Preclinical characterization and phase 1 results of ADG106 in patients with advanced solid tumors and non-Hodgkin's lymphoma.

ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies, revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg, resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%), neutropenia (22.6%), elevated alanine aminotransferase (22.6%), rash (21.0%), itching (17.7%), and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin's lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T, B, and natural killer cells and cytokines interferon γ and interleukin-6, which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955).

The association between methylmalonic acid, a biomarker of mitochondrial dysfunction, and risk of prostate cancer.

BACKGROUND: The aim of the study was to investigate the association between methylmalonic acid (MMA), a biomarker of mitochondrial dysfunction, and the risk of prostate cancer (PCa). METHODS AND MATERIALS: The relevant data were collected from the National Health and Nutrition Examination Survey (NHANES). Weighted univariable and multivariable logistic regression analyses were performed to investigate the association between MMA and risk of PCa. A stratified analysis was also carried out. The dose-response relationship was elucidated by conducting a restricted cubic spline function. RESULTS: A total of 2451 participants were included, of which 95 were PCa participants. The fully-adjusted model 2 constructed by weighted multivariable logistic regression analysis showed that the risk of PCa decreased by 53% when every MMA unit was added [OR: 0.47 (0.22-1.00), P = 0.049]. And a decrease in PCa risk was associated with a higher MMA level in MMA subgroups [OR: 0.34 (0.15-0.82), P = 0.02]. The results from a stratified analysis showed that participants in subgroups of other race, BMI (> 30 kg/m2), smoking (former and now), and hypertension (yes), an increase in every MMA unit was linked to a decrease in PCa risk. MMA and the risk of PCa were negatively correlated in a linear manner. CONCLUSION: It was discovered in the study that an increase in MMA level is connected to a decrease in PCa risk. The serum MMA level may be helpful in assessing PCa risk.

Least squares reverse time migration imaging with illumination preconditioned based on improved PRP conjugate gradients.

Least squares reverse time migration (LSRTM) imaging is the one of the most accurate methods for migration imaging at present, and Polak-Ribiere-Polyak conjugate gradient (PRPCG) for LSRTM has the good numerical performance but weak convergence, so we construct an optimization factor to improve the iteration direction of the gradient, which can automatically generate a sufficient descent direction. The improved PRPCG (IPRPCG) can reduce the data residual values and speed up the iteration. And the illumination preconditioned (IP) operator is employed to IPRPCG-LSRTM which solves the problem of low resolution due to the insufficient iterative gradient information. In this paper, the experiments show that the imaging results of the proposed method (IPRPCG-IP-LSRTM) is improved greatly in detail characterization and events continuity, the iterative curve converged faster significantly, and the normalized data residual was reduced by 6.55% on average, which improved the accuracy of migration imaging effectively.

Targeting CD137 (4-1BB) towards improved safety and efficacy for cancer immunotherapy.

T cells play a critical role in antitumor immunity, where T cell activation is regulated by both inhibitory and costimulatory receptor signaling that fine-tune T cell activity during different stages of T cell immune responses. Currently, cancer immunotherapy by targeting inhibitory receptors such as CTLA-4 and PD-1/L1, and their combination by antagonist antibodies, has been well established. However, developing agonist antibodies that target costimulatory receptors such as CD28 and CD137/4-1BB has faced considerable challenges, including highly publicized adverse events. Intracellular costimulatory domains of CD28 and/or CD137/4-1BB are essential for the clinical benefits of FDA-approved chimeric antigen receptor T cell (CAR-T) therapies. The major challenge is how to decouple efficacy from toxicity by systemic immune activation. This review focuses on anti-CD137 agonist monoclonal antibodies with different IgG isotypes in clinical development. It discusses CD137 biology in the context of anti-CD137 agonist drug discovery, including the binding epitope selected for anti-CD137 agonist antibody in competition or not with CD137 ligand (CD137L), the IgG isotype of antibodies selected with an impact on crosslinking by Fc gamma receptors, and the conditional activation of anti-CD137 antibodies for safe and potent engagement with CD137 in the tumor microenvironment (TME). We discuss and compare the potential mechanisms/effects of different CD137 targeting strategies and agents under development and how rational combinations could enhance antitumor activities without amplifying the toxicity of these agonist antibodies.

Image-fusion-based object detection using a time-of-flight camera.

In this work, we demonstrate an innovative object detection framework based on depth and active infrared intensity images fusion with a time-of-flight (ToF) camera. A slide window weight fusion (SWWF) method provides fuse image with two modalities to localize targets. Then, the depth and intensity information is extracted to construct a joint feature space. Next, we utilize four machine learning methods to achieve object recognition. To verify this method, experiments are performed on an in-house dataset containing 1066 images, which are categorized into six different surface materials. Consequently, the approach performs well on localization with a 0.778 intersection over union (IoU). The best classification results are obtained with K-Nearest Neighbor (KNN) with a 98.01% total accuracy. Furthermore, our demonstrated method is less affected by various illumination conditions.

Federated Deep Reinforcement Learning-Based Task Offloading and Resource Allocation for Smart Cities in a Mobile Edge Network.

Mobile edge computing (MEC) has become an indispensable part of the era of the intelligent manufacturing industry 4.0. In the smart city, computation-intensive tasks can be offloaded to the MEC server or the central cloud server for execution. However, the privacy disclosure issue may arise when the raw data is migrated to other MEC servers or the central cloud server. Since federated learning has the characteristics of protecting the privacy and improving training performance, it is introduced to solve the issue. In this article, we formulate the joint optimization problem of task offloading and resource allocation to minimize the energy consumption of all Internet of Things (IoT) devices subject to delay threshold and limited resources. A two-timescale federated deep reinforcement learning algorithm based on Deep Deterministic Policy Gradient (DDPG) framework (FL-DDPG) is proposed. Simulation results show that the proposed algorithm can greatly reduce the energy consumption of all IoT devices.

[Normalized diagnosis and treatment of small penis: Advances in studies].

Small penis is abnormal development of the male external genitalia with unknown etiology. It is closely related to abnormal endocrine or pubertal development, chromosomal or genetic abnormalities. Pubertal growth retardation and secondary hypogonadism are commonly complicated by small penis or small testis; primary hypogonadal lesion develops in the testis; testosterone deficiency often results in small penis and short stature; sexual dysfunction and male infertility tend to occur in adult men. Attention should be paid to the four aspects concerning the clinically standardized diagnosis and treatment of small penis, namely, accurate measurement of the stretched penile length, active screening of possible causes, diagnosis and differential diagnosis, and active and effective clinical interventions for the purpose of increasing the penile length and improving the prognosis, patient's quality of life, and natural pregnancy rate.

A Method for Improving the Detection Accuracy of the Spot Position of the Four-Quadrant Detector in a Free Space Optical Communication System.

In a free space optical communication system, the beacon light will lose most of its energy after long-distance transmission, and the background light from the universe will strongly interfere with it. The four-quadrant detector (4QD) has been widely used in optical communication systems as a high-precision spot position detection sensor. However, if the light signal falling on the 4QD is too weak, the electrical signal of the output position will be very weak, and it will easily be affected by or even submerged in noise. To solve this problem, we propose a method for improving the spot position detection accuracy. First, we analyzed the solution relationship between the actual position of the spot and the output signal of the 4QD, with a Gaussian spot as the incident light model. The output current signal of the detector was then transimpedance-amplified by an analog circuit and the output voltage signal with noise was digitally filtered. An error compensation factor and the gap size of the detector were introduced into the traditional spot position detection model. High-precision spot position information for the 4QD in a complex environment was then obtained using the improved spot position detection model. Experimental results show that the maximum spot position detection error for this method was only 0.0277 mm, and the root mean square error was 0.0065 mm, when the 4QD was in a high background noise environment. The spot position detection accuracy was significantly improved compared with traditional detection algorithms. Real-time detection can therefore be achieved in practical applications.

[Normative diagnosis and treatment of small penis].

Small penis is a disease of sexual dysplasia, which might be related to chromosome or genetic abnormalities, pubertal dysplasia, endocrine abnormality, and other factors. Hypogonadism is common in small penis. Children with small penis often have small testes, short stature, and male secondary sexual deficiencies, and the incidence of infertility is high in adulthood. Small penis can be early detected by accurately measuring the stretched penile length, screening the pathogenic causes, and differentiating it from buried or concealed penis. Once definite diagnosis is made, positive clinical intervention should be initiated. Early treatment can improve the prognosis of small penis, the patient's quality of life and the rate of natural pregnancy.

Preclinical Study of a Fully Human Anti-PD-L1 Antibody as a Theranostic Agent for Cancer Immunotherapy.

Recently, inhibiting the PD-1/PD-L1 checkpoint pathway utilizing anti-PD-1 or anti-PD-L1 antibodies has achieved great clinical success in cancer treatment. However, anti-PD-1 immunotherapy cannot be applied to all cancer patients, no more than 25% showed a positive response. Immunohistochemistry (IHC) is the gold standard to determine the PD-L1 expression level in malignant lesions, but a noninvasive imaging-meditated strategy is urgently required for clinical diagnosis to cover the shortcomings of invasive techniques. MX001, which is an anti-PD-L1 antibody, was labeled with Cu-64 ( t1/2 = 12.7 h) and purified by PD-10 chromatography. Comprehensive studies including positron emission tomography (PET), ex vivo biodistribution, IHC, and immunotherapy have been performed in mice bearing MC38 (PD-L1 positive (+)) and 4T1 (PD-L1 negative (-)) xenografts. PET imaging of [18F]FDG was taken before and after therapy to monitor the therapeutic efficacy. [64Cu]Cu-NOTA-MX001 exhibited 2.3 ± 1.2, 5.6 ± 2.1, 5.6 ± 1.2, 6.1 ± 1.1, 6.1 ± 0.5, and 10.2 ± 1.7%ID/g uptake in MC38 xenografts at 0.5, 12, 24, 36, 48, and 62 h post-injection (p.i.), respectively. Meanwhile, the uptake in the liver and muscle at corresponding time points was 17.5 ± 2.2, 8.4 ± 2.4, 11.3 ± 3.2, 7.2 ± 2.1, 7.9.1 ± 3.5, and 3.8 ± 1.8%ID/g, and 1.2 ± 0.5, 1.3 ± 0.4, 1.5 ± 0.5, 0.7 ± 0.1, 0.6 ± 0.2, and 0.2 ± 0.1%ID/g, respectively. The uptake of [18F]FDG in MC38 and 4T1 xenografts at 1-h p.i. was 5.3 ± 0.4 and 6.4 ± 0.6%ID/g, while the uptake of [64Cu]Cu-NOTA-MX001 was 5.6 ± 0.3 and 1.3 ± 0.4%ID/g at 12-h p.i. IHC analysis confirmed that the MC38 tumor exhibited high PD-L1 expression, and the 4T1 tumor, liver, and muscle exhibited low PD-L1 expression. In addition, MC38 xenografts were suppressed by MX001 about 88% in the immunotherapy study. MX001 was successfully developed as a fully human anti-PD-L1 antibody with a high binding affinity in mouse, monkey, and human. The in vivo pharmacokinetics of MX001 was evaluated with PET imaging after being radiolabeled with Cu-64. The uptake of [64Cu]Cu-NOTA-MX001 was clearly correlated to the PD-L1 expression on various types of cancer. Subsequent immunotherapy studies demonstrated that MX001 could effectively suppress tumor growth with positive PD-L1 expression, but had poor antitumor efficacy on tumors which exhibited low PD-L1 expression. Together with the above results, MX001 has the potential to be further developed as an antibody theranostic agent for both PET imaging and immunotherapy of cancers in clinics.

Content Adaptive Lagrange Multiplier Selection for Rate-Distortion Optimization in 3-D Wavelet-Based Scalable Video Coding.

Rate-distortion optimization (RDO) plays an essential role in substantially enhancing the coding efficiency. Currently, rate-distortion optimized mode decision is widely used in scalable video coding (SVC). Among all the possible coding modes, it aims to select the one which has the best trade-off between bitrate and compression distortion. Specifically, this tradeoff is tuned through the choice of the Lagrange multiplier. Despite the prevalence of conventional method for Lagrange multiplier selection in hybrid video coding, the underlying formulation is not applicable to 3-D wavelet-based SVC where the explicit values of the quantization step are not available, with on consideration of the content features of input signal. In this paper, an efficient content adaptive Lagrange multiplier selection algorithm is proposed in the context of RDO for 3-D wavelet-based SVC targeting quality scalability. Our contributions are two-fold. First, we introduce a novel weighting method, which takes account of the mutual information, gradient per pixel, and texture homogeneity to measure the temporal subband characteristics after applying the motion-compensated temporal filtering (MCTF) technique. Second, based on the proposed subband weighting factor model, we derive the optimal Lagrange multiplier. Experimental results demonstrate that the proposed algorithm enables more satisfactory video quality with negligible additional computational complexity.

Extracellular LDLR repeats modulate Wnt signaling activity by promoting LRP6 receptor endocytosis mediated by the Itch E3 ubiquitin ligase.

The LOW-density lipoprotein related protein 6 (LRP6) receptor is an important effector of canonical Wnt signaling, a developmental pathway, whose dysregulation has been implicated in various diseases including cancer. The membrane proximal low-density lipoprotein (LDL) receptor repeats in LRP6 exhibit homology to ligand binding repeats in the LDL receptor (LDLR), but lack known function. We generated single amino acid substitutions of LRP6-LDLR repeat residues, which are highly conserved in the human LDLR and mutated in patients with Familial Hypercholesteremia (FH). These substitutions negatively impacted LRP6 internalization and activation of Wnt signaling. By mass spectrometry, we observed that the Itch E3 ubiquitin ligase associated with and ubiquitinated wild type LRP6 but not the LDLR repeat mutants. These findings establish the involvement of LRP6-LDLR repeats in the regulation of canonical Wnt signaling.

Comparative Study of Data Compression Methods for Large Aperture Static Imaging Spectrometer.

Facing the problem of choosing different data source as compressing object results in different compression effect, several techniques are investigated to explore a better data source which can reduce the loss of image and spectral information while getting higher compression ratio in the compression work of the large aperture static imaging spectrometer. In this paper the optical path difference dimension data source of LASIS was proposed after analyzing the characteristic of LASIS and then compared with the LASIS and LAMIS data source in detail. The SWIR data collected with the principle prototype of LASIS were used in our experiment. Firstly, three forms of data sources were extracted after detailedly introducing their data characteristic and extracting methods. Secondly, the mature algorithms in engineering JPEG and JPEG2000 were employed to compress and reconstruct the three forms of data sources respectively. Finally, the compression effect was evaluated in the aspect of image content, interference dimension, spectral dimension and compression ratio respectively, and the original spectral curves of three materials choosing from the field of view and those after reconstruction were extracted next, then the loss of spectral information of these three materials were measured by using the SA (Spectral Angle) and RQE (Relative Quadratic Error) values of the spectral curves to evaluate the compression effect. It is demonstrated that using the optical path difference dimension data as compressing object shows obvious advantages compared with LASIS and LAMIS, which achieves a combination of higher compression ratio, lower mean square error, lower peak signal noise ratio and less information loss that is competitive with the best results from the literature. The results show that the proposed optical path difference dimension data source has good performance in preserving the spatial and spectral information during the compression of LASIS than the other two common forms data sources of LASIS.

[Experiment Research and Analysis of Spectral Prediction on Soil Leaking Oil Content].

The spectral analysis method was applied experimentally to extract the spectral indices, measure and analyze the spectral characteristics and their difference of the mixture which are composed in soil in Central Shaanxi Plain and the diesel and motor oil respectively, aiming to provide solutions to practical difficulties in detecting, analyzing the spectral characteristics and difference between the soil leaking with equal content diesel and motor oil and predicting the leaking content of diesel in the soil. The spectral response curves of the soil leaking with different oil respectively and the soil leaking with diesel with different content were collected. Then the spectral prediction model for the leaking content of diesel in the soil was built based on the reflectance characteristics. The coefficient of the detection (R2) was introduced to evaluate the stability of the built model，and the parameter root mean squared error (RMSE) was introduced to estimate the precision and the predictability of the model built in this work. It is demonstrated that : (1) The reflectance of soil leaking with diesel is less than that of the equal content motor oil. And there is a double absorption trough of the reflectance curve of both soil leaking with diesel and motor oil at 1 740 and 2 328 nm. The spectral absorption indices and absorption depth of the soil leaking with diesel keep less than the equal content motor oil. (2) The built spectral prediction model for the leaking content of diesel in the soil demonstrates good stability with the coefficient of determination at R2=0.854, and performs favorable predictability (Root-Mean-Square Error, RMSE=0.016), which can benefit the effective prediction and quick estimation methods of the leaking content of diesel in the soil, enrich and progress the experimental method and theoretical research work of spectral prediction on soil leaking oil content and promote the application of remote sensing in safety production and environmental protection.

Cdo suppresses canonical Wnt signalling via interaction with Lrp6 thereby promoting neuronal differentiation.

Canonical Wnt signalling regulates expansion of neural progenitors and functions as a dorsalizing signal in the developing forebrain. In contrast, the multifunctional co-receptor Cdo promotes neuronal differentiation and is important for the function of the ventralizing signal, Shh. Here we show that Cdo negatively regulates Wnt signalling during neurogenesis. Wnt signalling is enhanced in Cdo-deficient cells, leading to impaired neuronal differentiation. The ectodomains of Cdo and Lrp6 interact via the Ig2 repeat of Cdo and the LDLR repeats of Lrp6, and the Cdo Ig2 repeat is necessary for Cdo-dependent Wnt inhibition. Furthermore, the Cdo-deficient dorsal forebrain displays stronger Wnt signalling activity, increased cell proliferation and enhanced expression of the dorsal markers and Wnt targets, Pax6, Gli3, Axin2. Therefore, in addition to promoting ventral central nervous system cell fates with Shh, Cdo promotes neuronal differentiation by suppression of Wnt signalling and provides a direct link between two major dorsoventral morphogenetic signalling pathways.

Transverse Bragg reflection filtering in a dielectric waveguide.

We demonstrate that transverse Bragg stacks symmetrically placed about a dielectric waveguide can effectively filter a fundamental mode in the dielectric waveguide. A narrow bandpass dielectric waveguide filter based on transverse Bragg reflection is proposed and investigated numerically. The results calculated indicate that for the filter with Bragg stacks of longitudinal length 3.86 µm, there is high transmission (≥95%) in the wavelength range of 1294-1326 nm, whereas there is loss as high as 93.4% at 1550 nm. Owing to its simple and compact structure, this filter is expected to be applied to highly dense photonic integrated circuits.

Localized Multiple Kernel Learning Via Sample-Wise Alternating Optimization.

Our objective is to train support vector machines (SVM)-based localized multiple kernel learning (LMKL), using the alternating optimization between the standard SVM solvers with the local combination of base kernels and the sample-specific kernel weights. The advantage of alternating optimization developed from the state-of-the-art MKL is the SVM-tied overall complexity and the simultaneous optimization on both the kernel weights and the classifier. Unfortunately, in LMKL, the sample-specific character makes the updating of kernel weights a difficult quadratic nonconvex problem. In this paper, starting from a new primal-dual equivalence, the canonical objective on which state-of-the-art methods are based is first decomposed into an ensemble of objectives corresponding to each sample, namely, sample-wise objectives. Then, the associated sample-wise alternating optimization method is conducted, in which the localized kernel weights can be independently obtained by solving their exclusive sample-wise objectives, either linear programming (for l1-norm) or with closed-form solutions (for lp-norm). At test time, the learnt kernel weights for the training data are deployed based on the nearest-neighbor rule. Hence, to guarantee their generality among the test part, we introduce the neighborhood information and incorporate it into the empirical loss when deriving the sample-wise objectives. Extensive experiments on four benchmark machine learning datasets and two real-world computer vision datasets demonstrate the effectiveness and efficiency of the proposed algorithm.

Lack of association between methylenetetrahydrofolate dehydrogenase 1 G1958A polymorphism and prostate cancer risk: a meta-analysis.

The methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) polymorphism G1958A has been extensively investigated as a potential risk factor for prostate cancer (PCa), but the results have thus far been inconclusive. This meta-analysis was performed to derive a more precise estimation of the association. A comprehensive search was conducted to identify all case-control studies of MTHFD1 G1958A polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Statistical analyses were performed using Review Manage version 5.0 and Stata 10.0. A total of six available studies were considered in the present meta-analysis, with 7,493 patients and 36,941 controls. When all groups were pooled, there was no evidence that G1958A had significant association with PCa under additive, recessive, dominant, and allelic models. This meta-analysis suggests that MTHFD1 G1958A polymorphism might not be a risk factor for PCa. However, further large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.

ß-Catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through interaction with ATF2 transcription factors.

The role of Wnt signaling in embryonic development and stem cell maintenance is well established and aberrations leading to the constitutive up-regulation of this pathway are frequent in several types of human cancers. Upon ligand-mediated activation, Wnt receptors promote the stabilization of ß-catenin, which translocates to the nucleus and binds to the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to regulate the expression of Wnt target genes. When not bound to ß-catenin, the TCF/LEF proteins are believed to act as transcriptional repressors. Using a specific lentiviral reporter, we identified hematopoietic tumor cells displaying constitutive TCF/LEF transcriptional activation in the absence of ß-catenin stabilization. Suppression of TCF/LEF activity in these cells mediated by an inducible dominant-negative TCF4 (DN-TCF4) inhibited both cell growth and the expression of Wnt target genes. Further, expression of TCF1 and LEF1, but not TCF4, stimulated TCF/LEF reporter activity in certain human cell lines independently of ß-catenin. By a complementary approach in vivo, TCF1 mutants, which lacked the ability to bind to ß-catenin, induced Xenopus embryo axis duplication, a hallmark of Wnt activation, and the expression of the Wnt target gene Xnr3. Through generation of different TCF1-TCF4 fusion proteins, we identified three distinct TCF1 domains that participate in the ß-catenin-independent activity of this transcription factor. TCF1 and LEF1 physically interacted and functionally synergized with members of the activating transcription factor 2 (ATF2) family of transcription factors. Moreover, knockdown of ATF2 expression in lymphoma cells phenocopied the inhibitory effects of DN-TCF4 on the expression of target genes associated with the Wnt pathway and on cell growth. Together, our findings indicate that, through interaction with ATF2 factors, TCF1/LEF1 promote the growth of hematopoietic malignancies in the absence of ß-catenin stabilization, thus establishing a new mechanism for TCF1/LEF1 transcriptional activity distinct from that associated with canonical Wnt signaling.

Compact wavelength splitter based on self-imaging principles in Bragg reflection waveguides.

The self-imaging phenomena in multimode Bragg reflection waveguides (BRWs) have been predicted and investigated by using the plane-wave expansion method and the finite-difference time-domain method. A compact wavelength splitter based on self-imaging principles in BRWs is presented, and its transmission characteristics are investigated by using the finite-difference time-domain method. Calculated results indicate that, for the wavelength splitter without any waveguide bend optimizations, two optical waves with different wavelengths can be spatially separated, and corresponding transmittances are 95.6% and 90.1%, respectively. The simple and compact wavelength splitter is expected to be applied to highly dense photonic integrated circuits.