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Based on the consecutive synoptic magnetic maps, we devise a new method to calculate the solar differential rotation coefficients. This method is very easy to implement and has a high accuracy. Firstly, based on the two-term or three-term differential rotation formula, we simulate a synoptic map CR |$_{n}$| evolves one Carrington Rotation (CR) time only under the effect of the differential rotation, and thereby a stretched synoptic map CR |$_{n*}$| is obtained. Then, through searching the maximum covariance between the maps CR |$_{n*}$| and CR |$_{n+1}$| by the grid search method, the rotation coefficients can be determined. Based on the synoptic maps of CRs 1625 to 2278 (during the years 1975–2023), the two-term coefficients A and B for latitude region between |$\pm 40^{\circ }$| are calculated. The rotation coefficient B shows an obvious 11-yr period. From the time series of B , we find that the Sun usually rotates more differentially in the rising phases of the sunspot cycles than in the falling phases. Moreover, the strong magnetic field corresponds to an increasing of B (note that B has a negative sign) or decreasing of differential. The evolutionary trend of B also indicates that there are several years until the maximum value of B will be reached in solar cycle 25, and the coefficient B will be still in the rising phase in the few coming years. The two-term rotation coefficients for the two hemispheres are also calculated separately, and in the studied time-scale, the largest N–S asymmetry of the rotation rate appeared in October 2007. [ABSTRACT FROM AUTHOR]

Field measurements at the Qingtu Lake Observation Array site were performed to explore the features of large scale structures relevant to very large scale motions (VLSMs) and large scale motions (LSMs) in the atmospheric surface layer during dust weather events. The three velocity components, PM10 concentrations (particles with size less than 10 μm), and sand saltation fluxes at different heights were measured synchronously. By comparing with the results in clean-air flows, the influences of sand particles on the VLSMs were investigated. The present results indicate that the streamwise turbulent kinetic energy across all scales is enhanced in the sand-laden flows. However, the energy enhancement of small-scale motions is more pronounced than that of large scale structures, resulting in a decreased energy fraction of the large scale structures in the sand-laden flows. The inclination angles of the large scale structures are found to increase with sand concentration, owing to the decreased velocity gradient. The streamwise length scale of large scale structures and the size of the most energetic turbulent structures are found to be unchanged in the sand-laden flows relative to those in the clean-air flows. This is the study on the particle-laden wall turbulence at the largest Reynolds number to date, and the results demonstrate that the dispersed tiny particles in very dilute particle–gas flows can affect the turbulence even for the large scale structures. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the properties of resistant starch (RS) from Chinese chestnut ( Castanea mollissima), which was prepared by autoclaving treatment and pullulanase hydrolysis. Scanning electron microscopy (SEM) revealed that the chestnut resistant starch (CRS) granules had a cohesive structure, an irregular shape, and diameters ranging from 6.0 to 7.2 µm. The enzymatic and retrogradation processes increased the yield of RS, and also decreased its swelling power, water solubility, and viscosity. An increase in transparency was also observed. The percent syneresis of the two starches increased steadily over time. X-ray diffraction (XRD) analyses revealed that autoclaving and pullulanase hydrolysis converted C-type native starch into a B-type pattern and increased the crystallinity. In addition, differential scanning calorimetry (DSC) results indicated a reduction in gelatinization temperature and enthalpy compared with native starch. The thermal properties of RS increased due to the retrogradation and recrystallization ( p < .05). Practical applications Chinese chestnut ( Castanea mollissima) is an important nut crop with high nutrition and planted in China widely. High water content in fresh chestnut leads to mildew attack easily, which will affect the chestnut market value and trade business. Therefore, it has great significance and practical demand to develop the deep processing technology and diversify its products. The resistant starch has been implemented as an ingredient for its resistant digestion properties for making flour food and functional food. However, the research and application of resistant starch from Chinese chestnut ( Castanea mollissima) has been rarely seen. This study investigated the structural and physicochemical properties of chestnut resistant starch and provided a reference for the application of chestnut resistant starch in the food processing industries. For example, an increase in transparency and syneresis suggested chestnut resistant starch could be potentially used as a functional ingredient in jelly, beverages, and other food products, but not be possible for use in the frozen food industry. [ABSTRACT FROM AUTHOR]

Background: The Nuss bar is commonly used for minimally invasive correction of pectus excavatum and is usually removed within 2-3 years. Here, we report a case of 10-year bar placement after the Nuss procedure accompanied by unique complications of thoracic malformation that have not been described before. The asymmetric pectus carinatum caused by bar displacement and significant rib periosteal hyperplasia is described for the first time.Case Presentation: A 23-year-old man was admitted to our hospital due to the main complaint of obvious chest discomfort when lifting heavy weights. The bar removal was seriously delayed due to his loss to follow-up. Chest asymmetry and distant heart sounds were found during a physical examination. A chest CT scan demonstrated that the right end of the lower bar originally fixed outside the ribs had shifted into the thoracic cavity, and the left costal cartilage was obviously protruding. Additionally, the displaced bars were separated from the sternum and tightly attached to the pericardium, resulting in abnormalities of the anterior mediastinum. These secondary thoracic deformities made the patient extremely prone to massive hemorrhage or multiple rib fractures when sliding the bars out. However, serious consequences were avoided due to reasonable adjustments to the usual bar removal procedures.Conclusion: This case demonstrates a specific type of bar displacement caused by prolonged placement of the bars and highlights the importance of rigorous follow-up of patients after the Nuss procedure. [ABSTRACT FROM AUTHOR]

The construction and operation of the Sichuan-Tibet railway require constructing extensive supporting facilities along its route. Sichuan-Tibet transportation corridor features high mountains and deep valleys where land resources suitable for such purposes are very limited. As a result, safe utilization of the torrential fan along the railway becomes essential. Focus on buildings at the torrential fan, this paper aims to develop a vulnerability model that can assess their maximum potential damage and support the planning and development of the torrential fan. The model was developed based on 51 building damage data collected at 11 torrential fans. The hazard intensity was defined by the geometric configuration of torrential fans and the location of assessed buildings. In addition, a physical experiment was carried out to study the shielding effect of building groups. The results show that the shielding effect range is about 25 times the building size, and the maximum reduction in impact force can reach 60%. The advantage of the proposed vulnerability assessment model is that it only requires the spatial information of the site that can be easily derived from the satellite image. In addition, the model can reflect the complex torrential process and the shielding effect of building groups. This study provides an alternative approach to building vulnerability assessment. It supports the planning and development of torrential fans when constructing the supporting facilities for the railway construction and operation. • The intensity of torrential hazards at each building is defined by the fan's geometric configuration and the assessed building's position. • The proposed model is easily adaptable since the required data is widely accessible from the satellite image. • The shielding effect of building groups when subject to torrential hazards is considered in this vulnerability assessment model [ABSTRACT FROM AUTHOR]

Pairings on elliptic curves are currently of great interest due to their applications in a number of cryptographic protocols such as identity-based encryption, group signatures, short signatures, and the tripartite Diffie-Hellman. Miller's algorithm is the most commonly used method of computing Tate pairing. Denominator elimination can improve Miller's algorithm when the embedding degree has the form 2i3j. However, if the embedding degree does not have the above form, how can the speed of Miller's algorithm be increased? In this article, the authors modified Miller's algorithm over Huff curves. It is about 20.38% faster than the original algorithm. [ABSTRACT FROM PUBLISHER]

Based on synoptic magnetic maps, we use spherical harmonic functions to decompose the global magnetic field of the Sun. Through the expansion coefficients, the power spectrum C l , and its zonal component C l Z and sectorial component C l S for order l are defined. Through two sampled synoptic maps, it is easy to show that the multipole moments in solar active years are much stronger than those in the quiet years. We decomposed the synoptic maps for Carrington rotations (CRs) 1625 to 2224, i.e., corresponding Solar Cycles 21 – 24, and studied the evolution of multipole moments. Except for the monopole, the power spectra C l for most moments have an obvious 11-year period. The dipole and octupole in Solar Cycle 22 are much stronger than in the other three cycles. The zonal components of dipole and octupole are opposite to the phases of most modes, while the sectorial components of them are consistent with most phases. In addition, compared to the phase of the yearly sunspot number, the phases of most multipoles are relatively delayed, except for the zonal modes of the quadrupole and 32-pole (l = 5 ). We find that the zonal mode of l = 5 is very strong, which leads ahead of the phase of the yearly sunspot number for about 10 CRs. Additionally, unlike the other modes, it has a strong 5.5-year period. Then, the zonal mode of l = 5 is mainly induced by the magnetic field of the sunspots, which is further confirmed in this work. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined the level of miR-490-3p in A549 lung cancer cells compared with normal bronchial epithelial cell line. [•] We are the first to show the function of miR-490-3p in A549 lung cancer cells. [•] We demonstrate CCND1 may be one of the targets of miR-490-3p. [Copyright &y& Elsevier]

Scalar multiplication nP is the core operation of elliptic curve public-key cryptosystems. Double bases representation of n is proposed to speed up scalar multiplication. Avanzi et al. presented a recoding algorithm for Koblitz curves which works in all cases with optimal constants [1]. However, their algorithm may be expensive to implement because it requires many divisions in [τ]. In this paper, we show that divisions in [τ] can be replaced by divisions in . Our improved version of the algorithm runs in about 33% of the time of the Avanzi et al. algorithm on the Koblitz curve K-163, with larger improvements as the size of the curve increases. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether there is a significant relationship between hemodynamic models and pre-eclampsia outcomes. Method: A controlled experimental study was performed. We analyzed 2910 hemodynamic series systematically sampled from 970 pregnant women three times every 2 weeks from the definite diagnosis of pre-eclampsia until delivery. Women were divided into three groups based on total peripheral resistance (TPR): a low-TPR group, a normal-TPR group and a high-TPR group. Every group was divided into three subgroups based on cardiac index (CI): a low-CI subgroup, a normal-CI group and high-CI group. Common lab tests, electrocardiographic examination, fundus examination, cardiac function, liver function and kidney function were measured after every hemodynamic monitoring. Primary outcomes included various maternal and neonatal morbidity and neonatal and infant mortality. Results: In our study we found seven hemodynamic models in pre-eclampsia during the third trimester of pregnancy. No significant differences in maternal age, weight, and height were observed between the three groups. The low-TPR and normal-TPR groups showed better disease results than the high-TPR group in respect of HELLP ( P < 0.01), lung edema ( P < 0.01), acute renal failure ( P < 0.01), heart failure ( P < 0.01), neonatal intensive care unit admission ( P < 0.01), infant weight ( P < 0.01), neonatal mortality ( P < 0.01) and infant mortality ( P < 0.01). The low-TPR group had better results than the normal-TPR group in respect of eclampsia ( P < 0.01), liver hemorrhage ( P < 0.01), birthweight ( P < 0.01) and gestational week at birth ( P < 0.05). Conclusion: Among all the subgroups, the highest maternal and neonatal morbidity was in the high-TPR-high-CI subgroup. There is clear relationship between hemodynamic and disease outcomes during the third trimester. [ABSTRACT FROM AUTHOR]

Abstract: Let denote the “Euler polynomial” if and if . Set to be the number of prime factors (counting multiplicity) of the positive integer n. The Ono invariant of is defined to be except when in which case is defined to be 1. Finally, let denote the class number of K. In 2002 J. Cohen and J. Sonn conjectured that and is a prime. They verified that the conjecture is true for . Moreover, they proved that the conjecture holds for assuming the extended Riemann Hypothesis. In this paper, we show that the conjecture holds for by the aid of computer. And using a result of Bach, we also proved that the conjecture holds for assuming the extended Riemann Hypothesis. In conclusion, we proved the conjecture is true assuming the extended Riemann Hypothesis. [Copyright &y& Elsevier]

Src homology-2 (SH2) domain-containing phosphatases (Shps) are a small, highly conserved subfamily of protein-tyrosine phosphatases, members of which are present in both vertebrates and invertebrates. The mechanism of regulation of Shps by ligand binding is now well understood. Much is also known about the normal signaling pathways regulated by each Shp and the consequences of Shp deficiency. Recent studies have identified mutations in human Shp2 as the cause of the inherited disorder Noonan syndrome. Shp2 mutations might also contribute to the pathogenesis of some leukemias. In addition, Shp2 might be a key virulence determinant for the important human pathogen Helicobacter pylori. Despite these efforts, however, the key targets of each Shp have remained elusive. Identifying these substrates remains a major challenge for future research. [Copyright &y& Elsevier]

Tyrosine phosphorylation plays an important role in controlling cellular growth, differentiation and function. Abnormal regulation of tyrosine phosphorylation can result in human diseases such as cancer. A major challenge of signal transduction research is to determine how the initial activation of protein-tyrosine kinases (PTKs) by extracellular stimuli triggers multiple downstream signaling cascades, which ultimately elicit diverse cellular responses. Recent studies reveal that members of the Gab/Dos subfamily of scaffolding adaptor proteins (hereafter, ‘Gab proteins’) play a crucial role in transmitting key signals that control cell growth, differentiation and function from multiple receptors. Here, we review the structure, mechanism of action and function of these interesting molecules in normal biology and disease. [Copyright &y& Elsevier]

Provides information on a study which examined the role for Gab2 in the allergic response experimentally. Composition of the Gab2; Function of Gab2 in signaling; Results; How the study was conducted.

Therapy-related leukemia carries a poor prognosis, and leukemia after chemotherapy is a growing risk in clinic, whose mechanism is still not well understood. Ikaros transcription factor is an important regulator in hematopoietic cells development and differentiation. In the absence of Ikaros, lymphoid cell differentiation is blocked at an extremely early stage, and myeloid cell differentiation is also significantly affected. In this work, we showed that chemotherapeutic drug etoposide reduced the protein levels of several isoforms of Ikaros including IK1, IK2 and IK4, but not IK6 or IK7, by accelerating protein degradation, in leukemic cells. To investigate the molecular mechanism of Ikaros degradation induced by etoposide, immunoprecipitation coupled with LC-MS/MS analysis was conducted to identify changes in protein interaction with Ikaros before and after etoposide treatment, which uncovered KCTD5 protein. Our further study demonstrates that KCTD5 is the key stabilizing factor of Ikaros and chemotherapeutic drug etoposide induces Ikaros protein degradation through decreasing the interaction of Ikaros with KCTD5. These results suggest that etoposide may induce leukemic transformation by downregulating Ikaros via KCTD5, and our work may provide insights to attenuate the negative impact of chemotherapy on hematopoiesis. [ABSTRACT FROM AUTHOR]

Background: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson's disease (PD) in human through its metabolite MPP+ by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP+-treated SH-SY5Y cells and MPTP-treated mice were used as the PD cell culture and mouse models respectively. The recombinant NDI1 lentivirus was transduced into SH-SY5Y cells, or the recombinant NDI1 adeno-associated virus (rAAV5-NDI1) was injected into substantia nigra pars compacta (SNpc) of mice. Results: The study in vitro showed NDI1 prevented MPP+-induced change in cell morphology and decreased cell viability, mitochondrial coupling efficiency, complex I-dependent oxygen consumption, and mitochondria-derived ATP. The study in vivo revealed that rAAV-NDI1 injection significantly improved the motor ability and exploration behavior of MPTP-induced PD mice. Accordingly, NDI1 notably improved dopaminergic neuron survival, reduced the inflammatory response, and significantly increased the dopamine content in striatum and complex I activity in substantia nigra. Conclusions: NDI1 compensates for the defective complex I in MPP+/MPTP-induced models, and vastly alleviates MPTP-induced toxic effect on dopaminergic neurons. Our study may provide a basis for gene therapy of sporadic PD with defective complex I caused by MPTP-like substance. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the leading cause of cancer death for women worldwide. Most of the breast cancer death are due to disease recurrence and metastasis. Increasingly accumulating evidence indicates that mitochondria play key roles in cancer progression and metastasis. Our recent study revealed that transmembrane protein PRRG4 promotes the metastasis of breast cancer. However, it is not clear whether PRRG4 can affect the migration and invasion of breast cancer cells through regulating mitochondria function. Methods: RNA-seq analyses were performed on breast cancer cells expressing control and PRRG4 shRNAs. Quantitative PCR analysis and measurements of mitochondrial ATP content and oxygen consumption were carried out to explore the roles of PRRG4 in regulating mitochondrial function. Luciferase reporter plasmids containing different lengths of promoter fragments were constructed. Luciferase activities in breast cancer cells transiently transfected with these reporter plasmids were analyzed to examine the effects of PRRG4 overexpression on promoter activity. Transwell assays were performed to determine the effects of PRRG4-regulated pathway on migratory behaviors of breast cancer cells. Results: Analysis of the RNA-seq data revealed that PRRG4 knockdown decreased the transcript levels of all the mitochondrial protein-encoding genes. Subsequently, studies with PRRG4 knockdown and overexpression showed that PRRG4 expression increased mitochondrial DNA (mtDNA) content. Mechanistically, PRRG4 via Src activated STAT3 in breast cancer cells. Activated STAT3 in turn promoted the transcription of mtDNA polymerase POLG through a STAT3 DNA binding site present in the POLG promoter region, and increased mtDNA content as well as mitochondrial ATP production and oxygen consumption. In addition, PRRG4-mediated activation of STAT3 also enhanced filopodia formation, migration, and invasion of breast cancer cells. Moreover, PRRG4 elevated migratory behaviors and mitochondrial function of breast cancer cells through POLG. Conclusion: Our results indicate that PRRG4 via the Src-STAT3-POLG axis enhances mitochondrial function and promotes migratory behaviors of breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is one of the most aggressive malignancies without effective targeted therapies. MUC1 has emerged as a potential common target for cancer therapy because it is overexpressed in a variety of different cancers including the majority of pancreatic cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1 have been reported. Recently, we generated a humanized MUC1 antibody (HzMUC1) specific to the interaction region between MUC1-N and MUC1-C. In this study, we generated the antibody drug conjugate (ADC) by conjugating HzMUC1 with monomethyl auristatin (MMAE), and examined the efficacy of HzMUC1-MMAE against the MUC1-positive pancreatic cancer in vitro and in vivo. Methods: Western blot and immunoprecipitation were used to detect MUC1 in pancreatic cancer cells. MUC1 localization in pancreatic cancer cells was determined by confocal microscopy. HzMUC1 was conjugated with the monomethyl auristatin (MMAE), generating the HzMUC1-MMAE ADC. Colony formation assay and flow cytometry were used to assess the effects of the HzMUC1-MMAE cell viability, cell cycle progression and apoptosis. Capan-2 and CFPAC-1 xenograft model were used to test the efficacy of HzMUC1-MMAE against pancreatic cancer. Results: HzMUC1 antibody binds to MUC1 on the cell surface of pancreatic cancer cells. HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in pancreatic cancer cells. Importantly, HzMUC1-MMAE significantly reduced the growth of pancreatic xenograft tumors by inhibiting cell proliferation and enhancing cell death. Conclusion: Our results indicate that HzMUC1-ADC is a promising novel targeted therapy for pancreatic cancer. HzMUC1-ADC should also be an effective drug for the treatment of different MUC1-positive cancers. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is one of the most aggressive malignancies without effective targeted therapies. MUC1 has emerged as a potential common target for cancer therapy because it is overexpressed in a variety of different cancers including the majority of pancreatic cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1 have been reported. Recently, we generated a humanized MUC1 antibody (HzMUC1) specific to the interaction region between MUC1-N and MUC1-C. In this study, we generated the antibody drug conjugate (ADC) by conjugating HzMUC1 with monomethyl auristatin (MMAE), and examined the efficacy of HzMUC1-MMAE against the MUC1-positive pancreatic cancer in vitro and in vivo. Methods: Western blot and immunoprecipitation were used to detect MUC1 in pancreatic cancer cells. MUC1 localization in pancreatic cancer cells was determined by confocal microscopy. HzMUC1 was conjugated with the monomethyl auristatin (MMAE), generating the HzMUC1-MMAE ADC. Colony formation assay and flow cytometry were used to assess the effects of the HzMUC1-MMAE cell viability, cell cycle progression and apoptosis. Capan-2 and CFPAC-1 xenograft model were used to test the efficacy of HzMUC1-MMAE against pancreatic cancer. Results: HzMUC1 antibody binds to MUC1 on the cell surface of pancreatic cancer cells. HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in pancreatic cancer cells. Importantly, HzMUC1-MMAE significantly reduced the growth of pancreatic xenograft tumors by inhibiting cell proliferation and enhancing cell death. Conclusion: Our results indicate that HzMUC1-ADC is a promising novel targeted therapy for pancreatic cancer. HzMUC1-ADC should also be an effective drug for the treatment of different MUC1-positive cancers. [ABSTRACT FROM AUTHOR]

Purpose: Parkinson's disease (PD) is the second most common neurodegenerative disease without cure or effective treatment. This study explores whether the yeast internal NADH-quinone oxidoreductase (NDI1) can functionally replace the defective mammalian mitochondrial complex I, which may provide a gene therapy strategy for treating sporadic PD caused by mitochondrial complex I dysfunction. Method: Recombinant lentivirus expressing NDI1 was transduced into SH-SY5Y cells, or recombinant adeno-associated virus type 5 expressing NDI1 was transduced into the right substantia nigra pars compacta (SNpc) of mouse. PD cell and mouse models were established by rotenone treatment. The therapeutic effects of NDI1 on rotenone-induced PD models in vitro and vivo were assessed in neurobehavior, neuropathology, and mitochondrial functions, by using the apomorphine-induced rotation test, immunohistochemistry, immunofluorescence, western blot, complex I enzyme activity determination, oxygen consumption detection, ATP content determination and ROS measurement. Results: NDI1 was expressed and localized in mitochondria in SH-SY5Y cells. NDI1 resisted rotenone-induced changes in cell morphology, loss of cell viability, accumulation of α-synuclein and pS129 α-synuclein, mitochondrial ROS production and mitochondria-mediated apoptosis. The basal and maximal oxygen consumption, mitochondrial coupling efficiency, basal and oligomycin-sensitive ATP and complex I activity in cell model were significantly increased in rotenone + NDI1 group compared to rotenone + vector group. NDI1 was efficiently expressed in dopaminergic neurons in the right SNpc without obvious adverse effects. The rotation number to the right side (NDI1-treated side) was significantly increased compared to that to the left side (untreated side) in mouse model. The number of viable dopaminergic neurons, the expression of tyrosine hydroxylase, total and maximal oxygen consumption, mitochondrial coupling efficiency and complex I enzyme activity in right substantia nigra, and the content of dopamine in right striatum were significantly increased in rotenone + NDI1 group compared to rotenone + vector group. Conclusion: Yeast NDI1 can rescue the defect of oxidative phosphorylation in rotenone-induced PD cell and mouse models, and ameliorate neurobehavioral and neuropathological damages. The results may provide a basis for the yeast NDI1 gene therapy of sporadic PD caused by mitochondrial complex I dysfunction. [ABSTRACT FROM AUTHOR]

Transformation of fibroblasts by V-SEA involves activation of the ERK and phosphatidylinositol 3-kinase (PI3K) pathways. Effector proteins that are key mediators of the ERK and PI3K pathways, namely Grb2, the tyrosine phosphatase, SHP2 and PI3K, interact with the two phosphotyrosines found in the bidentate motif in the carboxy-terminal region of V-SEA. Genetic analysis demonstrated that while Y557 was a primary binding site and thus activator of the PI3K-Akt pathway, Y564 also contributed to the activation of this pathway. Y564 was located within a Grb2-binding motif, this raised the possibility that a protein that associated with Grb2 might be important for this PI3K activation. The scaffolding proteins Gab1 and/or Gab2 were candidates for this role. In this report, we demonstrate that V-SEA preferentially interacts with Gab2. Furthermore by using Gab2 null fibroblasts, we demonstrate that Gab2 is essential for fibroblast transformation by V-SEA. Using mutant forms of Gab2, we show that activation of the PI3K-Akt pathway via Gab2 is required for V-SEA-induced transformation. However, efficient fibroblast transformation also requires the SHP2 interaction site on Gab2.Oncogene (2003) 22, 6311-6318. doi:10.1038/sj.onc.1206742 [ABSTRACT FROM AUTHOR]

Background: Synchronous multiple primary lung cancers are becoming more common with increasing use of computed tomography for screening. Intraoperative localization and resection of ill-defined pulmonary ground-glass opacities during thoracoscopic resection is challenging. This study aimed to determine the clinical feasibility of non-invasive visual localization of these nodules by three-dimensional computed tomography lung reconstruction before sublobar resection.Methods: Forty-four patients with synchronous multiple primary lung cancers underwent thoracoscopic pulmonary resection at our institution between June 2017 and August 2019. Preadmission computed tomography images were downloaded and reconstructed into a three-dimensional model. Small nodules (< 15 mm) were localized non-invasively by three-dimensional computed tomography lung reconstruction before surgery. Patient demographics, nodule characteristics, procedural details, pathological data, and outcomes were obtained from the medical records.Results: One hundred and twenty-one pulmonary nodules from the 44 patients were scheduled for video-assisted thoracic surgery; 54 (44.6%) were pure ground-glass opacities and 57 (47.1%) were mixed ground-glass opacities. One hundred and seventeen nodules were localized preoperatively. The mean nodule diameter was 7.67 ± 3.87 mm. The mean distance from the nodule to the pleura was 14.84 ± 14.43 mm. All nodules were removed successfully by wedge resection (27 patients), lobectomy (26 patients), or segmentectomy (25 patients). Most lesions (85.1%) were malignant. Paraffin pathology revealed 12 cases of atypical adenomatous hyperplasia (9.92%), 13 of adenocarcinoma in situ (10.74%), 16 of minimally invasive adenocarcinoma (13.22%), and 73 of invasive adenocarcinoma (60.33%).Conclusions: Three-dimensional computed tomography lung reconstruction is a feasible and alternative method of visual localization for small lung nodules before sublobar resection in some suitable patients. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is one of the most common types of acute leukemia in adults with the lowest survival rate of all leukemia. Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure. Thus, finding new drugs with anti-leukemia activities and minimal side effect is urgently needed. Here through screening more than 1000 drugs approved by the Food and Drug Administration (FDA) of United States, the anthelmintic drug mebendazole (MBZ) was found to inhibit the growth of AML cell lines (THP-1, U937, NB4 and K562) and bone marrow mononuclear cells (BM-MNCs) from AML patients at pharmacologically achievable concentrations. In contrast, similar concentration of MBZ had little inhibitory effect on the growth of normal peripheral blood mononuclear cells (PBMC) or human umbilical vein endothelial cells (HUVEC). In addition, MBZ induced mitotic arrest and mitotic catastrophe in AML cells based on nuclear morphology, cell cycle distribution, mitotic marker analyses and the number of multinucleated cells and apoptotic cells. Furthermore, MBZ treatment inhibited activation of Akt and Erk in AML leukemic cells. Finally, MBZ repressed the progression of leukemic cells in vivo and prolonged survival in AML xenograft mouse model. Taken together, our results suggest that MBZ could be a potential new therapeutic agent for the treatment of AML patients. [ABSTRACT FROM AUTHOR]

Our previous study generated a series of cybrids containing mitochondria of synaptosomes from mice at different ages. The following functional analysis on these cybrids revealed an age-dependent decline of mitochondrial function. To understand the underlying mechanisms that contribute to the age-related mitochondrial dysfunction, we focused on three cybrids carrying mitochondria derived from synaptosomes of the old mice that exhibited severe respiratory deficiencies. In particular, we started with a comprehensive analysis of mitochondrial genome by high resolution, high sensitive deep sequencing method. Compared with young control, we detected a significant accumulation of heteroplasmic mtDNA mutations. These mutations included six alterations in main control region that has been shown to regulate overall gene-expression, and four alterations in protein coding region, two of which led to significant changes in complex I subunit ND5 and complex III subunit CytB. Interestingly, a reduced mtDNA-encoded protein synthesis was associated with the changes in the main control region. Likewise, mutations in ND5 and CytB were associated with defects in assembly of respiratory complexes. Altogether, the identified age-dependent accumulation of mtDNA mutations in mouse brain likely contributes to the decline in mitochondrial function. [ABSTRACT FROM AUTHOR]

SH2-domain containing protein tyrosine phosphatase 1 (Shp1/PTPN6) is mainly expressed in hematopoietic cells and acts a negative signaling regulator. Although Shp1 is also expressed in epithelial cells, the function of shp1 in normal epithelial is still less well understood, especially in regulating the growth of epithelial cells. In this study, different shRNAs and siRNAs against Shp1 were used to knockdown Shp1 expression in MCF10A, an immortalized mammary epithelial cell line. Shp1 knockdown resulted in inhibited cell growth in part due to lower percentage of MCF10A cells entering into S phase and reduced cyclin D1 expression. Accordingly, EGF-induced tyrosyl phosphorylation of EGFR and Stat5 was significantly inhibited in cells with Shp1 knockdown compared with control whereas EGF-induced Akt and Erk phosphorylation was not affected by Shp1 knockdown. Further analysis revealed that Shp1 knockdown lead to decreased EGFR protein expression without affecting EGFR mRNA expression or increasing EGFR protein degradation. Our data indicate that Shp1 functions as a positive regulator and acts in a novel mechanism through promoting EGFR protein expression in mammary epithelial cells. [ABSTRACT FROM AUTHOR]

Besides its well-known function in allergic response, mast cell, one of the key immune cells present in tumor microenvironment, plays important roles in cancer progression. However, the functional role of mast cells in breast cancer development and metastasis is not well understood. To test the involvement of mast cells in breast cancer, we examined the effects of loss of mast cells on mammary tumor development by crossing the well-known mast cell deficient mouse strain sash (KitW-sh/W-sh) with the mammary tumor transgenic mouse strain MMTV-Polyoma Middle T antigen (Py MT). Although mammary tumor onset was not affected in the absence of mast cells, mammary growth and metastasis were reduced in Py MT/KitW-sh/W-sh mice compared with Py MT/wild-type mice ( WT). Histological and immunofluorescent analyses showed that tumors from Py MT/KitW-sh/W-sh mice showed largely differentiated morphology with reduced angiogenesis compared with MMTV-Py MT/ WT mice. Our results suggest that mast cells may promote breast cancer growth and metastasis. Agents that can block mast cells growth are potential new therapies to treat metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Both dietary fat and carbohydrates (Carbs) may play important roles in the development of insulin resistance. The main goal of this study was to further define the roles for fat and dietary carbs in insulin resistance. C57BL/6 mice were fed normal chow diet (CD) or HFD containing 0.1–25.5% carbs for 5 weeks, followed by evaluations of calorie consumption, body weight and fat gains, insulin sensitivity, intratissue insulin signaling, ectopic fat, and oxidative stress in liver and skeletal muscle. The role of hepatic gluconeogenesis in the HFD-induced insulin resistance was determined in mice. The role of fat in insulin resistance was also examined in cultured cells. HFD with little carbs (0.1%) induced severe insulin resistance. Addition of 5% carbs to HFD dramatically elevated insulin resistance and 10% carbs in HFD was sufficient to induce a maximal level of insulin resistance. HFD with little carbs induced ectopic fat accumulation and oxidative stress in liver and skeletal muscle and addition of carbs to HFD dramatically enhanced ectopic fat and oxidative stress. HFD increased hepatic expression of key gluconeogenic genes and the increase was most dramatic by HFD with little carbs, and inhibition of hepatic gluconeogenesis prevented the HFD-induced insulin resistance. In cultured cells, development of insulin resistance induced by a pathological level of insulin was prevented in the absence of fat. Together, fat is essential for development of insulin resistance and dietary carb is not necessary for HFD-induced insulin resistance due to the presence of hepatic gluconeogenesis but a very small amount of it can promote HFD-induced insulin resistance to a maximal level. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH.Methods: The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB.Results: HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB.Conclusion: In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH. [ABSTRACT FROM AUTHOR]

Abstract: Gab1 was previously described as a positive modulator of Akt, Src, ERK1/2, endothelial cell migration, and capillary formation in response to vascular endothelial growth factor (VEGF). However, its involvement in endothelial cell survival, as well as the potential contribution of the other family member Gab2 to signalling and biological responses remained unknown. Here, we show that Gab2 is tyrosine phosphorylated in a Grb2-dependent manner downstream of activated VEGF receptor-2 (VEGFR2), and that it associates with signalling proteins including PI3K and SHP2, but apparently not with the receptor. Similarly to Gab1, over-expression of Gab2 induces endothelial cell migration in response to VEGF, whereas its depletion using siRNAs results in its reduction. Importantly, depletion of both Gab1 and Gab2 leads to an even greater inhibition of VEGF-induced cell migration. However, contrary to what has been reported for Gab1, the silencing of Gab2 results in increased Src, Akt and ERK1/2 activation, slightly reduced p38 phosphorylation, and up-regulation of Gab1 protein levels. Accordingly, re-expression of Gab2 in Gab2−/− fibroblasts leads to opposite results, suggesting that the modulation of both Gab2 and Gab1 expression in these conditions might contribute to the impaired signalling observed. Consistent with their opposite roles on Akt, the depletion of Gab1, but not of Gab2, results in reduced FOXO1 phosphorylation and VEGF-mediated endothelial cell survival. Mutation of VEGFR2 Y801 and Y1214, which abrogates the phosphorylation of Gab1, also correlates with inhibition of Akt. Altogether, these results underscore the non-redundant and essential roles of Gab1 and Gab2 in endothelial cells, and suggest major contributions of these proteins during in vivo angiogenesis. [Copyright &y& Elsevier]

The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of Gab2 potentiates, whereas deficiency of Gab2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both. [ABSTRACT FROM AUTHOR]

The BCR/ABL oncogene causes chronic myelogenous leukemia (CML) in humans and a CML-like disease, as well as lymphoid leukemia, in mice. p210 BCR/ABL is an activated tyrosine kinase that phosphorylates itself and several cellular signaling proteins. The autophosphorylation site tyrosine 177 binds the adaptor Grb2 and helps determine the lineage and severity of BCR/ABL disease: Tyr177 mutation (BCR/ABL-Y177F) dramatically impairs myeloid leukemogenesis, while diminishing lymphoid leukemogenesis. The critical signal(s) from Tyr177 has remained unclear. We report that Tyr177 recruits the scaffolding adaptor Gab2 via a Grb2/Gab2 complex. Compared to BCR/ABL-expressing Ba/F3 cells, BCR/ABL-Y177F cells exhibit markedly reduced Gab2 tyrosine phosphorylation and association of phosphatidylinositol-3 kinase (PI3K) and Shp2 with Gab2 and BCR/ABL, and decreased PI3K/Akt and Ras/Erk activation, cell proliferation, and spontaneous migration. Remarkably, bone marrow myeloid progenitors from Gab2 (−/−) mice are resistant to transformation by BCR/ABL, whereas lymphoid transformation is diminished as a consequence of markedly increased apoptosis. BCR/ABL-evoked PI3K/Akt and Ras/Erk activation also are impaired in Gab2 (−/−) primary myeloid and lymphoid cells. Our results identify Gab2 and its associated proteins as key determinants of the lineage and severity of BCR/ABL transformation. [Copyright &y& Elsevier]

Scaffolding adaptor Gab2 is overexpressed in a subset of high-grade ovarian cancer. Our published work shows that Gab2 via PI3K enhances migratory behaviors and epithelial to mesenchymal transition (EMT) features of ovarian cancer cells in vitro. However, it is still unclear how Gab2/PI3K pathway reuglates EMT characteristics and whether Gab2 promotes the growth of ovarian cancer stem cell (CSC)-like population and metastatic growth. In this study, we examined the effects of Gab2 expression on CSC-like cell growth using Aldefluor and tumorshpere assays commonly used for assessing ovarian cancer cells with CSC properties. Gab2 overexpression increased the number of ALDH+ cells and tumorsphere formation in two different ovarian cancer cell lines OVCAR5 and OVCAR8, whereas knockdown of Gab2 decreased the number of ALDH+ cells and tumorsphere formation in Caov-3 cells. Furthermore, Gab2 promoted metastatic tumor growth of OVCAR5 in nude mice. Mechanistically, we uncovered that Gab2 via PI3K specifically inhibited miR-200c expression. miR-200c downregulation contributed to the Gab2-enhanced cell migratory behaviors, EMT properties, and the expansion of ALDH+ cells and tumorspheres. Furthermore, Gab2 promoted CD44 expression and cell migration/invasion through miR-200c downregulation. Our findings support a model that Gab2-PI3K pathway via miR-200c downregulation promotes CD44 expression, EMT characteristics, and CSC-like cell growth. Therapies involving miR-200c or targeting CD44 should help treat ovarian cancer with high Gab2 expression. • Gab2 promotes the growth of CSC-like population of ovarian cancer cells. • Gab2 promotes metastatic growth of ovarian cancer cells in xenograft. • Gab2 via PI3K inhibits miR-200c expression in ovarian cancer cells. • Gab2 via miR-200c downregulation promotes phenotypes of EMT and CSC. • Gab2 inhibition of miR-200c enhances CD44 expression and cell migration/invasion. [ABSTRACT FROM AUTHOR]