Alpha-crystallin B chains in trastuzumab-resistant breast cancer cells promote endothelial cell tube formation through activating mTOR.

The specific human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibody trastuzumab shows considerable clinical efficacy in patients with HER2-overexpressing breast cancer. However, about 20% of patients who receive trastuzumab in the adjuvant setting relapse, and approximately half of patients with metastatic HER2-positive breast cancer develop resistance to trastuzumab within 1 year. Although the mechanism of trastuzumab resistance has been explored broadly, whether and how angiogenesis participates in trastuzumab resistance is unclear. Here, we examined the association between angiogenesis and trastuzumab resistance by using a trastuzumab-resistant cell line (SKBR3-TR). Compared with that from the parental trastuzumab-sensitive SKBR3 cells, the culture supernatant from SKBR3-TR cells significantly increased the sprouting of endothelial cells. To identify intercellular features that contribute to the induction of endothelial tube formation, proteomics revealed that α-crystallin B chain (αB-crystallin) was upregulated in SKBR3-TR cells. Moreover, silencing of αB-crystallin significantly repressed SKBR3-TR-induced tube formation, and knockdown of αB-crystallin in SKBR3-TR cells suppressed the activation of mechanistic target of rapamycin (mTOR) in endothelial cells. In addition, treatment with rapamycin, an inhibitor of mTOR, reversed the SKBR3-TR-induced promotion of tube formation. In summary, αB-crystallin enhanced the ability of SKBR3-TR cells to activate mTOR in endothelial cells and thus promote angiogenesis.

Monolithic integration of electro-absorption modulators and photodetectors on III-V CMOS photonics platform by quantum well intermixing.

Quantum well intermixing (QWI) on a III-V-on-insulator (III-V-OI) substrate is presented for active-passive integration. Shallow implantation at a high temperature, which is essential for QWI on a III-V-OI substrate, is accomplished by phosphorus molecule ion implantation. As a result, the bandgap wavelength of multi-quantum wells (MQWs) on a III-V-OI substrate is successfully tuned by approximately 80 nm, enabling the monolithic integration of electro-absorption modulators and waveguide photodetectors using a lateral p-i-n junction formed along the InP/MQW/InP rib waveguide. Owing to the III-V-OI structure and the rib waveguide structure, the parasitic capacitance per unit length can be reduced to 0.11 fF/µm, which is suitable for high-speed and low-power modulators and photodetectors. The presented QWI can extend the possibility of a III-V complementary metal-oxide-semiconductor (CMOS) photonics platform for large-scale photonic integrated circuits.

Si microring resonator optical switch based on optical phase shifter with ultrathin-InP/Si hybrid metal-oxide-semiconductor capacitor.

We propose a microring resonator (MRR) optical switch based on III-V/Si hybrid metal-oxide-semiconductor (MOS) optical phase shifter with an ultrathin InP membrane. By reducing the thickness of the InP membrane, we can reduce the insertion loss of the phase shifter, resulting in a high-quality-factor (Q-factor) MRR switch. By optimizing the device structure using numerical analysis, we successfully demonstrated a proof-of-concept MRR optical switch. The optical switch exhibits 0.3 pW power consumption for switching, applicable to power-efficient, thermal-crosstalk-free, Si programmable photonic integrated circuits (PICs) based on wavelength division multiplexing (WDM).

Inhibition of Akt/mTOR pathway overcomes intrinsic resistance to dasatinib in triple-negative breast cancer.

Currently, the only therapeutic choice for the treatment of triple-negative breast cancer (TNBC) is chemotherapy. In TNBC, despite strong preclinical data, clinical trials of molecular targeted drugs, such as the Src tyrosine kinase inhibitor dasatinib, have failed because of the heterogeneity of TNBC cells. Here, we examined the mechanism of intrinsic resistance to dasatinib in five TNBC cell lines. First, we divided the TNBC cell lines into those sensitive or resistant to dasatinib and found that activation of Src was inhibited in all of the cell lines. In contrast, we found that dasatinib inhibited Akt phosphorylation in only the dasatinib-sensitive cell lines. Consequently, we found that combination treatment with dasatinib and an inhibitor of Akt or mTOR suppressed cell proliferation more than did either monotherapy in the dasatinib-resistant cell lines. Finally, to mimic intrinsic resistance, we established a dasatinib-tolerant TNBC cell line. In this cell line, the combinational effect of Akt/mTOR inhibition with dasatinib was observed, as it was in the cell lines with intrinsic resistance. Together, the present results show that the effect of dasatinib in TNBC is independent of Src inhibition, and that Akt/mTOR inhibition might be an effective strategy to overcome TNBC cells with intrinsic dasatinib resistance.

Numerical analyses of optical loss and modulation bandwidth of an InP organic hybrid optical modulator.

We numerically analyzed the modulation characteristics of an InP organic hybrid (IOH) optical modulator consisting of an InP slot waveguide and an electro-optic (EO) polymer. Since InP has a higher electron mobility and a lower electron-induced free-carrier absorption than Si, the series resistance of an InP slot waveguide can be significantly reduced with relatively smaller optical loss than an Si slot waveguide. As a result, the trade-off between optical loss and modulation bandwidth can be remarkably improved compared with a Si organic hybrid (SOH) optical modulator. When the modulation bandwidth was designed to be 100 GHz, the optical loss of the IOH modulator was 13-fold smaller than that of the SOH one. The simulation of the eye diagram revealed that the improved optical modulation amplitude enabled the clear eye opening with a 100 Gbps non return-to-zero signal using the IOH modulator. The IOH integration is promising for a high-speed modulator with low energy consumption beyond 100 Gbps.

Taperless Si hybrid optical phase shifter based on a metal-oxide-semiconductor capacitor using an ultrathin InP membrane.

We propose a III-V/Si hybrid metal-oxide-semiconductor (MOS) optical phase shifter using an ultrathin InP membrane, which allows us to eliminate the III-V taper required for mode conversion between Si and hybrid waveguides. We numerically revealed that thinning a III-V membrane can reduce the insertion loss of the phase shifter while maintaining high modulation efficiency because the optical phase shift is induced by carrier accumulation at the MOS interface. We experimentally demonstrated the proposed optical phase shifter with an ultrathin InP membrane and achieved the modulation efficiency of 0.54 Vcm and the insertion loss of 0.055 dB. Since the taperless structure makes the hybrid integration easier and more flexible, the hybrid MOS optical phase shifter with an ultrathin III-V membrane is promising for large-scale Si programmable photonic integrated circuits.

Nonvolatile optical phase shift in ferroelectric hafnium zirconium oxide.

A nonvolatile optical phase shifter is a critical component for enabling the fabrication of programmable photonic integrated circuits on a Si photonics platform, facilitating communication, computing, and sensing. Although ferroelectric materials such as BaTiO3 offer nonvolatile optical phase shift capabilities, their compatibility with complementary metal-oxide-semiconductor fabs is limited. Hf0.5Zr0.5O2 is an emerging ferroelectric material, which exhibits complementary metal-oxide-semiconductor compatibility. Although extensively studied for ferroelectric transistors and memories, its application to photonics remains relatively unexplored. Here, we show the optical phase shift induced by ferroelectric Hf0.5Zr0.5O2. We observed a negative change in refractive index at a 1.55 µm wavelength in a pristine device regardless of the direction of the applied electric field. The nonvolatile phase shift was only observed once in a pristine device. This non-reversible phase shift can be attributed to the spontaneous polarization within the Hf0.5Zr0.5O2 film along the external electric field.

Zinc supplementation improves the outcome of chronic hepatitis C and liver cirrhosis.

We treated patients with C-viral chronic hepatitis (CH) and liver cirrhosis (LC) with polaprezinc and determined prospectively the effect on long-term outcome. 62 patients were enrolled. Of these, 32 were administered 1.0 g polaprezinc and the remainder were not administered polaprezinc. We measured the serum zinc concentrations using conventional atomic absorption spectrometry and conducted a prospective study to determine the long-term outcome of the polaprezinc therapy. Changes of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the polaprezinc administration group were significantly lower than those of the untreated group. The decrease in platelet count was clearly less than that of the untreated group. The factors that inhibited increases in serum zinc concentrations following administration of polaprezinc included low serum zinc concentration states. Furthermore, the reductions of AST and ALT levels in the low zinc group were significantly greater than those of the high zinc group. When the patients who were administered polaprezinc were divided into two groups whose zinc concentrations increased (zinc responders) or remained stable or decreased (zinc non-responders), the zinc responders had a clearly lower cumulative incidence of HCC than the zinc non-responders. We conclude zinc supplementation improved the long-term outcome in C-viral CH and LC patients.