Lymphopenia at diagnosis predicts survival of patients with immunodeficiency-associated lymphoproliferative disorders

The number of patients who are administered immunosuppressive agents has been increasing. Accordingly, more patients face higher risks for developing immunodeficiency-associated lymphoproliferative disorders (LPD). Although immunodeficiency-associated LPD are distinct from other lymphoid neoplasms in terms of their immunocompromised backgrounds, little is known about the impact of lymphopenia at diagnosis on survival in patients with these LPD. Seventy-one immunodeficiency-associated LPD in Kyoto University Hospital (post-transplant LPD (PTLD), n = 26; other iatrogenic immunodeficiency-associated LPD, n = 45) were reviewed and analyzed. The median age at diagnosis was 63 years (range, 3–83). Diffuse large B cell lymphoma was the most common subtype (n = 33), followed by Hodgkin lymphoma (n = 12), B cell monomorphic LPD not specified (n = 11), and polymorphic LPD or early-phase diseases (n = 15). The median follow-up period for survivors was 2.5 years and overall survival (OS) and progression-free survival (PFS) at 2.5 years were 75% and 67%, respectively. Multivariate analysis showed that lymphopenia (≤ 800/μL) at diagnosis predicted inferior OS (HR, 3.72; P = 0.043) and PFS (HR, 3.82; P = 0.012). Serum albumin values also strongly affected OS (> 3.18 g/dL vs. ≤ 3.18 g/dL; HR, 0.21; P = 0.010) and PFS (HR, 0.26; P = 0.013). Lymphopenia at diagnosis is suggested to predict inferior OS and PFS in patients with immunodeficiency-associated LPDs. Immunocompromised status might affect disease progression in these distinct lymphoid neoplasms growing under immunocompromised backgrounds

Non-volatile hybrid optical phase shifter driven by a ferroelectric transistor

Optical phase shifters are essential elements in photonic integrated circuits (PICs) and function as a direct interface to program the PIC. Non-volatile phase shifters, which can retain information without a power supply, are highly desirable for low-power static operations. Here a non-volatile optical phase shifter is demonstrated by driving a III-V/Si hybrid metal-oxide-semiconductor (MOS) phase shifter with a ferroelectric field-effect transistor (FeFET) operating in the source follower mode. Owing to the various polarization states in the FeFET, multistate non-volatile phase shifts up to 1.25{\pi} are obtained with CMOS-compatible operation voltages and low switching energy up to 3.3 nJ. Furthermore, a crossbar array architecture is proposed to simplify the control of non-volatile phase shifters in large-scale PICs and its feasibility is verified by confirming the selective write-in operation of a targeted FeFET with a negligible disturbance to the others. This work paves the way for realizing large-scale non-volatile programmable PICs for emerging computing applications such as deep learning and quantum computing

Isolation of Nebulin from Rabbit Skeletal Muscle and Its Interaction with Actin

Nebulin is about 800 kDa filamentous protein that binds the entire thin filament of vertebrate skeletal muscle sarcomeres. Nebulin cannot be isolated from muscle except in a completely denatured form by direct solubilization of myofibrils with SDS because nebulin is hardly soluble under salt conditions. In the present study, nebulin was solubilized by a salt solution containing 1 M urea and purified by DEAE-Toyopearl column chromatography via 4 M urea elution. Rotary-shadowed images of nebulin showed entangled knit-like particles, about 20 nm in diameter. The purified nebulin bound to actin filaments to form loose bundles. Nebulin was confirmed to bind actin, α-actinin, β-actinin, and tropomodulin, but not troponin or tropomyosin. The data shows that full-length nebulin can be also obtained in a functional and presumably native form, verified by data from experiments using recombinant subfragments

Non-volatile optical phase shift in ferroelectric hafnium zirconium oxide

A non-volatile optical phase shifter is a critical component for enabling large-scale, energy-efficient programmable photonic integrated circuits (PICs) on a silicon (Si) photonics platform. While ferroelectric materials like BaTiO3 offer non-volatile optical phase shift capabilities, their compatibility with complementary metal-oxide-semiconductor (CMOS) fabs is limited. Hence, the search for a novel CMOS-compatible ferroelectric material for non-volatile optical phase shifting in Si photonics is of utmost importance. Hafnium zirconium oxide (HZO) is an emerging ferroelectric material discovered in 2011, which exhibits CMOS compatibility due to the utilization of high-k dielectric HfO2 in CMOS transistors. Although extensively studied for ferroelectric transistors and memories, its application in photonics remains relatively unexplored. Here, we show the optical phase shift induced by ferroelectric HZO deposited on a SiN optical waveguide. We observed a negative change in refractive index at a 1.55 um wavelength in the pristine device regardless of the direction of an applied electric filed. We achieved approximately pi phase shift in a 4.5-mm-long device with negligible optical loss. The non-volatile multi-level optical phase shift was confirmed with a persistence of > 10000 s. This phase shift can be attributed to the spontaneous polarization within the HZO film along the external electric field. We anticipate that our results will stimulate further research on optical nonlinear effects, such as the Pockels effect, in ferroelectric HZO. This advancement will enable the development of various devices, including high-speed optical modulators. Consequently, HZO-based programmable PICs are poised to become indispensable in diverse applications, ranging from optical fiber communication and artificial intelligence to quantum computing and sensing

Next‐generation sequencing in two cases of de novo acute basophilic leukaemia

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34⁺, CD203c⁻, CD117⁺, CD123dim⁺) and basophils (CD34⁻, CD203c⁺, CD117±, CD123⁺) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33⁺, CD34⁺, CD123⁻) and basophils (CD33⁺, CD34⁺, CD123⁺) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts

Low-molecular weight fractions of Japanese soy sauce act as a RAGE antagonist via inhibition of RAGE trafficking to lipid rafts

Advanced glycation end-products (AGE) have been implicated in aging and the pathogenesis of diabetic complications, inflammation, Alzheimer\u27s disease, and cancer. AGE engage the cell surface receptor for AGE (RAGE), which in turn elicits intracellular signaling, leading to activation of NF-κB to cause deterioration of tissue homeostasis. AGE are not only formed within our bodies but are also derived from foods, endowing them with flavor. In the present study, we assessed the agonistic/antagonistic effects of food-derived AGE on RAGE signaling in a reporter assay system and found that low-molecular weight AGE can antagonize the action of AGE-BSA. Foods tested were Japanese soy sauce, coffee, cola, and red wine, all of which showed fluorescence characteristics of AGE. Soy sauce and coffee contained Nε-carboxymethyl-lysine (CML). Soy sauce, coffee, and red wine inhibited the RAGE ligand-induced activation of NF-κB, whereas cola had no effect on the ligand induction of NF-κB. The liquids were then fractionated into high-molecular weight (HMW) fractions and low-molecular weight (LMW) fractions. Soy sauce-, coffee-, and red wine-derived LMW fractions consistently inhibited the RAGE ligand induction of NF-κB, whereas the HMW fractions of these foods activated RAGE signaling. Using the LMW fraction of soy sauce as a model food-derived RAGE antagonist, we performed a plate-binding assay and found that the soy sauce LMW fractions competitively inhibited AGE-RAGE association. Further, this fraction significantly reduced AGE-dependent monocyte chemoattractant protein-1 (MCP-1) secretion from murine peritoneal macrophages. The LMF from soy sauce suppressed the AGE-induced RAGE trafficking to lipid rafts. These results indicate that small components in some, if not all, foods antagonize RAGE signaling and could exhibit beneficial effects on RAGE-related diseases. © 2013 The Royal Society of Chemistry

Tumor size and proliferative marker geminin levels associated with SUVmax levels on PET for breast cancers

It has been well established that maximum standardized uptake value (SUVmax) for 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) is clinically useful for evaluating treatment efficacy as well as predicting prognosis of breast cancer patients. Although SUVmax reflects increased glucose uptake and metabolism possibly induced by activation of growth factor signaling or TP53 dysfunction, tumor characteristics of SUVmax-high breast cancers remain to be elucidated. For the present study, we used immunohistochemical staining to investigate expressions of phospho-ribosomal protein S6 (pS6, downstream molecule of phosphatidyl inositol 3-kinase/Akt/mammalian target of the rapamycin/S6K pathway) and phosphor-p44/42 mitogen-activated protein kinase (pMAPK). Expression levels of TP53 and proliferative marker geminin as well as Ki67 were also examined by means of immunostaining in 163 invasive breast cancers. Cutoff values were set at 10% for pS6, 20% for pMAPK and TP53, and 4% for geminin. The SUVmax levels were significantly higher in the pS6-positive (p = 0.0173), TP53-positive (p = 0.0207) and geminin-high cancers (p2cm and geminin-high showed SUVmax-high, while only 6 of 49 (12.2%) breast cancers ≤2cm in size and with low geminin levels were SUVmax-high. In conclusion, we could determine that breast cancers with a large tumor and a geminin-high rather than Ki67- high proliferative marker were significantly associated with high levels of SUVmax. These findings may signify that SUVmax reflects tumor characteristics with high proliferative activity but not activation of mTOR/S6K and MAPK pathways or increased glucose metabolism due to dysfunction of TP53