The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.     

Identification of a Maturation Plasma Cell Index through a Highly Sensitive Droplet Digital PCR Assay Gene Expression Signature Validation in Newly Diagnosed Multiple Myeloma Patients

DNA microarrays and RNA-based sequencing approaches are considered important discovery tools in clinical medicine. However, cross-platform reproducibility studies undertaken so far have highlighted that microarrays are not able to accurately measure gene expression, particularly when they are expressed at low levels. Here, we consider the employment of a digital PCR assay (ddPCR) to validate a gene signature previously identified by gene expression profile. This signature included ten Hedgehog (HH) pathways’ genes able to stratify multiple myeloma (MM) patients according to their self-renewal status. Results show that the designed assay is able to validate gene expression data, both in a retrospective as well as in a prospective cohort. In addition, the plasma cells’ differentiation status determined by ddPCR was further confirmed by other techniques, such as flow cytometry, allowing the identification of patients with immature plasma cells’ phenotype (i.e., expressing CD19+/CD81+ markers) upregulating HH genes, as compared to others, whose plasma cells lose the expression of these markers and were more differentiated. To our knowledge, this is the first technical report of gene expression data validation by ddPCR instead of classical qPCR. This approach permitted the identification of a Maturation Index through the integration of molecular and phenotypic data, able to possibly define upfront the differentiation status of MM patients that would be clinically relevant in the future.     

平台化ASIC迅速打开市场

平台化专用集成电路(Platform ASIC)是一类新推出的产品,其应用目标是减少上市时间和降低设计成本.从日渐增多的相应新设计可以看出,平台化ASIC前景一片光明.     

Parametric-gain approach to the analysis of single-channel DPSK/DQPSK systems with nonlinear phase noise

This paper presents a novel method based on a parametric gain (PG) approach to study the impact of nonlinear phase noise in single-channel dispersion-managed differentially phase-modulated systems. This paper first shows through Monte Carlo simulations that the received amplified spontaneous emission (ASE) noise statistics, before photodetection, can be reasonably assumed to be Gaussian, provided a sufficiently large chromatic dispersion is present in the transmission fiber. This paper then evaluates in a closed form the ASE power spectral density by linearizing the interaction between a signal and a noise in the limit of a distributed system. Even if the received ASE is nonstationary in time due to pulse shape and modulation, this paper shows that it can be approximated by an equivalent stationary process, as if the signal were continuous wave (CW). This paper then applies the CW-equivalent ASE model to bit-error-rate evaluation by using an extension of a known Karhunen-Loe/spl acute/ve method for quadratic detectors in colored Gaussian noise. Such a method avoids calculation of the nonlinear phase statistics and accounts for intersymbol interference due to a nonlinear waveform distortion and optical and electrical postdetection filtering. This paper compares binary and quaternary schemes with both nonreturn- and return-to-zero (RZ) pulses for various values of nonlinear phases and bit rates. The results confirm that PG deeply affects the system performance, especially with RZ pulses and with quaternary schemes. This paper also compares ON-OFF keying (OOK) differential phase-shifted keying (DPSK) systems, showing that the initial 3-dB advantage of DPSK is lost for increasing nonlinear phases because DPSK is less robust to PG than OOK.     

Surgical repair of postinfarction left ventricular lesion type I

Left ventricular rupture is the most frequent cause of death following myocardial infarction after ventricular arrhytmias and cardiogenic shock. Under these circumstances, only a prompt diagnosis and urgent surgical treatment can be lifesaving. A review of the literature is made and a simple surgical technique with GRF glue application is presented.     

Sex Steroids and the Shaping of the Peripubertal Brain: The Sexual-Dimorphic Set-Up of Adult Neurogenesis

Steroid hormones represent an amazing class of molecules that play pleiotropic roles in vertebrates. In mammals, during postnatal development, sex steroids significantly influence the organization of sexually dimorphic neural circuits underlying behaviors critical for survival, such as the reproductive one. During the last decades, multiple studies have shown that many cortical and subcortical brain regions undergo sex steroid-dependent structural organization around puberty, a critical stage of life characterized by high sensitivity to external stimuli and a profound structural and functional remodeling of the organism. Here, we first give an overview of current data on how sex steroids shape the peripubertal brain by regulating neuroplasticity mechanisms. Then, we focus on adult neurogenesis, a striking form of persistent structural plasticity involved in the control of social behaviors and regulated by a fine-tuned integration of external and internal cues. We discuss recent data supporting that the sex steroid-dependent peripubertal organization of neural circuits involves a sexually dimorphic set-up of adult neurogenesis that in turn could be relevant for sex-specific reproductive behaviors.     

UV-Visible Spectroscopy and Multivariate Classification as a Screening Tool for Determining the Adulteration of Sauces

A rapid, simple, and economic multivariate screening methodology based on UV-visible spectroscopy and multivariate classification is proposed to test for adulteration in sauces. Two classification strategies were evaluated to compare their ability to detect food fraud: untargeted modeling (class modeling) and targeted classification (discriminant analysis). As a case study, the possible adulteration of ketchups and barbecue sauces with the banned Sudan I dye was considered. The classification models were built with a new classification tool for class modeling (partial least squares-density modeling, PLS-DM) and with the classical discriminant partial least squares-discriminant analysis (PLS-DA). Very satisfactory classification results were obtained with both strategies: regarding untargeted modeling, only original samples (class 1) were modeled obtaining a 94.5 % of correct classification and regarding targeted classification, two classes were considered (class 1 original samples and class 2 adulterated samples) with an overall classification rate of 97.3 %. The two strategies are useful and adequate as screening tools for monitoring the quality of sauces especially in situations that require quick responses.