Clinically Applicable Assessment of Tisagenlecleucel CAR T Cell Treatment by Digital Droplet PCR for Copy Number Variant Assessment

Chimeric antigen receptor (CAR) T cell therapy is an innovative immunotherapy for treating cancers in both children and adults with proven utility in numerous clinical trials. Significantly, some CAR T cell therapies have now been approved by relevant national regulatory bodies across numerous countries for clinical therapeutic use outside of clinical trials. One such recently licensed product is tisagenlecleucel, a CAR T therapy approved for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) using autologous T cells from the patient. The genetically engineered T cells target a protein called CD19, common to B cells, through a CAR incorporating a 4-1BB costimulatory domain to improve response. Since tisagenlecleucel is now a standard of care treatment for B-ALL, it is clinically essential to be able to accurately monitor these CAR T cells in patients. Assessment of the copy number variant (CNV) of the CAR T cell products allows this within a clinically acceptable timeframe for optimal patient benefit. However, no standardized method with high reproducibility and efficiency has been described within a routine clinical laboratory setting. Here, we demonstrated a novel digital droplet PCR (ddPCR)-based methodology for the study of CNV (ddPCR-CNV) in 4-1BB CD19-specific CAR T cells with universal applicability across clinical diagnostic laboratories.     

Primary Aldosteronism and Resistant Hypertension: A Pathophysiological Insight

Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in patients with resistant hypertension (RH). Both PA and RH are “high-risk phenotypes”, associated with increased cardiovascular morbidity and mortality compared to non-PA and non-RH patients. Aldosterone excess, as occurs in PA, can contribute to the development of a RH phenotype through several mechanisms. First, inappropriate aldosterone levels with respect to the hydro-electrolytic status of the individual can cause salt retention and volume expansion by inducing sodium and water reabsorption in the kidney. Moreover, a growing body of evidence has highlighted the detrimental consequences of “non-classical” effects of aldosterone in several target tissues. Aldosterone-induced vascular remodeling, sympathetic overactivity, insulin resistance, and adipose tissue dysfunction can further contribute to the worsening of arterial hypertension and to the development of drug-resistance. In addition, the pro-oxidative, pro-fibrotic, and pro-inflammatory effects of aldosterone may aggravate end-organ damage, thereby perpetuating a vicious cycle that eventually leads to a more severe hypertensive phenotype. Finally, neither the pathophysiological mechanisms mediating aldosterone-driven blood pressure rise, nor those mediating aldosterone-driven end-organ damage, are specifically blocked by standard first-line anti-hypertensive drugs, which might further account for the drug-resistant phenotype that frequently characterizes PA patients.     

Fully integrated MIXLER based on VHF CMOS-MEMS clamped-clamped beam resonator

The design and test of a fully integrated CMOS-MEMS-MIXLER, using a commercial technology (AMS 0.35 mum) is presented. The MEMS structure is basically a clamped-clamped beam resonator implemented with the polysilicon capacitance module of the selected technology, showing a fundamental lateral resonance frequency of 22.5 MHz. Two different approaches based, respectively, on the nonlinearity of the voltage against the excitation force and on the amplitude modulation of the excitation signal, have been proposed in order to operate the MEMS as a MIXLER     

Recurrent pattern matching based stereo image coding using linear predictors

The Multidimensional Multiscale Parser (MMP) is a pattern-matching-based generic image encoding solution which has been investigated earlier for the compression of stereo images with successful results. While first MMP-based proposals for stereo image coding employed dictionary-based techniques for disparity compensation, posterior developments have demonstrated the advantage of using predictive methods. In this paper, we focus on recent investigations on the use of predictive methods in the MMP algorithm and propose a new prediction framework for efficient stereo image coding. This framework comprises an advanced intra directional prediction model and a new linear predictive scheme for efficient disparity compensation. The linear prediction model is the main novelty of this work, combining adaptive linear models estimated by least-squares algorithm with fixed linear models provided by the block-matching algorithm. The performance of the proposed intra prediction and disparity compensation methods when applied in an MMP encoder has been evaluated experimentally. Comparisons with the current stereo image coding standards showed that the proposed MMP algorithm significantly outperforms the Stereo High Profile of H.264/AVC standard. In addition, it presents a competitive performance relative to the MV-HEVC standard. These results also suggest that current stereo image coding standards may benefit from the proposed linear prediction scheme for disparity compensation, as an extension to the omnipresent block-matching solution.     

Influence of an inhibitor of monoaminooxidase (nialamide) on the serum levels, urinary excretion and plasma clearance of urea, uric acid and creatinine in adult and growing rats

Serum levels, urinary excretion and plasma clearance of urea, uric acid and creatinine were studied in adult (230 g) and growing (75 g) rats under the influence of nialamide (an IMAO) administered in daily doses of 20 mg/100 g diet during 15 or 30 days in adults and 10 mg/100 g diet during 15 days in growing rats. A pair feeding design was used in both ages. Serum levels of urea rose in adult rats fed nialamide for 30 days while urinary excretion decreased. No change in serum levels were noted in growing rats although urinary excretion showed a net increase. Serum uric acid levels were increased in adult female rats given nialamide for 30 days, while urinary excretion fell in both sexes. Growing rats showed a drop in urinary excretion of uric acid. Serum creatinine levels were unchanged in adult and growing rats after treatment with nialamide, although a marked increase was recorded in urinary excretion in both groups.