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Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC.

Triple-negative breast cancer (TNBC) is associated with a high rate of early recurrence and distant metastasis, frequent development of therapeutic resistance, and a poor prognosis. There is a lack of targeted therapies for this aggressive subtype of breast cancer. Identifying novel effective treatment modalities for TNBC remains an urgent and unmet clinical need. In this study, we investigated the anti-cancer effect of triptonide, a natural compound derived from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, in TNBC. We found that triptonide inhibits human TNBC cell growth in vitro and growth of TNBC xenograft mammary tumors. It induces apoptosis and suppresses stem-like properties as indicated by reduced mammosphere formation and aldehyde dehydrogenase activity in TNBC cells. We show that triptonide downregulates multiple cancer stem cell-associated genes but upregulates SNAI1 gene expression. In support of SNAI1 induction as a negative feedback response to triptonide treatment, in vitro-derived triptonide-resistant HCC1806 cells display a markedly higher expression of SNAI1 compared with parental cells. Mechanistically, the increase of SNAI1 expression is mediated by the activation of JNK signaling, but not by ERK and AKT, two well-established SNAI1 regulators. Furthermore, knockdown of SNAI1 in the triptonide-resistant HCC1806 cells increases sensitivity to triptonide and reduces mammosphere formation. These results indicate that triptonide holds promise as a novel anti-tumor agent for TNBC treatment. Our study also reveals a SNAI1-associated feedback mechanism which may lead to acquired resistance to triptonide.

In the discretely amplified transmission systems with erbium-doped fiber amplifiers, the system performance of nonlinearity-compensated optical transmission based on pre-dispersed spectral inversion (PSI) is investigated numerically. We find that PSI offers more significant performance improvement in dispersion-managed (DM) links than that in non-dispersion-managed (noDM) links. On the other hand, the DM link is more sensitive to the span offset from the center of the transmission link than noDM link. The performance difference between DM and noDM links is 1 dB if the span offset equals four spans in 20 × 90 km nonlinear transmission. Furthermore, we show that for the dispersion-managed transmission, in order to obtain the best system performance, the amount of pre-dispersion of the PSI, should be optimized over different dispersion maps.

All-optical non-inverted half-subtracter, half-adder, comparator, and decoder are pointed out based on a single semiconductor optical amplifier. We have replaced the continuous wave probe light with the clock pulse sequences light, which guarantees the non-inverted code output. All-optical AND, NOR, XNOR, XOR, A • B¯ , and A¯ • B logic gates are realized by four-wave mixing and cross-gain modulation of SOA, which are used to drive half-subtracter, half-adder, comparator, and decoder with 10 Gb / s return-to-zero code. Extinction ratio (ER) and optical signal-to-noise ratio (OSNR) are improved by a depolarizer. Compared with no depolarizer, for A = B output of comparator, it corresponds to XNOR; ER and OSNR are improved by about 1 dB. For d0 output of decoder, it corresponds to NOR; ER and OSNR are improved to 1.1 dB compared with the original value. However, for borrow of half-subtracter, greater than and less than of comparator, d1 and d2 of decoder, it corresponds to A • B¯ and A¯ • B; ER and OSNR show only slight deterioration about 0.4 dB. For carry of half-adder and d3 of the decoder, it corresponds to AND; OSNR has hardly changed and ER has improved by about 2 dB. It has potential applications in more complex optical computing and optical signal processing systems.

An all-optical non-inverted parity generator and checker based on semiconductor optical amplifiers (SOAs) are proposed with four-wave mixing (FWM) and cross-gain modulation (XGM) non-linear effects. A 2-bit parity generator and checker using by exclusive NOR (XNOR) and exclusive OR (XOR) gates are implemented by first SOA and second SOA with 10 Gb/s return-to-zero (RZ) code, respectively. The parity and check bits are provided by adjusting the center wavelength of the tunable optical bandpass filter (TOBPF). A saturable absorber (SA) is used to reduce the negative effect of small signal clock (Clk) probe light to improve extinction ratio (ER) and optical signal-to-noise ratio (OSNR). For Pe and Ce (even parity bit and even check bit) without Clk probe light, ER and OSNR still maintain good performance because of the amplified effect of SOA. For Po (odd parity bit), ER and OSNR are improved to 1 dB difference for the original value. For Co (odd check bit), ER is deteriorated by 4 dB without SA, while OSNR is deteriorated by 12 dB. ER and OSNR are improved by about 2 dB for the original value with the SA. This design has the advantages of simple structure and great integration capability and low cost.

Proteolysis targeting chimeric molecule ARV 825 causes ubiquitination of bromodomains resulting in their efficient degradation by proteasome activity. Bromodomain degradation down-regulates MYC transcription contributing to growth inhibition of various human cancers. We examined the therapeutic potential of ARV 825 against multiple myeloma (MM) cells both in vitro and in vivo. In a dose-dependent manner, ARV 825 inhibited proliferation of 13 human MM cell lines and three fresh patient samples, and was associated with cell cycle arrest and apoptosis. ARV 825 rapidly and efficiently degraded BRD 2 and BRD 4. Sensitivity of MM cells to ARV 825 was positively correlated with cereblon levels. RNA sequencing analysis showed important genes such as CCR1, RGS, MYB and MYC were down-regulated by ARV 825. A total of 170 small molecule inhibitors were screened for synergy with ARV 825. Combination of ARV 825 with inhibitor of either dual PI3K/mTOR, CRM1, VEGFR, PDGFRα/b, FLT3, IGF-1R, protein kinase C, CBP-EP300 or JAK1/2 showed synergistic activity. Importantly, ARV 825 significantly inhibited the growth of MM xenografts and improved mice survival. Taken together, our results, in conjunction with recently published findings, provide a rationale for investigating the efficacy of ARV 825 for MM, use of cereblon as a biomarker for therapy of MM patients, and the combination of ARV 825 with small molecule inhibitors to improve the outcome of MM patients.

This letter presents a photonic scheme to generate frequency-multiplied microwave signals with nearly constant amplitude. Optical injection locking and an optical fiber active loop filter are utilized to generate a frequency-multiplied microwave signal and equalize its amplitude, respectively. The significance of the scheme is that optical injection locking and nonlinear modulation are simultaneously implemented by a semiconductor distributed feedback laser, making this system compact and low-cost compared with other similar photonic implementations. Corresponding experiments display the effects of amplitude equalization for 10th and 11th harmonics with an initial frequency of 1.5 GHz and an 18th harmonic with an initial frequency of 1 GHz, respectively. The harmonic suppression ratios reach over 20 dB, and the SSB phase noises (

Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.

A single longitudinal mode (SLM) Brillouin fiber laser (BFL) with cascaded ring (CR) Fabry–Perot resonator, a SLM triple ring (TR) BFL with a saturable absorber ring (SAR) resonator and a stable multiwavelength (MW) SLM dual ring BFL (MW-SLM-DRBFL) are proposed and demonstrated. By optimizing the CR length of the single-mode fiber cavity at 100 m (or 50 m) and 10 m, stable SLM operation is obtained with 0.41 kHz (or 3.23 kHz). TR-BFL with approximately 65-Hz linewidth and 185 linewidth-reduction ratio is composed of a 1-km-long single-mode fiber (SMF) ring, a 100-m-long SMF ring, and an SAR with 8-m-long unpumped Erbium-doped fiber (UP-EDF), respectively. 7 stable SLM lasing wavelengths with DR configuration of 100 and 10 m length SMF are obtained with 0.084 nm wavelength spacing and 15 dB average optical signal-to-noise ratio (OSNR) through the cascaded stimulated Brillouin scattering (cSBS) and four-wave mixing (FWM). A MW SLM Brillouin–Erbium fiber laser (BEFL) sensor with ultrahigh resolution is proposed and demonstrated and Iezzi et al. proposed and investigated experimentally a distributed higher order Stokes SBS temperature fiber sensor. The one short common cavity of MW-SLM-BEFL with 50 m of SMF as the fiber under test (FUT) and 100 m of SMF as the reference realize 3.104 MHz/°C sensitivity and approximately 10−6 °C ultrahigh resolution in the short term of the third-order Stokes wavelength. While maintaining a fairly normal spatial resolution over a few kilometers of sensing length using time gating technology, sensitivity is increased by several folds to over 4 MHz/°C.

Breast cancers arising in the setting of the hereditary breast cancer genes BRCA1 and BRCA2 are most commonly classified as basal-like breast cancer (BLBC) or luminal breast cancer, respectively. BLBC is an aggressive subtype of breast cancer associated with liver and lung metastases and poorer prognosis than other subtypes and for which chemotherapy is the only systemic therapy. Multiple immunohistochemical markers are used to identify the basal-like subtype, including the absence of estrogen receptor alpha, progesterone receptor, and human epidermal growth factor receptor 2. Forkhead box C1 (FOXC1) has been identified as a specific marker expressed in BLBC in general breast cancer cohorts. We examined an institutional cohort of breast cancer patients with germline BRCA1 (n=46) and BRCA2 (n=35) mutations and found that FOXC1 expression on immunohistochemical staining is associated with BRCA1 vs BRCA2 mutations [30/46 vs. 6/35]. In BRCA1 mutant tumors, FOXC1 was expressed in 28/31 BLBC tumors and 2/13 non-BLBC tumors, In BRCA2 mutant tumors, FOXC1 was expressed in 5/5 BLBC tumors and 1/30 non-BLBC tumors. In cell culture models of BRCA1-mutant breast cancer, FOXC1 is associated with increased proliferation and may serve as a marker for sensitivity to PARP-inhibitor therapy with olaparib.

The impact of polarization mode dispersion (PMD) on the performance of coherent transmission systems employing different digital nonlinearity compensation (NLC) schemes is numerically investigated for a seven-channel PM-16QAM Nyquist-wavelength division multiplexing system at 256 Gbit / s. In these nonlinearity compensation schemes, the digital signal processing is divided between the transmitter (Tx) and receiver (Rx) with different splitting ratios. We demonstrate that by splitting the NLC equally between the Tx and Rx, one can always obtain the best performance improvement regardless of whether PMD is present or not. Results of 1000-km dispersion-unmanaged transmission show that when fiber PMD is equal to 0.05 ps / km, splitting the NLC can give a signal-to-noise ratio improvement of 1.1-dB over receiver-side NLC, while it is 0.9 dB for 0.1 ps / km of the fiber PMD coefficient.

Aiming at the problem of the low sensitivity of conventional optical fiber-based gas refractive index sensors, an ultrasensitive tapered optical fiber coupler-based gas refractive index sensor enhanced by the Vernier effect is proposed and demonstrated. The birefringence property of the tapered optical fiber coupler allows it to support two passes of interferences in two orthogonal polarized states, and the superposition of these two interferences forms the Vernier effect. Theoretical analysis and numerical calculations indicate that, for the fiber couplers working in the gas medium when the waist width is within the range of 1.2 to 2.0 μm, the group birefringence difference between the even mode and odd mode equals zero. Thus the sensitivity toward the ambient gas refractive index can be enhanced significantly. To demonstrate these theoretical results, a tapered fiber coupler with a width of 1.6 μm and a length of 16.5 mm was fabricated, and ultrahigh sensitivities up to 22015.4 and −22690.0 nm / RIU were experimentally achieved. The proposed sensor has the merits of being easy to fabricate, having compact structure, and being cost effective. It has significant application prospects in the petrochemical and biomedical detection fields.

Resistance to anti-tumor therapeutics is an important clinical problem. Tumor-targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a "Trojan-Horse" approach to combating these tumors by using a receptor-targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non-covalent self-assembly with therapeutic cargo, forming HER3-homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naïve tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re-introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here.

All-optical reconfigurable non-inverted logic gates with a single semiconductor optical amplifier (SOA) is proposed. Compared with the probe light of continuous light, the clock (Clk) pulse sequences light is regarded as the probe light so that the output of logic gates is a non-inverted code which is suitable to the further combination of different logic gates. The scheme is based on a single SOA with four-wave mixing and cross-gain modulation. Multiple functional logic operations are implemented and switched by adjusting the center wavelength of tunable optical band-pass filter without altering the experimental device. In the experiment, all-optical multiple logic gates with 10 Gb/s return-to-zero of NOT, NOR, XNOR, AND, A¯•B and A•B¯ are realized. Meanwhile, because Clk probe light is a small signal, a saturable absorber (SA) is configured to improve the extinction ratio (ER) and optical signal to noise ratio (OSNR). For logic gates NOT, NOR and XNOR with Clk probe light, ER and OSNR are only deteriorated by 1 dB with the SA. For logic gate AND with Clk probe light, ER is improved by about 2 dB based on four-wave mixing and OSNR keep the original values with the SA respectively. For logic gates A¯•B and A•B¯ without Clk probe light, ER and OSNR are both only deteriorated by 0.5 dB. It has the potential to obtain more complex combinational logic gates.

Sidewall profile reconstruction of microstructures with the high aspect ratio is a problem urgently to be solved in MEMS field. In this paper, a measuring method based on near-infrared light scanning interferometry (NILSI) is presented according to the transmission principle of semiconductor materials in the infrared light region. The NILSI is extended from the white light to near-infrared light and from surface profile reconstruction to sidewall profile reconstruction. The NILSI system is constituted by a near-infrared light source, an interference microscope, infrared CCD, piezoelectric ceramics (PZT) with high accuracy and the data acquisition system. The test sample is taken from GaAs microstructures with high aspect ratio and made by two different height steps for measuring with different typical testing equipment. Near-infrared light vertical scanning interference (NILVSI) is improved to compensate optical path difference (OPD) and the large surface roughness. The sidewall profile of the sample is obtained and compared with that of scanning electron microscopy (SEM) and white light scanning interferometry (WLSI). Test results demonstrate that the steps have 2.115 μm and 0.762 μm relative heights and 1.34 % and 2.14% relative errors respectively. There is a good agreement with the results of SEM and WLSI. The system can reconstruct the sidewall profile of microstructures with high aspect ratio.

We demonstrate a novel all-optical half-adder based on two semiconductor optical amplifiers (SOAs). Two optical bandpass filters are used to select the two idlers generated by four-wave mixing (FWM) effect of the first SOA. Therefore, the AND gate and XNOR logic are realized simultaneously. The second SOA acts as a NOT gate, in which the NOR logic is achieved with the input of the logic XNOR. As a result, the output is the sum of the two input bits and the carry. In the experiment, all-optical half-addition calculation is achieved between two 10 Gb/s signals.

We experimentally demonstrate a regenerative multiwavelength conversion (MWC) of an input 10-Gbit/s RZ signal to four output copies by using a single semiconductor optical amplifier (SOA) and a tunable band pass filter (TBPF). Experiment results indicate that improvements in detected Q factor can be observed because of the compression of the input noise. Furthermore, as the probe light we used is a multiwavelength pulses-train with the same frequency as the data signal, this configuration can realize 3R regenerative MWC without any change. © 2008 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 466–469, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24095

Background We investigated the effect of basal protein expression on trastuzamab response in patients with HER2-positive (HER2 + ) breast cancer who received trastuzamab (T) and in HER2 + breast cancer cell lines. Patients and Methods Expression of cytokeratin (CK) 5/6, CK14, and epidermal growth factor receptor (EGFR) was evaluated after immunohistochemical staining in paraffin-embedded tissue of 97 patients with stage I to III HER2 + breast cancer treated with chemotherapy/T. Groups with and without basal protein expression were compared with respect to clinicopathologic parameters and survival. We treated 4 cell lines (2 basal-HER2 [HCC1569, HCC1954] and 2 nonbasal HER2 [BT474, SKBR3]) each with vehicle, T 20 μg/mL, paclitaxel 0.01 μM (P), and T with P (T + P). Cell viability was assessed and HER2 pathway suppression was compared between groups using immunoblot analysis. Mammosphere formation was used to assess breast cancer stem cell properties. Results EGFR expression was significantly associated with cancer-specific survival (CSS) ( P = .05). CK5/6 expression strongly correlated with overall and disease-free survival, and CSS ( P = .03, P = .04, and P = .03, respectively). Statistical significance was maintained for EGFR and CK5/6 after adjustment for covariates. CK14 was not associated with survival. All cell lines expressed similar levels of HER2. T and P alone inhibited proliferation of nonbasal cell lines; T + P had an additive cytotoxic effect. Basal cells were resistant to T, P inhibited proliferation, but T + P had no additive cytotoxic effect on cell growth in basal cells. Immunoblot analysis showed a significant decrease in phosphorylated Akt levels after treatment with T or T + P in nonbasal cells but not in basal cells. Akt blockade suppressed growth of basal and nonbasal HER2 + cells. Furthermore, basal HER2 cell lines had increased mammosphere formation, which suggests increased stem cell properties compared with nonbasal HER2 cell lines. Conclusion CK5/6 and EGFR expression are predictive of worse prognosis in HER2 + breast cancer patients treated with T. Basal HER2 breast cancer cell lines are resistant to trastuzamab, which is mediated through the Akt pathway; AKT inhibition abrogates this resistance. Basal HER2 cell lines also have increased stem cell properties, which might play a role in the resistance pathway.

© 2014, Society of Surgical Oncology. Background: Human basal-like breast cancer (BLBC) has a poor prognosis and is often identified by expression of the epidermal growth factor receptor (EGFR). BLBC remains a major clinical challenge because its pathogenesis is not well understood, thus hindering efforts to develop targeted therapies. Recent data implicate the forkhead box C1 (FOXC1) transcription factor as an important prognostic biomarker and functional regulator of BLBC, but its regulatory mechanism and impact on BLBC tumorigenesis remain unclear.Methods: The association between FOXC1 and EGFR expression in human breast cancer was examined by immunohistochemistry in formalin-fixed tissues and analysis of the TCGA database. The regulation of FOXC1 by EGFR activation was investigated in MDA-MB-468 cells using immunoblotting, qRT-PCR, and luciferase activity assays. This EGFR effect on FOXC1 expression was confirmed using the MDA-MB-468 xenograft model.Results: Both FOXC1 mRNA and protein levels significantly correlated with EGFR expression in human breast tumors. EGFR activation induced FOXC1 transcription through the ERK and Akt pathways in BLBC. EGFR inhibition in vivo reduced FOXC1 expression in xenograft tumors. We also found that FOXC1 knockdown impaired the effects of EGF on BLBC cell proliferation, migration, and invasion.Conclusions: Our findings uncover a novel EGFR-FOXC1 signaling axis critical for BLBC cell functions, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.

An all-optical frequency-upconversion is presented by injecting a low bit rate signal into a Fabry-Perot laser diode (FP-LD) without any radio-frequency local oscillator. One of the FP-LD lasing modes is locked by generated sideband through four-wave-mixing effect in FP-LD. The generated microwave subcarrier could be tunable by varying the power and polarization of the injected signal. The input signal at the data rate of 1.25, 2.5, and 2.7 Gb/s with nonreturn-to-zero format are upconverted to a subcarrier modulation signal at upcoversion frequencies of 20, 10, and 16.2 GHz, respectively. The single sideband phase noise of -81.2 and -87.7 dBc/Hz (10-kHz frequency deviation) at 16.2-GHz subcarrier are demonstrated. The difference of sidemode suppression ratio at the FP-LD output point is also analyzed.

We propose a novel scheme for simultaneous retiming and reshaping of two wavelength-division-multiplexing channels using two independent phase clock pump and polarization multiplexing in fiber-optic parametric amplification, with the benefits of suppressing the interchannel cross-phase-modulation effect induced by the clock pumps and four-wave-mixing crosstalk. Operation of two 10-Gb/s channels is demonstrated experimentally. In both single- and dual-channel operation, eye diagrams after regeneration are significantly cleared with pulsewidth narrowed, and the nonlinear interferences are effectively reduced. An average 2-dB power penalty improvement at a bit-error rate of 10-9 is obtained in both single- and dual-channel operation.

An all-optical frequency-upconversion based on fractional talbot effect is experimentally reported. The 2.5-Gb/s baseband signal carried on 10GHz pulse trains is upconverted to 40GHz millimeter wave after 18.49km transmission via repetition frequency multiplication of pulse trains. The phase noise of the 40GHz is as well as −92dBc/Hz at 10kHz frequency detuning. This scheme can operate in 60GHz band by employing the appropriate fiber length based on fractional talbot effect.

A novel scheme to realize all-optical logic gates is proposed bases on nonlinear polarization rotation (NPR) in high nonlinear fiber (HNLF). Two optical signals A and B with return-to-zero data format are injected into the HNLF together with a continuous wave C. Thanks to the optical power variation in HNLF, nonlinear birefringence will be induced between the two polarization axes. Thus it results in the nonlinear polarization rotation of the lightwave in the HNLF. Both the optical signal and continuous wave are filtered out at the output of HNLF using optical band-pass filter. By adjusting the optical power and polarization of the optical signal as well as the polarization of the polarizer with respect to the polarization of optical signal/continuous wave, multiple all-optical logic gates can be realized. Theoretical analysis of the simultaneously realization of the multiple optical logic gates based on NPR in HNLF is provided. And we demonstrated the feasibility of the scheme by realizing all optical “and”, “not”, “nxor”, “A • B”, “A• B ”, half-adder and half-subtracter at 10Gb/s operation.

Simultaneously wavelength conversion of two input data signals based on four-wave mixing (FWM) in a single semiconductor optical amplifier (SOA) is proposed. The two input data signals in the wavelength conversion have a poor extinction ratio (ER) and the data "0" and data "1" are orthogonally polarized. When properly setting the relative polarization state of the two unconventional signals, replicas of the two input signals can be obtained at the idler's wavelength. Simultaneous wavelength conversion for two 10-Gb/s channels is demonstrated experimentally. The ER of two input signals is 4.83dB and 4.81dB respectively before wavelength conversion, while the ER of converted signals is 11.75dB and 10.34dB respectively.

A high frequency optoelectronic oscillator (OEO) using only low frequency optical and microwave devices is attractive as it provides a low cost and high quality solution at the same time. In this paper, a novel OEO scheme is reported. The proposed optoelectronic oscillator includes a 5GHz directly modulated DFB laser, an optical circulator, a 10GHz photodetector, a 10GHz RF amplifier, and a bandpass RF filter with a central frequency at 5GHz. The OEO oscillates at the 5GHz and with a continuous wave injected into the directly modulated DFB laser, higher harmonics will be generated. The harmonic order can be controlled by the frequency difference between the free running DFB laser and injection lightwave. An optical domain combined dual-loop configuration with polarization-beam splitter and a polarization-beam combiner is employed to suppress the sidemodes in each single loop. Experiment results are proposed to verify the scheme, in which 40GHz microwave is obtained.

40 Gb/s optical demultiplexing with amplitude regeneration is demonstrated based on data pump fiber-optical parametric amplification while a 10 GHz short pulse is used as the probe. Four 10 Gb/s output channels with at least 14 dB extinction ratio enhancement and an average 5.5 Q factor is obtained after demultiplexing.

We propose a novel technique to achieve optical frequency up-conversion in millimeter wave band without any local microwave oscillator. By utilizing injection locking of Febry-Perot Laser diode, a suitable negative dispersion device and polarization interferometer, a 2.5Gb/s baseband signal is frequency up-conversion to a subcarrier modulation signal at 30.8GHz.

We propose a novel technique to extent the tunable range of the RF frequency generated by optoelectronic oscillators. By utilizing injection locking of Febry-Perot Laser diode rather than the commonly used radio-frequency bandpass filter, a tunable range from 11.074 GHz to 39.400GHz is demonstrated experimentally.

40-Gb/s 2-Channel all-optical 3R regeneration with simultaneous wavelength conversion has been realised by a fiber parametric amplifier(FPA) with the data signal to be regenerated as the pump,eliminating the unequal suppression of noise between bit0 and bit1. Signal to noise ratio is improved respectively from 2.7,2.4 to4.9,5.2.

The optical pulse trains at a multiplied repetition frequency is generated by Fractional Talbot effects in optical fiber. The principles of Talbot effects and Fractional Talbot effects in fiber are analyzed in this paper. The 20GHz, 40GHz and 50GHz optical pulse trains are obtained from the original pulse trains with 2.8ps width at 10GHz repetition frequency. An optical pulse at 40GHz repetition frequency is also produced by upshifting the repetition frequency of 5GHz pulse trains. The degradation of 40GHz and 50GHz pulse trains is discussed by spectrum analysis of the pulse trains and some methods are proposed to enhance the performance of the pulse trains.

A simultaneous optical signal extracting and erasing scheme is presented by utilizing four-wave mixing (FWM) in optical fiber. Two synchronized gate and negation gate pulses are used as control signal, which are coupled with data stream and produce FWM effect in high nonlinear fiber (HNLF). Through filtering the idler light generated between each control signal and data stream, simultaneous signal extracting and erasing functions can be obtained. Experimental results are successfully demonstrated with NRZ data format at 10 Gbit/s. This system is able to operate at higher bit rates and other data modulation formats.

An all-optical regenerator based on single pump fiber-optic parametric amplifier (FOPA) is demonstrated and assessed experimentally. The static power transfer function of the FOPA is measured, and a clear saturation behavior is observed with the saturation much easier to achieve at a larger the pump power. The regenerator performance is further investigated by changing parameters of the input signal. Results show that the SNR and timing jitter of the regenerated signal is maintained around 15 dB and 2 ps regardless of the transmission distance of the input signal, and above 7 dB SNR improvement can be achieved when the input SNR is within the range of 3 to 10 dB. The regeneration performance is also tested by varying the input signal wavelength, and at least 6 dB SNR improvement is obtained within the range of the gain bandwith of the single pump FOPA.

A novel approach is proposed to reduce the cross phase modulation between multiple clock pump in the multi-wavelength optical decision based optical fiber parametric amplifier. The dispersive media is used to preprocess the pump clock, and then the clock pump is changed from intensity modulation into phase modulation. In our experiment, cross phase modulation is obviously restrained between the adjacent channels.

The optical pulse trains at a multiplied repetition frequency is generated by Fractional Talbot effects in optical fiber. The principles of Talbot effects and Fractional Talbot effects in fiber are analyzed in this paper. The 20GHz, 40GHz and 50GHz optical pulse trains are obtained from the original pulse trains with 2.8ps width at 10GHz repetition frequency. An optical pulse at 40GHz repetition frequency is also produced by upshifting the repetition frequency of 5GHz pulse trains. The degradation of 40GHz and 50GHz pulse trains is discussed by spectrum analysis of the pulse trains and some methods are proposed to enhance the performance of the pulse trains.

A time- and wavelength-interleaved (T- W-interleaved) optical pulse source based on optoelectronic oscillator is presented. By utilizing spectral slicing, a multi-loop configuration is formed in OEO system, which can effectively suppress side-modes. In addition, this configuration is able to generate multi-wavelength optical pluses which can be arranged T- W-interleaved optical pulse stream at different nodes. In this system, 10-ps-wide optical pulses at 5GHz repetition rate are generated with 1ps timing jitter (in the 100Hz-1MHz range) and -100dBc/Hz spurious modes suppression, Along with the optical outputs, 5GHz electrical signal with low phase noise (-113dBc/Hz at 10kHz offset from the carrier) is also obtained.

Short locking and unlocking time is essepecially important in the packet clock recovery, as it determines the network resource utilization. This paper presents a novel 10-GHz all-optical packet clock extractor with ultrafast locking and unlocking time via self-phase modulation (SPM) effect of the semiconductor optical amplifier (SOA). Low finesse Fabry-Perot (F-P) filter and a saturated SOA, in cascade, are used to directly extract the packet clock from the data stream. An optical bandpass filter(OBPF) is used to filter out the red-shifted parts of the packet clock in order to reduce the locking and unlocking time. We analytically investigate the impact of the locking and unlocking time thanks to the self-gain modulation (SGM) effect and self-phase modulation(SPM) effect induced by the SOA, and demonstrate 10GHz clock extraction with the establishing time of 200ps and vanishing time of 600ps experimentally.

We demonstrate a tunable chromatic dispersion (CD) compensation technique using a semiconductor optical amplifier (SOA) and a coil of dispersion compensation fiber (DCF). Based on cross-phase modulation (XPM) in the SOA, the transient chirp of the received signal can be adjusted by tuning the drive current of the SOA and the power of clock pulse. In this way, a 10-Gbit/s tunable CD compensation setup, ranging from -40ps/nm to 60ps/nm, is realized without changing the length of the DCF.

A time- and wavelength-interleaved optical pulse source, which is based on spectral slicing and dispersion management, is proposed and experimentally demonstrated. The pulse source has a simple configuration, and both the repetition rate and the wavelength channels can be tuned easily.

A novel 10Gbit/s all-optical packet clock extractor, which comprises a Fabry-Perot (F-P) filter and a semiconductor optical amplifier (SOA), is proposed in this paper. Low Finesse Fabry-Perot (F-P) filter was used to directly extract the packet clock from the data packet stream, which ensures that the clock locks fast and vanishes quickly. The clock, amplitude modulated as a result of low-Q filter, then goes into SOA to reduce the low-frequency amplitude noise. The impact of F-P filter and SOA on the locking and unlocking time of the packet clock is theoretically analyzed. The result shows that the locking time is reduced while the unlocking time is increased, due to the self-gain modulation (SGM) effect. We demonstrate instantaneous 10.075GHz clock extraction experimentally with the establishing time of about 8 code-periods and vanishing time of about 22 code-periods.

We demonstrate a novel 40-Gb/s all-optical serial to parallel converter (AOSPC), which can convert 40-Gb/s serial optical signals to 4-channel 10-Gb/s parallel optical signals. Moreover, based on the sequential multi-wavelength conversion the AOSPC shows the regeneration ability.

Basal-like breast cancer (BLBC), an aggressive subtype of breast cancer, are usually associated with high histologic grade, high recurrence rate, short recurrence-free survival, younger patient age, poor outcome, and a propensity to metastasize to the brain and lung. So far, developing targeted therapies against BLBC still remains a great challenge. Uncovering the underlying molecular events and identify therapeutic target becomes highly urgent. Forkhead Box C1 (FOXC1), a biomarker for BLBC, is associated with poor prognosis in patients with BLBC. Here, we found that FOXC1 increases cancer stem cells (CSCs) properties in BLBC cells in vitro and in vivo. FOXC1 activates SMO-independent non-canonical Hedgehog (Hh) signaling pathway, which mediates the effects of FOXC1 on CSCs properties in BLBC cells. Further study showed that the N-terminal of FOXC1 bind directly to the Gli2 transcription factor, which has the highest transcriptional activity in Hh signaling pathway. Here we also found that the elevated expression of FOXC1 induces anti-Hh pathway drug resistance. All of these data demonstrate a novel mechanism underlying the regulation of CSC properties and the poor prognosis of BLBC patients, and may provide new insight into anti-CSC therapy resistance. Thus, our study provides a strong rationale for developing FOXC1-targeted therapy for treating BLBC patients. Citation Format: Bingchen Han, Yanli Jin, Shikha Bose, Xiao Zhang, Ying Qu, Beth Y. Karlan, Armando E. Giuliano, Xiaojiang Cui. FOXC1 regulates cancer stem cells properties via inducing SMO-independent Gli activation and confers anti-Hedgehog drug resistance in basal-like breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1906. doi:10.1158/1538-7445.AM2014-1906

154 Background: Trastuzumab (Herceptin) resistance remains a clinical challenge but the mechanism is not well understood. Recently, studies have identified a subset of Her2+ breast cancer called basal HER2 that expresses basal genes. We investigated the effect of basal gene expression on Herceptin response in HER2+ breast cancer cell lines and on prognosis in HER2+ breast cancer patients. Methods: Non-basal (BT474, SKBR3) and basal (HCC1569, HCC1954, JIMT-1) HER2+ cell lines were chosen based on basal cytokeratin expression. Cell proliferation was assessed after treatment with vehicle, Herceptin (H), Paclitaxel (P), H+P, Akt Inhibitor (AI), and H+AI. HER2 signaling was examined using immunoblotting of p-Akt and p-ERK. Because breast cancer stem cells (BCSC) are linked to basal breast tumors and treatment resistance, we assessed BCSC activity using mammosphere formation and aldehyde dehydrogenase (ALDH) positivity. Immunohistochemical staining of HER2+ breast cancers for basal markers CK5/6, CK14, and EGFR was correlated with clinicopathologic features and survival in 88 patients with Stage 1-3 HER2+ breast cancer treated with Herceptin. Results: Basal HER2 cells were resistant to Herceptin compared to non-basal HER2 cells but this resistance was overcome by Akt inhibition. Immunoblotting showed that non-basal HER2 cells had decreased p-Akt after Herceptin treatment which was not seen in basal HER2 cells. There was no difference in p-ERK levels after Herceptin therapy in all cell lines. Basal HER2 cells had increased mammosphere formation and ALDH positivity suggesting higher stem cell activity compared to non-basal HER2 cells. Of the HER2+ patients, 33/88 (37.5%) expressed at least one basal marker. Basal Her2 tumors were associated with higher grade (p = 0.04) and more ER/PR negativity (p < 0.01). CK14 expression correlated with worse overall survival by log-rank test (p = 0.02), while EGFR showed a similar trend (p = 0.06). Conclusions: Basal HER2 breast cancer cell lines have Herceptin resistance which may be due to constitutively active Akt signaling and increased stem cell activity. Clinically, basal marker expression predicts Herceptin resistance and worse outcomes in HER2+ breast cancer patients.

Basal-like breast cancer (BLBC) is an aggressive malignancy that is associated with high histological grade, aggressive clinical behavior, a high rate of metastasis to the lung and brain, and poor prognosis. Currently, chemotherapy is the only systemic therapy for BLBC, which underexpresses estrogen receptor (ER), progesterone receptor (PR), and HER2. To date, little is known about the molecular basis of BLBC. We and others recently reported that the forkhead box C1 (FOXC1) transcription factor is a critical maker for BLBC and predicts poor clinical outcome in human breast cancer. Overexpression of FOXC1 increases BLBC cell growth, migration, invasion, epithelial-mesenchymal transition, and chemoresistance. However, how its expression is induced exclusively in BLBC is not understood. Previous studies have shown that EGFR is overexpressed in BLBC and is associated with poor prognosis in breast cancer patients. We thus hypothesize that activated EGFR signaling may regulate FOXC1 expression. In this study, we show that EGF treatment upregulates FOXC1 expression in BLBC cells at the transcription level through MEKK1/ERK and PI3K/AKT pathways. AKT3, which was recently found to be enriched in ER/PR/HER2 triple-negative breast cancer, is a potent activator of FOXC1 transcription. Overexpression of EGFRvIII, a truncated constitutively active form of EGFR that does not bind to the ligand, also induced FOXC1 expression. Pharmacologic inhibition of EGFR suppressed FOXC1 expression in BLBC cells. Immunohistochemistry and microarray analysis demonstrated that FOXC1 expression was positively, significantly correlated with EGFR expression in human BLBC tumors at protein and RNA levels. Moreover, we identified the nuclear factor κB (NF-κB) transcription factor as a pivotal regulator of EGF-induced FOXC1 expression, downstream of AKT and ERK. NF-κB directly activates FOXC1 transcription through binding to the FOXC1 promoter. Deletion or mutation of the NF-κB binding sites in the FOXC1 promoter abolished the EGF induction of FOXC1 expression. Knockdown of FOXC1 levels in BLBC cells by RNA interference markedly attenuated EGF-elicited cell proliferation, migration and invasion, suggesting that FOXC1 mediates the effects of EGF on BLBC cell functions. Taken together, our findings uncovered a novel mechanism of FOXC1 regulation and shed light on the role of EGFR-NF-κB-FOXC1 signaling in BLBC pathogenesis. Intervention of this signaling pathway would provide potential modalities for BLBC treatment. FOXC1 levels may serve as a readout of EGFR activity and a marker for selecting breast cancer patients who may benefit from anti-EGFR therapy. Citation Format: Yanli Jin, Bingchen Han, Wolf Ruprecht Wiedemeyer, Sandra Orsulic, Beth Karlan, Armando Giuliano, Xiaojiang Cui. FOXC1 is a critical mediator of EGFR function in basal-like breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5443. doi:10.1158/1538-7445.AM2013-5443

A time- and wavelength-interleaved optical pulse source, which is based on spectral slicing and dispersion management, is proposed and experimentally demonstrated. The pulse source has a simple configuration, and both the repetition rate and the wavelength channels can be tuned easily.