Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy.

Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable development of drug resistance. Intense protein synthesis is a distinctive trait of MM cells, supporting the massive production of clonal immunoglobulins or free light chains. The mammalian target of rapamycin (mTOR) kinase is appreciated as a master regulator of vital cellular processes, including regulation of metabolism and protein synthesis, and can be found in two multiprotein complexes, mTORC1 and mTORC2. Dysregulation of these complexes is implicated in several types of cancer, including MM. Since mTOR has been shown to be aberrantly activated in a large portion of MM patients and to play a role in stimulating MM cell survival and resistance to several existing therapies, understanding the regulation and functions of the mTOR complexes is vital for the development of more effective therapeutic strategies. This review provides a general overview of the mTOR pathway, discussing key discoveries and recent insights related to the structure and regulation of mTOR complexes. Additionally, we highlight findings on the mechanisms by which mTOR is involved in protein synthesis and delve into mTOR-mediated processes occurring in MM. Finally, we summarize the progress and current challenges of drugs targeting mTOR complexes in MM.

AXL-specific single domain antibodies show diagnostic potential and anti-tumor activity in Acute Myeloid Leukemia.

Rationale: AXL expression has been identified as a prognostic factor in acute myeloid leukemia (AML) and is detectable in approximately 50% of AML patients. In this study, we developed AXL-specific single domain antibodies (sdAbs), cross-reactive for both mouse and human AXL protein, to non-invasively image and treat AXL-expressing cancer cells. Methods: AXL-specific sdAbs were induced by immunizing an alpaca with mouse and human AXL proteins. SdAbs were characterized using ELISA, flow cytometry, surface plasmon resonance and the AlphaFold2 software. A lead compound was selected and labeled with 99mTc for evaluation as a diagnostic tool in mouse models of human (THP-1 cells) or mouse (C1498 cells) AML using SPECT/CT imaging. For therapeutic purposes, the lead compound was fused to a mouse IgG2a-Fc tail and in vitro functionality tests were performed including viability, apoptosis and proliferation assays in human AML cell lines and primary patient samples. Using these in vitro models, its anti-tumor effect was evaluated as a single agent, and in combination with standard of care agents venetoclax or cytarabine. Results: Based on its cell binding potential, cross-reactivity, nanomolar affinity and GAS6/AXL blocking capacity, we selected sdAb20 for further evaluation. Using SPECT/CT imaging, we observed tumor uptake of 99mTc-sdAb20 in mice with AXL-positive THP-1 or C1498 tumors. In THP-1 xenografts, an optimized protocol using pre-injection of cold sdAb20-Fc was required to maximize the tumor-to-background signal. Besides its diagnostic value, we observed a significant reduction in tumor cell proliferation and viability using sdAb20-Fc in vitro. Moreover, combining sdAb20-Fc and cytarabine synergistically induced apoptosis in human AML cell lines, while these effects were less clear when combined with venetoclax. Conclusions: Because of their diagnostic potential, sdAbs could be used to screen patients eligible for AXL-targeted therapy and to follow-up AXL expression during treatment and disease progression. When fused to an Fc-domain, sdAbs acquire additional therapeutic properties that can lead to a multidrug approach for the treatment of AXL-positive cancer patients.

Success of susceptibility-guided eradication of Helicobacter pylori in a region with high secondary clarithromycin and levofloxacin resistance rates.

BACKGROUND: Resistance to clarithromycin (CLA) and levofloxacin (LFX) of Helicobacter pylori (H. pylori) is increasing in severity, and successful eradication is essential. Presently, the eradication success rate has greatly declined, leaving a large number of patients with previous treatment histories. AIM: To investigate secondary resistance rates, explore risk factors for antibiotic resistance, and assess the efficacy of susceptibility-guided therapy. METHODS: We recruited 154 subjects positive for Urea Breath Test who attended The First Affiliated Hospital of China Medical University between July 2022 and April 2023. Participants underwent a string test after an overnight fast. The gastric juice was obtained and transferred to vials containing storage solution. Subsequently, DNA extraction and the specific DNA amplification were performed using quantitative polymerase chain reaction (qPCR). Demographic information was also analyzed as part of the study. Based on these results, the participants were administered susceptibility-guided treatment. Efficacy was compared with that of the empiric treatment group. RESULTS: A total of 132 individuals tested positive for the H. pylori ureA gene by qPCR technique. CLA resistance rate reached a high level of 82.6% (n = 109), LFX resistance rate was 69.7% (n = 92) and dual resistance was 62.1% (n = 82). Gastric symptoms [odds ratio (OR) = 2.782; 95% confidence interval (95%CI): 1.076-7.194; P = 0.035] and rural residence (OR = 5.152; 95%CI: 1.407-18.861; P = 0.013) were independent risk factors for secondary resistance to CLA and LFX, respectively. A total of 102 and 100 individuals received susceptibility-guided therapies and empiric treatment, respectively. The antibiotic susceptibility-guided treatment and empiric treatment groups achieved successful eradication rates of 75.5% (77/102) and 59.0% (59/411) by the intention-to-treat (ITT) analysis and 90.6% (77/85) and 70.2% (59/84) by the per-protocol (PP) analysis, respectively. The eradication rates of these two treatment strategies were significantly different in both ITT (P = 0.001) and PP (P = 0.012) analyses. CONCLUSION: H. pylori presented high secondary resistance rates to CLA and LFX. For patients with previous treatment failures, treatments should be guided by antibiotic susceptibility tests or regional antibiotic resistance profile.

S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability in multiple myeloma.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy and is incurable because of the inevitable development of drug resistance. Methionine adenosyltransferase 2α (MAT2A) is the primary producer of the methyl donor S-adenosylmethionine (SAM) and several studies have documented MAT2A deregulation in different solid cancers. As the role of MAT2A in MM has not been investigated yet, the aim of this study was to clarify the potential role and underlying molecular mechanisms of MAT2A in MM, exploring new therapeutic options to overcome drug resistance. By analyzing publicly available gene expression profiling data, MAT2A was found to be more highly expressed in patient-derived myeloma cells than in normal bone marrow plasma cells. The expression of MAT2A correlated with an unfavorable prognosis in relapsed patients. MAT2A inhibition in MM cells led to a reduction in intracellular SAM levels, which resulted in impaired cell viability and proliferation, and induction of apoptosis. Further mechanistic investigation demonstrated that MAT2A inhibition inactivated the mTOR-4EBP1 pathway, accompanied by a decrease in protein synthesis. MAT2A targeting in vivo with the small molecule compound FIDAS-5 was able to significantly reduce tumor burden in the 5TGM1 model. Finally, we found that MAT2A inhibition can synergistically enhance the anti-MM effect of the standard-of-care agent bortezomib on both MM cell lines and primary human CD138+ MM cells. In summary, we demonstrate that MAT2A inhibition reduces MM cell proliferation and survival by inhibiting mTOR-mediated protein synthesis. Moreover, our findings suggest that the MAT2A inhibitor FIDAS-5 could be a novel compound to improve bortezomib-based treatment of MM.

Why Batch Normalization Damage Federated Learning on Non-IID Data?

As a promising distributed learning paradigm, federated learning (FL) involves training deep neural network (DNN) models at the network edge while protecting the privacy of the edge clients. To train a large-scale DNN model, batch normalization (BN) has been regarded as a simple and effective means to accelerate the training and improve the generalization capability. However, recent findings indicate that BN can significantly impair the performance of FL in the presence of non-i.i.d. data. While several FL algorithms have been proposed to address this issue, their performance still falls significantly when compared to the centralized scheme. Furthermore, none of them have provided a theoretical explanation of how the BN damages the FL convergence. In this article, we present the first convergence analysis to show that under the non-i.i.d. data, the mismatch between the local and global statistical parameters in BN causes the gradient deviation between the local and global models, which, as a result, slows down and biases the FL convergence. In view of this, we develop a new FL algorithm that is tailored to BN, called FedTAN, which is capable of achieving robust FL performance under a variety of data distributions via iterative layer-wise parameter aggregation. Comprehensive experimental results demonstrate the superiority of the proposed FedTAN over existing baselines for training BN-based DNN models.

Clinical features and relapse risks factors of IgG4 related disease: a single-center retrospective study.

OBJECTIVE: The aim of this study was to observe the demographic and clinical characteristics of immunoglobulin (Ig) G4-related disease (IgG4-RD). We aimed to compare different treatment methods and to identify the risk factors for non-response and relapse after treatment. METHODS: We performed a retrospective study of 201 IgG4-RD patients initially diagnosed and treated at the First Affiliated Hospital of China Medical University from January 2016 to December 2020. Patients' sex, age, clinical manifestations, baseline biochemical values, the number of organs involved, and the type of organ involvement were recorded. All patients received glucocorticoid (GC) monotherapy or GC + immunosuppressant combination therapy. The serum IgG4 concentration as well as the details of clinical response, relapse, and side effects were recorded at 1, 3, 6, and 12 months after treatment. RESULTS: The incidence of IgG4-RD was primarily centered in the age group of 50-70 years old, and the proportion of affected male patients increased with age. The most common clinical symptom was swollen glands or eyes (42.79%). The rates of single- and double-organ involvement were 34.83% and 46.27%, respectively. The pancreas (45.77%) was the most frequently involved organ in cases of single-organ involvement, and the pancreas and biliary tract (45.12%) was the most common organ combination in cases of double-organ involvement. Correlation analysis showed that the number of organs involved was positively related to the serum IgG4 concentration (r = 0.161). The effective rate of GC monotherapy was 91.82%, the recurrence rate was 31.46%, and the incidence of adverse reactions was 36.77%. Meanwhile, the effective rate of GC + immunosuppressant combination therapy was 88.52%, the recurrence rate was 19.61%, and the adverse reaction rate was 41.00%. There were no statistically significant differences in response, recurrence, and adverse reactions. The overall response rate within 12 months was 90.64%. Age (< 50 years old) and aorta involvement were significantly associated with non-response. The overall recurrence rate within 12 months was 26.90%. Age (< 50 years old), low serum C4 concentration, a high number of involved organs, and lymph node involvement were significantly associated with recurrence. CONCLUSION: The clinical features vary among different age groups and according to gender. The number of organs involved in IgG4-RD is related to the serum IgG4 concentration. Age (< 50 years old), low serum C4 concentration, a high number of involved organs, and lymph node involvement are risk factors for recurrence.

Antibiotic resistance characteristics and risk factors analysis of Helicobacter pylori strains isolated from patients in Liaoning Province, an area in North China.

Background: The prevalence of Helicobacter pylori (H. pylori) keeps rising while the eradication rate continues to decline due to the increasing antibiotic resistance. Regional variations of antimicrobial resistance to H. pylori have been recommended by guidelines in recent years. This study aims to investigate the antibiotic resistance rate of H. pylori and its association with infected subjects' characteristics in Liaoning Province, an area in north China. Methods: Gastric tissues from 178 H. pylori positive participants without previous antibiotic use within four weeks were collected for H. pylori culture. Antibiotic susceptibility to furazolidone (AOZ), tetracycline (TC), levofloxacin (LFX), metronidazole (MET), clarithromycin (CLA), and amoxicillin (AMX) were examined with the agar dilution method. Associations between H. pylori resistance and patient characteristics were further analysed. Results: No resistance was observed in AOZ or TC. For LFX, MET, CLA, and AMX, the overall resistance rates were 41.10%, 79.14%, 71.78%, and 22.09% respectively. There were significant differences between resistance to CLA and MALToma (P = 0.021), and between resistance to MET and age (P < 0.001). Conclusions: The primary resistant rates of LEX, MET, CLA, and AMX were relatively high in Liaoning. Treatment effectiveness improvement could be achieved by prior antimicrobial susceptibility tests before antibiotic prescription.

Adversarial Knowledge Distillation Based Biomedical Factoid Question Answering.

Biomedical factoid question answering is an essential application for biomedical information sharing. Recently, neural network based approaches have shown remarkable performance for this task. However, due to the scarcity of annotated data which requires intensive knowledge of expertise, training a robust model on limited-scale biomedical datasets remains a challenge. Previous works solve this problem by introducing useful knowledge. It is found that the interaction between question and answer (QA-interaction) is also a kind of knowledge which could help extract answer accurately. This research develops a knowledge distillation framework for biomedical factoid question answering, in which a teacher model as the knowledge source of QA-interaction is designed to enhance the student model. In addition, to further alleviate the problem of limited-scale dataset, a novel adversarial knowledge distillation technique is proposed to robustly distill the knowledge from teacher model to student model by constructing perturbed examples as additional training data. By forcing the student model to mimic the predicted distributions of teacher model on both original examples and perturbed examples, the knowledge of QA-interaction can be learned by student model. We evaluate the proposed framework on the widely used BioASQ datasets, and experimental results have shown the proposed method's promising potential.

Improving Biomedical ReQA With Consistent NLI-Transfer and Post-Whitening.

Retrieval Question Answering (ReQA) is an essential mechanism of information sharing which aims to find the answer to a posed question from large-scale candidates. Currently, the most efficient solution is Dual-Encoder which has shown great potential in the general domain, while it still lacks research on biomedical ReQA. Obtaining a robust Dual-Encoder from biomedical datasets is challenging, as scarce annotated data are not enough to sufficiently train the model which results in over-fitting problems. In this work, we first build ReQA BioASQ datasets for retrieving answers to biomedical questions, which can facilitate the corresponding research. On that basis, we propose a framework to solve the over-fitting issue for robust biomedical answer retrieval. Under the proposed framework, we first pre-train Dual-Encoder on natural language inference (NLI) task before the training on biomedical ReQA, where we appropriately change the pre-training objective of NLI to improve the consistency between NLI and biomedical ReQA, which significantly improve the transferability. Moreover, to eliminate the feature redundancies of Dual-Encoder, consistent post-whitening is proposed to conduct decorrelation on the training and trained sentence embeddings. With extensive experiments, the proposed framework achieves promising results and exhibits significant improvement compared with various competitive methods.

Tuberous Sclerosis Complex With Multiple Organ Tumors: Case Report and Literature Review.

Pancreatic neuroendocrine neoplasms (PNEN) are tumors that originate from neuroendocrine cells. Only about 1% patients are related to mutation of tuberous sclerosis complex gene. Here, we reported a rare case with involvement of multiple organs and space-occupying lesions. Initially, the patient was thought to have metastasis of a pancreatic tumor. However, the patient was diagnosed as pancreatic neuroendocrine tumors, liver perivascular epithelioid tumors, splenic hamartoma, and renal angiomyolipoma by pathological examination after surgery. We performed genetic mutation detection to identify that tuberous sclerosis complex 2 gene presented with a heterozygous variant. Tuberous sclerosis often presents with widespread tumors, but it is less common to present with pancreatic neuroendocrine tumors and liver perivascular tumors as highlighted in the case. So we analyzed the relationship between TSC gene mutations and related tumors. And we also reviewed the current molecular mechanisms and treatments for tuberous sclerosis complex.

System Xc- inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance.

Multiple myeloma (MM) cells derive proliferative signals from the bone marrow (BM) microenvironment via exosomal crosstalk. Therapeutic strategies targeting this crosstalk are still lacking. Bortezomib resistance in MM cells is linked to elevated expression of xCT (the subunit of system Xc-). Extracellular glutamate released by system Xc- can bind to glutamate metabotropic receptor (GRM) 3, thereby upregulating Rab27-dependent vesicular trafficking. Since Rab27 is also involved in exosome biogenesis, we aimed to investigate the role of system Xc- in exosomal communication between BM stromal cells (BMSCs) and MM cells. We observed that expression of xCT and GRMs was increased after bortezomib treatment in both BMSCs and MM cells. Secretion of glutamate and exosomes was simultaneously enhanced which could be countered by inhibition of system Xc- or GRMs. Moreover, glutamate supplementation increased exosome secretion by increasing expression of Alix, TSG101, Rab27a/b and VAMP7. Importantly, the system Xc- inhibitor sulfasalazine reduced BMSC-induced resistance to bortezomib in MM cells in vitro and enhanced its anti-MM effects in vivo. These findings suggest that system Xc- plays an important role within the BM and could be a potential target in MM.

External features enriched model for biomedical question answering.

BACKGROUND: Biomedical question answering (QA) is a sub-task of natural language processing in a specific domain, which aims to answer a question in the biomedical field based on one or more related passages and can provide people with accurate healthcare-related information. Recently, a lot of approaches based on the neural network and large scale pre-trained language model have largely improved its performance. However, considering the lexical characteristics of biomedical corpus and its small scale dataset, there is still much improvement room for biomedical QA tasks. RESULTS: Inspired by the importance of syntactic and lexical features in the biomedical corpus, we proposed a new framework to extract external features, such as part-of-speech and named-entity recognition, and fused them with the original text representation encoded by pre-trained language model, to enhance the biomedical question answering performance. Our model achieves an overall improvement of all three metrics on BioASQ 6b, 7b, and 8b factoid question answering tasks. CONCLUSIONS: The experiments on BioASQ question answering dataset demonstrated the effectiveness of our external feature-enriched framework. It is proven by the experiments conducted that external lexical and syntactic features can improve Pre-trained Language Model's performance in biomedical domain question answering task.

Corrigendum to "Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways".

[This corrects the article DOI: 10.1155/2020/4598476.].

ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation.

BACKGROUND: Bone destruction is a hallmark of multiple myeloma (MM). It has been reported that proteasome inhibitors (PIs) can reduce bone resorption and increase bone formation in MM patients, but the underlying mechanisms remain unclear. METHODS: Mesenchymal stem cells (MSCs) were treated with various doses of PIs, and the effects of bortezomib or carfilzomib on endoplasmic reticulum (ER) stress signaling pathways were analyzed by western blotting and real-time PCR. Alizarin red S (ARS) and alkaline phosphatase (ALP) staining were used to determine the osteogenic differentiation in vitro. Specific inhibitors targeting different ER stress signaling and a Tet-on inducible overexpressing system were used to validate the roles of key ER stress components in regulating osteogenic differentiation of MSCs. Chromatin immunoprecipitation (ChIP) assay was used to evaluate transcription factor-promoter interaction. MicroCT was applied to measure the microarchitecture of bone in model mice in vivo. RESULTS: We found that both PERK-ATF4 and IRE1α-XBP1s ER stress branches are activated during PI-induced osteogenic differentiation. Inhibition of ATF4 or XBP1s signaling can significantly impair PI-induced osteogenic differentiation. Furthermore, we demonstrated that XBP1s can transcriptionally upregulate ATF4 expression and overexpressing XBP1s can induce the expression of ATF4 and other osteogenic differentiation-related genes and therefore drive osteoblast differentiation. MicroCT analysis further demonstrated that inhibition of XBP1s can strikingly abolish bortezomib-induced bone formation in mouse. CONCLUSIONS: These results demonstrated that XBP1s is a master regulator of PI-induced osteoblast differentiation. Activation of IRE1α-XBP1s ER stress signaling can promote osteogenesis, thus providing a novel strategy for the treatment of myeloma bone disease.

Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways.

Natural killer (NK) cells are innate immune effectors with potent antitumor activity. However, tumor cells can create an immunosuppressive microenvironment to escape immune surveillance. Although accumulating evidence indicates that microenvironmental hypoxia plays an important role in favoring tumor development and immune evasion, it remains unclear by what means hypoxia directly impairs NK cell antitumor activity. In this study, we confirmed that hypoxic NK cells showed significantly lower cytotoxicity against tumor cells. Consistent with this finding, we found that the reduction in NK cell cytotoxicity resulting from hypoxia correlated to the lower expression of granzyme B, IFN-γ, and degranulation marker CD107a, as well as activating receptors including NKp30, NKp46, and NKG2D expressed on the surface of NK cells. More importantly, we further demonstrated that a reduction in the phosphorylation levels of ERK and STAT3 secondary to hypoxia was strongly associated with the attenuated NK cell cytotoxicity. Focusing on the mechanism responsible for reduced phosphorylation levels of ERK and STAT3, we reveal that the activation of protein tyrosine phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) following hypoxia might play an essential role in this process. By knocking down SHP-1 or blocking its activity using a specific inhibitor TPI-1, we were able to partially restore NK cell cytotoxicity under hypoxia. Taken together, we demonstrate that hypoxia could impair NK cell cytotoxicity by decreasing the phosphorylation levels of ERK and STAT3 in a SHP-1-dependent manner. Therefore, targeting SHP-1 could provide an approach to enhance NK cell-based tumor immunotherapy.

A novel CD2 staining-based flow cytometric assay for assessment of natural killer cell cytotoxicity.

BACKGROUND: Assessing cytotoxicity is fundamental to studying natural killer (NK) cell function. Various radioactive and non-radioactive cytotoxicity assays measuring target cell death have been developed. Among these methods, the most commonly used 51 Chromium-release assay (CRA) and flow cytometry-based cytotoxicity assays (FCCs) are the major representatives. Nonetheless, several drawbacks, including dye leakage and the potential effects of prior labeling on cells, curb the broad applicability of the FCCs. METHODS: Here, we report a rapid FCC for quantifying target cell death after co-incubation with NK cells. In this assay, after 4 hours of NK cell-target cell co-incubation, fluorochrome-conjugated CD2 antibody was used to identify NK cells, and SYTOX Green and Annexin V-FITC were further used to detect target cell death in CD2-negative population. In parallel, both CRA and FCC assay using CFSE/ 7-AAD were performed to validate the reproducibility and replicability. RESULTS: We observed that CD2 is exclusively positive on NK cells other than the most common hematological target tumor cells, such as K562, HL60, MOLM13, Raji, NCI-H929, rpmi8226, MM.1S, and KMS11. Assessment of target cell death using the CD2-based FCC shows a significantly higher percent specific lysis of the target cells compared to the standard CRA and the FCC assay using CFSE and 7-AAD. CONCLUSIONS: We demonstrated that this CD2-based FCC is a fast, simple, and reliable method for evaluating NK cell cytotoxicity.

Cell cycle exit during bortezomib-induced osteogenic differentiation of mesenchymal stem cells was mediated by Xbp1s-upregulated p21Cip1 and p27Kip1.

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into a variety of cell types. Bortezomib, the first approved proteasome inhibitor used for the treatment of multiple myeloma (MM), has been shown to induce osteoblast differentiation, making it beneficial for myeloma bone disease. In the present study, we aimed to investigate the effects and underlying mechanisms of bortezomib on the cell cycle during osteogenic differentiation. We confirmed that low doses of bortezomib can induce MSCs towards osteogenic differentiation, but high doses are toxic. In the course of bortezomib-induced osteogenic differentiation, we observed cell cycle exit characterized by G0 /G1 phase cell cycle arrest with a significant reduction in cell proliferation. Additionally, we found that the cell cycle exit was tightly related to the induction of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 . Notably, we further demonstrated that the up-regulation of p21Cip1 and p27Kip1 is transcriptionally dependent on the bortezomib-activated ER stress signalling branch Ire1α/Xbp1s. Taken together, these findings reveal an intracellular pathway that integrates proteasome inhibition, osteogenic differentiation and the cell cycle through activation of the ER stress signalling branch Ire1α/Xbp1s.

Blockade of HSP70 by VER-155008 synergistically enhances bortezomib-induced cytotoxicity in multiple myeloma.

Proteasome inhibitor bortezomib is one of the most effective drugs currently available for the treatment of multiple myeloma (MM). However, the intrinsic and acquired resistance to bortezomib can limit its effectiveness. The activation of heat shock response has been characterized as a potential resistance mechanism protecting MM cells from bortezomib-induced cell death. In this study, in response to bortezomib therapy, we discovered that HSP70 is one of the most substantially upregulated heat shock proteins. In order to further explore approaches to sensitizing bortezomib-based treatment for MM, we investigated whether targeting HSP70 using a specific inhibitor VER-155008 combined with bortezomib could overcome the acquired resistance in MM. We found that HSP70 inhibitor VER-155008 alone significantly decreased MM cell viability. Moreover, the combination of VER-155008 and bortezomib synergistically induced MM cell apoptosis markedly in vitro. Notably, the combined treatment was found to increase the cleavage of PARP, an early marker of chemotherapy-induced apoptosis. Importantly, the reduction of anti-apoptotic Bcl-2 family member Bcl-2, Bcl-xL, and Mcl-1 and the induction of pro-apoptotic Bcl-2 family member BH3-only protein NOXA and Bim were confirmed to be tightly associated with the synergism. Finally, the ER stress marker CHOP (CCAAT-enhancer binding protein homologous protein), which can cause transcriptional activation of genes involved in cell apoptosis, was markedly induced by both VER-155008 and bortezomib. Taken together, our finding of a strong synergistic interaction between VER-155008 and bortezomib may support for combination therapy in MM patients in the future.

Hypoxia promotes osteosarcoma cell proliferation and migration through enhancing platelet-derived growth factor-BB/platelet-derived growth factor receptor-ß axis.

Osteosarcoma is a primary malignant bone tumor, characterized by high therapeutic resistance and poor outcomes, due to unclear pathological mechanisms. It has been shown recently that the platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) pathway is closely associated with the pathogenesis of osteosarcoma. Hypoxia is a critical hallmark of tumor microenvironment that promotes the malignant phenotype in many solid tumors and a fundamental impediment to effective tumor therapy. In this study, we confirmed that hypoxia is an important feature of osteosarcoma, validated by the positive immunohistochemistry staining of hypoxia marker hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase IX (CAIX) in osteosarcoma tissue samples. More importantly, we discovered that hypoxia could transcriptionally upregulate the expression of both PDGF-BB and PDGFR-ß in osteosarcoma cells in vitro. Likewise, we also established that hypoxia-induced PDGF-BB is strongly related to the enhanced cell proliferation and migration, by activating AKT, ERK1/2, and STAT3 signaling pathways. Notably, when using an antibody to block the autocrine of PDGF-BB, cell proliferation and migration were partially aborted in hypoxia. Collectively, we demonstrated that the hypoxia-activated PDGF-BB/PDGFR-ß axis plays essential roles in osteosarcoma progression. These findings may shed light on the molecular pathogenesis of osteosarcoma, and provide a novel strategy for osteosarcoma treatment by combinational targeting hypoxia and PDGF-BB/PDGFR signaling.

PRIMAL: Page Rank-Based Indoor Mapping and Localization Using Gene-Sequenced Unlabeled WLAN Received Signal Strength.

Due to the wide deployment of wireless local area networks (WLAN), received signal strength (RSS)-based indoor WLAN localization has attracted considerable attention in both academia and industry. In this paper, we propose a novel page rank-based indoor mapping and localization (PRIMAL) by using the gene-sequenced unlabeled WLAN RSS for simultaneous localization and mapping (SLAM). Specifically, first of all, based on the observation of the motion patterns of the people in the target environment, we use the Allen logic to construct the mobility graph to characterize the connectivity among different areas of interest. Second, the concept of gene sequencing is utilized to assemble the sporadically-collected RSS sequences into a signal graph based on the transition relations among different RSS sequences. Third, we apply the graph drawing approach to exhibit both the mobility graph and signal graph in a more readable manner. Finally, the page rank (PR) algorithm is proposed to construct the mapping from the signal graph into the mobility graph. The experimental results show that the proposed approach achieves satisfactory localization accuracy and meanwhile avoids the intensive time and labor cost involved in the conventional location fingerprinting-based indoor WLAN localization.