A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

Predicting lncRNA-disease associations based on combining selective similarity matrix fusion and bidirectional linear neighborhood label propagation.

Recent studies have revealed that long noncoding RNAs (lncRNAs) are closely linked to several human diseases, providing new opportunities for their use in detection and therapy. Many graph propagation and similarity fusion approaches can be used for predicting potential lncRNA-disease associations. However, existing similarity fusion approaches suffer from noise and self-similarity loss in the fusion process. To address these problems, a new prediction approach, termed SSMF-BLNP, based on organically combining selective similarity matrix fusion (SSMF) and bidirectional linear neighborhood label propagation (BLNP), is proposed in this paper to predict lncRNA-disease associations. In SSMF, self-similarity networks of lncRNAs and diseases are obtained by selective preprocessing and nonlinear iterative fusion. The fusion process assigns weights to each initial similarity network and introduces a unit matrix that can reduce noise and compensate for the loss of self-similarity. In BLNP, the initial lncRNA-disease associations are employed in both lncRNA and disease directions as label information for linear neighborhood label propagation. The propagation was then performed on the self-similarity network obtained from SSMF to derive the scoring matrix for predicting the relationships between lncRNAs and diseases. Experimental results showed that SSMF-BLNP performed better than seven other state of-the-art approaches. Furthermore, a case study demonstrated up to 100% and 80% accuracy in 10 lncRNAs associated with hepatocellular carcinoma and 10 lncRNAs associated with renal cell carcinoma, respectively. The source code and datasets used in this paper are available at: https://github.com/RuiBingo/SSMF-BLNP.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

Near 2π solid angle fluorescence collection for laser-induced breakdown spectroscopy.

Detecting heavy metal and radioactive elements distributed in the environment and human body is crucial for life and environmental safety. A lens with a high numerical aperture (NA) is used in laser-induced breakdown spectroscopy to collect the plasma fluorescence as much as possible and improve the limit of detection. However, even a lens with NA up to 0.6, only the fluorescence in a solid angle of 0.4π can be collected. In this work, a novel, to our knowledge, fluorescence collecting scheme composed of a parabolic mirror and a lens is proposed which can collect the plasma fluorescence in a solid angle of ∼1.4π for an opaque material and ∼1.9π for a transparent material. Simulation results show that for opaque samples, this method can improve the fluorescence collection ability by 3.8 times compared to a single lens (NA = 0.5) collection scheme, and for transparent samples 4.5 times may be achieved. In experiments, a 2.8-fold enhancement in the fluorescence collection ability is demonstrated, and the signal-to-noise ratio is increased by 2.5 times for opaque samples.

Coupled air lasing gain and Mie scattering loss: an aerosol effect in filament-induced plasma spectroscopy.

Femtosecond laser filament-induced plasma spectroscopy (FIPS) demonstrates great potential in remote sensing for identifying atmospheric pollutant molecules. Due to the widespread aerosols in the atmosphere, remote detection based on FIPS would be affected by both the excitation and the propagation of fingerprint fluorescence, which still remain elusive. Here the physical model of filament-induced aerosol fluorescence is established to reveal the combined effect of Mie scattering and amplification spontaneous emission, which is subsequently proven by experimental results, the dependence of the backward fluorescence on the interaction length between filaments and aerosols. These findings provide an insight into the complicated aerosol effect in the overall physical process of FIPS including propagation, excitation, and emission, paving the way to its practical application in atmospheric remote sensing.

Polo-like kinase 1 inhibitor NMS-P937 represses nasopharyngeal carcinoma progression via induction of mitotic abnormalities.

Polo-like kinase 1 (PLK1) inhibitor NMS-P937 is a targeted therapeutic agent with good preclinical efficacy in various human cancers, and its therapeutic effect on nasopharyngeal carcinoma (NPC) remains to be determined. Here, to explore biological activity of NMS-P937 in NPC, multiple types of NPC cells were utilized. We tested IC50 values, carried out flow cytometry, western blot analysis analysis, immunofluorescence, and constructed subcutaneous xenograft mouse models. We found that treatment with NMS-P937 increased the proportion of G2/M phase NPC cells, where CyclinB1 expression was upregulated and CyclinE1 expression was downregulated. Besides, NMS-P937 treatment-induced NPC cell apoptosis with increased cleavage of PARP and caspase-3. Mechanistically, NMS-P937 treatment led to aberrant mitosis, causing increased reactive oxygen species (ROS) levels. ROS scavenger N-acetylcysteine partially reversed ROS levels induced by NMS-P937. Furthermore, NMS-P937 administration restrained NPC xenografts growth in nude mice. Overall, NMS-P937 suppressed NPC cell proliferation and increased ROS levels, causing cell cycle abnormalities and apoptosis. NMS-P937 holds great promise as a therapeutic agent for treating nasopharyngeal carcinoma.

Multi-functional terahertz metamaterials based on nano-imprinting.

This paper reports a multi-functional terahertz (THz) metamaterial based on a nano-imprinting method. The metamaterial is composed of four layers: 4 L resonant layer, dielectric layer, frequency selective layer, and dielectric layer. The 4 L resonant structure can achieve broadband absorption, while the frequency selective layer can achieve transmission of specific band. The nano-imprinting method combines electroplating of nickel mold and printing of silver nano-particle ink. Using this method, the multilayer metamaterial structures can be fabricated on ultrathin flexible substrates to achieve visible light transparency. For verification, a THz metamaterial with broadband absorption in low frequency and efficient transmission in high frequency is designed and printed. The sample's thickness is about 200 µm and area is 65 × 65 mm2. Moreover, a fiber-based multi-mode terahertz time-domain spectroscopy system was built to test its transmission and reflection spectra. The results are consistent with the expectations.

Detection of 1.4 µg/m3 Na+ in aerosol at a 30 m distance using 1 kHz femtosecond laser filamentation in air.

An optimized remote material detection scheme based on the laser filament-induced plasma spectroscopy and light detection and ranging (FIPS-LIDAR) is proposed in this work. The elemental composition and concentration of aerosol are measured by FIPS-LIDAR. By focusing the femtosecond laser with a large aperture (Φ41 cm) concave mirror and coaxial fluorescence collection scheme, the remote detection of aerosol in air at µg/m3 level has been realized at a distance of 30 m. The limit of detection for Na+ in aerosol droplets is 8 ppm (3 µg/m3 in air), which is the lowest detection limit that has been reported using millijoule femtosecond laser pulse (4.4 mJ). Furthermore, using spectral preprocessing and optimization of the proposed significance of peak (SOP) algorithm, feature peak signals are extracted from weak signals and the limit of detection can be further decreased to 1.4 µg/m3.

Sub-ppb NaCl aerosol detection at a distance of 30 meters by femtosecond laser induced plasma spectroscopy.

In this work, sub-ppb aerosol detection is achieved by femtosecond laser filament with a single pulse energy of 4 mJ at a distance of 30 m. A concave mirror with an open aperture of 41.4 cm is employed in an off-axis optical system to focus the femtosecond laser beam and collect the fluorescence of NaCl aerosol. The simulation and experimental results show that the astigmatism can be greatly reduced when femtosecond laser beam is incident non-symmetrically on the concave mirror. Compared with the case that femtosecond laser strikes at the center of the concave mirror, the intensity of acoustic signal emitted from the optical filament is increased by 69.5 times, and the detection of limit of sodium element in aerosol is reduced by 86%, which is down to 0.32 ppb. The improved excitation scheme in this work utilizes the nonsymmetrical beam spot on the concave mirror to compensate the non-symmetry induced by the off-axis setup, reducing the astigmatism of the focusing laser beam and decreasing the sodium chloride aerosol's detection of limit.

Galgravin Isolated from Piper kadsura Ameliorates Lipopolysaccharide (LPS)-Induced Endotoxemia in Mice.

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases.

Giant enhancement of acoustic and fluorescence emission from an off-axis reflective femtosecond laser filamentation system.

Femtosecond laser filamentation propagating tens of meters to several kilometers with high intensity in the atmosphere has been demonstrated as a powerful tool for remote sensing. In contrast to the refractive systems, the reflective optical systems possess a variety of advantages including broad bandwidth, large aperture, light weight and low energy loss. However, astigmatic aberration is inevitably introduced by off-axis reflective mirrors. It can greatly affect the filament quality, which is critical for exciting and detecting the fluorescence of target molecules. Here we elaborately design a free-form phase plate to correct the astigmatism in off-axis reflective optical systems. It is demonstrated that the free-form surface exhibits excellent performance, significantly reducing the astigmatic difference from 44 cm to 4 cm and increasing the maximum acoustic intensity by a factor of 53. In addition, extremely strong nitrogen fluorescence spectra have been detected. These results indicate that the free-form phase plate can effectively compensate for astigmatic aberration in off-axis reflective system, providing a guiding significance for the optimal control of filamentation and remote sensing.

Effect of laser repetition rate on the fluorescence characteristic of a long-distance femtosecond laser filament.

In this paper, the effect of the laser repetition rate on the long-distance femtosecond laser filament in air is investigated by measuring the fluorescence characteristic of the filament. A femtosecond laser filament emits fluorescence due to the thermodynamical relaxation of the plasma channel. Experimental results show that as the repetition rate of femtosecond laser increases, the fluorescence of the filament induced by a single laser pulse weakens, and the position of the filament moves away from the focusing lens. These phenomena may be attributed to the slow hydrodynamical recovery process of air after being excited by a femtosecond laser filament, whose characteristic time is on the millisecond time scale and comparable to the inter-pulse duration of the femtosecond laser pulse train. This finding suggests that at a high laser repetition rate, to generate an intense laser filament, the femtosecond laser beam should scan across the air to eliminate the adverse effect of slow air relaxation, which is beneficial to laser filament remote sensing.

Beam Wander Restrained by Nonlinearity of Femtosecond Laser Filament in Air.

The filamentation process under atmospheric turbulence is critical to its remote-sensing application. The effects of turbulence intensity and location on the spatial distribution of femtosecond laser filaments in the air were studied. The experimental results show that the nonlinear effect of the filament can restrain the beam wander. When the turbulence intensity was 3.31×10−13 cm−2/3, the mean deviation of the wander of the filament center was only 27% of that of the linear transmitted beam. The change in turbulence location would lead to a change in the standard deviation of the beam centroid drift. Results also show that the filament length would be shortened, and that the filament would end up earlier in a turbulent environment. Since the filamentation-based LIDAR has been highly expected as an evolution multitrace pollutant remote-sensing technique, the study promotes our understanding of how turbulence influences filamentation and advances atmospheric remote sensing by applying a filament.

Investigation of Focusing Properties on Astigmatic Gaussian Beams in Nonlinear Medium.

Ultra-short laser filamentation has been intensively studied due to its unique optical properties for applications in the field of remote sensing and detection. Although significant progress has been made, the quality of the laser beam still suffers from various optical aberrations during long-range transmission. Astigmatism is a typical off-axis aberration that is often encountered in the off-axis optical systems. An effective method needs to be proposed to suppress the astigmatism of the beam during filamentation. Herein, we numerically investigated the impact of the nonlinear effects on the focusing properties of the astigmatic Gaussian beams in air and obtained similar results in the experiment. As the single pulse energy increases, the maximum on-axis intensity gradually shifted from the sagittal focus to the tangential focus and the foci moved forward simultaneously. Moreover, the astigmatism could be suppressed effectively with the enhancement of the nonlinear effects, that is, the astigmatic difference and the degree of beam distortion were both reduced. Through this approach, the acoustic intensity of the filament (located at the tangential focal point) increased by a factor of 22.8. Our work paves a solid step toward the practical applications of the astigmatism beam as the nonlinear lidar.

Sensing with Femtosecond Laser Filamentation.

Femtosecond laser filamentation is a unique nonlinear optical phenomenon when high-power ultrafast laser propagation in all transparent optical media. During filamentation in the atmosphere, the ultrastrong field of 1013-1014 W/cm2 with a large distance ranging from meter to kilometers can effectively ionize, break, and excite the molecules and fragments, resulting in characteristic fingerprint emissions, which provide a great opportunity for investigating strong-field molecules interaction in complicated environments, especially remote sensing. Additionally, the ultrastrong intensity inside the filament can damage almost all the detectors and ignite various intricate higher order nonlinear optical effects. These extreme physical conditions and complicated phenomena make the sensing and controlling of filamentation challenging. This paper mainly focuses on recent research advances in sensing with femtosecond laser filamentation, including fundamental physics, sensing and manipulating methods, typical filament-based sensing techniques and application scenarios, opportunities, and challenges toward the filament-based remote sensing under different complicated conditions.

Nonlinear optical properties of human cornea measured by spectral domain Z-scan method.

In the myopia correction surgery by femtosecond laser, such as Laser in Situ Keratomileusis (LASIK) and Small Incision Lenticule Extraction (SMILE), the nonlinear refractive index of the cornea may cause the deviation of cutting depth. In order to improve the cornea cutting's accuracy and reduce the possibility of undercorrection, the nonlinear refractive index coefficient n2 of the human cornea must be measured with high accuracy. The spectral domain Z-scan technique can measure n2 of the highly scattering biological tissues with much better signal to noise ratio and thus better accuracy than the conventional methods. In this paper, the n2 coefficient of one ex-vivo human corneal sample was measured by the spectral domain Z-scan technique. Experimental results show that as this corneal sample gradually dehydrates, its n2 coefficients are 1.1 ± 0.1×10-19 m2/W, 1.4 ± 0.2×10-19 m2/W and 1.6 ± 0.2 ×10-19 m2/W respectively for the corneal sample with water contents of 89%, 82%, and 78%. The increase of the water content reduces the value of n2, which is reasonable since the nonlinear refractive index coefficient of water is one order of magnitude smaller than that of the cornea.

Curved periodic ripples fabricated by double time-delayed femtosecond laser beams on the silicon surface.

Laser-induced periodic surface structure (LIPSS) is an important, high-throughput surface nano-structuring method, which has been used to fabricate various functional surfaces. In this paper, we fabricate double time-delayed orthogonally polarized femtosecond laser beams with a fixed beam power ratio of 1.5:1 that are employed to irradiate the silicon surface and curved periodic ripples with a sub-wavelength period. It is found that the local orientation of the ripples on the silicon surface can be modulated in a range of 0-80° by adjusting the fabrication parameters, such as the laser fluence, the target scanning speed, and the time delay between double laser beams. The transition from the curved ripples to the straight ripples can be achieved by increasing the target scanning speed. Different from previous studies that the curved periodic ripples are fabricated by modulating the laser polarization, the method demonstrated here utilizes the interaction between the linearly polarized subsequent laser beam and the preceding laser beam excited silicon to form curved ripples.

Targeting the KDM4B-AR-c-Myc axis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer.

The histone demethylase KDM4B functions as a key co-activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti-androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next-generation anti-androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide-resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c-Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA, which regulates the sensitivity to next-generation AR-targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c-Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti-androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR-dependent c-Myc expression and overcome resistance to AR-targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Diterpenoid Compounds Isolated from Chloranthus oldhamii Solms Exert Anti-Inflammatory Effects by Inhibiting the IKK/NF-κB Pathway.

Chloranthus oldhamii Solms (CO) is a folk medicine for treating infection and arthritis pain but its pharmacological activity and bioactive compounds remain mostly uncharacterized. In this study, the anti-inflammatory compounds of C. oldhamii were identified using an LPS-stimulated, NF-κB-responsive RAW 264.7 macrophage reporter line. Three diterpenoid compounds, 3α-hydroxy-ent-abieta-8,11,13-triene (CO-9), 3α, 7ß-dihydroxy-ent-abieta-8,11,13-triene (CO-10), and decandrin B (CO-15) were found to inhibit NF-κB activity at nontoxic concentrations. Moreover, CO-9 and CO-10 suppressed the expression of IL-6 and TNF-α in LPS-stimulated RAW 264.7 cells. The inhibitory effect of CO-9 on TNF-α and IL-6 expression was further demonstrated using LPS-treated bone marrow-derived macrophages. Furthermore, CO-9, CO-10, and CO-15 suppressed LPS-triggered COX-2 expression and downstream PGE2 production in RAW 264.7 cells. CO-9 and CO-10 also reduced LPS-triggered iNOS expression and nitrogen oxide production in RAW 264.7 cells. The anti-inflammatory mechanism of the most effective compound, CO-9, was further investigated. CO-9 attenuated LPS-induced NF-κB activation by reducing the phosphorylation of IKKα/ß (Ser176/180), IκBα (Ser32), and p65 (Ser534). Conversely, CO-9 did not affect the LPS-induced activation of MAPK signaling pathways. In summary, this study revealed new anti-inflammatory diterpenoid compounds from C. oldhamii and demonstrated that the IKK-mediated NK-κB pathway is the major target of these compounds.

Comparative biotransformation of luteolin and apigenin from the flower extract and the stem-and-leaf extract of Dendranthema morifolium Ramat. Tzvel. in rats.

BACKGROUND: The flower of Dendranthema morifolium Ramat Tzvel has been widely used as a nutritional health supplement worldwide. However, most of the studies have focused on the flower and the rest of the plant was neglected. Our hypothesis is that similar flavonoids may be present at different parts of D. morifolium, and the flavonoids may undergo a similar biotransformation pathway within the body. To investigate this hypothesis, an in vivo pharmacokinetic experimental model was developed to explore the comparative biotransformation of luteolin and apigenin after administration of D. morifolium extracts (10 g kg-1 , p.o.) in freely moving rats. Because luteolin and apigenin mainly underwent phase II metabolism, the metabolic enzymes of ß-glucuronidase/sulfatase or ß-glucuronidase were used to hydrolyze the plasma sample, depending on the biotransformation pathway involved. RESULTS: The results revealed that luteolin and apigenin mainly went through glucuronide and sulfate conjugations, respectively, in both the extract of flowers and the stem-and-leaf group. In addition, the area under the concentration curve (AUClast ) of luteolin glucuronides and sulfates in the group administered the stem-and-leaf extract was approximately 4.6 times higher than that of the flower extract group. The dominant products of biotransformation for apigenin were sulfates. CONCLUSION: These findings support our hypothesis that not only the flower parts of D. morifolium, but also the stem-and-leaf parts contain rich flavones, including glycosides and aglycone, and they undergo similar biotransformation pathways. © 2021 Society of Chemical Industry.