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The intricate microenvironment in which malignant cells reside is essential for the progression of tumor growth. Both the physical and biochemical features of the tumor microenvironment (TME) play a critical role in promoting the differentiation, proliferation, invasion, and metastasis of cancer cells. It is therefore essential to understand how malignant cells interact and communicate with an assortment of supportive tumor-associated cells including macrophages, fibroblasts, endothelial cells, and other immune cells. To study the complex mechanisms behind cancer progression, 3D spheroid and organoid models are widely in favor because they replicate the stromal environment and multicellular structure present within an in vivo tumor. It provides more precise data about the cell–cell interactions, tumor characteristics, drug discovery, and metabolic profile of cancer cells compared to oversimplified 2D systems and unrepresentative animal models. This review provides a description of the key elements of the tumor microenvironment as well as early research using cell-line derived, 3D spheroid tumor models that paved the way for the adoption of patient-derived spheroid and organoid models. In particular, 3D spheroid and organoid models provide a method for drug screening with a particular emphasis on influence of the TME in cancer immunotherapy.

The realm of cell-based immunotherapy holds untapped potential for the development of next-generation cancer treatment through genetic engineering of chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapies for targeted eradication of cancerous malignancies. Such allogeneic “off-the-shelf” cell products can be advantageously manufactured in large quantities, stored for extended periods, and easily distributed to treat an exponential number of cancer patients. At current, patient risk of graft-versus-host disease (GvHD) and host-versus-graft (HvG) allorejection severely restrict the development of allogeneic CAR-T cell products. To address these limitations, a variety of genetic engineering strategies have been implemented to enhance antitumor efficacy, reduce GvHD and HvG onset, and improve the overall safety profile of T-cell based immunotherapies. In this review, we summarize these genetic engineering strategies and discuss the challenges and prospects these approaches provide to expedite progression of translational and clinical studies for adoption of a universal cell-based cancer immunotherapy.

The immunosuppressive tumor microenvironment (TME) remains one of the most prevailing barriers obstructing the implementation of effective immunotherapy against solid-state cancers. Eminently composed of immunosuppressive tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) among others, the TME attenuates the effects of immune checkpoint blockade and adoptive cell therapies, mandating a novel therapy capable of TME remediation. In this review we explore the potential of three innate-like T cell subsets, invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT) cells, and gamma delta T (γδT) cells, that display an intrinsic anti-TAM/MDSC capacity. Exhibiting both innate and adaptive properties, innate-like T cell types express a subset-specific TCR with distinct recombination, morphology, and target cell recognition, further supplemented by a variety of NK activating receptors. Both NK activating receptor and TCR activation result in effector cell cytotoxicity against targeted immunosuppressive cells for TME remediation. In addition, innate-like T cells showcase moderate levels of tumor cell killing, providing dual antitumor and anti-TAM/MDSC function. This latent antitumor capacity can be further bolstered by chimeric antigen receptor (CAR) engineering for recognition of tumor specific antigens to enhance antitumor targeting. In contrast with established CAR-T cell therapies, adoption of these innate-like cell types provides an enhanced safety profile without the risk of graft versus host disease (GvHD), due to their non-recognition of mismatched major histocompatibility complex (MHC) molecules, for use as widely accessible, allogeneic “off-the-shelf” cancer immunotherapy.

Human mucosal-associated invariant T (MAIT) cells are characterized by their expression of an invariant TCR α chain Vα7.2-Jα33/Jα20/Jα12 paired with a restricted TCR β chain. MAIT cells recognize microbial peptides presented by the highly conserved MHC class I-like molecule MR1 and bridge the innate and acquired immune systems to mediate augmented immune responses. Upon activation, MAIT cells rapidly proliferate, produce a variety of cytokines and cytotoxic molecules, and trigger efficient antitumor immunity. Administration of a representative MAIT cell ligand 5-OP-RU effectively activates MAIT cells and enhances their antitumor capacity. In this review, we introduce MAIT cell biology and their importance in antitumor immunity, summarize the current development of peripheral blood mononuclear cell-derived and stem cell-derived MAIT cell products for cancer treatment, and discuss the potential of genetic engineering of MAIT cells for off-the-shelf cancer immunotherapy.

Allo-HSCT is a curative therapy for hematologic malignancies owing to GvL effect mediated by alloreactive T cells; however, the same T cells also mediate GvHD, a severe side effect limiting the widespread application of allo-HSCT in clinics. Invariant natural killer T (iNKT) cells can ameliorate GvHD while preserving GvL effect, but the clinical application of these cells is restricted by their scarcity. Here, we report the successful generation of third-party HSC-engineered human iNKT (

Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has been limited because of their low numbers in cancer patients and difficulties in infiltrating solid tumors. In this study, we aimed to overcome these critical limitations by using α-GalCer, a synthetic glycolipid ligand specifically activating iNKT cells, to recruit iNKT to solid tumors. By adoptively transferring human iNKT cells into tumor-bearing humanized NSG mice and administering a single dose of tumor-localized α-GalCer, we demonstrated the rapid recruitment of human iNKT cells into solid tumors in as little as one day and a significantly enhanced tumor killing ability. Using firefly luciferase-labeled iNKT cells, we monitored the tissue biodistribution and pharmacokinetics/pharmacodynamics (PK/PD) of human iNKT cells in tumor-bearing NSG mice. Collectively, these preclinical studies demonstrate the promise of an αGC-driven iNKT cell-based immunotherapy to target solid tumors with higher efficacy and precision.

The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption and implementation. Recent developments in innate immune cell-based CAR therapy have opened several doors for the expansion of this therapy, especially as it relates to allogeneic cell sources and solid tumor infiltration. This study establishes in vitro killing assays to examine the TAM-targeting efficacy of MAIT, iNKT, and γδT cells. This study also assesses the antitumor ability of CAR-engineered innate T cells, evaluating their potential adoption for clinical therapies. The in vitro trials presented in this study demonstrate the considerable TAM-killing abilities of all three innate T cell types, and confirm the enhanced antitumor abilities of CAR-engineered innate T cells. The tumor- and TAM-targeting capacity of these innate T cells suggest their potential for antitumor therapy that supplements cytotoxicity with remediation of tumor microenvironment (TME)-immunosuppression.

Allogeneic cell therapies, defined by genetically mismatched transplantation, have the potential to become a cost-effective solution for cell-based cancer immunotherapy. However, this type of therapy is often accompanied by the development of graft-versus-host disease (GvHD), induced by the mismatched major histocompatibility complex (MHC) between healthy donors and recipients, leading to severe complications and death. To address this issue and increase the potential for allogeneic cell therapies in clinical practice, minimizing GvHD is a crucial challenge. Innate T cells, encompassing subsets of T lymphocytes including mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, and gamma delta T (γδ T) cells, offer a promising solution. These cells express MHC-independent T-cell receptors (TCRs), allowing them to avoid MHC recognition and thus GvHD. This review examines the biology of these three innate T-cell populations, evaluates research on their roles in GvHD modulation and allogeneic stem cell transplantation (allo HSCT), and explores the potential futures for these therapies.

Background New COVID-19 treatments are desperately needed as case numbers continue to rise and emergent strains threaten vaccine efficacy. Cell therapy has revolutionized cancer treatment and holds much promise in combatting infectious disease, including COVID-19. Invariant natural killer T (iNKT) cells are a rare subset of T cells with potent antiviral and immunoregulatory functions and an excellent safety profile. Current iNKT cell strategies are hindered by the extremely low presence of iNKT cells, and we have developed a platform to overcome this critical limitation. Methods We produced allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells through TCR engineering of human cord blood CD34+ hematopoietic stem cells (HSCs) and differentiation of these HSCs into iNKT cells in an Ex Vivo HSC-Derived iNKT Cell Culture. We then established in vitro SARS-CoV-2 infection assays to assess AlloHSC-iNKT cell antiviral and anti-hyperinflammation functions. Lastly, using in vitro and in vivo preclinical models, we evaluated AlloHSC-iNKT cell safety and immunogenicity for off-the-shelf application. Results We reliably generated AlloHSC-iNKT cells at high-yield and of high-purity; these resulting cells closely resembled endogenous human iNKT cells in phenotypes and functionalities. In cell culture, AlloHSC-iNKT cells directly killed SARS-CoV-2 infected cells and also selectively eliminated SARS-CoV-2 infection-stimulated inflammatory monocytes. In an in vitro mixed lymphocyte reaction (MLR) assay and an NSG mouse xenograft model, AlloHSC-iNKT cells were resistant to T cell-mediated alloreaction and did not cause GvHD. Conclusions Here, we report a method to robustly produce therapeutic levels of AlloHSC-iNKT cells. Preclinical studies showed that these AlloHSC-iNKT cells closely resembled endogenous human iNKT cells, could reduce SARS-CoV-2 virus infection load and mitigate virus infection-induced hyperinflammation, and meanwhile were free of GvHD-risk and resistant to T cell-mediated allorejection. These results support the development of AlloHSC-iNKT cells as a promising off-the-shelf cell product for treating COVID-19; such a cell product has the potential to target the new emerging SARS-CoV-2 variants as well as the future new emerging viruses.

Intraperitoneal (i.p.) experimental models in mice can recapitulate the process of i.p. dissemination in abdominal cancers and may help uncover critical information about future successful clinical treatments. i.p. cellular composition is studied in preclinical models addressing a wide spectrum of other pathophysiological states such as liver cirrhosis, infectious disease, autoimmunity, and aging. The peritoneal cavity is a multifaceted microenvironment that contains various immune cell populations, including T, B, NK, and various myeloid cells, such as macrophages. Analysis of the peritoneal cavity is often obtained by euthanizing mice and performing terminal peritoneal lavage. This procedure inhibits continuous monitoring of the peritoneal cavity in a single mouse and necessitates the usage of more mice to assess the cavity at multiple timepoints, increasing the cost, time, and variability of i.p. studies. Here, we present a simple, novel method termed in vivo intraperitoneal lavage (IVIPL) for the minimally invasive monitoring of cells in the peritoneal cavity of mice. In this proof-of-concept, IVIPL provided real-time insights into the i.p. tumor microenvironment for the development and study of ovarian cancer therapies. Specifically, we studied CAR-T cell therapy in a human high-grade serous ovarian cancer (HGSOC) xenograft mouse model, and we studied the immune composition of the i.p. tumor microenvironment (TME) in a mouse HGSOC syngeneic model.

In this paper, we study the resource allocation and trajectory design for secure unmanned aerial vehicle (UAV)-enabled communication systems, where multiple multi-purpose UAV base stations are dispatched to provide secure communications to multiple legitimate ground users (GUs) in the existence of multiple eavesdroppers (Eves). Specifically, by leveraging orthogonal frequency division multiple access (OFDMA), active UAV base stations can communicate to their desired ground users via the assigned subcarriers while idle UAV base stations can serve as jammer simultaneously for communication security provisioning. To achieve fairness in secure communication, we maximize the average minimum secrecy rate per user by jointly optimizing the communication/jamming subcarrier allocation policy and the trajectory of UAVs, while taking into account the constraints on the minimum safety distance among multiple UAVs, the maximum cruising speed, the initial/final locations, and the existence of cylindrical no-fly zones (NFZs). The design is formulated as a mixed integer non-convex optimization problem which is generally intractable. Subsequently, a computationally-efficient iterative algorithm is proposed to obtain a suboptimal solution. Simulation results illustrate that the performance of the proposed iterative algorithm can significantly improve the average minimum secrecy rate compared to various baseline schemes., Accepted for publication, IEEE TCOM

Cross-reactivity and direct killing of target cells remain underexplored for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific CD8+ T cells. Isolation of T cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T cell reactivity profiling. We identify SARS-CoV-2 RNA-dependent RNA polymerase (RdRp/NSP12) as highly conserved, likely due to its critical role in the virus life cycle. We perform single-cell TCRαβ sequencing in human leukocyte antigen (HLA)-A∗02:01-restricted, RdRp-specific T cells from SARS-CoV-2-unexposed individuals. Human T cells expressing these TCRαβ constructs kill target cell lines engineered to express full-length RdRp. Three TCR constructs recognize homologous epitopes from common cold coronaviruses, indicating CD8+ T cells can recognize evolutionarily diverse coronaviruses. Analysis of individual TCR clones may help define vaccine epitopes that can induce long-term immunity against SARS-CoV-2 and other coronaviruses., Graphical abstract, Nesterenko et al. identify T cell responses with potential to confer long-term immunity against SARS-CoV-2. The machinery responsible for replicating the viral genome is highly conserved and, as shown by Nesterenko et al., can be effectively targeted by CD8+ T cells.

Summary Cell-based immunotherapy has become the new-generation cancer medicine, and “off-the-shelf” cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development., Graphical abstract, Highlights • Allogeneic HSC-iNKT cells are generated in vitro at high yield and purity • Allogeneic HSC-iNKT cells effectively target tumor cells using multiple mechanisms • Allogeneic HSC-iNKT cells exhibit high safety and low immunogenicity • A preclinical study demonstrated feasibility, safety, and cancer therapy potential, Li et al. report the preclinical development of allogeneic-hematopoietic-stem-cell-engineered invariant natural killer T (HSC-iNKT) cells for off-the-shelf cancer therapy. Allogeneic HSC-iNKT cells demonstrate cancer therapy potential and a high safety profile.

Cell-based cancer immunotherapy has revolutionized the treatment of hematological malignancies. Specifically, autologous chimeric antigen receptor-engineered T (CAR-T) cell therapies have received approvals for treating leukemias, lymphomas, and multiple myeloma following unprecedented clinical response rates. A critical barrier to the widespread usage of current CAR-T cell products is their autologous nature, which renders these cellular products patient-selective, costly, and challenging to manufacture. Allogeneic cell products can be scalable and readily administrable but face critical concerns of graft-versus-host disease (GvHD), a life-threatening adverse event in which therapeutic cells attack host tissues, and allorejection, in which host immune cells eliminate therapeutic cells, thereby limiting their antitumor efficacy. In this review, we discuss recent advances in developing stem cell-engineered allogeneic cell therapies that aim to overcome the limitations of current autologous and allogeneic cell therapies, with a special focus on stem cell-engineered conventional αβ T cells, unconventional T (iNKT, MAIT, and γδ T) cells, and natural killer (NK) cells.

In the smart distribution network scenario, we investigate the physical layer security performance of power line communication in FBL. The results show that the system secure transmission rate increases with increasing channel block length and eventually converges to a constant value. Compared with the traditional SE maximization algorithm based on FBL, the total secrecy rate is improved by about 13%. Compared with the traditional linear precoder (ZF), the secrecy rate is improved by about 30%. Therefore, the proposed scheme is superior in supporting the power line communication system based on FBL.

Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes that recognize lipid antigens presented by nonpolymorphic major histocompatibility complex (MHC) I-like molecule CD1d. iNKT cells play essential roles in regulating immune responses against cancer, viral infection, autoimmune disease, and allergy. However, the study and application of iNKT cells have been hampered by their very small numbers (0.01-1% in mouse and human blood). Here, we describe protocols to (1) generate mouse iNKT cells from mouse mononuclear cells or from mouse hematopoietic stem cells engineered with iNKT T cell receptor (TCR) gene (denoted as mMNC-iNKT cells or mHSC-iNKT cells, respectively), (2) generate human iNKT cells from human peripheral blood mononuclear cells or from human HSC cells engineered with iNKT TCR gene (denoted as hPBMC-iNKT cells or hHSC-iNKT cells, respectively), and (3) characterize mouse and human iNKT cells in vitro and in vivo.

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy., Monoamine oxidase A (MAO-A) is an outer mitochondrial membrane-bound enzyme best known for its function in the brain, but also linked to cancer progression. Here, the authors show that MAO-A is expressed in tumor associated macrophages, promoting their immunosuppressive properties, and that MAO inhibition suppresses tumor growth in preclinical models.

Engineering stem cells presents an attractive paradigm for cancer immunotherapy. Stem cells engineered to stably express various chimeric antigen receptors (CARs) or T-cell receptors (TCRs) against tumor-associated antigens are showing increasing promise in the treatment of solid tumors and hematologic malignancies. Stem cells engraft for long-term immune cell generation and serve as a sustained source of tumor-specific effector cells to maintain remissions. Furthermore, engineering stem cells provides 'off-the-shelf' cellular products, obviating the need for a personalized and patient-specific product that plagues current autologous cell therapies. Herein, we summarize recent progress of stem cell-engineered cancer therapies, and discuss the utility, impact, opportunities, and challenges of cellular engineering that may facilitate the translational and clinical research.

Tumor-associated macrophages (TAMs) accumulate in the solid tumor microenvironment (TME) and have been shown to promote tumor growth and dampen antitumor immune responses. TAM-mediated suppression of T-cell antitumor reactivity is considered to be a major obstacle for many immunotherapies, including immune checkpoint blockade and adoptive T/CAR-T-cell therapies. An ex vivo culture system closely mimicking the TME can greatly facilitate the study of cancer immunotherapies. Here, we report the development of a 3D TME-mimicry culture that is comprised of the three major components of a human TME, including human tumor cells, TAMs, and tumor antigen-specific T cells. This TME-mimicry culture can readout the TAM-mediated suppression of T-cell antitumor reactivity, and therefore can be used to study TAM modulation of T-cell-based cancer immunotherapy. As a proof-of-principle, the studies of a PD-1/PD-L1 blockade therapy and a MAO-A blockade therapy were performed and validated.

A rapidly growing area of interest in biomedical science involves the reciprocal crosstalk between the sensory nervous and immune systems. Both of these systems are highly integrated, detecting potential environmental harms and restoring homeostasis. Many different cytokines, receptors, neuropeptides, and other proteins are involved in this bidirectional communication that are common to both systems. One such family of proteins includes the transient receptor potential vanilloid (TRPV) proteins. Though much progress has been made in understanding TRPV proteins in the nervous system, their functions in the immune system are not well elucidated. Hence, further understanding their role in the peripheral immune system and as regulators of neuroimmunity is critical for evaluating their potential as therapeutic targets for numerous inflammatory disorders, cancers, and other disease states. Here, we focus on the latest advancements in understanding TRPV1 and TRPV2's roles in the immune system, TRPV1 in neuroimmunity, and TRPV1's potential involvement in anti-tumor therapy.

Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain, where it breaks down neurotransmitters and thereby influences mood and behavior. Small-molecule MAO inhibitors (MAOIs) have been developed and are clinically used for treating depression and other neurological disorders. However, the involvement of MAO-A in antitumor immunity has not been reported. Here, we observed induction of the Maoa gene in tumor-infiltrating immune cells. Maoa knockout mice exhibited enhanced antitumor T cell immunity and suppressed tumor growth. MAOI treatment significantly suppressed tumor growth in preclinical mouse syngeneic and human xenograft tumor models in a T cell-dependent manner. Combining MAOI and anti-PD-1 treatments generated synergistic tumor suppression effects. Clinical data correlation studies associated intratumoral MAOA expression with T cell dysfunction and decreased patient survival in a broad range of cancers. We further demonstrated that MAO-A restrains antitumor T cell immunity through controlling intratumoral T cell autocrine serotonin signaling. Together, these data identify MAO-A as an immune checkpoint and support repurposing MAOI antidepressants for cancer immunotherapy.

Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes that recognize lipid antigens presented by nonpolymorphic major histocompatibility complex (MHC) I-like molecule CD1d. iNKT cells play essential roles in regulating immune responses against cancer, viral infection, autoimmune disease, and allergy. However, the study and application of iNKT cells have been hampered by their very small numbers (0.01-1% in mouse and human blood). Here, we describe protocols to (1) generate mouse iNKT cells from mouse mononuclear cells or from mouse hematopoietic stem cells engineered with iNKT T cell receptor (TCR) gene (denoted as mMNC-iNKT cells or mHSC-iNKT cells, respectively), (2) generate human iNKT cells from human peripheral blood mononuclear cells or from human HSC cells engineered with iNKT TCR gene (denoted as hPBMC-iNKT cells or hHSC-iNKT cells, respectively), and (3) characterize mouse and human iNKT cells in vitro and in vivo.

Targeting tumour-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumour microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observed MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibited decreased TAM immunosuppressive functions corresponding with enhanced antitumour immunity. MAOI treatment induced TAM reprogramming and suppressed tumour growth in preclinical mouse syngeneic and human xenograft tumour models. Combining MAOI and anti-PD-1 treatments resulted in synergistic tumour suppression. Clinical data correlation studies associated high intratumoural MAOA expression with poor patient survival in a broad range of cancers. We further demonstrated that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

In this paper, we study the trajectory and resource allocation design for downlink energy-efficient secure unmanned aerial vehicle (UAV) communication systems, where an information UAV assisted by a multi-antenna jammer UAV serves multiple ground users in the existence of multiple ground eavesdroppers. The resource allocation strategy and the trajectory of the information UAV, and the jamming policy of the jammer UAV are jointly optimized for maximizing the system energy efficiency. The joint design is formulated as a non-convex optimization problem taking into account the quality of service (QoS) requirement, the security constraint, and the imperfect channel state information (CSI) of the eavesdroppers. The formulated problem is generally intractable. As a compromise approach, the problem is divided into two subproblems which facilitates the design of a low-complexity suboptimal algorithm based on alternating optimization approach. Simulation results illustrate that the proposed algorithm converges within a small number of iterations and demonstrate some interesting insights: (1) the introduction of a jammer UAV facilitates a highly flexible trajectory design of the information UAV which is critical to improving the system energy efficiency; (2) by exploiting the spatial degrees of freedom brought by the multi-antenna jammer UAV, our proposed design can focus the artificial noise on eavesdroppers offering a strong security mean to the system., Accepted by IEEE Transactions on Communications, 18 pages, 12 figures

In order to improve distribution equipment reliability and emergency repair response speed, a distribution equipment monitoring system based on Internet of things and multi-agent is designed by building a hierarchical model. The system is based on the power Internet of things, which is divided into sensing layer, device layer and data center layer. The sensing layer realizes multi-source data acquisition through sensors and acquisition devices; the device layer deploys edge computing agents to realize device-level monitoring; and the data center layer deploys coordinating agents to realize system-level analysis. The dual-way communication is used to realize data transmission between up layer and down layer. The system has the characteristics of distribution, autonomy and multi-objective interaction, which can meet and adapt to the demand and development trend of intelligent operation and maintenance of distribution equipment.

Over 10% of genetic diseases are caused by mutations that introduce a premature termination codon in protein-coding mRNA. Nonsense-mediated mRNA decay (NMD) is an essential cellular pathway that degrades these mRNAs to prevent the accumulation of harmful partial protein products. NMD machinery is also increasingly appreciated to play a role in other essential cellular functions, including telomere homeostasis and the regulation of normal mRNA turnover, and is misregulated in numerous cancers. Hence, understanding and designing therapeutics targeting NMD is an important goal in biomedical science. The central regulator of NMD, the Upf1 protein, interacts with translation termination factors and contextual factors to initiate NMD specifically on mRNAs containing PTCs. The molecular details of how these contextual factors affect Upf1 function remain poorly understood. Here, we review plausible models for the NMD pathway and the evidence for the variety of roles NMD machinery may play in different cellular processes.

// Yan-Ruide Li 1 , Ai Zhong 1 , Han Dong 1 , Lu-Han Ni 1 , Fu-Qing Tan 2 and Wan-Xi Yang 1 1 The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, China 2 The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China Correspondence to: Wan-Xi Yang, email: wxyang@spermlab.org Keywords: myosin Va, testicular cancer, prostate cancer, tumorigenesis, actin Received: April 15, 2017 Accepted: May 03, 2017 Published: May 17, 2017 ABSTRACT Myosin Va, a member of Class V myosin, functions in organelle motility, spindle formation, nuclear morphogenesis and cell motility. The purpose of this study is to explore the expression and localization of myosin Va in testicular cancer and prostate cancer, and its specific roles in tumor progression including cell division, migration and proliferation. We detected myosin Va in testicular and prostate tumor tissues using sqRT-PCR, western blot, and immunofluorescence. Tumor samples showed an increased expression of myosin Va, abnormal actin and myosin Va distribution. Immunofluorescence images during the cell cycle showed that myosin Va tended to gather at cytoplasm during anaphase but co-localized with nucleus during other phases, suggesting the roles of myosin Va in disassembly of spindle microtubule, movement of chromosomes and normal cytokinesis. In addition, multi-nucleation and aberrant nuclear morphology were observed in myosin Va-knockdown cells. Wounding assay and CCK-8-based cell counting were conducted to explore myosin Va roles in cell migration, viability and proliferation. Our results suggest that myosin Va plays essential roles in maintaining normal mitosis, enhancing tumor cell motility and viability, and these properties are the hallmark of tumor progression and metastasis development. Therefore, an increased understanding of myosin Va expression and function will assist in the development of future oncodiagnosis and -therapy.

Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been greatly hindered by their extremely low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient’s lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the intended HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.

In this paper, we study the resource allocation and trajectory design for energy-efficient secure unmanned aerial vehicle (UAV) communication systems where a UAV base station serves multiple legitimate ground users in the existence of a potential eavesdropper. We aim to maximize the energy efficiency of the UAV by jointly optimizing its transmit power, user scheduling, trajectory, and velocity. The design is formulated as a non-convex optimization problem taking into account the maximum tolerable signal-to-noise ratio (SNR) leakage, the minimum data rate requirement of each user, and the location uncertainty of the eavesdropper. An iterative algorithm is proposed to obtain an efficient suboptimal solution. Simulation results demonstrate that the proposed algorithm can achieve a significant improvement of the system energy efficiency while satisfying communication security constraint, compared to some simple scheme adopting straight flight trajectory with a constant speed., Comment: 9 pages, 4 figures. This paper has been accepted for presentation at IEEE WCNC 2019

// Yan-Ruide Li 1 and Wan-Xi Yang 1 1 The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, China Correspondence to: Wan-Xi Yang, email: // Keywords : myosin, cancer, tumorigenesis, metastasis development, chromomyosin Received : February 28, 2016 Accepted : April 10, 2016 Published : April 19, 2016 Abstract Myosin is a kind of actin-based motor protein. As the crucial functions of myosin during tumorigenesis have become increasingly apparent, the profile of myosin in the field of cancer research has also been growing. Eighteen distinct classes of myosins have been discovered in the past twenty years and constitute a diverse superfamily. Various myosins share similar structures. They all convert energy from ATP hydrolysis to exert mechanical stress upon interactions with microfilaments. Ongoing research is increasingly suggesting that at least seven kinds of myosins participate in the formation and development of cancer. Myosins play essential roles in cytokinesis failure, chromosomal and centrosomal amplification, multipolar spindle formation and DNA microsatellite instability. These are all prerequisites of tumor formation. Subsequently, myosins activate various processes of tumor invasion and metastasis development including cell migration, adhesion, protrusion formation, loss of cell polarity and suppression of apoptosis. In this review, we summarize the current understanding of the roles of myosins during tumorigenesis and discuss the factors and mechanisms which may regulate myosins in tumor progression. Furthermore, we put forward a completely new concept of “chromomyosin” to demonstrate the pivotal functions of myosins during karyokinesis and how this acts to optimize the functions of the members of the myosin superfamily.

Ubiquitous in-network caching is one of key features of Information Centric Network, together with receiver-drive content retrieval paradigm, Information Centric Network is better support for content distribution, multicast, mobility, etc. Cache placement strategy is crucial to improving utilization of cache space and reducing the occupation of link bandwidth. Most of the literature about caching policies considers the overall cost and bandwidth, but ignores the limits of node cache capacity. This paper proposes a G-FMPH algorithm which takes into account both constrains on the link bandwidth and the cache capacity of nodes. Our algorithm aims at minimizing the overall cost of contents caching afterwards. The simulation results have proved that our proposed algorithm has a better performance.

Internet of Things (IoT) is the inter-networking of people, physical devices, vehicles and other objects to collect and exchange data, which has been receiving lots of attention in recent years. Named Data Networking (NDN) is a new paradigm perceived for the next generation network architecture to deal with the explosive growth in the volume of global IoT traffic. Although researches on Quality of Service (QoS) and Quality of Experience (QoE) are popular all the time, correlation models between QoS and QoE remain unexplored in IoT-NDN. In this paper, we propose application layer QoE and discuss correlation models between QoS and application layer QoE in IoT-NDN. Simulation results conclude concrete mapping relations between QoS and application layer QoE, which are useful to take further actions to improve network performance.

Spermatogenesis is a fundamental process in sexual development and reproduction, in which the diploid spermatogonia transform into haploid mature spermatozoa. This process is under the regulation of multiple factors and pathway. Myosin has been implicated in various aspects during spermatogenesis. Myosins constitute a diverse superfamily of actin-based molecular motors that translocate along microfilament in an ATP-dependent manner, and six kinds of myosins have been proved that function during spermatogenesis. In mitosis and meiosis, myosins play an important role in spindle assembly and positioning, karyokinesis and cytokinesis. During spermiogenesis, myosins participate in acrosomal formation, nuclear morphogenesis, mitochondrial translocation and spermatid individualization. In this review, we summarize current understanding of the functions of myosin in spermatogenesis and some reproductive system diseases such as testicular tumors and prostate cancer, and discuss the roles of possible upstream molecules which regulate myosin in these processes.