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Objective. The main objective is to compare the clinical efficacy of the early use of dynamic orthosis in patients with a finger extensor digitorum rupture. Methods. A total of 50 patients with hand and foot trauma who received surgical treatment in our hospital from March 2017 to February 2021 were selected, and two patients were excluded from the study. The patients were randomly divided into two groups. The control group (group A) was treated with plaster fixation and routine rehabilitation, and the study group (group B) underwent dynamic low-temperature thermoplastic plate fixation and routine rehabilitation. Total active motion (TAM) and total passive motion (TPM) of the injured finger before treatment, one month after treatment, two months after treatment, and after corrective treatment were compared. Results. After treatment following a finger extensor digitorum rupture, the TAM and TPM of the injured fingers increased significantly in both groups. The TAM and TPM in group B were significantly better than those in group A after one and two months of treatment ( P < 0.05 ). After two months of treatment, the rates of improvement in TAM and TPM in group B were significantly higher than those in group A. Conclusion. The early use of dynamic orthosis can significantly improve the motor function and motion amplitude of the injured finger, increase the elasticity and extension of the finger extensor digitorum, and promote the recovery of muscle strength. It is an effective corrective method for tendon contracture after finger extensor digitorum rupture and has great value in clinical application.

Argonaute 2 (Ago2) is an essential component of the RNA-induced silencing complex (RISC) and it participates in diverse physiological processes, while dysregulation of Ago2 activity is closely linked to a variety of human diseases including cancers. The reported Ago2 assays often suffer from laborious procedures, complicated reaction schemes, and unsatisfactory sensitivity. Herein, we develop a new gold nanoparticle (AuNP)-based single-molecule biosensor for simple and sensitive detection of Ago2 activity. The Ago2-responsive AuNP nanoprobe is constructed through the self-assembly of multiple Cy5-labeled signal probes onto the AuNP, in which the Cy5 fluorescence is efficiently quenched by the AuNP. Target Ago2 can bind with guide RNA to form an active RISC, inducing the cyclic cleavage of the signal probes and the release of Cy5 moieties from the AuNP nanoprobe. The released Cy5 molecules can be simply quantified by single-molecule counting. This single-molecule biosensor enables detection of Ago2 activity with the involvement of only a single AuNP nanoprobe, eliminating the use of any extra antibodies and protein enzymes. This single-molecule biosensor achieves good specificity and high sensitivity with a detection limit of 9.1 pM, and it can be exploited for the screening of Ago2 inhibitors, Ago2 kinetic analysis, and the imaging of intracellular Ago2 activity in live cells, holding great promise in Ago2-related biomedical research and clinical diagnosis.

Protein kinase can catalyze the phosphorylation of peptides/proteins, and it is closely associated with various human diseases such as cancer, immune deficiencies, and Alzheimer's disease. Sensitive monitoring of protein kinase activity is significant for biochemical research and drug discovery. Herein, we develop a phos-tag-based fluorescent biosensor for sensitive detection of cAMP-dependent protein kinase (PKA) activity in cancer cells. We design a peptide-DNA conjugate and a signal probe for PKA activity assay, and employ a biotinylated phos-tag (a selective phosphate-binding agent) to recognize and capture the phosphorylated peptide-DNA substrate. The peptide-DNA conjugates as the catalytic substrates can translate the peptide signal to a nucleotide signal for the initiation of the RNase HII-driven cycling signal amplification. The magnetic nanobeads (MBs) as the carriers can separate and enrich the phosphorylated peptide in complex matrices. Meanwhile, the combination of MBs with the phos-tag-mediated phosphate group recognition can effectively eliminate the interference from the complex matrix, and the introduction of single-molecule detection endows this assay with high sensitivity. This biosensor can achieve a detection limit of 1.98 × 10

Background Abnormal alternative splicing is frequently associated with carcinogenesis. In B-cell acute lymphoblastic leukemia (B-ALL), double homeobox 4 fused with immunoglobulin heavy chain (DUX4/IGH) can lead to the aberrant production of E-26 transformation-specific family related gene abnormal transcript (ERGalt ) and other splicing variants. However, the molecular mechanism underpinning this process remains elusive. Here, we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia. Methods The differential intron retention analysis was conducted to identify novel DUX4/IGH-driven splicing in B-ALL patients. X-ray crystallography, small angle X-ray scattering (SAXS), and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element (DRE)-DRE sites. The ERGalt biogenesis and B-cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity. To check whether recombination-activating gene 1/2 (RAG1/2) was required for DUX4/IGH-driven splicing, the proximity ligation assay, co-immunoprecipitation, mammalian two hybrid characterizations, in vitro RAG1/2 cleavage, and shRNA knock-down assays were performed. Results We reported previously unrecognized intron retention events in C-type lectin domain family 12, member A abnormal transcript (CLEC12Aalt ) and chromosome 6 open reading frame 89 abnormal transcript (C6orf89alt ), where also harbored repetitive DRE-DRE sites. Supportively, X-ray crystallography and SAXS characterization revealed that DUX4 homeobox domain (HD)1-HD2 might dimerize into a dumbbell-shape trans configuration to crosslink two adjacent DRE sites. Impaired DUX4/IGH-mediated crosslinking abolishes ERGalt , CLEC12Aalt , and C6orf89alt biogenesis, resulting in marked alleviation of its inhibitory effect on B-cell differentiation. Furthermore, we also observed a rare RAG1/2-mediated recombination signal sequence-like DNA edition in DUX4/IGH target genes. Supportively, shRNA knock-down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERGalt , CLEC12Aalt , and C6orf89alt . Conclusions All these results suggest that DUX4/IGH-driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE-DRE sites, catalyzing V(D)J-like recombination and oncogenic splicing in acute lymphoblastic leukemia.

Purpose: The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from all-trans-retinoic acid (ATRA) and chemotherapy to ATRA–arsenic trioxide-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed. Experimental Design: This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score). Results: Through combining NRAS mutations, APL9 score, and WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall (P = 0.00031), event-free (P < 0.0001), and disease-free (P = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset. Conclusions: We have proposed a two-category system for improving prognosis in patients with APL. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy.

Math and science motivational beliefs are essential in understanding students' science, technology, engineering, and math (STEM) achievement and choices in high school and college. Drawing on the Eccles' expectancy-value theory and Arnett's emerging adulthood framework, this study examined the relations among high school students' motivational beliefs in ninth grade and their STEM course taking and grade point average (GPA) throughout high school as well as their STEM major choice in college. In addition, we examined subgroup differences across (a) gender and (b) college generation status by testing mean-level differences as well as whether these relations between math and science motivational beliefs and STEM outcomes varied by gender and college generation status. Using nationally representative data from the High School Longitudinal Study (N = 14,040; Mage = 14; 51% female students), this study found that adolescents' math and science motivational beliefs at the beginning of high school were positively associated with STEM achievement and course taking throughout high school and college major choices 7 years later. The results showed that female and first-generation college students had lower math and science self-concept of ability and were less likely to pursue a STEM major in college. However, in most cases, the relations among indicators did not vary by gender and college generation status. This study provided insights for policymakers and practitioners that gender and college generation gaps in STEM are evident at least by the beginning of high school and carry forward to their STEM college choices. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Oxidative stress induces the formation of oxidized low‑density lipoprotein (ox‑LDL), which accelerates the development of atherosclerosis and the rupture of atherosclerotic plaques by promoting lipid accumulation and inhibiting autophagy in vascular cells. Lipophagy is known to be involved in maintaining the balance of neutral lipid metabolism; however, the phenomenon of lipophagy deficiency in ox‑LDL‑treated endothelial cells (ECs) remains to be elucidated. It has been demonstrated that lipid accumulation caused by ox‑LDL inhibits autophagy, which promotes apoptosis in ECs. The aim of the present study was to investigate the association between decreased autophagy and lipid accumulation in ECs treated with ox‑LDL. Electron microscopy demonstrated that the formation of autolipophagosomes was decreased in ox‑LDL‑treated human umbilical vein ECs compared with that in the LDL‑treated group and was accompanied by a decrease in the autophagy‑associated proteins via western blotting analysis. Using laser focal colocalization detection, decreased lipid processing was observed in the lysosomes of ox‑LDL‑treated ECs, which indicated that lipophagy may be attenuated and subsequently result in lipid accumulation in ox‑LDL‑treated ECs.

Background Cushing’s syndrome has been described as a complex endocrine disorder characterized with high cortisol concentration. Correct and early diagnosis of Cushing’s syndrome is challenging. According to the latest guideline, bilateral inferior petrosal sinus sampling (BIPSS) is considered to be the gold standard for the differential diagnosis. However, in some unusual cases, this method may be false positive. Here, we presented a rare case of orbital neuroendocrine tumor secreting adrenocorticotrophic hormone with false positive inferior petrosal sinus sampling. Case presentation A 48-year-old woman was admitted to West China Hospital of Sichuan University, presenting with fatigue, whole body edema for 1 year, alopecia and skin pigmentation for 5 months. Hormonal profiles including plasma cortisol and adrenocorticotrophic hormone (ACTH) measurements and low-dose dexamethasone inhibition test suggested that the patient had Cushing’s syndrome. However, during tumor location phase, the results of high-dose dexamethasone inhibition test (HDDST) contradicted desmopressin (DDAVP) stimulation test. Thus, BIPSS was employed, and its results indicated a pituitary origin. Interestingly, MRI of sellar region showed an innocent pituitary but caught a serendipitous lesion in the lateral rectus muscle of left eye, which was later proved to be an orbital neuroendocrine tumor secreting ACTH by pathological and immunohistochemical results. ACTH level of the patients was Conclusion We reported a rare case of endogenous Cushing’s syndrome due to ectopic ACTH secreting from an orbital neuroendocrine tumor. This unique case of orbital EAS suggests that orbital venous blood backflow, owning to abnormal anatomic structures, may possibly lead to false positive BIPSS results.

Circulating tumor DNA (ctDNA) is a type of cell-free DNA released by tumor cells after necrosis and apoptosis, and it can be actively secreted by tumor cells. Since ctDNA is derived from various tumor sites, it can provide far more comprehensive genomic and epigenomic information than a single-site biopsy. Therefore, ctDNA can overcome tumor heterogeneity, which is the major limitation of a traditional tissue biopsy approach. Noninvasive ctDNA assays allow continuous real-time monitoring of the molecular status of cancers. Recently, ctDNA assays have been widely used in clinical practice, including cancer diagnosis, evaluation of therapeutic efficacy and prognosis, and monitoring of relapse and metastasis. Although ctDNA shows a high diagnostic performance in advanced esophageal cancer, it is far from satisfactory for early diagnosis of esophageal cancer. Monitoring the dynamic changes of ctDNA is beneficial for the evaluation of therapeutic efficacy and prediction of early recurrence in esophageal cancer. It is necessary to establish standards for individualized ctDNA detection in the evaluation of treatment response and surveillance of esophageal cancer and to develop clinical practice guideline for the systemic treatment of patients with "ctDNA recurrence." This review aims to provide an update on the role of ctDNA in the diagnosis and monitoring of esophageal cancer.

We demonstrate for the first time the simultaneous measurement of the acetyltransferase (HAT) and crotonyltransferase (HCT) activities of histone acetylation writer p300 by integrating antibody-based fluorescence labeling with single molecule detection. This methods exhibits good specificity and high sensitivity. Moreover, it can accurately evaluate the kinetic parameters of both the HAT and HCT activities of p300 and screen inhibitors.

Our previous investigation suggested that faster seventh cervical nerve (C7) regeneration occurs in patients with cerebral injury undergoing contralateral C7 transfer. This finding needed further verification, and the mechanism remained largely unknown. Here, Tinel's test revealed faster C7 regeneration in patients with cerebral injury, which was further confirmed in mice by electrophysiological recordings and histological analysis. Furthermore, we identified an altered systemic inflammatory response that led to the transformation of macrophage polarization as a mechanism underlying the increased nerve regeneration in patients with cerebral injury. In mice, we showed that, as a contributing factor, serum amyloid protein A1 (SAA1) promoted C7 regeneration and interfered with macrophage polarization in vivo. Our results indicate that altered inflammation promotes the regenerative capacity of the C7 nerve by altering macrophage behavior. SAA1 may be a therapeutic target to improve the recovery of injured peripheral nerves.

MicroRNAs are essential post-transcriptional regulators and may act as the noninvasive biomarkers for disease diagnosis. Sensitive and multiplexed detection of microRNAs may facilitate the accurate and early clinical diagnosis, but the available methods are usually compromised by using organic dyes as the signal probes, laborious chemical and enzymatic manipulations, and the complicated reaction schemes. Here we reported a siRNA-directed self-assembled quantum dot (QD) biosensor for facile and simultaneous detection of multiple microRNAs. In this biosensor, the binding of microRNA targets with corresponding QD nanoprobes leads to the formation of siRNA duplexes, which not only induces the spectrally resolved coding of microRNAs, but also facilitates the assembly of QDs:magnetic nanoparticle bioconjugates for the isolation and enrichment of target microRNAs. The disassembled QDs can be sensitively detected by single-molecule detection, enabling quantitatively sensing of microRNAs at the single-particle level. This biosensor employs only QDs as the signal reporters, which can simultaneously detect multiple microRNAs from the same sample and achieves femtomolar sensitivity and single-base mismatch selectivity without the involvement of any target labeling and amplification steps. Moreover, it can be successfully applied for simultaneous detection of circulating microRNAs in clinical serum samples, holding great potential in non-invasive early diagnosis and biomedical researches.

Background: Circular RNA (circRNA) is highly expressed in the brain tissue, but its molecular mechanism in cerebral ischemia-reperfusion remains unclear. Here, we explored the role and underlying mechanisms of circRNA antisense non-coding RNA in the INK4 locus (circ_ANRIL) in oxygen-glucose deprivation and reoxygenation (OGD/R)-induced cell injury. Results: The expression of circ_ANRIL in OGD/R-induced human brain microvascular endothelial cells (HBMECs) was significantly up-regulated, while that of miR-622 was significantly down-regulated. Overexpression of circ_ANRIL significantly inhibited the proliferation of OGD/R-induced HBMECs and aggravated OGD/R-induced cell apoptosis. Moreover, circ_ANRIL overexpression further increased the secretion of interleukin (IL)-1β, IL-6, tumor necrosis factor-a, and monocyte chemoattractant protein-1 in OGD/R-treated HBMECs. The results of bioinformatics analysis and luciferase reporter assay indicated that circ_ANRIL served as an miR-622 sponge to negatively regulate the expression of miR-622 in OGD/R-treated HBMECs. Additionally, circ_ANRIL silencing exerted anti-apoptotic and anti-inflammatory effects by positively regulating the expression of miR-622. Furthermore, inhibition of OGD/R-induced activation of the nuclear factor (NF)-kB pathway by circ_ANRIL silencing was significantly reversed by treatment with miR-622 inhibitor. Conclusions: Knockdown of circ_ANRIL improved OGD/R-induced cell damage, apoptosis, and inflammatory responses by inhibiting the NF-κB pathway through sponging miR-622.

Perchlorate (ClO4−) is harmful to human health, and knowledge on the levels and sources of natural ClO4− in different environments remains rather limited. Here, we investigate ClO4− in aerosol samples collected along a cross-hemisphere ship cruise between China and Antarctica and on a traverse between coastal East Antarctica and the ice sheet summit (Dome Argus). Perchlorate concentrations range from a few to a few hundred pg m−3. A clear latitudinal trend is found, with elevated ClO4− concentrations near populated areas and in the southern mid-high latitudes. Spatial patterns of atmospheric ClO4− over oceans near the landmasses support that terrestrial ClO4− is not transported efficiently over long distances. In the southern mid-latitudes, higher ClO4− concentrations in March than in November-December may be caused by significant stratospheric inputs in March. Perchlorate concentrations appear to be higher in the warm half than in the cold half of the year in the southern high latitudes, suggesting seasonal difference in main atmospheric sources. ClO4− may be formed in the reactions between chlorine free radical (Cl·) and ozone (O3) in the stratosphere when Antarctic ozone hole occurs during September-October. And the stratosphere-produced ClO4− is moved to the boundary layer in several months and may be responsible for the high ClO4− concentrations in the warm half of the year. Perchlorate produced by photochemical reactions between O3 and Cl· in the Antarctic stratosphere is likely responsible for the higher ClO4− concentrations in Antarctica than in Arctic.

Carpal tunnel syndrome (CTS) is a most common peripheral nerve entrapment neuropathy characterized by sensorimotor deficits in median nerve innervated digits. Block-design task-related functional magnetic resonance imaging (fMRI) studies have been used to investigate CTS-related neuroplasticity in the primary somatosensory cortices. However, considering the persistence of digital paresthesia syndrome caused by median nerve entrapment, spontaneous neuronal activity might provide a better understanding of CTS-related neuroplasticity, which remains unexplored. The present study aimed to investigate both local and extensive spontaneous neuronal activities with resting-state fMRI. A total of 28 bilateral CTS patients and 24 normal controls were recruited, and metrics, including amplitude of low-frequency fluctuation (ALFF) and voxel-wise functional connectivity (FC), were used to explore synaptic activity at different spatial scales. Correlations with clinical measures were further investigated by linear regression. Decreased amplitudes of low-frequency fluctuation were observed in the bilateral primary sensory cortex (SI) and secondary sensory cortex (SII) in CTS patients (AlphaSim corrected P < .05). This was found to be negatively related to the sensory thresholds of corresponding median nerve innervated fingers. In the voxel-wise FC analysis, with predefined seed regions of interest in the bilateral SI and primary motor cortex, we observed decreased interhemispheric and increased intrahemispheric FC. Additionally, both interhemispheric and intrahemispheric FC were found to be significantly correlated with the mean ALFF.

SETD2, the histone H3 lysine 36 methyltransferase, previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in myelodysplastic syndromes (MDSs) has been unclear. In this study, low expression of SETD2 correlated with shortened survival in patients with MDS, and the SETD2 levels in CD34+ bone marrow cells of those patients were increased by decitabine. We knocked out Setd2 in NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and found that loss of Setd2 accelerated the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhanced the ability of NHD13+ hematopoietic stem and progenitor cells (HSPCs) to self-renew, with increased symmetric self-renewal division and decreased differentiation and cell death. The growth of MDS-associated leukemia cells was inhibited though increasing the H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulated hematopoietic stem cell signaling and downregulated myeloid differentiation pathways in the NHD13+ HSPCs. Our RNA-seq and chromatin immunoprecipitation–seq analysis indicated that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in the NHD13+ HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, including Ikba and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrated that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.

As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.

IntroductionEarly adolescence is a developmental period in which peer victimization, bullying, relational aggression, and social exclusion are particularly prominent. As these behaviors have long-term implications for children, in this study, we investigated early variations of prosocial behaviors as one of the critical precedents that shape youth's subsequent peer relational outcomes. Specifically, we identified different profiles of prosocial behaviors in middle childhood (Grade 4) and related these profiles to peer relationships in early adolescence (Grade 6).MethodUsing longitudinal data from the NICHD Study of Early Child Care and Youth Development (N=914; 52% girls), a three-step latent profile analysis was conducted on Grade 4 prosocial behaviors, which were then related to Grade 6 teacher- and student-rated peer relationships (e.g., relational aggression).ResultsFour patterns of prosocial behaviors emerged: low prosocial (18%), high prosocial (67%), primarily friendly (8%), and primarily kind (7%). These four patterns of prosocial behaviors were differentially related to later problematic peer relationships: Low prosocial youth demonstrated the most problematic peer relationships (Mdiff=0.36-0.93, all p&nbsp

Objective: Contralateral C7 nerve root transfer surgery has been successfully applied to rescue motor function of a hemiplegic upper extremity in patients with central neurological injury. This surgical technique is challenging, and limited anatomical space makes it difficult to manipulate tissues and may lead to higher complication rates. The authors hypothesis a new surgical route in which cervical nerve roots of both donor and recipient sides are exposed from a posterior intradural approach and neurorrhaphy is performed easily and clearly. The feasibility of this operation is tested in a cadaver model. Methods: A fresh cadaver was placed prone. After a standard midline incision and extensive cervical laminectomy, the dura and arachnoid were widely opened, and the spinal nerve roots of C6, C7, and C8 were exposed bilaterally. Nerve grafting was attempted between pairs of donor and recipient nerve roots on contralateral sides of the spinal cord. After completion of neurorrhaphy, the dura was closed. Results: Precise neurorrhaphy could be performed intradurally between posterior and anterior nerve roots of C7 on both sides. Multiple anastomoses of C7 to various nerve roots on the contralateral side could also be performed within the same surgical field with an interposition nerve graft. Conclusion: The posterior intradural repair idea affords many advantages, the pathway is shorter and more straightforward, which provides more access to multiple nerve roots repair in one surgical field, and is more familiar to many neurosurgeons and spine surgeons. It may potentially be adapted for clinical use.

Spastic arm paralysis after central neurological injury has a long-term effect on the patient's quality of life. Effective neurosurgical treatment for this dysfunction has been described in our previous studies. It is of great significance to determine a set of unified and concise clinical standards for motor function grading in the neurosurgical treatment and management.We first conducted a retrospective study that included 51 hemiplegic patients from the Neurosurgery and Microsurgery outpatient database of Huashan Hospital. The neurosurgeons cooperated with rehabilitation experts to design and administer the new rating system (Hua-Shan Grading of Upper Extremity, H-S grading) after analyzing the scale scores and video records of these patients. We then randomly enrolled 64 patients with unilateral spastic arm paralysis after stroke or brain trauma. The Fugl-Meyer Assessment, the Ashworth scale and the new grading system were applied and analyzed to evaluate the participants' motor function.Based on rehabilitation medicine scales and long-term follow-up, a feasible and concise grading system was applied that was based on the patients' characteristics and the examination experiences of neurosurgeons and rehabilitation experts in clinical practice. This method could effectively grade upper extremity motor function, usually in 3-5 minutes. A significant correlation was found between H-S grading and the Fugl-Meyer score by the Spearman test (r = .937, P.01). The mean difference between any two levels of the new grading system was significant (P.05). And good test-retest reliability, the Cronbach's alpha coefficient and the validity indices were presented. In addition, it was more sensitive to motor function compared with the Ashworth scale.As a supplement to the classic scales, H-S grading was developed in the area of spastic hemiplegia treatment. It is standardized and simplified for patients in the chronic stage after central neurological injury.

Introduction: Histone modifying enzymes (HMEs)-catalyzed histone modifications are important epigenetic markers that play critical roles in the regulation of a variety of cellular functions, especially the regulation of gene expression. The aberrant histone modifying enzyme activity and the abnormal histone modification level are closely associated with various human diseases including cancers, making them become the promising and attractive disease biomarkers. Consequently, the development of efficient assays for accurate and sensitive detection of histone modifications and HMEs are crucial for disease diagnosis. Areas covered: In this review, we summarize the advances in histone modifications and HMEs assays in recent 5 years (2013-2018), including the development of various methods based on fluorescent, bioluminescent, colorimetric, electrochemical, surface-enhanced Raman scattering, and mass spectrometry strategies. Their principles and applications for in vitro and in vivo assays are reviewed, and the future directions are discussed as well. Expert commentary: In comparison with the conventional radioactive and Western blot assays, the newly developed histone modifications and HMEs assays exhibit distinct advantages. Especially, the introduction of novel nanomaterials and advanced analytical techniques in recent years has greatly improved the assay performances, promoting their further applications in biomedical research and clinical diagnosis.

Patients with cerebral palsy and spastic hemiplegia may have extremely poor upper extremity function. Unfortunately, many current therapies and treatments for patients with spastic hemiplegia offer very limited improvements. One innovative technique for treating these patients is the use a contralateral C7 nerve root transfer to neurotize the C7 nerve root in the affected limb. This may result not only in less spasticity in the affected limb, but also improved control and motor function vis-a-vis the new connection to the normal cerebral hemisphere. However, contralateral C7 transfers can require large incisions and long nerve grafts. The aim of this study was to test the feasibility of a contralateral C7 nerve root transfer procedure with the use of a prevertebral minimally invasive robot-assisted technique. In a cadaver, both sides of the C7 root were dissected. The right recipient C7 root was resected as proximally as possible, while the left donor C7 root was resected as distally as possible. With the use of the da Vinci (®) SI surgical robot (Intuitive Surgical ™, Sunnyvale, CA, USA), we were able to eliminate the large incision and use a much shorter nerve graft when performing contralateral C7 nerve transfer.

Human health is threatened by obesity which causes the increasing incidence of various diseases, especially stroke. Ischemic stroke (IS) is mostly caused by the rupture of arterial plaque, whose instability is positively associated with matrix metalloproteinases (MMPs) that degrades extracellular matrix components. Studies have shown that matrix metalloproteinase-12 (MMP-12) may be involved in the pathogenesis of IS. Because of the higher incidence of stroke in obese patients than that in normal weight people, it is urgent for obesity to forecast stroke early. Considering high levels MMP-12 in obesity, we put forward that MMP-12 may be a potential biomarker for IS in obese patients.

Background Cutaneous squamous cell carcinoma (CSCC) is a common type of skin malignancy. MicroRNA-221 (miRNA-221) is a critical non-coding RNA in tumor initiation and progression. However, the molecular mechanisms of miRNA-221 in the development of CSCC remain unknown. This study investigated the expression of miRNA-221 in CSCC and its potential tumor biological functions. Methods MTT assay, colony assay, PCR, and Western blot were adopted. Results In this study, miRNA-221 expression was significantly higher in CSCC tissues and cell lines than in normal tissues and cells (P

Background Spasticity and muscle weakness are common severe neurologic sequelae after stroke. Contralateral peripheral neurotization has been applied successfully to promote motor function of the hemiplegic upper extremity in patients with central neurological injury. To our knowledge, we present the first report of contralateral lumbar to sacral nerve transfer for the lower extremities in hemiplegic patients after stroke. Case Description Two patients were enrolled in the study. The first patient is a 57-year-old man who experienced permanent muscle weakness in his left leg after a right cerebral infarction. The second patient is a 42-year-old man who had spasticity and hemiplegia in both upper and lower limbs on the right side 32 months after a left cerebral hemorrhage. Both patients underwent contralateral lumbar–to–sacral nerve rerouting to improve lower-limb motor function. Twenty months after surgery, both patients experienced significant improvement in ambulatory status. Conclusions Although long-term follow-up and a randomized controlled trial are required, this study demonstrates the safety and possible benefits of contralateral lumbar–to–sacral nerve transfer for hemiplegic patients after stroke. This novel surgical approach could provide a new means for lower-limb motor functional recovery.

OBJECTIVEContralateral C7 (CC7) nerve root has been used as a donor nerve for targeted neurotization in the treatment of total brachial plexus palsy (TBPP). The authors aimed to study the contribution of C7 to the innervation of specific upper-limb muscles and to explore the utility of C7 nerve root as a recipient nerve in the management of TBPP.METHODSThis was a 2-part investigation. 1) Anatomical study: the C7 nerve root was dissected and its individual branches were traced to the muscles in 5 embalmed adult cadavers bilaterally. 2) Clinical series: 6 patients with TBPP underwent CC7 nerve transfer to the middle trunk of the injured side. Outcomes were evaluated with the modified Medical Research Council scale and electromyography studies.RESULTSIn the anatomical study there were consistent and predominantly C7-derived nerve fibers in the lateral pectoral, thoracodorsal, and radial nerves. There was a minor contribution from C7 to the long thoracic nerve. The average distance from the C7 nerve root to the lateral pectoral nerve entry point of the pectoralis major was the shortest, at 10.3 ± 1.4 cm. In the clinical series the patients had been followed for a mean time of 30.8 ± 5.3 months postoperatively. At the latest follow-up, 5 of 6 patients regained M3 or higher power for shoulder adduction and elbow extension. Two patients regained M3 wrist extension. All regained some wrist and finger extension, but muscle strength was poor. Compound muscle action potentials were recorded from the pectoralis major at a mean follow-up of 6.7 ± 0.8 months; from the latissimus dorsi at 9.3 ± 1.4 months; from the triceps at 11.5 ± 1.4 months; from the wrist extensors at 17.2 ± 1.5 months; from the flexor carpi radialis at 17.0 ± 1.1 months; and from the digital extensors at 22.8 ± 2.0 months. The average sensory recovery of the index finger was S2. Transient paresthesia in the hand on the donor side, which resolved within 6 months postoperatively, was reported by all patients.CONCLUSIONSThe C7 nerve root contributes consistently to the lateral pectoral nerve, the thoracodorsal nerve, and long head of the triceps branch of the radial nerve. CC7 to C7 nerve transfer is a reconstructive option in the overall management plan for TBPP. It was safe and effective in restoring shoulder adduction and elbow extension in this patient series. However, recoveries of wrist and finger extensions are poor.

BACKGROUND Central neurological injury (CNI) is a major contributor to physical disability that affects both adults and children all over the world. The main sequelae of chronic stage CNI are spasticity, paresis of specific muscles, and poor selective motor control. Here, we apply the concept of contralateral peripheral neurotization in spasticity releasing and motor function restoration of the affected upper extremity. OBJECTIVE A clinical investigation was performed to verify the clinical efficacy of contralateral C7 neurotization for rescuing the affected upper extremity after CNI. METHODS In the present study, 6 adult hemiplegia patients received the nerve transfer surgery of contralateral C7 to C7 of the affected side. Another 6 patients with matched pathological and demographic status were assigned to the control group that received rehabilitation only. During the 2-year follow-up, muscle strength of bilateral upper extremities was assessed. The Modified Ashworth Scale and Fugl-Meyer Assessment Scale were used for evaluating spasticity and functional use of the affected upper extremity, respectively. RESULTS Both flexor spasticity release and motor functional improvements were observed in the affected upper extremity in all 6 patients who had surgery. The muscle strength of the extensor muscles and the motor control of the affected upper extremity improved significantly. There was no permanent loss of sensorimotor function of the unaffected upper extremity. CONCLUSION This contralateral C7 neurotization approach may open a door to promote functional recovery of upper extremity paralysis after CNI.

Craniopharyngioma (CP), a rare benign and slow-growing epithelial tumor, is mainly located within the sellar/parasellar region. Primary CP involving the nasal cavity and the sellar region with extensive erosion of the skull base and ossification simultaneity has not been described previously. The authors report a 23-year-old man who presented to our institute with complaints of repeated nasal cavity bloodshed, liquid flow, and progressive visual loss. A neuroimaging examination showed a giant cranionasal and cystic-solid CP extending from the suprasellar region to the nasopharynx with inhomogeneous enhancement, which is associated with extensive erosion of the skull base and ossification. The patient underwent a transsphenoidal surgery to resect the nasopharyngeal component of CP and a subfrontal craniotomy with a total removal of intracranial component by grinding 3 months later. A histopathologic examination revealed characteristic features of adamantinomatous CP associated with ossification. The current study demonstrates that CP can exhibit cranionasal growth pattern and arise from residue of craniopharyngeal duct. Extensive erosion of the skull base, calcification, and ossification can present in tumor simultaneity. A 2-stage stratagem is important for its total removal because of the peculiar hardness. Postsurgical course is unevenly and should be dealt with carefully.

Spatial disorientation in airplane pilots is a leading factor in many fatal flying accidents. Spatial orientation is the product of integrative inputs from the proprioceptive, vestibular, and visual systems. One condition that can lead to sudden pilot incapacitation in fight is vestibular neuritis. Vestibular neuritis is commonly diagnosed by a finding of unilateral vestibular failure, such as a loss of caloric response. However, because caloric response testing reflects the function of only the superior part of the vestibular nerve, it cannot detect cases of neuritis in only the inferior part of the nerve. We describe the case of a Chinese naval command fighter pilot who exhibited symptoms suggestive of vestibular neuritis but whose caloric response test results were normal. Further testing showed a unilateral loss of vestibular evoked myogenic potentials (VEMPs). We believe that this pilot had pure inferior nerve vestibular neuritis. VEMP testing plays a major role in the diagnosis of inferior nerve vestibular neuritis in pilots. We also discuss this issue in terms of aeromedical concerns.

The present study was performed in China to compare the efficacy and safety of an advanced wound dressing made of crystalline cellulose (Veloderm) to a conventional treatment of three Vaseline gauzes in the management of skin donor sites of burns or reconstructive plastic surgery. In this prospective, multicenter, open-labeled, randomized clinical trial performed in three Chinese burn centers in China, 96 patients who required autologous split skin graft were randomized into either the test (Veloderm) group or the control (Vaseline gauze) group. Average healing times in the test group and in the control group were 8.40±2.90 and 8.92±2.58 days, respectively, with median values of 7.00 and 8.00 days, respectively: the difference between two groups was statistically significant (P=.045). Scores for exudates, pain intensity, and peripheral erythema showed no difference between the groups; however, composite scores of three variables on day 10 postoperatively was significantly lower in the test group (0.00±0.00 vs. 0.13±0.49; P = .043). The need for a dressing change was also significantly lower in the test group (12.5 vs. 31.25%; P = .036). Veloderm is a safe and effective dressing that may offer some advantages over the traditional application of Vaseline gauze in the management of donor sites in burn or reconstructive plastic surgery patients.

Objective There is little information available regarding Chinese patients with Hodgkin lymphoma (HL). We analyzed the clinical features, outcome, and prognostic factors of Chinese patients with HL, aiming to establish a new risk model for better risk-adapted therapeutic strategy. Patients and Methods Patients with newly diagnosed HL at 4 medical centers from January 2000 to August 2014 were recruited. Results A total of 150 patients were reviewed. The median age was 30 years (range, 15-91 years). At completion of initial therapy, 73.65% of patients achieved complete remission. The 5-year event-free survival (EFS) of the entire cohort was 61.1%, the overall survival was 84.7%, and the disease-free survival was 78.8%. B symptoms, extranodal involvement, and International Prognostic Score ≥ 3 remained as independent prognostic factors of EFS. Patients who failed to reach complete remission on interim positron emission tomography/computed tomography or computed tomography had a significantly worse outcome than those who did. A new risk model incorporating traditional risk factors and interim response stratified patients into 3 classes, with a 5-year EFS of 100%, 83.1%, and 33.1%, respectively ( P Conclusions General clinical features were comparable with those of Western patients, whereas therapeutic outcomes were slightly inferior. The novel risk assessment model showed potential as a more powerful prognostic tool by identifying 3 subsets of patients with significantly distinct outcomes, which warrants further validations.

To evaluate the safety and effectiveness of Shenbei Guchang capsules in treatment of diarrhea type irritable bowel syndrome (yang deficiency of spleen and kidney) under widely used conditions, an open, multicenter, controlled, phase Ⅳ clinical trial was conducted in the drug clinical trial centers of 16 domestic hospitals. 2 123 patients from June 10, 2011 to November 29, 2012 were enrolled in the trial. Drug clinical trial was approved by Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital Ethics Committee before implementation. Before the start of trial, subjects were selected according to the research scheme and inclusion criteria, then they would step into the 14 d study after signing Informed Consent Form. All subjects were treated according to the research scheme, evaluated the conditions and filled in CFR sheet, to provide the evaluation data and information on safety and efficacy of Shenbei Guchang capsules. Shenbei Guchang capsules were used to treat diarrhea type irritable bowel syndrome in widely used conditions (2 123 cases), and 2 029 cases of them entered FAS set, cure+markedly effective in 1 921 cases, with a comprehensive curative effect rate of 94.68%; 2 010 cases of them entered PPS set, cure+markedly effective in 1 906 cases, with a comprehensive curative effect rate of 94.83%. The primary symptoms of IBS were abdominal pain and diarrhea. After treatment, both abdominal pain and diarrhea were improved, with significant differences (P

Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high-throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (P = .05). Importantly, SRSF2 mutations are associated with worsened overall survival in MPN patients who undergo LT in univariate (P = .03; HR, 2.77; 95% CI, 1.10-7.00) and multivariate analysis (P < .05; HR, 2.11; 95% CI, 1.01-4.42). These data suggest that SRSF2 mutations contribute to the pathogenesis of LT and may guide novel therapeutic approaches for MPN patients who undergo LT.

BACKGROUND A functional vestibular system is a prerequisite for motion sickness (MS) to occur. The otolithic organs (saccule and utricle) are currently considered to be important in the pathogenesis of MS. Recent investigations have demonstrated that the ocular vestibular evoked myogenic potentials (oVEMP) test is an objective evaluation of utricular function. To date, there is no functional guide that can serve as a diagnostic tool for individual susceptibility to MS. Therefore, we investigated the link between oVEMP and MS susceptibility. METHOD The oVEMP test was performed on 31 MS susceptible and 23 nonsusceptible individuals. MS susceptibility was determined by self-declaration and by using the MS susceptibility questionnaire (MSSQ) and the Hamilton Anxiety Scale (HAS). RESULTS Bilateral oVEMP responses were obtained in all subjects. HAS and MSSQ scores between the susceptible and nonsusceptible group were 18.27 +/- 5.23 vs. 2.34 +/- 1.21 and 28.12 +/- 6.53 vs. 2.34 +/- 1.45, respectively. Statistically significant differences in MSSQ and HAS scores were found between the MS susceptible and nonsusceptible groups. No differences were found between MS susceptible and nonsusceptible subjects in N10 and P15 wave latencies, N10-P15 interval, or peak-to-peak N10-P15 amplitude. However, there was a trend toward greater asymmetry ratio in the MS susceptible group than in the MS nonsusceptible group (18.55 +/- 10.24% vs. 13.25 +/- 9.47%), although statistical significance was not reached. DISCUSSION It appears that no relation exists between oVEMP results and MS susceptibility. Nevertheless, the differences in the asymmetry ratios of oVEMP interpeak amplitude between the two groups revealed a trend toward marginal statistical significance.

Objective: To investigate the gene mutation and the clinical features of CSF3R, SETBP1 and SRSF2 in chronic neutrophilic leukemia (CNL) and chronic myelomonocytic leukemia (CMML) patients. Method: Sequence analysis of CSF3R, SETBP1 and SRSF2 were performed in 10 CNL and 56 CMML patients whose clinical features were also studied. Result: Among 10 CNL patients, 8(8/10, 80%) patients had CSF3R mutations and 7(7/8, 87.5%) of them were with CSF3R T618I. In 56 cases of patients with CMML, SRSF2 mutations were found in 14(14/56,25%), CSF3R in 4(4/56,7.1%) and SETBP1 in 3(3/56, 5.3%) patients. In CMML, compared to wild-type(wt) SRSF2 patients, SRSF2 mutated patients appeared to be more possible with SETBP1 mutations [1/14(7.1%) vs. 2/42(4.8%), P>0.05], less possible with CSF3R mutation [0/14(0%) vs. 4/42(9.5%), P Conclusion: The majority of patients with WHO-defined CNL have oncogenic mutations in CSF3R and the T618I mutation type is a highly sensitive and specific molecular marker of the disease. While mutations of SRSF2 are common in CMML and may be of prognostic significance. As a non-specific molecular marker, SETBP1 was found in CNL, CMML and other blood cancers, which have poor prognosis. Disclosures No relevant conflicts of interest to declare.

The discovery of mutations activating JAK-STAT signaling in the majority of patients with myeloproliferative neoplasms (MPNs) led to identification of tyrosine kinase activation as the common predominant mechanism driving MPN pathogenesis. Nevertheless, the existence of additional genetic events that modify the MPN phenotype, predate JAK2 mutations, or contribute to leukemic transformation of MPNs was suspected. Recent advances in genomic technologies have led to the discovery of mutations in a number of epigenetic modifiers in patients with MPNs, including mutations in TET2, ASXL1, IDH1, IDH2, and EZH2. In addition to mutation, alterations in the expression or activity of chromatin-modifying/reading proteins PRMT5 and L3MBTL1 have been found to be important in MPN development. Moreover, the JAK2 mutation itself recently has been shown to directly affect histone post-translational modifications. This article reviews the clinical and functional implications of epigenetic alterations in the pathogenesis of MPNs.

NPM1 mutation is the most common molecular abnormality in patients with acute myeloid leukemia (AML), especially normal karyotype AML (NK-AML), and is associated with a favorable prognosis in the absence of concomitant FLT3-ITD. Like other molecular abnormalities such as FLT3-ITD, C/EBPα and c-Kit mutation, NPM1 mutation normally presents as a recurrent molecular abnormality. The NPM1 mutation is generally used as a molecular marker in the prognosis evaluation of a patient with AML. Here, we report a different case. He was first diagnosed with NPM1 mutation-positive acute monocytic leukemia. However, he achieved no remission, but the NPM1 mutation dramatically became negative after induction chemotherapy. Finally, he achieved complete remission after salvage chemotherapy and the NPM1 mutation was still negative. To our knowledge, this is a rare case according to the worldwide published literature.

For surgeries aimed at the dissection of full-length phrenic nerve, a full appreciation of its trajectory, blood supply and correlation with adjacent anatomical structures is necessary, especially for endoscopic manipulations. A fresh cadaver study was conducted with the purpose of avoiding surgical complications and ensuring further efficacy and efficiency of endoscopic manipulations. Ten fresh adult cadavers were dissected. Special attention was paid to the topography of the origin, the trajectory of the phrenic nerve, and its anatomic communication with the surrounding vessels and organs. In the second side of the cadavers, thoracic endoscopic manipulations and observations were also performed. The full length of the phrenic nerve was 24.6 ± 1.7 and 30.6 ± 1.8 cm on the right and left side, respectively; the blood supply of the phrenic nerve in the thoracic cavity came exclusively from the pericardiacophrenic artery; the distance between the origin of the pericardiacophrenic artery and that of the internal thoracic artery ranged from 0.5 to 5.2 cm on the right side, and from 1.4 to 5.6 cm on the left; most of the pericardiacophrenic veins intermingled with small vessels of pericardium and pleura, forming a venous network and joining the innominate vein. Endoscopic dissection of the thoracic phrenic nerve together with the accompanying pericardiacophrenic artery can be performed. Extreme attention should be paid during surgery to a section of about 6 cm in length of the artery originating from the internal thoracic artery, while the accompanying veins do not require to be spared.

INTRODUCTION Excellent vestibular function (including utricular function) is important for pilots to maintain correct spatial orientation during flight. Vestibular-evoked myogenic potential (VEMP) recorded from extraocular muscles, the so-called ocular VEMP (oVEMP), can be used to evaluate utricular function. However, oVEMP has not been applied to pilots because of lack of reliable normative data. Hence, this study is designed to establish preliminary normative data for oVEMP induced by air-conducted sound in pilots and student pilots. METHODS There were 62 healthy student pilots (30 male and 32 age-matched female) and 31 healthy male fighter pilots who were recruited as study participants. During binaural air-conducted sound stimulation oVEMP was recorded bilaterally. The latencies of nI and pI, nI-pI interval, peak-to-peak nI-pI amplitude, and asymmetry ratio (AR) of oVEMP in all participants were collected. Meanwhile, the effects of gender and age on oVEMP were also investigated. RESULTS The latencies of nI and pI, nI-pI interval, nI-pI interpeak amplitude, and AR of oVEMP in all participants were 10.35 +/- 0.66 ms, 15.18 +/- 1.07 ms, 4.75 +/- 0.99 ms, 6.75 +/- 4.13 microV, and 13.22 +/- 9.13%, respectively. No significant difference existed between male student pilots and male pilots in terms of oVEMP parameters. The only significant difference was the nI-pI amplitude between age-matched male and female student pilots: 6.96 +/- 3.85 microV for male student pilots and 5.47 +/- 3.10 microV for female student pilots. CONCLUSIONS oVEMP should be interpreted with the AR rather than raw amplitude itself. Each institution should determine its own normal values.

The Janus kinase 2 (JAK2) V617F mutation (JAK2 V617F), JAK2 exon 12 mutations and myeloproliferative leukemia virus oncogene W515L/K mutation (MPL W515L/K) have become three major molecular diagnosis criteria for myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) from 2005.1 However, diagnosing MPNs with non-mutated JAK2 and MPL remains a major diagnostic challenge.2–4 Some recent studies have reported calreticulin (CALR) gene mutations in patients with non-mutated JAK2 V617F MPNs.5–7 There are some distinct mutation types in MPN subtypes, but the differences in the clinical significance and prognosis among the different mutation types are obscure.8–10 Here, we report our data on CALR mutation in wild-type (wt) JAK2 MPN on patients. It should also be mentioned that this is undoubtedly the first report regarding CALR mutations in Chinese MPN patients. From January 2008 to December 2013, bone marrow or peripheral blood samples from 301 MPNs patients were collected in the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province, China, including ET (n=222), PV (n=37), PMF (n=33), post-ET MF (PET-MF; n=6), and post-PV MF (PPV-MF; n=3). We also obtained bone marrow samples from 174 patients with other myeloid neoplasms including: myelodysplastic syndrome (MDS; n=8), chronic myelogeneous leukemia (CML; n=55), acute myeloid leukemia (AML; n=104), and chronic myelomonocytic leukemia (CMML; n=7), as well as peripheral blood samples from 121 healthy controls. All participants provided their informed consent. Genomic PCR combined with direct and cloning sequencing was applied to screen CALR mutations. A total of 24.3% (73 of 301) patients with MPNs were found harboring CALR mutations. The CALR mutation was detected in 31.1% (69 of 222) and 12.1% (4 of 33) of patients with ET and PMF, respectively (Figure 1A). Moreover, CALR mutations were found in 57.0% (69 of 121) ET patients with wt JAK2 and 30.8% (4 of 13) PMF patients with wt JAK2. No CALR mutation in patients with PV, PET-MF, PPV-MF (Figure 1A) was found. The CALR mutations have multiple deletions or insertions including: L367fs*46 (33 of 74; 44.6%), K385fs*47 (25 of 74; 33.8%), K368fs*51 (3 of 74; 4.1%), Q365fs*50 (3 of 74; 4.1%), E364fs*49 (2 of 74; 2.7%), K374fs*56 (2 of 74; 2.7%), L367fs*48 (1 of 74; 1.4%), Q365fs*48 (1 of 74; 1.4%), E364fs*55 (1 of 74; 1.4%), K375fs*48 (1 of 74; 1.4%), K375fs*55 (1 of 74; 1.4%), and K377fs*50 (1 of 74; 1.4%). Figure 1. (A) Frequency of CALR mutations in myeloid neoplasms and healthy control. The CALR mutation was detected in 31.1% (69 of 222) and 12.1% (4 of 33) of ET and PMF patients, respectively. Approximately 1% of patients (1 of 104) with AML were found to harbor ... These patients with MPNs were simultaneously examined for the presence of other gene mutations. PV patients were screened for JAK2 V617F and JAK2 exon 12 mutations, while ET and MF patients were screened for JAK2 V617F and MPL W515L/K mutation. Among the total 301 patients with MPNs, 52.2% (157 of 301) were found to harbor JAK2 V617F mutation. Among the 222 patients with ET and 37 patients with PV, 0.9% (2 of 222) were found to harbor MPL W515L/K mutations and 2.7% (1 of 37) to harbor JAK2 exon 12 mutation, respectively (Figure 1B). JAK2 V617F, JAK2 exon 12 mutation, MPL W515L/K mutations and CALR mutations were found exclusively in these MPNs patients. We also screened CALR mutations in 104 AML patients, 55 CML patients, 7 CMML patients, and 8 MDS patients (including 5 refractory cytopenia with multilineage dysplasis, 2 refractory anemia with excess blasts, and one refractory anemia) to investigate whether CALR mutations were present in other myeloid neoplasms. Although most of these patients had negative results, one AML patient (59-years old, male, M2 subtype) was found to harbor CALR mutation (L367fs*46) without JAK2 V617F and MPL W515L/K mutations (Figure 1A). This patient had no previous history of MPN or MDS, Fms-related tyrosine kinase 3 internal tandem duplication, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog mutation, nucleophosmin mutation. CCAAT/enhancer binding protein alpha mutation was all negative and cytogenetics analysis showed normal karyotype. In addition, no CALR mutation was detected in the 121 healthy controls (Figure 1A). For mutation types, a total of 12 distinct variants of CALR mutation, including 11 deletions and one insertion, were identified in our patients. L367fs*46, which resulted from a 52-bp deletion, and K385fs*47, which resulted from a 5-bp insertion, were the most frequent CALR mutations. The two mutations accounted for 44.6% (33 of 74) and 33.8% (25 of 74) in all cases with mutant CALR, respectively. For ET patients, the two mutations were 14.0% (31 of 222) and 10.4% (23 of 222), respectively. For PMF patients, the two mutations were 3.0% (1 of 33) and 6.1% (2 of 33), respectively. There was no significant difference in the two mutation types between patients with ET and PMF (P=0.137 and P=0.645, respectively). Moreover, the two mutations were 44.9% (31 of 69) and 33.3% (23 of 69) in CALR mutation positive ET patients (Figure 1C), as well as 25% (1 of 4) and 50% (2 of 4) in CALR mutation positive PMF patients (P=0.793 and P=0.888, respectively). There were few other mutation types in the CALR-mutated samples (Figure 1C). ET patients with mutant CALR were significantly younger (P

Modern intensive chemotherapy regimens have improved the prognosis for adult patients with acute lymphocytic leukemia (ALL). With these regimens, the complete response (CR) rates are approximately 75% and long-term disease-free survival (DFS) rates are about 20-35%. For patients with high-risk ALL, DFS rates are only 20% or less. Hyper-CVAD regimen is effective in ALL and aggressive non-Hodgkin lymphomas (NHL) with increased CR rates and DFS rates. Between June 2002 and October 2006, 53 consecutive adult patients with newly diagnosed adult ALL were treated with Hyper-CVAD regimen for six to eight cycles. The alternating courses were given every 3-4 weeks or earlier if count recovery occurred. CR rates of 73.6% were achieved in 39 patients, the estimated 2-year survival rate was 82.9% and the estimated 2-year event-free survival (EFS) rate was 87.3%. Side effects were as expected, mostly attributed to myelosuppression. Analysis of prognostic factors suggested that some previously well-established poor prognostic factors such as the degree of leukocytosis and central nervous system (CNS) or testicular involvement were less important with this dose-intensive regimen. However, patients with mediastinal disease had lower CR rates (P

Recent studies have shown that Janus tyrosine kinase 2 (JAK2) V617F mutation is found in nearly all patients with polycythemia vera (PV) and underlie the basis of PV molecular pathogenesis. Moreover, JAK2 V617F patients with essential thrombocythemia (ET) have been found to have some clinical features similar to PV. To determine whether the same is true in a different Chinese patient population, we employed Allele-specific polymerase chain reaction in combination with sequence analysis to investigate the point mutation in a series of Chinese patients with hematological malignancies. A total of 99 Chinese myeloproliferative disorder patients and 120 additional patients with acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndromes were studied. The V617F mutation was detected in genomic DNA of peripheral blood samples of 16 of 23 PV patients (69.6%), 21 of 45 ET patients (46.7%) and 3 of 8 patients with idiopathic myelofibrosis (37.5%). There were striking differences in clinical features such as hemoglobin, hematocrit and neutrophils percentages between V617F positive and negative patients with ET. Hence, our data support the idea that JAK2 V617F mutation divides ET patients into two subtypes, with the V617F positive group showing phenotypic similar to that of PV.

As JAK2 V617F, MPL W515L is a novel acquired mutation that induces constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders (MPD). The discovery of this mutation provides a novel mechanism for activation of signal transduction in hematopoietic malignancies. To investigate its prevalence in Chinese patients with MPD, we introduced allele-specific PCR (AS-PCR) combined with sequence analysis to simultaneously screen MPL W515L and JAK2 V617F mutations in 190 MPD patients. MPL W515L mutation was found to be harbored in only one of 102 patients, who had essential thrombocythemia (ET, 1.0%) and was not detected in patients with polycythemia vera (PV), idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML). Sixty-eight BCR/ABL-negative MPD patients (46.3%) were found harboring JAK2 V617F mutation (PV, 62.5%; ET, 42.1%; IMF 38.1%). Furthermore, MPL W515L and JAK2 V617F mutations were not detected in patients of acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, and CML. It has been shown that MPL W515L mutations may contribute to the primary molecular pathogenesis of Chinese patients with ET.

// Jianyong Li 1,2,* , Yaoyu Chen 1,2,* , Yu Zhu 1,2 , Jianfeng Zhou 3 , Yanli Xu 4 , Yan Li 5 , Kang Yu 6 , Ling Pan 7 , Jianmin Wang 8 , Jiahua Ding 9 , Jian Gu 10 , Shanhua Zhou 11 , Jinning Shi 12 , Ming Hong 1,2 , Ji Xu 1,2 , Liangqin Pan 1,2 , Limin Duan 1,2 , Run Zhang 1,2 , Sujiang Zhang 1,2 , Huayuan Zhu 1,2 , Hua Lu 1,2 , Peng Liu 1,2 , Hongxia Qiu 1,2 , Hanxin Wu 1,2 and Sixuan Qian 1,2 1 First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China 2 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China 3 Tongji Hospital affiliated to Tongji medical college of Huazhong University of Science and Technology, Wuhan, China 4 Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China 5 First Affiliated Hospital of China Medical University, Shenyang, China 6 First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China 7 West China Hospital of Sichuan University, Chengdu, China 8 Changhai Hospital, Secondary Military Medical University, Shanghai, China 9 Zhongda Hospital, Southeast University, Nanjing, China 10 Clinic Medical College of Yangzhou University, Yangzhou, China 11 Zhongshan Hospital, Fudan University, Shanghai, China 12 Jiangning Hospital, Nanjing, China * The authors contributed equally to this work Correspondence: Sixuan Qian, email: // Keywords : D-CAG, elderly patients, AML Received : December 01, 2014 Accepted : January 13, 2015 Published : January 31, 2015 Abstract Purpose: This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML. Experimental Design: All patients in this study were treated with decitabine of 15 mg/m 2 for 5 days and G-CSF for priming, in combination with cytarabine of 10-mg/m 2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days (D-CAG). Results: Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged

Development of resistance to 1-beta-arabinofuranosylcytosine (AraC) is a major obstacle in the treatment of patients with acute myeloid leukaemia (AML). Deficiency of functional deoxycytidine kinase (dCK) plays an important role in AraC resistance in vitro. We screened 5378 bp sequences of the dCK gene, including all exons and the 5' flanking region, and identified two single nucleotide polymorphisms (SNPs) in the regulatory region (rSNPs) with high allele frequencies. These two rSNPs (-201C>T and -360C>G) formed two major haplotypes. Genotyping with sequencing and MassARRAY system among 122 AML patients showed that those with -360CG/-201CT and -360GG/-201TT compound genotypes (n = 41) displayed a favourable response to chemotherapy whereas those with -360CC/-201CC (n = 81) tended to have a poor response (P = 0.025). Moreover, real-time quantitative reverse transcriptase-polymerase chain reaction showed that patients with -360CG/-201CT and -360GG/-201TT genotypes expressed higher level of dCK mRNA compared to those with the -360CC/-201CC genotype (P = 0.0034). Luciferase-reporter assay showed that dCK 5' regulatory region bearing -360G/-201T genotype alone had an eight-fold greater transcriptional activation activity compared to that with -360C/-201C genotype, whereas co-transfection of both -360G/-201T and -360C/-201C constructs mimicked the heterozygous genotype, which exhibited a four-fold greater activity compared to that with -360C/-201C. These results indicate that rSNP haplotypes of dCK gene may serve as a genetic marker for predicting drug responsiveness, which will be beneficial in establishing more effective AML chemotherapeutic regimens.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder occurring as a familial disease (FHL) or secondary to other diseases including infection (IAHS), rheumatologic disease (MAS),...

Calreticulin, an endoplasmic reticulum protein with multiple functions involving chaperone activity and calcium homeostasis, plays an important role in cellular proliferation and differentiation. Calreticulin dysfunction is known to be associated with different cancers. Very recently, calreticulin mutations have been identified in myeloproliferative neoplasms (MPNs), with a particularly high frequency in MPNs without Janus kinase 2 (JAK2) mutations, which exhibit clinical characteristics different from those with mutant JAK2. Here, we focus on the structure, function and carcinogenicity of calreticulin, as well as its relationship with MPNs not involving JAK2 mutations.