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Several onco-virotherapy candidates have been developed and clinically evaluated for the treatment of cancer, and several are approved for clinical use. In this systematic review we explored the clinical impact of onco-virotherapy compared to other cancer therapies by analyzing factors such as trial design, patient background, therapy design, delivery strategies, and study outcomes. For this purpose, we retrieved clinical studies from three platforms: ClinicalTrials.gov, PubMed, and EMBASE. We found that most studies were performed in patients with advanced and metastatic tumors, using a broad range of genetically engineered vectors and mainly administered intratumorally. Therapeutic safety was the most frequently assessed outcome, while relatively few studies focused on immunological antitumor responses. Moreover, only 59 out of 896 clinical studies were randomized controlled trials reporting comparative data. This systemic review thus reveals the need of more, and better controlled, clinical studies to increase our understanding on the application of onco-virotherapy either as a single treatment or in combination with other cancer immunotherapies., Graphical abstract, Bhatt and colleagues demonstrate that onco-virotherapy has proven to be clinically safe due to efforts in vector design, rational choices of therapeutic dosage, and delivery strategies. However, the analysis reveals the need of more controlled trials in addition to including early stage cancer patients and evaluation of immune responses.

Oncolytic virotherapy is a promising form of cancer treatment that uses native or genetically engineered viruses to target, infect and kill cancer cells. Unfortunately, this form of therapy is not effective in a substantial proportion of cancer patients, partly due to the occurrence of infection-resistant tumor cells. To shed new light on the mechanisms underlying therapeutic failure and to discover strategies that improve therapeutic efficacy we designed a cell-based model of viral infection. The model allows to investigate the dynamics of infection-sensitive and infection-resistant cells in tumor tissue in presence of the virus. To reflect the importance of the spatial configuration of the tumor on the efficacy of virotherapy, we compare three variants of the model: two 2D models of a monolayer of tumor cells and a 3D model. In all model variants, we systematically investigate how the therapeutic outcome is affected by properties of the virus (e.g. the rate of viral spread), the tumor (e.g. production rate of resistant cells, cost of resistance), the healthy stromal cells (e.g. degree of resistance to virus) and the timing of treatment. We find that various therapeutic outcomes are possible when resistant cancer cells arise at low frequency in the tumor. These outcomes depend in an intricate but predictable way on the death rate of infected cells, where faster death leads to rapid virus clearance and cancer persistence. Our simulations reveal three different causes of therapy failure: rapid clearance of the virus, rapid selection of resistant cancer cells, and a low rate of viral spread due to the presence of infection-resistant healthy cells. Our models suggest that improved therapeutic efficacy can be achieved by sensitizing healthy stromal cells to infection, although this remedy has to be weighed against the toxicity induced in the healthy tissue.

An mm-Wave novel RF mixer with folded cascode Topology along with double balanced switching configuration that is designed in 130 nm Technology is presented. The proposed mixer uses current folding cascade topology for achieving high isolation between the RF and LO port, and an improved bandwidth (BW). Moreover, it has used source degeneration inductor in order to achieve high linearity and providing input matching over the wideband. The proposed mixer produces more than 21 dB of conversion gain (CG), less than −10 dB of input matching (S11), more than 65 dB of RF-LO isolation, and the third-order input intercept point (IIP3) of 11.5 dBm for the frequency ranges of 17 – 32 GHz.

Summary B cells orchestrate pro-survival and pro-apoptotic inputs during unfolded protein response (UPR) to translate, fold, sort, secrete and recycle immunoglobulins. In common variable immunodeficiency (CVID) patients, activated B cells are predisposed to an overload of abnormally processed, misfolded immunoglobulins. Using highly accurate transcript measurements, we show that expression of UPR genes and immunoglobulin chains differs qualitatively and quantitatively during the first 4 h of chemically induced UPR in B cells from CVID patients and a healthy subject. We tested thapsigargin or tunicamycin as stressors and 4-phenylbutyrate, dimethyl sulfoxide and tauroursodeoxycholic acid as chemical chaperones. We found an early and robust decrease of the UPR upon endoplasmic reticulum (ER) stress in CVID patient cells compared to the healthy control consistent with the disease phenotype. The chemical chaperones increased the UPR in the CVID patient cells in response to the stressors, suggesting that misfolded immunoglobulins were stabilized. We suggest that the AMP-dependent transcription factor alpha branch of the UPR is disturbed in CVID patients, underlying the observed expression behavior.

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals, In an inter-laboratory study, the authors compare the accuracy and performance of three optical density calibration protocols (colloidal silica, serial dilution of silica microspheres, and colony-forming unit (CFU) assay). They demonstrate that serial dilution of silica microspheres is the best of these tested protocols, allowing precise and robust calibration that is easily assessed for quality control and can also evaluate the effective linear range of an instrument.

A 1–10 GHz, radio frequency (RF) mixer with an active inductor (AI) designed in 0.18 μm Technology has been proposed in the paper. It uses a conventional single-balanced mixer and double-balanced mixer for demonstrating wideband performance without using an inductor. The AI-based single-balanced mixer achieves conversion gain (CG) of 6–3 dB, S11 of -12 dB, and the third-order input intercept point (IIP3) of 0.15-2 dBm. Moreover, the active transformer that is designed based on the proposed AI is used in the Gilbert cell mixer for improving the bandwidth (BW). The proposed AI-based Gilbert cell mixer achieves 4.5-3 dB of CG, and 2.7-3.8 dBm of IIP3. The 3-dB BWs of the proposed mixers are 1–10 GHz.

This study proposes a wide-band low-power low-noise amplifier (LNA) and switched transconductance (SwGm) mixer. The proposed mixer is realised with a fully differential complementary metal oxide semiconductor (CMOS) SwGm configuration. It provides a high bandwidth with a low noise figure (NF) and consumes a low amount of power. Moreover, an ultra-wideband LNA is designed by using a split-load inductive technique. The combination of the LNA and the mixer has provided competitive results in terms of power, bandwidth, NF, and gain. The LNA + mixer was designed and fabricated in the 65 nm radio frequency-CMOS technology. The proposed LNA achieves 2.5 ± 0.1 dB of NF and 17 ± 1.5 dB of gain over the band of 1-10 GHz and consumes 4.8 mW of power. The proposed SwGm mixer shows a maximum conversion gain (CG) of 10 dB, a minimum NF of 10 dB, and more than -8.5 dBm of third-order input intercept point (IIP3) over the band of 10 GHz. The implemented LNA + mixer achieves 19 dB of CG, 5 dB of NF, and -6 dBm of IIP3. The on-chip LNA and mixer consume only 1.65 mW and 530 μW, respectively, from a 1.2 V supply voltage.

Resistance to therapy is a frequently observed phenomenon in the treatment of cancer, and as with other cancer therapeutics, therapies based on oncolytic viruses also face the challenges of resistance, such as humoral and cellular antiviral responses, and tumor-associated interferon-mediated resistance. In order to identify additional mechanisms of resistance that may contribute to therapeutic failure, we developed a systematic search strategy for studies published in PubMed. We analyzed 6143 articles on oncolytic virotherapy and found that approximately 8% of these articles use resistance terms in the abstract and/or title. Of these 439 articles, 87 were original research. Most of the findings reported pertain to resistance mediated by tumor-cell-dependent interferon signaling. Yet, mechanisms such as epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus entry barriers, and spatiotemporal restriction to viral spread, although not frequently assessed, were demonstrated to play a major role in resistance. Similarly, our results suggest that the stromal compartment consisting of, but not limited to, myeloid cells, fibroblasts, and epithelial cells requires more study in relation to therapy resistance using oncolytic viruses. Thus, our findings emphasize the need to assess the stromal compartment and to identify novel mechanisms that play an important role in conferring resistance to oncolytic virotherapy.

A self-biased CMOS analog mixer for ultra-wideband (UWB) applications is presented in this paper. The proposed mixer is complementary and self-biased, and has lower power consumption, superior isolation, and larger bandwidth. The proposed low-power, down conversion mixer is designed and fabricated in UMC $0.18\mu \text{m}$ CMOS technology. The measurement results show that it can operate at UWB frequencies that range from 1 to 6 GHz. The proposed mixer provides a maximum conversion gain of 13 dB, −4.5 dBm of third-order input intercept point, and a minimum double sideband noise figure of 12 dB. The maximum values of the measured local oscillator LO-to-RF, RF-to-IF, and LO-to-IF isolations are 50, 45, and 52 dB, respectively.

This paper presents an integrated radio frequency (RF) downconversion folded mixer that operates in the 2.4 GHz industrial, scientific, and medical (ISM) band by using UMC 180 nm RF CMOS. It is implemented by using a double-balanced transconductance switch (GmSw) configuration. The proposed mixer converts the incoming signal to a small signal RF current followed by a PMOS current mirror structure. The circuit can operate with a power supply of less than 1.8 V. A superior isolation is achieved by incorporating a novel folded structure with a CMOS local oscillator (LO) stage. The proposed folded mixer achieves 7 dB of conversion gain and 8.5 dBm of the third order input intermodulation product. The highest measured isolation between the LO-IF, RF-IF, and LO-RF ports is 50, 45, and 65 dB, respectively. (c) 2016 Wiley Periodicals, Inc. Microwave Opt Technol Lett 58:2461-2466, 2016

A compact and highly selective triple band notch UWB (3.3 GHz -10.7 GHz) filter is presented. Low insertion loss UWB pass band characteristics is achieved by two coupled multi mode resonators (MMR1 and MMR2). Desired triple band notch characteristics and sharp UWB filter characteristics are achieved by introducing transmission zeroes (TZs). Three band notches are implemented to mitigate the potential interferer signals at 4.42 GHz (Radio altimeter ITU band), 5.54 GHz (WLAN) and 7.64 GHz (Satellite communications). Wide upper stop band is realized by incorporating a stepped impedance low pass filter structure. The filter is realized on a RT/Duroid 5880 substrate ( $\varepsilon _{\mathrm {r}}=2.2$ and thickness = 0.8 mm) and measured to validate the predicted results. The group delay of the filter is relatively constant and less than 0.45 ns over the desired pass band.

Cancer immunotherapy and immunization are the next steps towards safe and effective cancer treatment [...]

A novel high third-order intermodulation product (IIP3), low-power, inverter-based bulk-injection mixer design is presented in this letter. The architecture of the proposed mixer consists of four complementary MOS (CMOS) inverters that are connected to form a double-balanced mixer. Radio frequency (RF) signals are applied to the input of the inverters, while local oscillator (LO) signals are applied directly to the bulk voltage terminals of the inverters. The proposed mixer achieves a IIP3 of 0 dBm, a 3-dB RF bandwidth that spans 1 GHz to 6 GHz with an intermediate frequency (IF) of 100 MHz.

A high-gain, low-power, and low-noise amplifier (LNA) is designed in UMC 65 nm radio frequency (RF)-CMOS technology for operation over the 1 to 11 GHz RF band. This LNA design is based on an m-derived inductive peaking circuit with a shunt feedback inverter. The m-derived inductive peaking circuit is placed between two shunt feedback inverters. Further, a split inductor topology is introduced in the circuit. The procedure for the integrating of an m-derived inductive peaking circuit in LNA is explained in detail. The proposed circuit achieves more than 14 dB of power gain over an ultra-wideband of 1 to 11 GHz. The measurement of the proposed LNA achieves a minimum of 2.5 dB of noise figure, and more than -8 dBm of third-order input intercept point, while consuming 11.3 mW of power. (C) 2017 Wiley Periodicals, Inc.

A 2.4GHz novel RF Mixer with folded structure designed in 180nm RF-Mixed signal technology has been investigated. It is implemented by using double balanced transconductance switch (GmSw) configuration. The proposed mixer converts incoming signal to small signal RF current followed by PMOS current mirror structure. The circuit is designed and optimized such that it can operate at less than 1.8V of power supply. This paper proposes a design which focuses on the isolation between mixer ports. The high isolation achieved by incorporating folded structure with CMOS LO stage. In addition to that, the Mixer Common Mode Rejection Ratio (MCMRR) for the proposed folded mixer is defined in this paper. The post layout simulation has achieved 5 dB of conversion gain and 9 dBm third order input intermodulation product (IIP3). The highest isolation between LO-IF, RF-IF and LO-RF observed were up to 69 dB, 55 dB and 86 dB respectively.