Subtype and targeted therapy for TNBC

Triple-negative breast cancer (TNBC) is a heterogenous disease. For personalized medicine, it is essential to identify and classify tumor subtypes to develop effective therapeutic strategies. Although gene expression profiling has identified several TNBC subtypes, classification of these tumors remains complex. Most TNBCs exhibit an aggressive phenotype, but some rare types have a favorable clinical course. In this review, we summarize the classification and characteristics related to the various TNBC subtypes, including the rare types. Therapeutic methods that are suitable for each subtype are also discussed. Of the intrinsic breast cancer subtypes identified by gene expression analysis, the basal-like subtype specifically displayed decreased expression of an estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) cluster. We also present results that characterize the TNBC and basal-like phenotypes. TNBC may be categorized into four major classes : basal-like, immune-enriched, mesenchymal, and luminal androgen receptor. Therapeutic strategies for each subtype have been proposed along with newly approved targeted therapies for TNBC, such as immune checkpoint inhibitors. Understanding the classification of TNBC based on gene expression profiling in association with clinicopathological factors will facilitate accurate pathological diagnosis and effective treatment selection

Effects of excitation light intensity on parathyroid autofluorescence

The intraoperative identification and preservation of the parathyroid glands are vital techniques, which are largely dependent on a surgeon’s experience. Therefore, a simple and reproducible technique to identify the parathyroid glands during surgery is needed. Parathyroid tissue shows near-infrared (NIR) autofluorescence, which enables the intraoperative identification of the parathyroid gland. We herein present two cases that underwent surgery on the parathyroid glands, which were observed using the NIR fluorescence imaging system LIGHTVISION® (Shimazu, Kyoto, Japan). In a case of papillary thyroid carcinoma, the system was adopted to preserve normal parathyroid glands during left hemithyroidectomy. The left lower parathyroid gland was identified using the imaging system under white light; however, its autofluorescence was visualized more clearly with the excitation light of NIR. In a case of primary hyperparathyroidism due to MEN1, the system was adopted to identify and remove all of the parathyroid glands during total parathyroidectomy. The autofluorescence of diseased glands was weaker than that of normal glands, even with the excitation light of NIR. When the parathyroid glands were irradiated with a red laser pointer, the intensity of autofluorescence significantly increased. However, the largest gland, which was pathologically proven to contain strongly proliferating chief cells, did not show autofluorescence. These results suggest that normal or less diseased parathyroid glands, which are generally small and difficult to identify during surgery, showed relatively strong autofluorescence. A stronger excitation light increases the autofluorescence of parathyroid glands, which enhances sensitivity for detecting parathyroid glands during surgery. In conclusion, LIGHTVISION® is a useful device to identify parathyroid glands and an additional excitation light of a red laser pointer increases the detection sensitivity

Necroptosis and acute pancreatitis

The sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3-/- or Mlkl-/- mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3-/- mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl-/- mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl-/- mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment

Adipose tissue : Critical contributor to the development of prostate cancer

The prostate is surrounded by periprostatic adipose tissue. Although adipose tissue was thought to play limited physiological roles, it has recently been recognized as an active endocrine organ, secreting growth factors and adipokines. Epidemiologically, obesity is associated with prostate cancer progression. A major mechanism to explain the link between obesity and cancer includes the insulin and insulin-like growth factor (IGF)-1 axis, sex steroids, and adipokines. When prostate cancer cells invade periprostatic adipose tissue, adipose tissue contributes to create the tumor microenvironment, mainly via adipokine secretion. Furthermore, direct crosstalk between adipocytes and cancer cells can exist.We showed that fatty acid-binding protein 4 (FABP4) released from adipocytes was taken up into prostate cancer cells and may act as a carrier of an energy source for the invasion. Bone is an adipocyte-rich organ and is the common metastatic site of prostate cancer. In the microenvironment of bone metastases, tumor cells, osteoblasts, osteoclasts, adipocytes, and other stromal cells are interacting with one another and organizing a complex system. Thus, growing evidence implicates adipose tissue as a critical contributor to the development of prostate cancer. A deeper understanding of the mechanisms leads to more effective therapeutic strategies for prostate cancer

The Atomic and Electronic structure of 0{\deg} and 60{\deg} grain boundaries in MoS2

We have investigated atomic and electronic structure of grain boundaries in monolayer MoS2, where relative angles between two different grains are 0 and 60 degree. The grain boundaries with specific relative angle have been formed with chemical vapor deposition growth on graphite and hexagonal boron nitride flakes; van der Waals interlayer interaction between MoS2 and the flakes restricts the relative angle. Through scanning tunneling microscopy and spectroscopy measurements, we have found that the perfectly stitched structure between two different grains of MoS2 was realized in the case of the 0 degree grain boundary. We also found that even with the perfectly stitched structure, valence band maximum and conduction band minimum shows significant blue shift, which probably arise from lattice strain at the boundary

A New Constraint on the Lyα\alpha Fraction of UV Very Bright Galaxies at Redshift 7

We study the extent to which very bright (-23.0 < MUV < -21.75) Lyman-break selected galaxies at redshifts z~7 display detectable Lya emission. To explore this issue, we have obtained follow-up optical spectroscopy of 9 z~7 galaxies from a parent sample of 24 z~7 galaxy candidates selected from the 1.65 sq.deg COSMOS-UltraVISTA and SXDS-UDS survey fields using the latest near-infrared public survey data, and new ultra-deep Subaru z'-band imaging (which we also present and describe in this paper). Our spectroscopy has yielded only one possible detection of Lya at z=7.168 with a rest-frame equivalent width EW_0 = 3.7 (+1.7/-1.1) Angstrom. The relative weakness of this line, combined with our failure to detect Lya emission from the other spectroscopic targets allows us to place a new upper limit on the prevalence of strong Lya emission at these redshifts. For conservative calculation and to facilitate comparison with previous studies at lower redshifts, we derive a 1-sigma upper limit on the fraction of UV bright galaxies at z~7 that display EW_0 > 50 Angstrom, which we estimate to be < 0.23. This result may indicate a weak trend where the fraction of strong Lya emitters ceases to rise, and possibly falls between z~6 and z~7. Our results also leave open the possibility that strong Lya may still be more prevalent in the brightest galaxies in the reionization era than their fainter counterparts. A larger spectroscopic sample of galaxies is required to derive a more reliable constraint on the neutral hydrogen fraction at z~7 based on the Lya fraction in the bright galaxies.Comment: 20 pages, 7 figures, accepted for publication in Ap

The Subaru Deep Field Project: Lymanα\alpha Emitters at Redshift of 6.6

We present new results of a deep optical imaging survey using a narrowband filter ($NB921$) centered at $\lambda =$ 9196 \AA ~ together with $B$, $V$, $R$, $i^\prime$, and $z^\prime$ broadband filters in the sky area of the Subaru Deep Field which has been promoted as one of legacy programs of the 8.2m Subaru Telescope. We obtained a photometric sample of 58 Ly$\alpha$ emitter candidates at $z \approx$ 6.5 -- 6.6 among $\sim 180$ strong $NB921$-excess ($z^\prime - NB921 > 1.0$) objects together with a color criterion of $i^\prime - z^\prime > 1.3$. We then obtained optical spectra of 20 objects in our $NB921$-excess sample and identified at least nine Ly$\alpha$ emitters at $z \sim 6.5$ -- 6.6 including the two emitters reported by Kodaira et al. (2003). Since our Ly$\alpha$ emitter candidates are free from strong amplification of gravitational lensing, we are able to discuss their observational properties from a statistical point of view. Based on these new results, we obtain a lower limit of the star formation rate density of $\rho_{\rm SFR} \simeq 5.5 \times 10^{-4}$ $h_{0.7}$ $M_\odot$ yr$^{-1}$ Mpc$^{-3}$ at $z \approx 6.6$, being consistent with our previous estimate. We discuss the nature of star-formation activity in galaxies beyond $z=6$.Comment: 49 pages, 16 figures, PASJ, Vol. 57, No. 1, in pres

SILVERRUSH. III. Deep Optical and Near-Infrared Spectroscopy for Lya and UV-Nebular Lines of Bright Lya Emitters at z=6-7

We present Lya and UV-nebular emission line properties of bright Lya emitters (LAEs) at z=6-7 with a luminosity of log L_Lya/[erg s-1] = 43-44 identified in the 21-deg2 area of the SILVERRUSH early sample developed with the Subaru Hyper Suprime-Cam (HSC) survey data. Our optical spectroscopy newly confirm 21 bright LAEs with clear Lya emission, and contribute to make a spectroscopic sample of 96 LAEs at z=6-7 in SILVERRUSH. From the spectroscopic sample, we select 7 remarkable LAEs as bright as Himiko and CR7 objects, and perform deep Keck/MOSFIRE and Subaru/nuMOIRCS near-infrared spectroscopy reaching the 3sigma-flux limit of ~ 2x10^{-18} erg s-1 for the UV-nebular emission lines of He II1640, C IV1548,1550, and O III]1661,1666. Except for one tentative detection of C IV, we find no strong UV-nebular lines down to the flux limit, placing the upper limits of the rest-frame equivalent widths (EW_0) of ~2-4 A for He II, C IV, and O III] lines. Here we also investigate the VLT/X-SHOOTER spectrum of CR7 whose 6 sigma detection of He II is claimed by Sobral et al. Although two individuals and the ESO-archive service carefully re-analyze the X-SHOOTER data that are used in the study of Sobral et al., no He II signal of CR7 is detected, supportive of weak UV-nebular lines of the bright LAEs even for CR7. Spectral properties of these bright LAEs are thus clearly different from those of faint dropouts at z~7 that have strong UV-nebular lines shown in the various studies. Comparing these bright LAEs and the faint dropouts, we find anti-correlations between the UV-nebular line EW_0 and UV-continuum luminosity, which are similar to those found at z~2-3.Comment: 26 pages, 12 figures. Accepted for publication in PASJ special issu

Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis

Engagement of the Fas receptor (CD95) initiates multiple signaling pathways that lead to apoptosis, such as the formation of death-inducing signaling complex (DISC), activation of caspase cascades, and the generation of the lipid messenger, ceramide. Sphingomyelin (SM) is a major component of lipid rafts, which are specialized structures that enhance the efficiency of membrane receptor signaling and are a main source of ceramide. However, the functions of SM in Fas-mediated apoptosis have yet to be clearly defined, as the responsible genes have not been identified. After cloning a gene responsible for SM synthesis, SMS1, we established SM synthase–defective WR19L cells transfected with the human Fas gene (WR/Fas-SM(−)), and cells that have been functionally restored by transfection with SMS1 (WR/Fas-SMS1). We show that expression of membrane SM enhances Fas-mediated apoptosis through increasing DISC formation, activation of caspases, efficient translocation of Fas into lipid rafts, and subsequent Fas clustering. Furthermore, WR/Fas-SMS1 cells, but not WR/Fas-SM(−) cells, showed a considerable increase in ceramide generation within lipid rafts upon Fas stimulation. These data suggest that a membrane SM is important for Fas clustering through aggregation of lipid rafts, leading to Fas-mediated apoptosis