Multi-longitudinal mode laser beat-frequency optical fiber vibration sensing system based on an FM radio module.

A multi-longitudinal mode (MLM) laser beat-frequency optical fiber vibration sensor using a frequency modulation (FM) radio integrated circuit module as the FM demodulation scheme is presented and demonstrated. To the best of our knowledge, this is the first case where a fiber-optic sensing system is combined with an FM radio module, and dynamic sensing is well achieved. As the carrier of the vibration source, the beat-frequency signal (BFS) generated by the MLM laser is transmitted to the FM radio module for FM and demodulation. The experimental results show that the system can successfully detect the vibration signal in the frequency range of 20 Hz to 18 kHz and accurately demodulate the waveform and amplitude of the vibration signal source. The minimum shape variable detected by the system is 20.67 nm, based on the performance of the commercial FM radio module itself, which can effectively solve the problem of detecting tiny vibration. The idea of the optical fiber vibration sensing system is extremely innovative, with high sensitivity, high signal-to-noise ratio (SNR), good stability, and strong resistance to electromagnetic interference.

Constructing a Tregs-associated signature to predict the prognosis of colorectal cancer patients: A STROBE-compliant retrospective study.

Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality worldwide. Regulatory T cells (Tregs) are a key constituent of immune cells in the tumor microenvironment (TME) and are significantly associated with patient outcomes. Our study aimed to construct a Treg-associated signature to predict the prognosis of CRC patients. The genes' expression values and patients' clinicopathological features were downloaded from TCGA and gene expression omnibus (GEO) databases. The single-cell RNA (scRNA) sequencing data of CRC were analyzed through the Deeply Integrated human Single-Cell Omics database. WGCNA analysis was used to select Tregs-associated genes (TrAGs). The infiltrated levels of immune and stromal cells were accessed through the ESTIMATE algorithm. Cox regression analysis and the LASSO algorithm were implemented to construct prognostic models. Gene set enrichment analysis (GSEA) was performed to annotate enriched gene sets. Based on scRNA sequencing data, our study uncovered that more Tregs were significantly enriched in the TME of CRC. Then we identified 123 differentially expressed TrAGs which mainly participated in immune regulation. Given that CRC patients were reclassified into 2 subgroups with distinct overall survival based on 26 differentially expressed TrAGs with prognostic values, we subsequently constructed a signature for CRC. After training and validating in independent cohorts, we proved that this prognostic model can be well applied to predict the prognosis of CRC patients. Further analysis exhibited that more tumor-suppressing immune cells and higher immune checkpoint genes were enriched in CRC patients with high-risk scores. Moreover, immunohistochemistry analysis validated that the genes in the prognostic model were significantly elevated in CRC tissues. We were the first to construct a prognostic signature for CRC based on TrAGs and further revealed that the poor prognosis of patients was mainly attributed to the tumor-suppressing microenvironment and upregulated immune checkpoint genes in tumor tissues.

Singular Configuration Analysis and Singularity Avoidance with Application in an Intelligent Robotic Manipulator.

Recently, robotic sensor systems have gained more attention annually in complex system sense strategies. The robotic sensors sense the information from itself and the environment, and fuse information for the use of perception, decision, planning, and control. As an important supplement to traditional industrial robots, co-bots (short for co-working robots) play an increasingly vital role in helping small and medium-sized enterprises realize intelligent manufacturing. They have high flexibility and safety so that they can assist humans to complete highly repetitive and high-precision work. In order to maintain robot safe operation in the increasing complex working environment and human-computer intelligent interactive control, this paper is concerned with the problem of applicant accuracy analysis and singularity avoidance for co-bots. Based on the dynamic model with load and torque sensors, which is used to detect the external force at the end of the robot, this paper systematically analyzes the causes of singularity phenomenon in the robot motion control. The inverse solution is obtained by analytical method and numerical method, respectively. In order to ensure the smooth and safe operation in the whole workspace, it is necessary for a robot to avoid singularity. Singularity avoidance schemes are utilized for different control tasks, including point-to-point control and continuous path control. Corresponding simulation experiments are designed to verify the effectiveness of different evasion schemes, in which the advantages and disadvantages are compared and analyzed.

Myeloid-derived suppressor cells infiltration in non-small-cell lung cancer tumor and MAGE-A4 and NY-ESO-1 expression.

Cancer/testis antigens melanoma-associated antigen 4 (MAGE-A4) and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) are of clinical interest as biomarkers and present valuable targets for immunotherapy; however, they are poor prognostic markers in non-small cell lung cancer (NSCLC). In addition, myeloid derived suppressor cells (MDSCs) are recognized as a key element in tumor escape and progression. The aim of the present study was to investigate the diagnostic and prognostic value of MAGE-A4 and NY-ESO-1, and their association with MDSCs in NSCLC samples. The expression levels of MAGE-A4 and NY-ESO-1, and the infiltration of MDSCs (CD33+), were analyzed by immunohistochemistry of 67 tissue samples from patients with NSCLC. Overall, 58.33% of the NSCLC squamous cell carcinoma tissues and 94.7% of adenocarcinoma tissues were positive for MAGE-A4. NY-ESO-1 expression was observed in 52.78% of the squamous cell carcinoma tissues and 80% of the adenocarcinoma tissues. In primary adenocarcinoma tumor tissues, MAGE-A4 and NY-ESO-1 demonstrated a higher intensity of expression compared with the squamous cell carcinoma tissues. A total of 33 (91.7%) squamous cell carcinoma and 19 (95.0%) adenocarcinoma specimens were positive for CD33. The expression of MAGE-A4 and NY-ESO-1 antigens and infiltration of MDSCs was associated with poor prognosis of patients with NSCLC. Further studies investigating the association between these findings and underlying molecular mechanisms are required.

MicroRNA-221 promotes breast cancer resistance to adriamycin via modulation of PTEN/Akt/mTOR signaling.

As a prevalent tumor among women, breast cancer is still an incurable disease due to drug resistance. In this study, we report microRNA-221 to have a significant effect on breast cancer resistance to adriamycin. The microRNA-221 is elevated in tumor tissue compared with nearby nontumor samples, as well as in breast cancer cell line with adriamycin resistance (MCF-7/ADR) compared to its parental line (MCF-7) and the normal breast epithelial cell line (MCF-10A). Enforced level of microRNA-221 promotes cancer resistance to adriamycin, which in turn sustains cell survival and exacerbates malignant formation. Reciprocally, the silence of microRNA-221 in cancer cells augments the sensitivity to chemotherapy, thereby resulting in enhanced apoptosis of MCF-7/ADR cells. Mechanistically, we identify PTEN as a direct target of microRNA-221, which was conversely associated with a microRNA-221 level in breast tumors. The knock-down of PTEN partially reversed the stimulatory role of microRNA-221 in the modulation of the Akt/mTOR signaling. Taken together, these findings suggest microRNA-221 suppresses PTEN transcription and activates Akt/mTOR pathway, which in turn enhances breast cancer resistance to adriamycin and promotes cancer development. Our data thus illuminate the microRNA-221/PTEN axis may act as a promising strategy for the treatment of chemotherapy-resistant breast tumors.

[Mid-term effectiveness of Coflex interspinous dynamic internal fixation combined with spinal fusion for lumbar disc degeneration].

Objective: To evaluate the effectiveness of Coflex interspinous dynamic internal fixation combined with spinal fusion for lumbar disc degeneration. Methods: The clinical data of 39 patients with two-level lumbar disc degeneration who met the selection criteria between June 2010 and December 2011 was retrospectively analyzed. They were divided into group A (20 cases, simple lumbar decompression and fusion) and group B (19 cases, Coflex interspinous dynamic internal fixation combined with spinal fusion) according to different surgical methods. There was no significant difference in age, gender, disease diagnosis, lesion segment, disease duration, Oswestry disability index (ODI), visual analogue scale (VAS) score, and the intervertebral height, foramen intervertebral height (FIH), and range of motion (ROM) of upper operative segment and adjacent segment between the two groups ( P>0.05). ODI and VAS score were used to evaluate the effectiveness before operation and at last follow-up, and the improvement rates were calculated. The intervertebral height [anterior disc height (ADH), middle disc height (MDH), and posterior disc height (PDH)], FIH, and ROM were measured and compared between the two groups. Results: The operation time and intraoperative blood loss in group A were significantly more than those in group B ( P<0.05), and there was no significant difference in hospitalization time between the two groups ( t=0.992, P=0.328). All patients were followed up; the follow-up time was 33-50 months (mean, 40.5 months) in group A and 39-51 months (mean, 42.6 months) in group B. No complication such as displacement, loosening, or rupture of internal fixator was found in both groups. At last follow-up, ODI and VAS score of the two groups significantly improved when compared with preoperative scores ( P<0.05). At last follow-up, there was no significant difference in ODI, VAS score, and improvement rate of ODI between the two groups ( P>0.05); the improvement rate of VAS score in group B was significantly higher than that in group A ( t=2.245, P=0.031). There was no significant difference in the intervertebral height and FIH of the upper operative segment at last follow-up between the two groups and between preoperation and last follow-up in the two groups ( P>0.05). At last follow-up, the ADH of adjacent segment in group B was significantly higher than that in group A, and MDH, PDH, and FIH were significantly lower than those in group A ( P<0.05). Compared with preoperation, the ADH of adjacent segment in group A decreased and MDH, PDH, and FIH increased at last follow-up ( P<0.05), while all indexes in group B did not change significantly ( P>0.05). The ROM of adjacent segment in group A increased significantly at last follow-up ( t=2.318, P=0.026). There was significant difference in ROM of adjacent segment between the two groups ( P<0.05). Conclusion: The mid-term effectiveness of Coflex interspinous dynamic internal fixation combined with spinal fusion is similar to that of simple decompression fusion. For those patients whose adjacent segments of the responsible segments have degeneration but have no symptoms or mild symptoms, this treatment can slow down the adjacent segment degeneration.

Suppression of FGFR3- and MYC-dependent oncogenesis by tubacin: association with HDAC6-dependent and independent activities.

Fibroblast growth factor receptor 3 (FGFR3) is amplified, translocated or mutated in a number of different human cancer types, but most commonly in bladder cancers. We previously found that the accumulation of FGFR3 is dependent on histone deacetylase 6 (HDAC6). Here we show that HDAC6 loss or inhibition reduces FGFR3 accumulation in cells made tumorigenic by ectopic expression of a mutant activated version of FGFR3 together with the MYC oncoprotein and in a bladder cancer cell line whose tumorigenicity is dependent on expression of a translocated version of FGFR3. In tumor xenoplant assays, HDAC6 deficiency or small molecule inhibition by the selective HDAC6 inhibitors tubacin or tubastatin A was found to significantly impede tumor growth. However, tubacin was more effective at inhibiting tumor growth than tubastatin A or HDAC6 deficiency. The superior anti-tumor activity of tubacin was linked to its ability to not only inhibit accumulation of mutant FGFR3, but also to cause robust downregulation of MYC and cyclin D1, and to induce a DNA damage response and apoptosis. Neither HDAC6 deficiency nor treatment with tubastatin A altered MYC or cyclin D1 levels, and neither induced a DNA damage response or apoptosis. Thus while tubacin and tubastatin A inhibit HDAC6 with similar selectivity and potency, our results reveal unique HDAC6-independent activities of tubacin that likely contribute to its potent anti-tumor activity.

HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia.

Mutations that cause increased and/or inappropriate activation of FGFR3 are responsible for a collection of short-limbed chondrodysplasias. These mutations can alter receptor trafficking and enhance receptor stability, leading to increased receptor accumulation and activity. Here, we show that wildtype and mutant activated forms of FGFR3 increase expression of the cytoplasmic deacetylase HDAC6 (Histone Deacetylase 6) and that FGFR3 accumulation is compromised in cells lacking HDAC6 or following treatment of fibroblasts or chondrocytes with small molecule inhibitors of HDAC6. The reduced accumulation of FGFR3 was linked to increased FGFR3 degradation that occurred through a lysosome-dependent mechanism. Using a mouse model of Thanatophoric Dysplasia Type II (TDII) we show that both HDAC6 deletion and treatment with the small molecule HDAC6 inhibitor tubacin reduced FGFR3 accumulation in the growth plate and improved endochondral bone growth. Defective endochondral growth in TDII is associated with reduced proliferation and poor hypertrophic differentiation and the improved bone growth was associated with increased chondrocyte proliferation and expansion of the differentiation compartment within the growth plate. These findings further define the mechanisms that control FGFR3 accumulation and contribute to skeletal pathology caused by mutations in FGFR3.

[Pollution Level and Health Risk Assessment of Heavy Metals in Atmospheric PM2.5 in Nanjing Before and After the Youth Olympic Games].

The influence of human activities on the atmospheric environment has attracted people's attention. This study reported the dynamic changes in PM2.5 concentration, its heavy metal compositions and health risk assessment from April to September, 2014 in Nanjing when the Youth Olympic Games ( YOG) was held. The results showed that the mass levels of PM2.5 ranged from 26.39 to 80.31 µg · m⁻³ from April to September. The mass levels of PM2.5 met the level II standard of ambient air quality in China (24 h average concentration, 75 µg · m⁻³) in months of April, May and July while met the level I standard (24 h average concentration, 35 µg · m⁻³) in August during the YOG. The average mass concentration of PM2.5 reached 76.14 µg · m⁻¹ after the YOG, showing resilience of air pollution. The variations of heavy metals were not consistent with each other throughout the observation period. Principal component analysis indicated that emission sources significantly affected the variations of PM2.5 and its heavy metals. PM2.5 and all of the heavy metals decreased to their minimum values during the YOG, indicating the effectiveness of those temporary measures for reducing atmospheric pollutant before and during the YOG. The health risks of Cd, Cu, Ni and Pb in PM2.5 via breathing and dermal contact exposure were all within the acceptable ranges, but potential carcinogenic risk existed for Cr in PM2.5. There was potential non-carcinogenic health risk for adult males via breathing of Mn and greater non-carcinogenic health risk for children via dermal contact exposures to all these 6 heavy metals.

Preparation and characterization of a novel injectable strontium-containing calcium phosphate cement with collagen.

PURPOSE: To develop a novel injectable strontium-containing calcium phosphate cement with collagen. METHODS: A novel calcium phosphate bone cement (CPC) was prepared with the addition of strontium element, collagenl, and modified starch; the injectability, solidification time, microstructure, phase composition, compressive strength, anti-collapsibility and histological properties of material were evaluated. RESULTS: The results showed that the material could be injected with an excellent performance; the modified starch significantly improved the anti-washout property of cement; with the liquid to solid ratio of 0.3, the largest compressive strength of cement was obtained (48.0 MPa ± 2.3 MPa); histological examination of repair tissue showed that the bone was repaired after 16 weeks; the degradation of cement was consistent with the new bone growth. CONCLUSION: A novel injectable collagen-strontium-containing CPC with excellent compressive strength and suitable setting time was prepared, with addition of modified starch. The CPC showed a good anti-washout property and the degradation time of the cement met with the new bone growing. This material is supposed to be used in orthopedic and maxillofacial surgery for bone defects.

Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes.

Fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the control of endochondral ossification, and bone growth and mutations that cause hyperactivation of FGFR3 are responsible for a collection of developmental disorders that feature poor endochondral bone growth. FGFR3 is expressed in proliferating chondrocytes of the cartilaginous growth plate but also in chondrocytes that have exited the cell cycle and entered the prehypertrophic phase of chondrocyte differentiation. Achondroplasia disorders feature defects in chondrocyte proliferation and differentiation, and the defects in differentiation have generally been considered to be a secondary manifestation of altered proliferation. By initiating a mutant activated knockin allele of FGFR3 (FGFR3K650E) that causes Thanatophoric Dysplasia Type II (TDII) specifically in prehypertrophic chondrocytes, we show that mutant FGFR3 induces a differentiation block at this stage independent of any changes in proliferation. The differentiation block coincided with persistent expression of SOX9, the master regulator of chondrogenesis, and reducing SOX9 dosage allowed chondrocyte differentiation to proceed and significantly improved endochondral bone growth in TDII. These findings suggest that a proliferation-independent and SOX9-dependent differentiation block is a key driving mechanism responsible for poor endochondral bone growth in achondroplasia disorders caused by mutations in FGFR3.

Prevalence of arterial stiffness in North China, and associations with risk factors of cardiovascular disease: a community-based study.

BACKGROUND: Brachial-ankle pulse wave velocity (baPWV), which reflects the stiffness of both central and peripheral muscular arteries, has been frequently used as a simple index for assessing arterial stiffness. The aim of the present study was to investigate the prevalence of arterial stiffness in North China based on baPWV measurements, and explore the associations between increased arterial stiffness and risk factors of cardiovascular diseases (CVD). METHODS: Twenty-three community populations were established in North China. For each participant, parameters for calculating baPWV, including blood pressures and pressure waveforms, were measured using a non-invasive automatic device. All participants were required to respond to an interviewer-led questionnaire including medical histories and demographic data, and to receive blood tests on biochemical indictors. RESULTS: A total of 2,852 participants were finally investigated. Among them, 1,201 people with low burden of CVD risk factors were chosen to be the healthy reference sample. The cut-off point of high baPWV was defined as age-specific 90th percentile of the reference sample. Thus, the prevalence of high baPWV was found to be 22.3% and 26.4% in men and women respectively. After adjusted for age, heart rate (HR), systolic blood pressure (SBP), fasting glucose level, and smoking were significantly associated with high baPWV in men; while level of serum total cholesterol (TC), HR, SBP, and diabetes were significantly associated with high baPWV in women. CONCLUSIONS: Based on the age-specific cut-off points, the middle-aged population has a higher prevalence of high baPWV in North China. There exists a difference between men and women in terms of the potential risk factors associated with arterial stiffness.

A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis.

Mnt (Max's next tango) is a Max-interacting transcriptional repressor that can antagonize both the proproliferative and proapoptotic functions of Myc in vitro. To ascertain the physiologically relevant functions of Mnt and to help define the relationship between Mnt and Myc in vivo, we generated a series of mouse strains in which Mnt was deleted in T cells in the absence of endogenous c-Myc or in the presence of ectopic c-Myc. We found that apoptosis caused by loss of Mnt did not require Myc but that ectopic Myc expression dramatically decreased the survival of both Mnt-deficient T cells in vivo and Mnt-deficient MEFs in vitro. Consequently, Myc-driven proliferative expansion of T cells in vitro and thymoma formation in vivo were prevented by the absence of Mnt. Consistent with T-cell models, mouse embryo fibroblasts (MEFs) lacking Mnt were refractory to oncogenic transformation by Myc. Tumor suppression caused by loss of Mnt was linked to increased apoptosis mediated by reactive oxygen species (ROS). Thus, although theoretically and experimentally a Myc antagonist, the dominant physiological role of Mnt appears to be suppression of apoptosis. Our results redefine the physiological relationship between Mnt and Myc and requirements for Myc-driven oncogenesis.

Disruption of a Sox9-ß-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II.

Mutations in fibroblast growth factor (FGF) receptors are responsible for a variety of skeletal birth defects, but the underlying mechanisms responsible remain unclear. Using a mouse model of thanatophoric dysplasia type II in which FGFR3(K650E) expression was directed to the appendicular skeleton, we show that the mutant receptor caused a block in chondrocyte differentiation specifically at the prehypertrophic stage. The differentiation block led to a severe reduction in hypertrophic chondrocytes that normally produce vascular endothelial growth factor, which in turn was associated with poor vascularization of primary ossification centers and disrupted endochondral ossification. We show that the differentiation block and defects in joint formation are associated with persistent expression of the chondrogenic factor Sox9 and down-regulation of ß-catenin levels and activity in growth plate chondrocytes. Consistent with these in vivo results, FGFR3(K650E) expression was found to increase Sox9 and decrease ß-catenin levels and transcriptional activity in cultured mesenchymal cells. Coexpression of Fgfr3(K650E) and Sox9 in cells resulted in very high levels of Sox9 and cooperative suppression of ß-catenin-dependent transcription. Fgfr3(K650E) had opposing effects on Sox9 and ß-catenin protein stability with it promoting Sox9 stabilization and ß-catenin degradation. Since both Sox9 overexpression and ß-catenin deletion independently blocks hypertrophic differentiation of chondrocytes and cause chondrodysplasias similar to those caused by mutations in FGFR3, our results suggest that dysregulation of Sox9 and ß-catenin levels and activity in growth plate chondrocytes is an important underlying mechanism in skeletal diseases caused by mutations in FGFR3.

Histopathology of femoral head donations: a retrospective review of 6161 cases.

BACKGROUND: Although total hip arthroplasty is one of the most common orthopaedic surgical procedures, it remains unclear whether histopathological examination of the excised femoral head adds to the quality of patient care. We propose that assessment of femoral heads resected during total hip arthroplasty and donated for allograft use may provide a profile of femoral head pathology that benefits total hip arthroplasty patients and bone donors. METHODS: We retrospectively analyzed the histological findings reported for 6161 femoral heads donated for allograft use between 1993 and 2006. Specimens obtained during total hip arthroplasty and specimens donated at death were reviewed. Follow-up investigations that resulted from abnormal histopathological findings were also reviewed. The Western Australian Cancer Registry was used to determine whether patients with a suspected neoplasm were subsequently diagnosed with such a disease. A retrospective review of the histopathological findings was conducted to evaluate and reclassify all previous observations of abnormalities. RESULTS: One hundred and five femoral heads demonstrated abnormal or reactive histopathological features not reported prior to surgery and were rejected for allograft use. A reactive lymphocytic infiltrate, most likely due to osteoarthritis, was the most commonly identified feature (forty-five cases). Other features observed in twenty-seven cases were also most likely due to the presence of severe osteoarthritis. Ten femoral heads demonstrated plasmacytosis, which may have been related to osteoarthritis. Two patients were diagnosed with Paget's disease, and two, with rheumatoid arthritis. Nineteen patients had a suspected neoplasm. Of these nineteen, eight cases of non-Hodgkin's lymphoma or chronic lymphocytic leukemia and one case of myelodysplastic syndrome were confirmed on further investigation. One subsequently confirmed malignancy was detected per 770 femoral heads examined. CONCLUSIONS: Our findings indicate that, even with a detailed medical history and careful physical examination, clinically important diseases including neoplasms and Paget's disease are observed in patients diagnosed with osteoarthritis prior to total hip arthroplasty. Histological examination plays an integral role in quality assurance in femoral head banking, and it also represents a possible early diagnostic test for bone and bone-marrow-related diseases in patients undergoing total hip arthroplasty.

Sequential and coordinated actions of c-Myc and N-Myc control appendicular skeletal development.

BACKGROUND: During limb development, chondrocytes and osteoblasts emerge from condensations of limb bud mesenchyme. These cells then proliferate and differentiate in separate but adjacent compartments and function cooperatively to promote bone growth through the process of endochondral ossification. While many aspects of limb skeletal formation are understood, little is known about the mechanisms that link the development of undifferentiated limb bud mesenchyme with formation of the precartilaginous condensation and subsequent proliferative expansion of chondrocyte and osteoblast lineages. The aim of this study was to gain insight into these processes by examining the roles of c-Myc and N-Myc in morphogenesis of the limb skeleton. METHODOLOGY/PRINCIPAL FINDINGS: To investigate c-Myc function in skeletal development, we characterized mice in which floxed c-Myc alleles were deleted in undifferentiated limb bud mesenchyme with Prx1-Cre, in chondro-osteoprogenitors with Sox9-Cre and in osteoblasts with Osx1-Cre. We show that c-Myc promotes the proliferative expansion of both chondrocytes and osteoblasts and as a consequence controls the process of endochondral growth and ossification and determines bone size. The control of proliferation by c-Myc was related to its effects on global gene transcription, as phosphorylation of the C-Terminal Domain (pCTD) of RNA Polymerase II, a marker of general transcription initiation, was tightly coupled to cell proliferation of growth plate chondrocytes where c-Myc is expressed and severely downregulated in the absence of c-Myc. Finally, we show that combined deletion of N-Myc and c-Myc in early limb bud mesenchyme gives rise to a severely hypoplastic limb skeleton that exhibits features characteristic of individual c-Myc and N-Myc mutants. CONCLUSIONS/SIGNIFICANCE: Our results show that N-Myc and c-Myc act sequentially during limb development to coordinate the expansion of key progenitor populations responsible for forming the limb skeleton.

The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects.

Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we show that birth defect and cancer-associated FGFR2 mutants promote DNA-damage signaling and p53-dependent senescence in primary mouse and human cells. Senescence promoted by FGFR mutants was associated with downregulation of c-Myc and forced expression of c-Myc facilitated senescence escape. Whereas c-Myc expression facilitated senescence bypass, mutant FGFR2 signaling suppressed c-Myc-dependent apoptosis and led to oncogenic transformation. Cells transformed by coexpression of a constitutively activated FGFR2 mutant plus c-Myc appeared to be become highly addicted to FGFR-dependent prosurvival activities, as small molecule inhibition of FGFR signaling resulted in robust p53-dependent apoptosis. Our data suggest that senescence-promoting activities of mutant FGFRs may normally limit their oncogenic potential and may be relevant to their ability to disrupt morphogenesis and cause birth defects. Our results also raise the possibility that cancers originating through a combination of constitutive FGFR activation and deregulated Myc expression may be particularly sensitive to small molecule inhibitors of FGF receptors.

An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Since only limited data on the Chinese population, which is the largest in the world, is available, we conducted an epidemiological study on the prevalence and risk factors of AF in mainland China. METHODS: This population-based study conducted by cluster sampling comprised 29079 participants forming 14 cohorts from 13 provinces across China, where the population was nearly 1 billion. Every participant underwent electrocardiogram and physical examinations and responded to the interviewer-led questionnaire(s). Univariate and multiple statistical analyses were conducted to explore the relationship between AF prevalence and risk factors. RESULTS: The age-standardized prevalence of AF in China (>or=30 y) was 0.65%, and it increased with age. Men showed a higher prevalence of AF than women (0.91% [age-standardized, 0.66%] vs. 0.65% [0.63%], P = 0.013); several significant risk factors (age, hyperthyroidism, coronary heart disease, and rheumatic heart disease) were identified for AF in the general population. Stroke prevalence was much higher in AF patients than in non-AF people (12.95% vs. 2.28%, P < 0.001). AF was confirmed to be a significant independent risk factor for stroke prevalence in the studied population (OR = 2.776, [1.814, 4.248], P < 0.001). We found that AF patients received poor treatment (2.7%, warfarin; 39.7%, aspirin). DISCUSSION: This study conducted on a large sample size demonstrates that AF prevalence in mainland China is slightly lower than that in Western countries and similar to that in Asian areas, and confirms that AF is a serious public health problem in China. We identified several potential risk factors, but their associations with AF still need to be further studied.

Activities of N-Myc in the developing limb link control of skeletal size with digit separation.

The developing limb serves as a paradigm for studying pattern formation and morphogenetic cell death. Here, we show that conditional deletion of N-Myc (Mycn) in the developing mouse limb leads to uniformly small skeletal elements and profound soft-tissue syndactyly. The small skeletal elements are associated with decreased proliferation of limb bud mesenchyme and small cartilaginous condensations, and syndactyly is associated with a complete absence of interdigital cell death. Although Myc family proteins have pro-apoptotic activity, N-Myc is not expressed in interdigital cells undergoing programmed cell death. We provide evidence indicating that the lack of interdigital cell death and associated syndactyly is related to an absence of interdigital cells marked by expression of Fgfr2 and Msx2. Thus, instead of directly regulating interdigital cell death, we propose that N-Myc is required for the proper generation of undifferentiated mesenchymal cells that become localized to interdigital regions and trigger digit separation when eliminated by programmed cell death. Our results provide new insight into mechanisms that control limb development and suggest that defects in the formation of N-Myc-dependent interdigital tissue may be a root cause of common syndromic forms of syndactyly.

Mnt-Max to Myc-Max complex switching regulates cell cycle entry.

The c-Myc oncoprotein is strongly induced during the G0 to S-phase transition and is an important regulator of cell cycle entry. In contrast to c-Myc, the putative Myc antagonist Mnt is maintained at a constant level during cell cycle entry. Mnt and Myc require interaction with Max for specific DNA binding at E-box sites, but have opposing transcriptional activities. Here, we show that c-Myc induction during cell cycle entry leads to a transient decrease in Mnt-Max complexes and a transient switch in the ratio of Mnt-Max to c-Myc-Max on shared target genes. Mnt overexpression suppressed cell cycle entry and cell proliferation, suggesting that the ratio of Mnt-Max to c-Myc-Max is critical for cell cycle entry. Furthermore, simultaneous Cre-Lox mediated deletion of Mnt and c-Myc in mouse embryo fibroblasts rescued the cell cycle entry and proliferative block caused by c-Myc ablation alone. These results demonstrate that Mnt-Myc antagonism plays a fundamental role in regulating cell cycle entry and proliferation.