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Purpose: OBI-3424 is a highly selective prodrug that is OBI-3424 significantly prolonged the event-free survival (EFS) converted by aldo-keto reductase family 1 member C3 of nine of nine ALL PDXs by 17.1–77.8 days (treated/control (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has values 2.5–14.0), and disease regression was observed in eight entered clinical testing for hepatocellular carcinoma and cas-of nine PDXs. A significant reduction (P < 0.0001) in bone trate-resistant prostate cancer, and it represents a potentially marrow infiltration at day 28 was observed in four of six novel treatment for acute lymphoblastic leukemia (ALL). evaluable T-ALL PDXs. The importance of AKR1C3 in the Experimental Design: We assessed AKR1C3 expression by in vivo response to OBI-3424 was verified using a B-ALL PDX RNA-Seq and immunoblotting, and evaluated the in vitro that had been lentivirally transduced to stably overexpress cytotoxicity of OBI-3424. We investigated the pharmacokinet-AKR1C3. OBI-3424 combined with nelarabine resulted in ics of OBI-3424 in mice and nonhuman primates, and assessed prolongation of mouse EFS compared with each single agent the in vivo efficacy of OBI-3424 against a large panel of patient-alone in two T-ALL PDXs. derived xenografts (PDX). Conclusions: OBI-3424 exerted profound in vivo efficacy Results: AKR1C3 mRNA expression was significantly higher against T-ALL PDXs derived predominantly from aggressive in primary T-lineage ALL (T-ALL; n ¼ 264) than B-lineage and fatal disease, and therefore may represent a novel treat-ALL (B-ALL; n ¼ 1,740; P < 0.0001), and OBI-3424 exerted ment for aggressive and chemoresistant T-ALL in an AKR1C3 potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, biomarker-driven clinical trial.

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4(+) T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4(+) T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

The authors propose a novel use of complete complementary (CC) sequences for increased spectral efficiency in a multiple-input–multiple-output (MIMO) code division multiple access (CDMA) system. The new method overcomes many of the problems and limitations persistent in single-input–single-output (SISO) and proves that under the proposed MIMO CC-CDMA system, the capacity for the number of supported users increases linearly by the number of transmitters. The paper also shows that the MIMO CC-CDMA system demonstrates a superior performance over those using traditional Walsh spreading sequences (Walsh-CDMA). Results include the bit error rate comparison for CC-CDMA frequency selective fading channels and that of the Walsh-CDMA under flat fading channels.

The authors propose a novel use of complete complementary (CC) sequences for increased spectral efficiency in a multiple-input–multiple-output (MIMO) code division multiple access (CDMA) system. The new method overcomes many of the problems and limitations persistent in single-input–single-output (SISO) and proves that under the proposed MIMO CC-CDMA system, the capacity for the number of supported users increases linearly by the number of transmitters. The paper also shows that the MIMO CC-CDMA system demonstrates a superior performance over those using traditional Walsh spreading sequences (Walsh-CDMA). Results include the bit error rate comparison for CC-CDMA frequency selective fading channels and that of the Walsh-CDMA under flat fading channels.

The monolithic integration of heterostructure tuneling diodes with other semiconductor devices, such as HFET’s, creates novel, quantum functional devices and circuits. The enhanced functionality of these devices enables design of both digital and analog circuits with reduced complexity, smaller size and better performance. Several types of QMMIC VCO’s operating in L-band frequency range have been designed and characterized. VCO’s achieved output power of 8-10 dBm at L-band frequency range. All VCO’s exhibited very low phase noise (in the range of –107 to –115 dBc/Hz) at 1.0 MHz away from the carrier frequency.

The monolithic integration of heterostructure tuneling diodes with other semiconductor devices, such as HFET’s, creates novel, quantum functional devices and circuits. The enhanced functionality of these devices enables design of both digital and analog circuits with reduced complexity, smaller size and better performance. Several types of QMMIC VCO’s operating in L-band frequency range have been designed and characterized. VCO’s achieved output power of 8-10 dBm at L-band frequency range. All VCO’s exhibited very low phase noise (in the range of –107 to –115 dBc/Hz) at 1.0 MHz away from the carrier frequency.

A bi-directional amplifier (BDA) utilizing the negative resistance of Heterojunction Interband Tunnel Diode (HITD) is proposed. Expected features of the BDA are: 1) symmetry and reciprocity of the associated scattering matrix; 2) gain at extremely low DC power consumption. These features make the circuits an enabling electronic function for RF identification tag. The BDA topology consisted of a pair of HITDs biased in the negative dynamic region (NDR) and a lumped element directional coupler with arbitrary impedance terminations. The design techniques along with an experimental validation are provided.

In this paper the design technique for MMIC lumped element directional couplers, based on arbitrary termination impedance, is described. Arbitrary impedance terminations allow matching the linear and nonlinear elements to the coupler without the requirement of transformer networks. The technique’s capability is demonstrated through the design of a single balanced mixer prototype at 1.8GHz for which measured and simulated data are provided.

In this paper the design technique for MMIC lumped element directional couplers, based on arbitrary termination impedance, is described. Arbitrary impedance terminations allow matching the linear and nonlinear elements to the coupler without the requirement of transformer networks. The technique’s capability is demonstrated through the design of a single balanced mixer prototype at 1.8GHz for which measured and simulated data are provided.