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Leptomeningeal metastases arise from cancer cell entry into the subarachnoid space, inflicting significant neurologic morbidity and mortality across a wide range of malignancies. The modern era of cancer therapeutics has seen an explosion of molecular-targeting agents and immune-mediated strategies for patients with breast, lung, and melanoma malignancies, with meaningful extracranial disease control and improvement in patient survival. However, the clinical efficacy of these agents in those with leptomeningeal metastases remains understudied, due to the relative rarity of this patient population, the investigational challenges associated with studying this dynamic disease state, and brisk disease pace. Nevertheless, retrospective studies, post hoc analyses, and small prospective trials in the last two decades provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds. The continued development of clinical trials devoted to patients with leptomeningeal metastases is critical to establish robust efficacy outcomes in this patient population, define drug pharmacokinetics in the intrathecal space, and uncover new avenues for treatment in the face of leptomeningeal therapeutic resistance.

Purpose Cytokeratin 19-positive cancer stem cells (CK9 + CSCs) and their tumor-associated macrophages (TAMs) have not been fully explored yet in the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Experimental Design: Single-cell RNA sequencing was performed on the viable cells obtained from 11 treatment-naïve HBV-associated HCC patients, including 8 CK19 + patients, to elucidate their transcriptomic landscape, CK19 + CSC heterogeneity, and immune microenvironment. Two in-house primary HCC cohorts (96 cases-related HBV and 89 cases with recurrence), multiple external cohorts, and in vitro and in vivo experiments were used to validate the results. Results A total of 64,581 single cells derived from the human HCC and adjacent normal tissues were sequenced, and 11 cell types were identified. The result showed that CK19 + CSCs were phenotypically and transcriptionally heterogeneous, co-expressed multiple hepatics CSC markers, and were positively correlated with worse prognosis. Moreover, the SPP1 + TAMs (TAM_SPP1) with strong M2-like features and worse prognosis were specifically enriched in the CK19 + HCC and promoted tumor invasion and metastasis by activating angiogenesis. Importantly, matrix metalloproteinase 9 (MMP9) derived from TAM_SPP1, as the hub gene of CK19 + HCC, was activated by the VEGFA signal. The patients with low TAM_SPP1 enrichment might benefit from trans-arterial chemoembolization. Conclusions This study revealed the heterogeneity and stemness characteristics of CK19 + CSCs and specific immunosuppressive TAM_SPP1 in CK19 + HCC. The VEGFA signal can activate TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. This might provide novel insights into the clinical treatment of HCC patients.

Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-γ signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-γ or its receptor, fail to control LM growth. Overexpression ofIfngthrough a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-γ actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-γ signaling and suggests a novel immune-therapeutic approach against tumors within this space.

Purpose Despite immune checkpoint inhibitor (ICI) has recently taken on an extremely important role in tumors, only a minority of hepatocellular carcinoma (HCC) patients are effective. The clinical value of PRC1 and DLGAP5 in HCC and its relationship with immune microenvironment have been rarely reported. Methods Key genes related to doubling time of HCC tumors were identified using WGCNA, and their expression was analyzed against our in-house RNA sequencing database, the Gene Expression Omnibus and the Cancer Genome Atlas database. We explored correlations between key genes and the immune microenvironment based on the TISCH and TIMER database, as well as clinicopathological characteristics and prognosis of HCC in patients at our center. Results WGCNA identified PRC1 and DLGAP5 as key genes in HCC. PRC1 and DLGAP5 were over-expressed in HCC tissues relative to normal tissues based on analysis of 2,154 patients and 1,344 controls. The genes gave respective areas under the summary receiver operator characteristic curve of 0.95 (95%CI 0.93–0.97) and 0.94 (95%CI 0.92–0.96). High expression of PRC1 and DLGAP5 positively correlated with tumor recurrence and microvascular invasion, was an independent risk factor for poor overall survival. PRC1 and DLGAP5 were co-expressed in proliferative T cells over-expressing immunosuppressive markers PDCD1, CTLA4, HAVCR2, LAG3 and TIGIT based on single-cell RNA-sequencing datasets. Conclusions PRC1 and DLGAP5 significantly upregulated in HCC are associated with poor prognosis and show strong diagnostic potential. PRC1 or DLGAP5 combined with CD8 T cell markers may serve as predictive biomarkers for the efficacy of ICI combination therapy.

Previous smaller meta-analyses comparing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) provided controversial results. This updated meta-analysis aimed to reliably identify any difference in the HCC incidence between TDF-treated or ETV-treated CHB patients in general or in specific subgroups.PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies with hazard ratios (HRs) for HCC between TDF-treated and ETV-treated CHB patients. Retrieved dates ranged from January 2009 to October 2021. HRs with or without adjustment were pooled with random-effects model.Twenty-four comparative studies involving 37 771 CHB patients treated with TDF and 72 094 treated with ETV were included. TDF was associated with lower risk of HCC compared with ETV, with pooled unadjusted HR of 0.76 (95% confidence interval [CI]: 0.67-0.86) (24 studies) and adjusted HR of 0.81 (95% CI: 0.72-0.91) (21 studies). In propensity score matching cohorts, the TDF superiority was confirmed for unadjusted HR 0.83 (95% CI: 0.71-0.97) (14 studies) and was close to significance for adjusted HR (0.78, 95% CI: 0.58-1.04) (8 studies). Subgroup analyses showed that TDF was associated with lower HCC risk than ETV treatment in CHB patients who were from Asia (adjusted HR: 0.76, 95% CI: 0.66-0.87; 15 studies) or nucleos(t)ide naïve (adjusted HR:0.74, 95% CI: 0.65-0.84; 18 studies).Current evidence from a sizable population suggests that TDF is associated with significantly lower HCC risk compared with ETV treatment in patients who are from Asia and/or nucleos(t)ide naïve.

This letter presents a high-efficiency circular-polarized (CP) rectenna at 5.8 GHz within wide input power range featuring low profile and radar cross section (RCS) reduction. Originating from the connection to a branch-line coupler, two identical subrectifiers in parallel combination are capable of extending the input power range and enabling the stability of dc output. The contribution of this combination in the performance of rectenna is experimentally demonstrated and a solution to RCS reduction by means of defected ground structure and complementary split-ring resonators is devised. The measured results show that the rectenna achieves a conversion efficiency of more than $60\%$ within the input power range from 2.2 to 17.6 dBm, and an in-band RCS reduction of 5.1 dB, verifying the applicability of wireless power transfer for CubeSats.

This letter presents a high-efficiency rectifier based on a miniaturized branch-line hybrid coupler (MBLHC), which can be applied to wireless power harvesting (WPH) featuring a wide input power range. Originating from the connection to the MBLHC, two identical subrectifiers are used to achieve less sensitivity to the impedance mismatching, and thus the input power range is extended. For validation, theoretical analysis is carried out and a rectifier working at 5.8 GHz is configured out. The measured results show that the rectifier can achieve a conversion efficiency of more than 60% within the input power range from 2 to 17.5 dBm, and a maximum efficiency of 81% with a more compact size.

The goal of this paper is to provide a review on the current emerging management strategies as described in the literature pertaining to breast cancer and central nervous system metastases. As systemic oncology treatments evolve, so are new approaches to the management of central nervous system metastases from breast cancer.In this review, we describe how novel treatment strategies have evolved from standard chemotherapy to more targeted approaches, innovative drug delivery methodologies, immunotherapeutics, and radiotherapeutic approaches. We describe innovative treatment strategies on the horizon for breast cancer and central nervous metastases. Future therapeutics may be better able to penetrate through the blood-brain-barrier bypassing limitations from standard therapies. These pioneering strategies will hopefully improve patients' quality of life as well as survival.

Many studies have demonstrated that monotherapy with tenofovir disoproxil fumarate (TDF) or entecavir (ETV) can reduce the risk of liver complications in individuals chronically infected with HBV (CHB). Unclear is whether one monotherapy is more effective than the other at preventing these outcomes. In a recent issue of this journal, Lee and coworkers1 reported data from a large population of treatment-naive CHB patients in which risk of hepatocellular carcinoma (HCC), all-cause mortality or liver transplantation was similar with either monotherapy. Similar results were observed in subgroups of patients with chronic hepatitis or cirrhosis. While this study involved more than 7000 South Korean patients who were enrolled during more than a decade and whose virological and biochemical data over several years were analysed, its findings must be treated with caution because the two groups differed substantially in median …

Meninges, or the membranous coverings of the brain and spinal cord, play host to dozens of morbid pathologies. In this study we provide a method to isolate the leptomeningeal cell layer, identify leptomeninges in histologic slides, and maintain leptomeningeal fibroblasts in in vitro culture. Using an array of transcriptomic, histological, and cytometric analyses, we identified ICAM1 and SLC38A2 as two novel markers of leptomeningeal cells in vivo and in vitro. Our results confirm the fibroblastoid nature of leptomeningeal cells and their ability to form a sheet-like layer that covers the brain and spine parenchyma. These findings will enable researchers in central nervous system barriers to describe leptomeningeal cell functions in health and disease.

Choroid plexus (CP) forms an anatomically functional barrier between the blood and cerebrospinal fluid (CSF) that dictates the cellular and humoral composition of the CSF. The immunological response of CP to inflammatory stimuli, such as cancer, remains unclear. Here, we find that CP orchestrates the immune composition of CSF in the steady state as well as in the presence of metastatic cancer. We show that the circulation-derived leptomeningeal monocyte-macrophages entering the CSF through CP promote the growth of leptomeningeal metastasis (LM) by perturbing the environment with a storm of dozens of pro- and anti-inflammatory cytokines. Functional manipulation of Type II Interferon pathway specifically within inflamed leptomeninges revealed that IFN-γ can serve as a dominant signal, further recruiting peripheral myeloid cells and activating their protective anti-tumoral response. This preclinical strategy was sufficient to controll the growth of syngeneic LM cancer cells and delay the onset of lethal LM.

With the development of the fifth generation (5G) and the Internet of Things (IoT), wireless charging is driving people’s life. The technology of rectifier is considered to be count. However, the conversion efficiency usually get a peak value at a narrow range of input power, which is not cost-effective. In this paper, a high efficiency rectifier with widening input power range is proposed. The results show that the power range can be widen from 8 to 15 dBm over the efficiency of 60%, of which the peak efficiency is over 72%.

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.

For microwave power transmission technology, improving the efficiency of rectifier can always be the crux of the matter. However, the performance of conventional rectifiers are highly dependent on the input power, and the external structures added together are not convenient for integration. Therefore, in this paper, a miniaturized high efficiency rectifier with wide input power range is proposed. According to the results, over 50% of the efficiency is obtained in a wide range (24.5 dBm and 21.8 dBm for simulated and measured results respectively), where the peak efficiency are 82% and 77% respectively.

Advanced engineering electromagnetics (AEE) is characterized by its many mathematical formulas and conceptual abstractions, making students particularly difficult to learn, which also leads students to be not interested in this course. How to help students to understand the content of AEE and increase students’ interest in learning is a problem faced by many universities. This paper proposes a "three-in-one" teaching program that combines Harkness table, flipping classrooms and simulations. In this way, the interaction between teachers and students, students and students can be increased, the quality of classroom teaching can be improved, and students’ interest in learning can be improved.

Electromagnetics (EM) and microwave technology have been the key theory and technology in the development of modern electronic devices and information system. However, their knowledge system and technologic contents could be very huge and complicated, leading to much difficulty in learning and understanding. Modeling and simulating are efficient to fix the problems. But, during past decades, these techniques were mostly used in research work in general and they were seldom incorporated with teaching and educational activities, especially for undergraduate students. Therefore, it is necessary to make a paradigm shift in the method of teaching and learning and cultivate the ability of using the modeling and simulation techniques in the courses related to EM and microwave technology. In this paper, the important function of modeling and simulation in teaching the courses related to EM and microwave technology is analyzed. In order to attach the important role of modeling and simulation to the courses and to stimulate the creativity of students, a novel teaching method is proposed. This method combines the advanced educational technologies and the characteristics of the courses related to EM and microwave technology so that the teaching effect and quality can be apparently improved. Teaching examples are provided to demonstrate the application of the teaching method.

With the development of Internet of Things (IoT), radio electronic equipment has played a vital role in various applications. Furthermore, the non-contact wireless power transmission technology has brought a new round of innovation for the power supply of electronic devices in the IoT. The energy of radio wave and various electromagnetic radiation can become the power source of electronic equipment. By using a rectifier circuit linked to a receiving antenna, this free radio wave energy can be captured and converted into usable a DC voltage for electronic applications. However, for miniaturized electronic equipment, the diodes in the microwave rectifier circuit will produce high-order harmonics, resulting in a large amount of power loss, which decreases the rectification efficiency dramatically. Therefore, it is particularly necessary to design a rectifier circuit that can suppress harmonics. In this paper, a class-F rectifier circuit working at 5.8 GHz is proposed and analyzed. The rectifier circuit can separate the consumption of voltage and current in the diode and realize a high-efficiency rectification. The simulation results show that the rectification efficiency can reach 77.0% at the input power of 16.5 dBm.

Comparators are widely used in Serializer-Deserializer (SerDes), analog-to-digital converters and so on. A SerDes is a pair of functional blocks commonly used in high speed communications to compensate for limited input/output. Transmitter plays a key role in the whole signal transmission system. A good receiver can make up for the shortcomings of the transmitter. Comparator is an important module of receiver. The role of the comparator is to compare the input with the reference signals, and output a logic level as the decision. High precision, high speed, low supply voltage operation, low power consumption, metastability and offset voltage are the critical aspects to be considered while designing CMOS dynamic comparators. In a 28nm CMOS technology, a comparator built by two cascaded pre-amplified dynamic comparators is proposed in this paper. With the presence of cascading, the proposed comparator has high sensitivity and low offset.

For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle' state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient's own immune system into an active weapon against pathogens and cancer. Citation Format: Jan Remsik, Xinran Tong, Ugur Sener, Min Jun Li, Jessica Wilcox, Danielle Isakov, Camille Derderian, Kiana Chabot, Andrea Schietinger, Adrienne Boire. Decoding the immune system response to leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1751.

With the development of the fifth generation (5G) mobile communication, the demands of the multiband antenna are on the increase [1]. In this paper, we proposed a design of multiband antenna using a pixel patch as a unit which elements are optimized by non-dominated sorting genetic algorithm (NSGA-II). The measured and simulation results presented contain three bands, which highlights the benefits of the antenna design with multiband for use in 5G applications.

The paper introduces a disaster tolerant system based on B/S mode and proposes a safe and effective communication protocol that combines with communicational needs. The protocol has been realized in this paper. This system has adopted remote management based on Web so that its construction is reasonable and operation is convenient. Through test,the system which is excellent in performance and stable in working is considered to be valuable for application and promotion.

TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.

Diamond-like carbon (DLC) films were prepared by PLD process using 308 nm(XeCl) laser beam with high power (500 W) and high frequency(300 Hz). The effects of nitrogen pressure on the structure and properties of the DLC films under such extremely high power and repetition rate were studied. The results indicate that the microstructures of the films are varied from amorphous carbon to graphitized carbon in long-order with the increase of N2 pressure, and the optical properties of the films are deteriorated as compared to that of DLC films without nitrogen.

This paper expounds professional characteristics of biomedical engineering in our school, and analyses some problems lying in it, emphatically discusses advantages and the problems combining biomedical engineering with the medical courses in order to offer targeted solutions. It summarizes the results and problems so as to provide reference value to a new major.

The fusion model in wavelet domain is proposed. To maximize fusion and enhances the hidden image's capability of resisting attacks. Method: we derive the image related scrambling transform based on least square error principle. The algorithm improves the extent of fusion. The fusion factor, the scrambling matrix and iteration number are used as secret keys with the intension of improving the algorithm's security. Result: Simulation experiments have proved that the proposed algorithm improves the fusion factor and the extent of fusion significantly, Conclusion: The algorithm can be widely used for copyright protection of electronic image products and encrypted transmission of important military information.

β-Secretase (β-site amyloid precursor protein-cleaving enzyme 1; BACE1) is a transmembrane aspartic protease that cleaves the β-amyloid precursor protein en route to generation of the amyloid β-peptide (Aβ) that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus a prime target for the development of inhibitors which may serve as drugs in the treatment and/or prevention of Alzheimer's disease. In the following determination of the crystal structures of both apo and complexed BACE1, structural analysis of all crystal structures of BACE1 deposited in the PDB and molecular dynamics (MD) simulations of monomeric and `dimeric' BACE1 were used to study conformational changes in the active-site region of the enzyme. It was observed that a flap able to cover the active site is the most flexible region, adopting multiple conformational states in the various crystal structures. Both the presence or absence of an inhibitor within the active site and the crystal packing are shown to influence the flap's conformation. An open conformation of the flap is mostly observed in the apo structures, while direct hydrogen-bonding interaction between main-chain atoms of the flap and the inhibitor is a prerequisite for the flap to adopt a closed conformation in the crystal structures of complexes. Thus, a systematic study of the conformational flexibility of the enzyme may not only contribute to structure-based drug design of BACE1 inhibitors and of other targets with flexible conformations, but may also help to better understand the mechanistic events associated with the binding of substrates and inhibitors to the enzyme.

Selective estrogen receptor modulators, such as 17β-estradiol derivatives bound to metal complexes, have been synthesized as targeted probes for the diagnosis and treatment of breast cancer. Here, we report the detailed 3D structure of estrogen receptor α ligand-binding domain (ERα-LBD) bound with a novel estradiol-derived metal complex, estradiol-pyridine tetra acetate europium(III), at 2.6 A resolution. This structure provides important information pertinent to the design of novel functional ERα targeted probes for clinical applications.

An endomicroscope with enhanced signal collection efficiency was developed using customized double-clad fiber and aspherical compound-lens. Ex vivo two-photon fluorescence imaging of epithelial tissues was demonstrated for the first time with an all-fiber-optic scanning endomicroscope.

We study bit-error-rate transients of optical protection switching in a two-fiber ring network with optical channel dedicated protection. The optical protection and add-drop multiplex is achieved with 2/spl times/1 and 1/spl times/1 wavelength selective switches and transient-gain controlled optical amplifiers.