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Development of novel therapeutic antibodies that not only kill tumor cells but modulate the adaptive immune response has the potential to produce long term anti-cancer immunity and a durable clinical response. We previously reported the discovery of an anti-complement factor H (CFH) autoantibody in lung cancer patients that were associated with early stage disease and exceptional outcomes. The human monoclonal antibody GT103, produced from a single CFH autoantibody-expressing B cell of a lung cancer patient, recognizes a conformationally distinct epitope on tumor cells, kills tumor cells, and inhibits tumor growth in animal studies. Recent experiments have shown that GT103 restructures the tumor microenvironment and initiates a robust antitumoral adaptive immune response. The current study further elucidates several mechanisms by which GT103 kills tumor cells and drives the immune program. Here we show GT103 has specificity for tumor cells without binding to native soluble CFH or normal tissues. GT103 causes complement C3 split product deposition on tumor cellsin vitroandin vivo,triggers antibody-dependent cellular phagocytosis, and increases translocation of the danger associated molecular pattern molecule calreticulin to the plasma membrane.We also demonstrate that GT103 causes B cell activation and that GT103 antitumor activityin vivois B cell dependent. The complex mechanism of GT103, a tumor specific antibody that kills tumor cells and stimulates an immune response, supports further development of this human-derived antibody as a novel therapeutic option for patients with lung cancer.

BACKGROUND: Biomarkers that predict which patients with early stage NSCLC will develop recurrent disease would be of clinical value. We previously discovered that an autoantibody to a complement regulatory protein, complement factor H (CFH), is associated with early stage, non-recurrent NSCLC, and hypothesized that the anti-CFH antibody inhibits metastasis. OBJECTIVES: The primary objective of this study was to evaluate the anti-CFH antibody as a prognostic marker for recurrence in stage I NSCLC. A secondary objective was to determine if changes in antibody serum level one year after resection were associated with recurrence. METHODS: Anti-CFH antibody was measured in the sera of 157 stage I NSCLC patients designated as a prognostic cohort: 61% whose cancers did not recur, and 39% whose cancers recurred following resection. Impact of anti-CFH antibody positivity on time to recurrence was assessed using a competing risk analysis. Anti-CFH antibody levels were measured before resection and one year after resection in an independent temporal cohort of 47 antibody-positive stage I NSCLC patients: 60% whose cancers did not recur and 40% whose cancers recurred following resection. The non-recurrent and recurrent groups were compared with respect to the one-year percent change in antibody level. RESULTS: In the prognostic cohort, the 60-month cumulative incidence of recurrence was 40% and 22% among antibody negative and positive patients, respectively; this difference was significant (Gray’s test, P= 0.0425). In the temporal cohort, the antibody persisted in the serum at one year post-tumor resection. The change in antibody levels over the one year period was not statistically different between the non-recurrent and recurrent groups (Wilcoxon two-sample test, P= 0.4670). CONCLUSIONS: The anti-CFH autoantibody may be a useful prognostic marker signifying non-recurrence in early stage NSCLC patients. However, change in the level of this antibody in antibody-positive patients one year after resection had no association with recurrence.

Complement-dependent cytotoxicity of A549 lung cancer cells by the alternative pathway.

Characterization of the humoral immune response in selected patients with cancer who uniformly do well may lead to the development of novel therapeutic strategies. We have previously shown an association between patients with early-stage nonmetastatic lung cancer and autoantibodies to complement factor H (CFH). CFH protects normal and tumor cells from destruction by the alternative complement pathway by inactivating C3b, a protein that is essential for formation of a lytic complex on the cell surface. Here, we show that CFH autoantibodies in lung cancer patients recognize a conformationally distinct form of CFH in vitro, are IgG3 subclass, and epitope map to a crucial functional domain of CFH known to interact with C3b. Purified CFH autoantibodies inhibited binding of CFH to A549 lung tumor cells, increased C3b deposition, and caused complement-dependent tumor cell lysis. This work demonstrates that CFH autoantibodies isolated from patients with lung cancer can kill tumor cells in vitro, suggesting that they may perform this function in vivo as well. Development of specific antibodies to the conformationally distinct epitope of CFH may lead to a useful biologic therapy for lung cancer. Cancer Immunol Res; 3(12); 1325–32. ©2015 AACR.

Deposition of C3-related fragments on A549 lung cancer cells.

Supplementary Figure S1. Complement regulates IL-10 production in CD8+ TILs. Supplementary Figure S2. Non-CD8+ T cell responses in tumor bearing mice. Supplementary Figure S3. T cell exhaustion markers expressed on CD8+ TILs after IL-10 culture. Supplementary Figure S4. Anaphylatoxins regulate IL-10 production through C3aR and C5aR.

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Compliant mechanisms are widely used for instrumentation and measuring devices for their precision and high bandwidth. In this paper, the mechatronic model of a compliant 3PRS parallel manipulator is developed, integrating the inverse and direct kinematics, the inverse dynamic problem of the manipulator and the dynamics of the actuators and the control. The kinematic problem is solved, assuming a pseudo-rigid model for the deflection in the compliant revolute and spherical joints. The inverse dynamic problem is solved, using the Principle of Energy Equivalence. The mechatronic model allows the prediction of the bandwidth of the manipulator motion in the 3 degrees of freedom for a given control and set of actuators, helping in the design of the optimum solution. A prototype is built and validated, comparing experimental signals with the ones from the model. Authors would like to thank the Ministerio de Ciencia e Innovación of the Spanish government for funding the project PID2019-105262RB-I00.

BackgroundSingle nucleotide polymorphisms (SNPs) are often associated with distinct phenotypes in cancer. The present study investigated associations of cancer risk and outcomes with SNPs discovered by whole exome sequencing of normal lung tissue DNA of 15 non-small cell lung cancer (NSCLC) patients, 10 early stage and 5 advanced stage.MethodsDNA extracted from normal lung tissue of the 15 NSCLC patients was subjected to whole genome amplification and sequencing and analyzed for the occurrence of SNPs. The association of SNPs with the risk of lung cancer and survival was surveyed using the OncoArray study dataset of 85,716 patients (29,266 cases and 56,450 cancer-free controls) and the Prostate, Lung, Colorectal and Ovarian study subset of 1,175 lung cancer patients.ResultsWe identified 4 SNPs exclusive to the 5 patients with advanced stage NSCLC: rs10420388 and rs10418574 in the CLPP gene, and rs11126435 and rs2021725 in the M1AP gene. The variant alleles G of SNP rs10420388 and A of SNP rs10418574 in the CLPP gene were associated with increased risk of squamous cell carcinoma (OR = 1.07 and 1.07; P = 0.013 and 0.016, respectively). The variant allele T of SNP rs11126435 in the M1AP gene was associated with decreased risk of adenocarcinoma (OR = 0.95; P = 0.027). There was no significant association of these SNPs with the overall survival of lung cancer patients (P > 0.05).ConclusionsSNPs identified in the CLPP and M1AP genes may be useful in risk prediction models for lung cancer. The previously established association of the CLPP gene with cancer progression lends relevance to our findings.

A common problem in motion control is the onset of vibrations due to the inertial forces when a compliant load is being displaced. It is the case of the vibration of large machine tools, but also the vibration of slender loads in pick&place. The main goal of the present work is to predict and minimise the overshoot that a compliant load moved by a servodrive suffers when it reaches the final position. Instead of modifying the control algorithm or adding dampers, the authors propose an optimal path planning based on the selection of a square sine velocity profile, a standard in machine tools NCs. Thus, a 3 degrees of freedom mechatronic model that integrates the dynamics of the drive-transmission-compliant load system and the control has been developed to predict the overshoot. Analysing the velocity profile, it has been possible to determine several values of the commanded jerk that minimize the overshoot and are related to the natural frequency of the compliant load. The prediction of the overshoot magnitude as well as the optimal jerk values have been experimentally validated in a workbench with a single axis with a ball screw transmission and a compliant load where a laser interferometer has been used to measure the overshoot.

Parallel continuum mechanisms are closed, kinematic, chained compliant mechanisms that are mobile due to flexible and slender elements. Large deformations and the force-moment equilibrium require a more complex modeling of the kinematic analysis than in their rigid-link counterparts. Although real-time solutions to the position problem using numerical iterative methods are available, a comprehensive kinematic analysis of such mechanisms has not yet been conducted. The first step to this end is a procedure that solves the full forward and inverse kinematic problems, and is proposed in this paper for planar systems to allow for an easier interpretation of their kinematic characteristics. This procedure provides the means to obtain multiple solutions arising from the closed-loop structure and the multiplicity of the buckling mode of slender links.

The objective of the present work is to develop a device for training the trunk balance and motion during the early stage of rehabilitation of patients who have suffered a stroke. It is coupled to a standing frame and is based on a parallel continuum manipulator where a wearable jacket is moved by four flexible limbs actuated by rotary motors, achieving the translation and rotation required in the trunk to perform a given exercise. The flexible limbs act as a natural mechanical filter in such a way that a smooth physiological motion is achieved, and it feels less intimidating to the patient. After measuring the kinematic requirements, a model has been developed to design the system. A prototype has been built and a preliminary experimental validation has been done where the jacket generates translation coupled to a rotation around the anteroposterior, medio-lateral and longitudinal axis. The measurements of the motors torque and the force sensors located in the flexible limbs have been compared with the simulations from the model. The results prove that the prototype can accomplish the motions required for the rehabilitation task, although further work is still required to control the interaction with the patient and improve the performance of the device.

Exosomes are a class of extracellular vesicles (EVs) that are mediators of normal intercellular communication, but exosomes are also used by tumor cells to promote oncogenesis and metastasis. Complement factor H (CFH) protects host cells from attack and destruction by the alternative pathway of complement-dependent cytotoxicity (CDC). Here we show that CFH can protect exosomes from complement-mediated lysis and phagocytosis. CFH was found to be associated with EVs from a variety of tumor cell lines as well as EVs isolated from the plasma of patients with metastatic non-small cell lung cancer. Higher levels of CFH-containing EVs correlated with higher metastatic potential of cell lines. GT103, a previously described antibody to CFH that preferentially causes CDC of tumor cells, was used to probe the susceptibility of tumor cell-derived exosomes to destruction. Exosomes were purified from EVs using CD63 beads. Incubation of GT103 with tumor cell-derived exosomes triggered exosome lysis primarily by the classical complement pathway as well as antibody-dependent exosome phagocytosis by macrophages. These results imply that GT103-mediated exosome destruction can be triggered by antibody Fc-C1q interaction (in the case of lysis), and antibody-Fc receptor interactions (in the case of phagocytosis). Thus, this work demonstrates CFH is expressed on tumor cell derived exosomes, can protect them from complement lysis and phagocytosis, and that an anti-CFH antibody can be used to target tumor-derived exosomes for exosome destruction via innate immune mechanisms. These findings suggest that a therapeutic CFH antibody has the potential to inhibit tumor progression and reduce metastasis promoted by exosomes.

The consequence of the population aging in last decades has been an increase of age-related disorders, such as multiple sclerosis, Parkinson’s disease, spinal cord injury or central nervous diseases, causing a deficiency in mobility and thus affecting the quality of life of adults [1, 2].

It is important for the mechatronic design of robotic systems to rely on accurate models. To that end, system identification methods are a convenient tool to obtain the values of the unknown dynamic parameters which play a key role. In this paper, it is investigated the application of the principle of energy equivalence to easily obtain a suitable model for identification of the inertial parameters and friction of planar mechanisms. The methodology here proposed is then applied to the prototype RePlaLink, a 5R haptic mechanism. Experimental data was obtained to carry out the identification, and the results were then validated by using a different trajectory than the one used for the identification of the unknown parameters. It was found that the identified model developed for the mechanism using the herein described methodology, was able to predict the dynamic behavior of the mechanism.

The photocatalytic activity in the degradation of 4-chlorophenol (4-ClPh) in aqueous medium (80 ppm) using 2.0 wt% Ag/Al2O3–Gd2O3 (Ag/Al–Gd-x; where x = 2.0, 5.0, 15.0, 25.0 and 50.0 wt% of Gd2O3) photocatalysts prepared by the sol–gel method was studied under UV light irradiation. The photocatalysts were characterized by N2 physisorption, X-ray diffraction, SEM, HRTEM, UV-Vis, XPS, FTIR and fluorescence spectroscopy. About 67.0% of 4-ClPh was photoconverted after 4 h of UV light irradiation using Ag/γ-–Al2O3. When Ag/Al–Gd-x photocatalysts were tested, the 4-ClPh photoconversion was improved and more than 90.0% of 4-ClPh was photoconverted after 3 h of UV light irradiation in the materials containing 15.0 and 25.0 wt% of Gd2O3. Ag/Al–Gd-25 was the material with the highest efficacy to mineralize dissolved organic carbon, mineralizing more than 85.0% after 4 h of UV light irradiation. Silver nanoparticles and micro-particles of irregular pentagonal shape intersected by plane nanobelts of Al2O3–Gd2O3 composite oxide were detected in the Ag/Al–Gd-25 photocatalyst. This material is characterized by a lowest recombination rate of electron–hole pairs. The low recombination rate of photo-induced electron–hole pairs in the Ag/Al–Gd-x photocatalysts with high Gd2O3 contents (≥15.0 wt%) confirmes that the presence of silver nanoparticles and microparticles interacting with Al2O3–Gd2O3 composite oxide entities favors the separation of photo-induced charges (e− and h+). These materials could be appropriate to be used as highly efficient photocatalysts to eliminate high concentrations of 4-ClPh in aqueous medium.

One of the main problems that large machine tool designers must face is the onset of deflection and vibration due to the forces involved during the process: the own weight of the elements of the machine, the cutting forces and the inertial forces. The last ones are especially relevant in the case of large and heavy machine tools with cantilever elements as rams or columns. To counteract these forces, the present work proposes the use of an inertial device, based on the rotation of two eccentric mases around the same axis. Hence, a simplified dynamic model of a column is first developed, and tested during a standard face milling operation. Then, the dynamic model of the device is also developed, and a Computed Torque Control is proposed to govern the action of the device. The simulations show that the use of this device has the potential to reduce drastically the effect of the inertial forces and even the lower frequency components of the cutting forces.

Introduction: Indeterminate pulmonary lesions (IPL) detected by CT pose a significant clinical challenge, frequently necessitating long-term surveillance or biopsy for diagnosis. In this pilot investigation, we performed whole exome sequencing (WES) of plasma cell free (cfDNA) and matched germline DNA in patients with CT-detected pulmonary lesions to determine the feasibility of somatic cfDNA mutations to differentiate benign from malignant pulmonary nodules.Methods: 33 patients with a CT-detected pulmonary lesions were retrospectively enrolled (n = 16 with a benign nodule, n = 17 with a malignant nodule). Following isolation and amplification of plasma cfDNA and matched peripheral blood mononuclear cells (PBMC) from patient blood samples, WES of cfDNA and PBMC DNA was performed. After genomic alignment and filtering, we looked for lung-cancer associated driver mutations and next identified high-confidence somatic variants in both groups.Results: Somatic cfDNA mutations were observed in both groups, with the cancer group demonstrating more variants than the benign group (1083 ± 476 versus 553 ± 519, p < 0.0046). By selecting variants present in >2 cancer patients and not the benign group, we accurately identified 82% (14/17) of cancer patients.Conclusions: This study suggests a potential role for cfDNA for the early identification of lung cancer in patients with CT-detected pulmonary lesions. Importantly, a substantial number of somatic variants in healthy patients with benign pulmonary nodules were also found. Such “benign” variants, while largely unexplored to date, have widespread relevance to all liquid biopsies if cfDNA is to be used accurately for cancer detection.

The development of large machinery in the industry of the machine tool implies moving heavy structural components and pieces. The consequence is the apparition of inaccuracies at the tool tip during the motion due to the high inertial forces acting on the compliant machine. To predict the dynamic behavior of these machines, a three degree of freedom mechatronic model has been developed considering the dynamics of the transmission chain of the drive, the machine structural element dynamics, and the control. The model can be used in the design stage to estimate the maximum jerk that can be commanded without the appearance of overshoot at the tool tip. Also, it can be used to predict the bandwidth of the whole mechatronic system. The model has been tested in a ball screw-based test bench with a compliant mass that simulates the structural compliance of a real large machine tool.

Current CAM and milling verification software packages are not ready to predict form and surface errors derived from non-ideal conditions such as runout tool error or tool–workpiece flexibility. As a consequence, high-end parts like integral blade rotors (IBR) suffer from this lack of estimation to achieve a sound manufacturing process preparation. This work describes the implementation of a cutting force prediction model that introduces the radial engagement reduction caused by (i) tool runout and (ii) workpiece flexibility. The model is used as the seed for a calculation module based on solid modeling to obtain the surface roughness and topography applying the cutting force–wall restitution equilibrium, making use of the power of CAM solid modelers for the final topography definition. This idea takes advantage of the good accuracy of current solid modelers in comparison with the z-map topographical approach for obtaining the cutter–workpiece engagement (CWE) at each tool path step. Several flank milling tests were carried out to validate the simulations. The results demonstrated a significant level of accuracy to predict shape errors. The model may be integrated in a CAM procedure, and it is a useful utility for reducing deformation on the manufacturing of blisks and impellers.

In contrast to its inhibitory effects on many cells, IL10 activates CD8+ tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8+ TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8+ TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell– and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. Significance: Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti–PD-1 to enhance anti–PD-1 efficacy; a targeted IL10 delivery to CD8+ TILs using anti–PD-1–IL10 or anti-CTLA4–IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022–35. ©2016 AACR. See related commentary by Peng et al., p. 953. This article is highlighted in the In This Issue feature, p. 932

Summary: Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery. : Bushey et al. clone antibodies against complement factor H (CFH) from single human B cells. CFH protects tumor cells from complement-dependent cytotoxicity (CDC). The authors demonstrate that a recombinant CFH antibody induces CDC of tumor cells, inhibits tumor growth in vivo, and stimulates infiltration of the tumor by lymphocytes.

One of the main advantages of parallel manipulators over serial manipulators is their capacity to achieve faster and more precise movements, which is why they are used in many industrial applications. A parallel manipulator is formed by two or more parallel sets of rigid elements connected in series, and the corresponding actuators. Nevertheless, a protection system is needed to prevent anyone from accessing the workspace and thus avoid accidents. In contrast, the alternative of using parallel manipulators formed by flexible elements has a potential advantage in the so called collaborative robotic applications, as the mechanism flexibility reduces the harm. In this paper, a planar continuum parallel mechanism prototype is presented. The position problem of the flexible rods is solved through nonlinear methods of deformation, using the Kirchhoff model. A mechatronic model has been developed integrating the dynamics of the robot, drives and control. Finally, the prototype has been assembled and experimentally tested, and the results of the tests carried out have been compared with the models developed in terms of displacement, velocity and torque.

This paper reports the sol-gel synthesis of Al2O3-Nd2O3 (Al-Nd-x, x = 5%, 10%, 15% and 25% of Nd2O3) binary oxides and the photodegradation of diclofenac activated by UV light. Al-Nd-based catalysts were analyzed by N2 physisorption, XRD, TEM, SEM, UV-Vis and PL spectroscopies. The inclusion of Nd2O3 in the aluminum oxide matrix in the 10&ndash, 25% range reduced the band gap energies from 3.35 eV for the &gamma, Al2O3 to values as low as 3.13&ndash, 3.20 eV, which are typical of semiconductor materials absorbing in the UV region. &gamma, Al2O3 and Al-Nd-x binary oxides reached more than 92.0% of photoconverted diclofenac after 40 min of reaction. However, the photocatalytic activity in the diclofenac degradation using Al-Nd-x with Nd2O3 contents in the range 10&ndash, 25% was improved with respect to that of &gamma, Al2O3 at short reaction times. The diclofenac photoconversion using &gamma, Al2O3 was 63.0% at 10 min of UV light exposure, whereas Al-Nd-15 binary oxide reached 82.0% at this reaction time. The rate constants determined from the kinetic experiments revealed that the highest activities in the aqueous medium were reached with the catalysts with 15% and 25% of Nd2O3, and these compounds presented the lowest band gap energies. The experimental results also demonstrated that Nd2O3 acts as a separator of charges favoring the decrease in the recombination rate of electron-hole pairs.

The aim of this work is to develop a mechatronic model for servodrives that move a compliant load, which is the case of large heavy machine tools. The model integrates the dynamics of the motor, transmission chain and compliant load as well as the dynamics of the control and is used to calculate the maximum overshoot in the load when it reaches the commanded final position as a function of the feed speed and the programmed jerk in the velocity profile. This overshoot must be, in applications as machining, always minimized. The result is a graph that indicates the region of safe values of jerk, where a given overshoot is never surpassed, but also there are several regions where much higher jerk values can be programmed with minimal overshoot. The location of these areas depending on the feed speed and the load natural frequency has been shown for a square sine profile. These optimal values of the jerk have been experimentally validated. Authors acknowledge the financial support from the Spanish Government through the MINECO DPI2015-64450-R MINECO/FEDER, UE) and the support through the project IT949-16, given by the Basque Government.

Parallel Continuum Manipulators are parallel mechanisms which movement is due to the deformation of some of their elements, usually flexible rods. Provided that rods are straight in their stress-free reference state and that the movement of the mechanism is within a plane, elliptic integral solution can be used in order to get the deformation of each rod. Since it is a parameterized method, it allows to control all possible solutions related to a certain buckling mode. We will show an unified method to solve both Forward and Inverse Kinematic Position problem of 2-DOF planar Parallel Continuum Manipulators in which two flexible rods are hinged at one extreme and are clamped to the other. The main characteristic of the method proposed is that static equilibrium equations and geometric equations are decoupled.

Parallel Continuum Mechanisms are manipulators whose end-effector is connected with several compliant legs. Continuum manipulators of such kind have been considered historically serial devices because most of them have a long slender form. Nevertheless, these architectures contain aspects resembling their rigid-link parallel analogs. In this paper, authors go over the parallelisms between both kinds of devices regarding several kinematic aspects. We will show that in the field of Parallel Continuum Mechanisms there are alter egos to concepts of rigid-link manipulators such as: assembly modes and working modes, or singularities. However, there are also distinct features that will be highlighted.

In this paper, the interaction between the dynamics of the routing process and the vibration behavior of the ARABA I lightweight machine is presented. Firstly, the dynamics of the routing is evaluated by the critical depth of cut of the lobes diagrams of the process. Secondly, the structural dynamics of the machine is analyzed by means of its experimentally validated finite element model. Considering the compliance of the machine as the only source of deformation, the interaction of the machine-process dynamics is evaluated and useful outputs are obtained. The critical depth of cut, the frequency of chatter, and the chatter-free workspace are depicted in the operational workspace of the machine. These results are finally used to propose some design and material improvements in the machine which lead to an enhanced performance in the routing process.

Characterization of the humoral immune response in selected patients with cancer who uniformly do well may lead to the development of novel therapeutic strategies. We have previously shown an association between patients with early-stage nonmetastatic lung cancer and autoantibodies to complement factor H (CFH). CFH protects normal and tumor cells from destruction by the alternative complement pathway by inactivating C3b, a protein that is essential for formation of a lytic complex on the cell surface. Here, we show that CFH autoantibodies in lung cancer patients recognize a conformationally distinct form of CFH in vitro, are IgG3 subclass, and epitope map to a crucial functional domain of CFH known to interact with C3b. Purified CFH autoantibodies inhibited binding of CFH to A549 lung tumor cells, increased C3b deposition, and caused complement-dependent tumor cell lysis. This work demonstrates that CFH autoantibodies isolated from patients with lung cancer can kill tumor cells in vitro, suggesting that they may perform this function in vivo as well. Development of specific antibodies to the conformationally distinct epitope of CFH may lead to a useful biologic therapy for lung cancer. Cancer Immunol Res; 3(12); 1325–32. ©2015 AACR.

Productivity and surface finish are typical user manufacturer requirements that are restrained by chatter vibrations sooner or later in every machining operation. Thus, manufacturers are interested in knowing, before building the machine, the dynamic behaviour of each machine structure with respect to another. Stability lobe graphs are the most reliable approach to analyse the dynamic performance. During heavy rough turning operations a model containing (a) several modes, or (b) modes with non-conventional (Cartesian) orientations is necessary. This work proposes two methods which are combined with multimode analysis to predict chatter in big horizontal lathes. First, a traditional single frequency model (SFM) is used. Secondly, the modern collocation method based on the Chebyshev polynomials (CCM) is alternatively studied. The models can be used to identify the machine design features limiting lathe productivity, as well as the threshold values for choosing good cutting parameters. The results have been compared with experimental tests in a horizontal turning centre. Besides the model and approach, this work offers real worthy values for big lathes, difficult to be got from literature. Basque Country Government, GAITEK program.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: Rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene. © 2018 The Author(s).

The photocatalytic activity in the degradation of 4-chlorophenol (4-ClPh) in aqueous medium (80 ppm) using 2.0 wt% Ag/Al

Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.

The application of laser cladding technology is becoming widely extended in the industrial environment due to its advantages of high added value and direct manufacturing or repair of complex parts. These complex parts require 5-axis laser cladding deposition processes whose programming demands optimized and continuous tool paths. The present work develops a programming methodology for a homogeneous material deposition of a continuous 5-axis laser cladding process applied to rapid manufacturing of blisk blades. Initially, the blisk blade geometry is defined and the process requirements are studied considering key factors such as the best parameters, nozzle trajectories, and feed values. Therefore, the proposed algorithm solution for feed variation control is applied to the process obtaining a more homogeneous structure. Finally, a blisk case study is developed according to the proposed solutions.