reads to the spotted gar (Lepisosteus oculatus) reference genome to reveal syntenic regions between these two species having diverged 360 Mya. We also showed that the approach is effective for synteny prediction at various evolutionary distances and allows one to clearly distinguish paralogous chromosomes in polyploid genomes. We postulated that after the acipenserid-specific WGD sterlet karyotype underwent multiple interchromosomal rearrangements, but different chromosomes were involved in this process unequally.Several whole genome duplication (WGD) events followed by rediploidization took place in the evolutionary history of vertebrates. Acipenserids represent a convenient model group for investigation of the consequences of WGD as their representatives underwent additional WGD events in different lineages resulting in ploidy level variation between species, and these processes are still ongoing. Earlier, we obtained a set of sterlet ( Whole genome duplications (WGDs), the events resulting in polyploid organisms’ appearance, are not very common among chordate animals  , but thePolyploidy among extant vertebrate animals quite often occurs in ray-finned fishes and amphibians , but it Representatives of the order Acipenseriformes are convenient objects to study the genome evolutionary transformations following WGDs, as this taxon has existed at least since the Early Jurassic . AcipensOne of the features of this group is that all extant species are derived from a putative 60-chromosomal non-polyploid ancestor ,19 afterAcipenser ruthenus, ARUT), a small sturgeon with 2n = 120, recently characterized by an ongoing rediploidization process after the ancestral acipenserid specific WGD [Lepisosteus oculatus, LOC), we predicted syntenic blocks between the two species. It is important to note that the spotted gar  did not undergo any WGDs after 2R [In this study, we focused on sterlet (ific WGD . We obtaafter 2R .As the evolutionary distance between sturgeons and gars is very high (divergence up to 360 Mya ), we alsAll sterlet specimens used here were obtained from fish farms and described previously . MicrodiWe used previously-described chromosome suspensions from the established cell lines . MicrodiGTG (G-banding by trypsin using Giemsa) staining, FISH and microscopy analysis were performed as previously described . To idenLibraries were prepared according to the Illumina TruSeq protocol for the HT Sample Preparation Kit (Illumina) skipping the DNA fragmentation step. 300 bp paired-end reads were generated on Illumina MiSeq using the Illumina MiSeq Reagent Kit v3 according to the manufacturer’s instructions.The analysis was performed with the degenerate oligonucleotide-primed (DOP)seq analyzer pipeline . BrieflyRegions of gar linkage groups showing the smallest pairwise distances between mapped read positions were considered as the target . Regions shorter than 4 kbp and regions with less than 20 mapped positions were not considered.Canis lupus familiaris chromosome 12 (CFA12), read archive SRA:PRJNA285957) [Felis catus, FCA, GCA_000181335.3), cattle , human , gray short-tailed opossum , chicken , spotted gar and zebrafish . The analysis was performed with the DOPseq analyzer pipeline [We used published sequencing data for the flow sorting derived canine chromosome 12 library (A285957)  to evaluFollowing the previously-proposed nomenclature , the 10 From over 90 sterlet chromosome-specific libraries obtained using microdissection. Here, we focused on ten libraries derived from macro- and mid-sized chromosomes of the karyotype, leaving hardly identifiable smaller chromosomes for subsequent studies. As sterlet has a high number of chromosomes 2n = 120), which are difficult to distinguish due to weak banding and similar morphologies (most of the sterlet chromosomes are metacentric), we microdissected anonymous chromosomes and identified the position in the karyotype only after subsequent FISH experiments . The lib0, which FISH experiments with chromosome-specific probes disclosed some features of sterlet paralogous chromosomes. In the absence of any interchromosomal rearrangements after the tetraploidization event, it is expected that one probe hybridizes with two  or four chromosomes  . Here, wHowever, the hybridization pattern was more complicated for other libraries. Most of them hybridized with a whole mid-sized chromosome pair and additionally labelled other regions: either arms of one or two other mid-sized pairs or a whole microchromosome pair. This means that several interchromosomal rearrangements took place during over 100 million years of evolution after the ancestral sturgeon WGD event  .Thus, in the case of R51, the chromosome ARUT13 was microdissected resulting in painting of thewhole ARUT13 and its paralogous regions: ARUT17q and the whole ARUT34 marked a. SimilaAll 10 sampled libraries were sequenced on Illumina MiSeq, an additional round of sequencing with a higher number of reads was performed for the libraries R53, R58, R61, R69 and R70 . Only abTo investigate how the evolutionary distance between the sampled species and the reference genome affects the efficiency of the algorithm for chromosomal region detection, we utilized the previously-sequenced library of the dog chromosome 12 . SynteniOverall, chromosome region predictions remain in a good agreement with cytogenetic and comparative genomics data when alignments are performed within mammals. Alignment to more distant species results in lower power predictions. Alongside, mean alignment lengths are reduced, indicating to the probability of accidental mappings without the underlying true homology. Higher alignment lengths from true sequence matches were also observed in target chromosomes for sterlet vs. gar data .However, alignment to the spotted gar genome still produces meaningful results: three regions of the five predicted seemingly represent true homology, and only two regions are missing. Lack of a specific signal upon the alignment to zebrafish genome is not surprising, given a teleost-specific WGD saturating the signals between two paralogous sequences and extensive rearrangements in teleosts resulting in decreased syntenic region sizes.This study presents the first comparison of Acipenseriformes (sterlet) and Lepisosteiformes (spotted gar) genomes on the chromosomal level. These two groups occupy basal positions among Actinopterygii, have low rates of evolution ,30 and rOur study allowed reconstructing syntenic relations between several sterlet chromosomes and linkage groups of the spotted gar genome. We focused on the sterlet chromosomes of large  and medium  sizes. Recovery of similar spotted gar genome regions from independent libraries derived from ARUT12 , as well as reasonable results of dog-to-gar analysis justified the applicability of the chosen method for chromosome comparisons between species diverging up to 450 Mya thanks to synteny conservation in most vertebrate lineages.The identification of large syntenic regions between genomes of basal Actinopterygii lineages confirmed the hypothesis of relative karyotype conservation in sturgeons . All samPairs of paralogous sterlet chromosomes demonstrate similar homology signals in the spotted gar genome. ARUT3 and ARUT4 are paralogous according to FISH results and share two homologous spotted gar regions (LOC9 and LOC11), but also have differing ones , which mDespite the fact that acipenserids with a similar ploidy level possess similar diploid numbers, some authors assumed species-specific chromosomal rearrangements based solely on the number and distribution of nucleolus organizer regions (NORs) . Ludwig Xenopus laevis has demonstrated that two subgenomes evolved differently after the WGD. While one of the parent genomes remains conserved, the chromosome of the second subgenome evolved much faster and underwent multiple rearrangements and pseudogenization [A recent genomic project on allopolyploid nization . Althougnization . It is nnization  and reptnization ,40. Accunization .To sum up, the sterlet karyotype, although it consists of 120 chromosomes, does not represent just a duplicated karyotype of the acipenseriform ancestor. A high number of interchromosomal rearrangements took place after ASGD. However, the fact that acipenserids easily hybridize and produce fertile offspring implies that most rearrangements have probably occurred in the acipenserid common ancestor. Additional molecular cytogenetic and genomic studies are necessary to investigate the complex genome evolution after WGD events in different acipenseriform species. The method of isolated chromosome sequencing coupled with FISH on other high ploidy level sturgeon species, as well as whole-genome-level synteny analysis would help characterize the karyotype evolution in sturgeons in a more detailed way.