Broadband frequency comb generation through cascaded quadratic nonlinearity in thin-film lithium niobate microresonators.

Broadband frequency comb generation through cascaded quadratic nonlinearity remains experimentally untapped in free-space cavities with bulk χ(2) materials mainly due to the high threshold power and restricted ability of dispersion engineering. Thin-film lithium niobate (LN) is a good platform for nonlinear optics due to the tight mode confinement in a nano-dimensional waveguide, the ease of dispersion engineering, large quadratic nonlinearities, and flexible phase matching via periodic poling. Here we demonstrate broadband frequency comb generation through dispersion engineering in a thin-film LN microresonator. Bandwidths of 150 nm (80 nm) and 25 nm (12 nm) for center wavelengths at 1560 and 780 nm are achieved, respectively, in a cavity-enhanced second-harmonic generation (doubly resonant optical parametric oscillator). Our demonstration paves the way for pure quadratic soliton generation, which is a great complement to dissipative Kerr soliton frequency combs for extended interesting nonlinear applications.

Liposome-tethered supported lipid bilayer platform for capture and release of heterogeneous populations of circulating tumor cells.

Because of scarcity, vulnerability, and heterogeneity in the population of circulating tumor cells (CTCs), the CTC isolation system relying on immunoaffinity interaction exhibits inconsistent efficiencies for all types of cancers and even CTCs with different phenotypes in individuals. Moreover, releasing viable CTCs from an isolation system is of importance for molecular analysis and drug screening in precision medicine, which remains a challenge for current systems. In this work, a new CTC isolation microfluidic platform was developed and contains a coating of the antibody-conjugated liposome-tethered-supported lipid bilayer in a developed chaotic-mixing microfluidic system, referred to as the "LIPO-SLB" platform. The biocompatible, soft, laterally fluidic, and antifouling properties of the LIPO-SLB platform offer high CTC capture efficiency, viability, and selectivity. We successfully demonstrated the capability of the LIPO-SLB platform to recapitulate different cancer cell lines with different antigen expression levels. In addition, the captured CTCs in the LIPO-SLB platform can be detached by air foam to destabilize the physically assembled bilayer structures due to a large water/air interfacial area and strong surface tension. More importantly, the LIPO-SLB platform was constructed and used for the verification of clinical samples from 161 patients with different primary cancer types. The mean values of both single CTCs and CTC clusters correlated well with the cancer stages. Moreover, a considerable number of CTCs were isolated from patients' blood samples in the early/localized stages. The clinical validation demonstrated the enormous potential of the universal LIPO-SLB platform as a tool for prognostic and predictive purposes in precision medicine.

Proliferative ability of circulating tumor cells is a prognostic factor in Early-Stage lung adenocarcinoma.

INTRODUCTION: Circulating tumor cells (CTCs) and their proliferative ability in lung adenocarcinoma (LUAD) were not well-investigated. We developed a protocol combining an efficient viable CTC isolation and in-vitro cultivation for the CTC enumeration and proliferation to evaluate their clinical significance. METHOD: The peripheral blood of 124 treatment-naïve LUAD patients were processed by a CTC isolation microfluidics, DS platform, followed by in-vitro cultivation. LUAD-specific CTCs were defined by immunostaining of DAPI+/CD45-/(TTF1/CK7)+ and were enumerated upon isolation and after 7-day cultivation. The CTC proliferative ability was evaluated by both the cultured number and the culture index, a ratio of cultured CTC number to the initial CTC number in 2 mL of blood. RESULT: All but two LUAD patients (98.4%) were detected with at least one CTC per 2 mL of blood. Initial CTC numbers did not correlate with metastasis (75 ± 126 for non-metastatic, 87 ± 113 for metastatic groups; P = 0.203). In contrast, both the cultured CTC number (mean: 28, 104, and 185 in stage 0/I, II/III, and IV; P < 0.001), and the culture index (mean: 1.1, 1.7 and 9.3 in stage 0/I, II/III, and IV; P = 0.043) were significantly correlated with the stages. Overall survival analysis within the non-metastatic group (N = 53) showed poor prognosis for patients with elevated cultured counts (cutoff ≥ 30; P = 0.027). CONCLUSION: We implemented a CTC assay in clinical LUAD patients with a high detection rate and cultivation capability. Cultured CTC count and proliferative ability, rather than the crude CTC numbers, highly associated with cancer prognosis.

Network Pharmacology and in vitro Experimental Verification on Intervention of Quercetin, Present in Chinese Medicine Yishen Qutong Granules, on Esophageal Cancer.

OBJECTIVE: To explore the potential mechanism of Yishen Qutong Granules (YSQTG) for the treatment of esophageal cancer using network pharmacology and experimental research. METHODS: The effective components and molecular mechanism of YSQTG in treating esophageal cancer were expounded based on network pharmacology and molecular docking. The key compound was identified by high-performance liquid chromatography and mass spectrometry (HPLC-MS) to verify the malignant phenotype of the key compounds in the treatment of esophageal cancer. Then, the interaction proteins of key compounds were screened by pull-down assay combined with mass spectrometry. RNA-seq was used to screen the differential genes in the treatment of esophageal cancer by key compounds, and the potential mechanism of key compounds on the main therapeutic targets was verified. RESULTS: Totally 76 effective compounds of YSQTG were found, as well as 309 related targets, and 102 drug and disease interaction targets. The drug-compound-target network of YSQTG was constructed, suggesting that quercetin, luteolin, wogonin, kaempferol and baicalein may be the most important compounds, while quercetin had higher degree value and degree centrality, which might be the key compound in YSQTG. The HPLC-MS results also showed the stable presence of quercetin in YSQTG. By establishing a protein interaction network, the main therapeutic targets of YSQTG in treating esophageal cancer were Jun proto-oncogene, interleukin-6, tumor necrosis factor, and RELA proto-oncogene. The results of cell function experiments in vitro showed that quercetin could inhibit proliferation, invasion, and clonal formation of esophageal carcinoma cells. Quercetin mainly affected the biological processes of esophageal cancer cells, such as proliferation, cell cycle, and cell metastasis. A total of 357 quercetin interacting proteins were screened, and 531 genes were significantly changed. Further pathway enrichment analysis showed that quercetin mainly affects the metabolic pathway, MAPK signaling pathway, and nuclear factor kappa B (NF- κ B) signaling pathway, etc. Quercetin, the key compound of YSQTG, had stronger binding activity by molecular docking. Pull-down assay confirmed that NF- κ B was a quercetin-specific interaction protein, and quercetin could significantly reduce the protein level of NF- κ B, the main therapeutic target. CONCLUSION: YSQTG can be multi-component, multi-target, multi-channel treatment of esophageal cancer, it is a potential drug for the treatment of esophageal cancer.

Automated meniscus segmentation and tear detection of knee MRI with a 3D mask-RCNN.

BACKGROUND: The diagnostic results of magnetic resonance imaging (MRI) are essential references for arthroscopy as an invasive procedure. A deviation between medical imaging diagnosis and arthroscopy results may cause irreversible damage to patients and lead to excessive medical treatment. To improve the accurate diagnosis of meniscus injury, it is urgent to develop auxiliary diagnosis algorithms to improve the accuracy of radiological diagnosis. PURPOSE: This study aims to present a fully automatic 3D deep convolutional neural network (DCNN) for meniscus segmentation and detects arthroscopically proven meniscus tears. MATERIALS AND METHODS: Our institution retrospectively included 533 patients with 546 knees who underwent knee magnetic resonance imaging (MRI) and knee arthroscopy. Sagittal proton density-weighted (PDW) images in MRI of 382 knees were regarded as a training set to train our 3D-Mask RCNN. The remaining data from 164 knees were used to validate the trained network as a test set. The masks were hand-drawn by an experienced radiologist, and the reference standard is arthroscopic surgical reports. The performance statistics included Dice accuracy, sensitivity, specificity, FROC, receiver operating characteristic (ROC) curve analysis, and bootstrap test statistics. The segmentation performance was compared with a 3D-Unet, and the detection performance was compared with radiological evaluation by two experienced musculoskeletal radiologists without knowledge of the arthroscopic surgical diagnosis. RESULTS: Our model produced strong Dice coefficients for sagittal PDW of 0.924, 0.95 sensitivity with 0.823 FPs/knee. 3D-Unet produced a Dice coefficient for sagittal PDW of 0.891, 0.95 sensitivity with 1.355 FPs/knee. The difference in the areas under 3D-Mask-RCNN FROC and 3D-Unet FROC was statistically significant (p = 0.0011) by bootstrap test. Our model detection performance achieved an area under the curve (AUC) value, accuracy, and sensitivity of 0.907, 0.924, 0.941, and 0.785, respectively. Based on the radiological evaluations, the AUC value, accuracy, sensitivity, and specificity were 0.834, 0.835, 0.889, and 0.754, respectively. The difference in the areas between 3D-Mask-RCNN ROC and radiological evaluation ROC was statistically significant (p = 0.0009) by bootstrap test. 3D Mask RCNN significantly outperformed the 3D-Unet and radiological evaluation demonstrated by these results. CONCLUSIONS: 3D-Mask RCNN has demonstrated efficacy and precision for meniscus segmentation and tear detection in knee MRI, which can assist radiologists in improving the accuracy and efficiency of diagnosis. It can also provide effective diagnostic indicators for orthopedic surgeons before arthroscopic surgery and further promote precise treatment.

Multiomic characterization and drug testing establish circulating tumor cells as an ex vivo tool for personalized medicine.

Matching the treatment to an individual patient's tumor state can increase therapeutic efficacy and reduce tumor recurrence. Circulating tumor cells (CTCs) derived from solid tumors are promising subjects for theragnostic analysis. To analyze how CTCs represent tumor states, we established cell lines from CTCs, primary and metastatic tumors from a mouse model and provided phenotypic and multiomic analyses of these cells. CTCs and metastatic cells, but not primary tumor cells, shared stochastic mutations and similar hypomethylation levels at transcription start sites. CTCs and metastatic tumor cells shared a hybrid epithelial/mesenchymal transcriptome state with reduced adhesive and enhanced mobilization characteristics. We tested anti-cancer drugs on tumor cells from a metastatic breast cancer patient. CTC responses mirrored the impact of drugs on metastatic rather than primary tumors. Our multiomic and clinical anti-cancer drug response results reveal that CTCs resemble metastatic tumors and establish CTCs as an ex vivo tool for personalized medicine.

Traditional Chinese Medicine reverses resistance to epidermal growth factor receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer: a narrative review.

OBJECTIVE: To review mechanisms of the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer and the reversal of this resistance by traditional Chinese herbal medicines (CHMs). METHODS: Searching China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, PubMed and Embase for related researches RESULTS: T790M mutation, MET amplification, C797S mutation, Inactivation of PTEN gene expression and Epithelial-mesenchymal transition (EMT) are the main mechanisms of the resistance to EGFR-TKIs. CHMs may reverse the resistance by inhibiting MET activation, inhibiting PI3K/AKT pathways, regulating apoptosis and P-glycoprotein (P-gp). CONCLUSION: Many resistance mechanisms of EGFR-TKIs in the treatment of non-small cell lung cancer still need to be explored. CHMs have great research potential in reversing the resistance to EGFR-TKIs.

Early Detection and Dynamic Changes of Circulating Tumor Cells in Transgenic NeuN Transgenic (NTTg) Mice with Spontaneous Breast Tumor Development.

BACKGROUND: This study used NeuN transgenic (NTTg) mice with spontaneous breast tumor development to evaluate the dynamic changes of circulating tumor cells (CTCs) prior to and during tumor development. METHODS: In this longitudinal, clinically uninterrupted study, we collected 75 µL of peripheral blood at the age of 8, 12, 16, and 20 weeks in the first group of five mice, and at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability in the second group of four mice. Diluted blood samples were run through a modified mouse-CMx chip to isolate the CTCs. RESULTS: The CTC counts of the first group of mice were low (1 ± 1.6) initially. The average CTC counts were 16 ± 9.5, 29.0 ± 18.2, and 70.0 ± 30.3 cells per 75 µL blood at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability, respectively. There was a significant positive correlation between an increase in CTC levels and tumor vascular density (p-value < 0.01). This correlation was stronger than that between CTC levels and tumor size (p-value = 0.076). The captured CTCs were implanted into a non-tumor-bearing NTTg mouse for xenografting, confirming their viability and tumorigenesis. CONCLUSION: Serial CTCs during an early stage of tumor progression were quantified and found to be positively correlated with the later tumor vascular density and size. Furthermore, the successful generation of CTC-derived xenografts indicates the tumorigenicity of this early onset CTC population.

Efficient and highly tunable second-harmonic generation in Z-cut periodically poled lithium niobate nanowaveguides.

Thin-film lithium-niobate-on-insulator (LNOI) has emerged as a superior integrated-photonics platform for linear, nonlinear, and electro-optics. Here we combine quasi-phase-matching, dispersion engineering, and tight mode confinement to realize nonlinear parametric processes with both high efficiency and wide wavelength tunability. On a millimeter-long, Z-cut LNOI waveguide, we demonstrate efficient (1900±500%W-1cm-2) and highly tunable (-1.71nm/K) second-harmonic generation from 1530 to 1583 nm by type-0 quasi-phase-matching. Our technique is applicable to optical harmonic generation, quantum light sources, frequency conversion, and many other photonic information processes across visible to mid-IR spectral bands.

Ultrabright Quantum Photon Sources on Chip.

Quantum photon sources of high rate, brightness, and purity are increasingly desirable as quantum information systems are quickly scaled up and applied to many fields. Using a periodically poled lithium niobate microresonator on chip, we demonstrate photon-pair generation at high rates of 8.5 and 36.3 MHz using only 3.4 and 13.4 µW pump power, respectively, marking orders of magnitude improvement over the state of the art, across all material platforms. These results constitute the first direct measurement of the device's giant single photon nonlinearity. The measured coincidence to accidental ratio is well above 100 at those high rates and reaches 14682±4427 at a lower pump power. The same chip enables heralded single-photon generation at tens of megahertz rates, each with low autocorrelation g_{H}^{(2)}(0)=0.008 and 0.097 for the microwatt pumps, which marks a new milestone. Such distinct performance, facilitated by the chip device's noiseless and giant optical nonlinearity, will contribute to the forthcoming pervasive adoption of quantum optical information technologies.

High-extinction electro-optic modulation on lithium niobate thin film.

Integrated nanophotonics using lithium-niobate-on-insulator promises much-awaited solutions for scalable photonics techniques. One of its core functions is electro-optic modulation, which currently suffers limited extinction (<30 dB) due to inevitable fabrication errors. We exploit a cascaded Mach-Zehnder interferometry design to offset those errors, demonstrating up to 53 dB modulation extinction for a wide range of wavelengths between 1500 nm and 1600 nm. Together, its favorable features of chip integration, high extinction, good stability, and being broadband may prove valuable in a plethora of flourishing photonics applications.

Snail-induced claudin-11 prompts collective migration for tumour progression.

Epithelial-mesenchymal transition (EMT) is a pivotal mechanism for cancer dissemination. However, EMT-regulated individual cancer cell invasion is difficult to detect in clinical samples. Emerging evidence implies that EMT is correlated to collective cell migration and invasion with unknown mechanisms. We show that the EMT transcription factor Snail elicits collective migration in squamous cell carcinoma by inducing the expression of a tight junctional protein, claudin-11. Mechanistically, tyrosine-phosphorylated claudin-11 activates Src, which suppresses RhoA activity at intercellular junctions through p190RhoGAP, maintaining stable cell-cell contacts. In head and neck cancer patients, the Snail-claudin-11 axis prompts the formation of circulating tumour cell clusters, which correlate with tumour progression. Overexpression of snail correlates with increased claudin-11, and both are associated with a worse outcome. This finding extends the current understanding of EMT-mediated cellular migration via a non-individual type of movement to prompt cancer progression.

Ultra-wideband and high-gain parametric amplification in telecom wavelengths with an optimally mode-matched PPLN waveguide.

We report a wideband optical parametric amplification (OPA) over 14 THz covering telecom S, C, and L bands with observed maximum parametric gain of 38.3 dB. The OPA is realized through cascaded second-harmonic generation and difference-frequency generation (cSHG-DFG) in a 2 cm periodically poled LiNbO3 (PPLN) waveguide. With tailored cross section geometry, the waveguide is optimally mode matched for efficient cascaded nonlinear wave mixing. We also identify and study the effect of competing nonlinear processes in this cSHG-DFG configuration.

Direct Generation and Detection of Quantum Correlated Photons with 3.2 um Wavelength Spacing.

Quantum correlated, highly non-degenerate photons can be used to synthesize disparate quantum nodes and link quantum processing over incompatible wavelengths, thereby constructing heterogeneous quantum systems for otherwise unattainable superior performance. Existing techniques for correlated photons have been concentrated in the visible and near-IR domains, with the photon pairs residing within one micron. Here, we demonstrate direct generation and detection of high-purity photon pairs at room temperature with 3.2 um wavelength spacing, one at 780 nm to match the rubidium D2 line, and the other at 3950 nm that falls in a transparent, low-scattering optical window for free space applications. The pairs are created via spontaneous parametric downconversion in a lithium niobate waveguide with specially designed geometry and periodic poling. The 780 nm photons are measured with a silicon avalanche photodiode, and the 3950 nm photons are measured with an upconversion photon detector using a similar waveguide, which attains 34% internal conversion efficiency. Quantum correlation measurement yields a high coincidence-to-accidental ratio of 54, which indicates the strong correlation with the extremely non-degenerate photon pairs. Our system bridges existing quantum technology to the challenging mid-IR regime, where unprecedented applications are expected in quantum metrology and sensing, quantum communications, medical diagnostics, and so on.

Observation of Quantum Zeno Blockade on Chip.

Overlapping in an optical medium with nonlinear susceptibilities, lightwaves can interact, changing each other's phase, wavelength, waveform shape, or other properties. Such nonlinear optical phenomena, discovered over a half-century ago, have led to a breadth of important applications. Applied to quantum-mechanical signals, however, these phenomena face fundamental challenges that arise from the multimodal nature of the interaction between the electromagnetic fields, such as phase noises and spontaneous Raman scattering. The quantum Zeno blockade allows strong interaction between lightwaves without physical overlap between them, thus offering a viable solution for the aforementioned challenges, as indicated in recent bulk-optics experiments. Here, we report on the observation of quantum Zeno blockade on chip, where a lightwave is modulated by another in a distinct "interaction-free" manner. For quantum applications, we also verify its operations on single-photon signals. Our results promise a scalable platform for overcoming several longstanding challenges in applied nonlinear and quantum optics, enabling manipulation and interaction of quantum signals without decoherence.

Strategies for Isolation and Molecular Profiling of Circulating Tumor Cells.

Cancer is the leading cause of death by disease worldwide, and metastasis is responsible for more than 90% of the mortality of cancer patients. Metastasis occurs when tumor cells leave the primary tumor, travel through the blood stream as circulating tumor cells (CTCs), and then colonize secondary tumors at sites distant from the primary tumor. The capture, identification, and analysis of CTCs offer both scientific and clinical benefits. On the scientific side, the analysis of CTCs could help elucidate possible genetic alterations and signaling pathway aberrations during cancer progression, which could then be used to find new methods to stop cancer progression. On the clinical side, non-invasive testing of a patient's blood for CTCs can be used for patient diagnosis and prognosis, as well as subsequent monitoring of treatment efficacy in routine clinical practice. Additionally, investigation of CTCs early in the progression of cancer may reveal targets for initial cancer detection and for anti-cancer treatment. This chapter will evaluate strategies and devices used for the isolation and identification of CTCs directly from clinical samples of blood. Recent progress in the understanding of the significance of both single CTCs and circulating tumor microemboli will be discussed. Also, advancements in the use of CTC-based liquid biopsy in clinical diagnosis and the potential of CTC-based molecular characterization for use in clinical applications will be summarized.

Sensitive and Specific Biomimetic Lipid Coated Microfluidics to Isolate Viable Circulating Tumor Cells and Microemboli for Cancer Detection.

Here we presented a simple and effective membrane mimetic microfluidic device with antibody conjugated supported lipid bilayer (SLB) "smart coating" to capture viable circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) directly from whole blood of all stage clinical cancer patients. The non-covalently bound SLB was able to promote dynamic clustering of lipid-tethered antibodies to CTC antigens and minimized non-specific blood cells retention through its non-fouling nature. A gentle flow further flushed away loosely-bound blood cells to achieve high purity of CTCs, and a stream of air foam injected disintegrate the SLB assemblies to release intact and viable CTCs from the chip. Human blood spiked cancer cell line test showed the ~95% overall efficiency to recover both CTCs and CTMs. Live/dead assay showed that at least 86% of recovered cells maintain viability. By using 2 mL of peripheral blood, the CTCs and CTMs counts of 63 healthy and colorectal cancer donors were positively correlated with the cancer progression. In summary, a simple and effective strategy utilizing biomimetic principle was developed to retrieve viable CTCs for enumeration, molecular analysis, as well as ex vivo culture over weeks. Due to the high sensitivity and specificity, it is the first time to show the high detection rates and quantity of CTCs in non-metastatic cancer patients. This work offers the values in both early cancer detection and prognosis of CTC and provides an accurate non-invasive strategy for routine clinical investigation on CTCs.

Clinical Significance of Circulating Tumor Microemboli as a Prognostic Marker in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Characterization of circulating tumor cells (CTCs) has been used to provide prognostic, predictive, and pharmacodynamic information in many different cancers. However, the clinical significance of CTCs and circulating tumor microemboli (CTM) in patients with pancreatic ductal adenocarcinoma (PDAC) has yet to be determined. METHODS: In this prospective study, CTCs and CTM were enumerated in the peripheral blood of 63 patients with PDAC before treatment using anti-EpCAM (epithelial cell adhesion molecule)-conjugated supported lipid bilayer-coated microfluidic chips. Associations of CTCs and CTM with patients' clinical factors and prognosis were determined. RESULTS: CTCs were abundant [mean (SD), 70.2 (107.6)] and present in 81% (51 of 63) of patients with PDAC. CTM were present in 81% (51 of 63) of patients with mean (SD) 29.7 (1101.4). CTM was an independent prognostic factor of overall survival (OS) and progression free survival (PFS). Patients were stratified into unfavorable and favorable CTM groups on the basis of CTM more or less than 30 per 2 mL blood, respectively. Patients with baseline unfavorable CTM, compared with patients with favorable CTM, had shorter PFS (2.7 vs 12.1 months; P < 0.0001) and OS (6.4 vs 19.8 months; P < 0.0001). Differences persisted if we stratified patients into early and advanced diseases. The number of CTM before treatment was an independent predictor of PFS and OS after adjustment for clinically significant factors. CONCLUSIONS: The number of CTM, instead of CTCs, before treatment is an independent predictor of PFS and OS in patients with PDAC.

Kocuria subflava sp. nov., isolated from marine sediment from the Indian Ocean.

A novel Gram-staining positive, catalase-positive, oxidase-negative, aerobic, non-motile coccus, designated strain YIM 13062(T), was isolated from a marine sediment sample collected from the Indian Ocean. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain YIM 13062(T) belongs to the genus Kocuria, and is closely related to Kocuria polaris NBRC 103063(T) (97.8 % similarity), Kocuria rosea NBRC 3768(T) (97.6 % similarity) and Kocuria carniphila JCM 14118(T) (97.4 % similarity). The strain grew optimally at 28 °C, pH 8.0 and in the presence of 2-4 % (w/v) NaCl. Cell-wall peptidoglycan type was Lys-Ala3 (type A3α). The major isoprenoid quinones were MK-6(H2) and MK-7(H2). The polar lipids of strain YIM 13062(T) consisted of diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), one unidentified phospholipid (PL), one unidentified aminophospholipid (APL), two unidentified aminolipids (AL) and four unidentified lipids (L). Major fatty acids of the novel isolate were anteiso-C15:0, iso-C14:0 and C18:1 2OH. The genomic DNA G+C content of strain YIM 13062(T) was 68.0 mol%. The level of DNA-DNA relatedness between strain YIM 13062(T) and K. polaris NBRC 103063(T), K. rosea NBRC 3768(T), K. carniphila JCM 14118(T) were 53.2, 48.8 and 42.6 %, respectively. On the basis of genotypic and phenotypic data, it is apparent that strain YIM 13062(T) represents a novel species of the genus Kocuria, for which the name Kocuria subflava sp. nov. is proposed. The type strain is YIM 13062(T) (=CGMCC 4.7252(T)=KCTC 39547(T)).

A synthetic podophyllotoxin derivative exerts anti-cancer effects by inducing mitotic arrest and pro-apoptotic ER stress in lung cancer preclinical models.

Some potent chemotherapy drugs including tubulin-binding agents had been developed from nature plants, such as podophyllotoxin and paclitaxel. However, poor cytotoxic selectivity, serious side-effects, and limited effectiveness are still the major concerns in their therapeutic application. We developed a fully synthetic podophyllotoxin derivative named Ching001 and investigated its anti-tumor growth effects and mechanisms in lung cancer preclinical models. Ching001 showed a selective cytotoxicity to different lung cancer cell lines but not to normal lung cells. Ching001 inhibited the polymerization of microtubule resulting in mitotic arrest as evident by the accumulation of mitosis-related proteins, survivin and aurora B, thereby leading to DNA damage and apoptosis. Ching001 also activated pro-apoptotic ER stress signaling pathway. Intraperitoneal injection of 2 mg/kg Ching001 significantly inhibited the tumor growth of A549 xenograft, while injection of 0.2 mg/kg Ching001 decreased the lung colonization ability of A549 cells in experimental metastasis assay. These anti-tumor growth and lung colonization inhibition effects were stronger than those of paclitaxel treatment at the same dosage. The xenograft tumor tissue stains further confirmed that Ching001 induced mitosis arrest and tumor apoptosis. In addition, the hematology and biochemistry tests of blood samples as well as tissue examinations indicated that Ching001 treatment did not show apparent organ toxicities in tested animals. We provided preclinical evidence that novel synthetic microtubule inhibitor Ching001, which can trigger DNA damage and apoptosis by inducing mitotic arrest and ER stress, is a potential anti-cancer compound for further drug development.