Biomarkers and coptis chinensis activity for rituximab-resistant diffuse large B-cell lymphoma: Combination of bioinformatics analysis, network pharmacology and molecular docking.

BACKGROUND: Rituximab resistance is one of the great challenges in the treatment of diffuse large B-cell lymphoma (DLBCL), but relevant biomarkers and signalling pathways remain to be identified. Coptis chinensis and its active ingredients have antitumour effects; thus, the potential bioactive compounds and mechanisms through which Coptis chinensis acts against rituximab-resistant DLBCL are worth exploring. OBJECTIVE: To elucidate the core genes involved in rituximab-resistant DLBCL and the potential therapeutic targets of candidate monomers of Coptis chinensis. METHODS: Using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), the Similarity Ensemble Approach and Swiss Target Prediction, the main ingredients and pharmacological targets of Coptis chinensis were identified through database searches. Through the overlap between the pharmacological targets of Coptis chinensis and the core targets of rituximab-resistant DLBCL, we identified the targets of Coptis chinensis against rituximab-resistant DLBCL and constructed an active compound-target interaction network. The targets and their corresponding active ingredients of Coptis chinensis against rituximab-resistant DLBCL were molecularly docked. RESULTS: Berberine, quercetin, epiberberine and palmatine, the active components of Coptis chinensis, have great potential for improving rituximab-resistant DLBCL via PIK3CG. CONCLUSION: This study revealed biomarkers and Coptis chinensis-associated molecular functions for rituximab-resistant DLBCL.

Immunogenic Cell Death-related Signature Evaluates the Tumor Microenvironment and Predicts the Prognosis in Diffuse Large B-Cell Lymphoma.

Current literatures suggest a growing body of evidence highlighting the pivotal role of Immunogenic Cell Death (ICD) in multiple tumor types. Nevertheless, the potential and mechanisms of ICD in diffuse large B-cell lymphoma (DLBCL) remain inadequately studied. To address this gap, our current study aims to examine the impact of ICD on DLBCL and identify a corresponding gene signature in DLBC. Using the expression profiles of ICD-associated genes, the gene expression omnibus (GEO) samples were segregated into ICD-high and ICD-low subtypes utilizing non-negative matrix factorization clustering. Next, univariate and LASSO Cox regression analyses were employed to establish the ICD-related gene signature. Subsequently, the CIBERSORT tool, ssGSEA, and ESTIMATE algorithm were utilized to examine the association between the signature and tumor immune microenvironment of DLBC. Finally, the oncoPredict algorithm was implemented to evaluate the drug sensitivity prediction of DLBCL patients. These findings suggest that the immune microenvironment of the ICD-high group with a poor prognosis was significantly suppressed. An 8-gene ICD-related signature was identified and validated to prognosticate and evaluate the tumor immune microenvironment in DLBCL. Similarly, the high-risk group exhibited a worse prognosis compared to the low-risk group, and the immune function was considerably suppressed. Moreover, the results of oncoPredict algorithm indicated that patients in the high-risk group exhibited higher sensitivity to Cisplatin, Cytarabine, Epirubicin, Oxaliplatin, and Vincristine with low IC50. In conclusion, the present study provides novel insights into the role of ICD in DLBCL by identifying a new biomarker for the disease and may have implications for the development of immune-targeted therapies for the tumor.

Gender-Specific Health-Adjusted Life Expectancy of Type 2 Diabetes Mellitus Among the Rural Elderly Population.

Objectives: This study aimed to estimate the life expectancy (LE) and health-adjusted life expectancy (HALE) of type 2 diabetes mellitus (T2DM) among the rural elderly population. Methods: A total of 10,318 participants aged 65 to 79 were derived from the Henan Rural Cohort. The LE and HALE were calculated via the Sullivan method and multistate life table. Results: Among 10,318 subjects, 1,325 suffered from T2DM at the baseline, and 394 participants had newly-developed T2DM. The results from the Sullivan method showed that the LE, HALE, and HALE/LE were 17.98, 16.18 years, and 89.95% for men aged 65 to 69, and the corresponding estimates for women were 21.81, 18.73 years, and 85.86%, respectively. The LE, HALE and HALE/LE calculated via multistate life table were 19.86, 17.53 years, and 88.29% for men at aged 65, and the corresponding values for women were 25.01, 20.87 years, and 83.44%, respectively. Conclusion: Rural elderly women have a longer LE and HALE of T2DM, but they have lower quality of life than men. More attention should be paid to T2DM among rural elderly people, especially in women. Clinical Trial Registration: The Henan Rural Cohort Study has been registered at Chinese Clinical Trial Register (Registration number: ChiCTR-OOC-15006699). Date of registration: 06 July 2015. http://www.chictr.org.cn/showproj.aspx?proj=11375.

Massive laser pulling of graphene nanosheets in water.

Light manipulation of graphene-based materials attracts much attentions. As a new light manipulation concept, optical pulling develops rapidly in the past decade. However, optical pulling of graphene in liquid is rarely reported. In this work, laser pulling of graphene nanosheets (GN) in pure water by using common gauss beams is presented. This phenomenon holds for multiple incident laser wavelengths including 405 nm, 488 nm, 532 nm and 650 nm. A particle image velocimetry software PIVlab is adopted to analyze the velocity field information of GN. The laser pulling velocity of the GN is approximately ∼ 0.5 mm/s corresponding to ∼ 103 body length/s, which increases with an increase of the incident laser energy. This work presents a contactless mothed to massively pull microscale graphene materials in simple liquid, which supplies a potential manipulation technique for micro-nanofluidic devices and also provides a platform to investigate laser-graphene interaction in a simple liquid phase medium.

An HPK1 inhibitor enhanced the tumour response to anti-PD-1 immunotherapy in non-Hodgkin's lymphoma.

Anti-PD-1 immunotherapy has been widely applied in patients with some types of lymphoma. Classical Hodgkin's lymphoma (cHL) is highly sensitive to immunotherapy, but non-Hodgkin's lymphoma (NHL) does not show a good response. Studies have indicated that haematopoietic progenitor kinase 1 (HPK1) suppresses T cells and reduces antitumour immunity. Therefore, HPK1 inhibitors may restore and elicit antitumour immune responses and are promising candidate drug targets for cancer immunotherapy. We first explored the Gene Expression Profile Interactive Analysis (GEPIA) database and predicted that HPK1 expression was increased in diffuse large B-cell lymphoma (DLBCL) and associated with Nod-like receptor protein 3 (NLRP3) expression. We investigated whether an HPK1 inhibitor could enhance the tumour response to anti-PD-1 immunotherapy in NHL and the association between HPK1 and NLRP3 expression. Employing shHPK1 and an inhibitor, we demonstrated that the HPK1 inhibitor increased anti-PD-1-mediated T-cell cytotoxicity in BJAB and WSU-DLCL2 cells cocultured with peripheral blood mononuclear cells (PBMCs). HPK1 inhibitor treatment increased PD-1, PD-L1, Bax, p53 and NK-kB expression but decreased NLRP3 expression, indicating that the HPK1 inhibitor promoted apoptosis and blocked the NLRP3 inflammasome pathway to affect anti-PD-1-mediated T-cell cytotoxicity. Moreover, the HPK1 inhibitor enhanced the efficiency of anti-PD-1 immunotherapy in vivo in a zebrafish xenograft model of NHL. In summary, this study provides evidence that an HPK1 inhibitor enhanced the tumour response to anti-PD-1 immunotherapy in NHL by promoting apoptosis and blocking the NLRP3 pathway. These findings provide a potential therapeutic option for NHL combining HPK1 inhibitor treatment and anti-PD-1 immunotherapy.

Cost-effectiveness analysis of adding durvalumab to chemotherapy as first-line treatment for advanced biliary tract cancer based on the TOPAZ-1 trial.

BACKGROUND: Durvalumab plus gemcitabine and cisplatin has a significant clinical benefit for advanced biliary tract cancer (BTC). However, the high price of durvalumab warrants an exploration of the economics. OBJECTIVE: To investigate the cost-effectiveness of adding durvalumab to gemcitabine and cisplatin compared with gemcitabine and cisplatin in first-line therapy of advanced BTC from the perspective of the Chinese healthcare system. METHODS: According to the TOPAZ-1 trial, a three-state Markov model was built by the TreeAge Pro 2022 software. The total costs and quality-adjusted life years (QALYs) were estimated, and the incremental cost-effectiveness ratio (ICER) was used as the evaluation index. The triple 2021 Chinese per capita gross domestic product (GDP) of $37,663.26/QALY was used as the willingness-to-pay (WTP) threshold. Outputs were analyzed for two scenarios with and without a durvalumab drug charity assistance policy. In the scenario analysis, the base-case model was run multiple times with different prices of durvalumab to determine the effect on the ICER. Moreover, the robustness of the model was tested through sensitivity analyses. RESULTS: Compared with chemotherapy alone, durvalumab plus chemotherapy resulted in an additional 0.12 QALY and an incremental cost of $18,555.19, the ICER was $159,644.70/QALY under the situation of charity assistance, and the ICER was $696,571.11/QALY without charity assistance, both exceeding the WTP threshold in China. The scenario analysis demonstrated that when the price of durvalumab fell by more than 94.2% to less than $0.33/mg, durvalumab plus chemotherapy will be more economical compared with chemotherapy alone under the situation of no charity assistance. One-way sensitivity analyses suggested that the cost of durvalumab had the greatest influence on the ICERs, and the probabilistic sensitivity analyses demonstrated that durvalumab plus chemotherapy was impossible to be cost-effective at the WTP threshold whether the charity assistance was available or not. CONCLUSIONS: Adding durvalumab to gemcitabine and cisplatin was not cost-effective for advanced BTC regardless of receiving and not receiving charitable assistance.

Characterizations for the photothermal effect of Rhodamine 6G using white-light interferometry and windowed Fourier transform.

Photothermal phenomenon is one of the natural responses in light-matter interactions in which the energy of the incident light is converted into heat, resulting in a temperature increase in the illuminated material. This effect has a direct influence on the refractive index of the material such that its change of spectral dependency with temperature can be exploited for different applications. However, it is also important to separate/identify the thermal effect from the optical/electronic resonance effect to expand potential applications of light-matter interactions. In this work, we demonstrate the use of a white-light interferometry approach combined with a windowed Fourier transform method and a consistency-checking peak-fitting method to obtain the refractive index of an Rh6G-ethanol dye solution with a sensitivity of about ∼10-6 (RIU) for the visible range. Moreover, we also perform both static and dynamic measurements to study the photothermal effect of the Rh6G solution under external excitation. Importantly, we separate the optical and thermal effects due to the external excitation and obtain very good agreement with the experimental results by modeling the relative refractive index of the Rh6G solution with an expression consisting of spectrally a Fano-like resonance term and a linear dependent thermal term. We find that the response due to the optical effect is about ∼0.2 × 10-3 of that due to the thermal effect in the low-light regime. Our approach to separating the optical and thermal effects could shed light on other fields for potential applications through precision measurements of the transmission phase or refractive index.

Macroscopic laser pulling based on the Knudsen force in rarefied gas.

Optical pulling is an attractive concept due to the counterintuitive feature, the profound mechanism underneath and promising applications. In recent ten years, optical pulling of micro-nano objects have been fully demonstrated. However, optical pulling of a macroscopic object is challenging. Herein, laser pulling of a macroscopic object is presented in rarefied gas. The pulling force is originated from the Kundsen force when a gauss laser beam irradiates a macroscopic structure composed of the absorptive bulk cross-linked graphene material and a SiO2 layer. A torsional pendulum device qualitatively presents the laser pulling phenomenon. A gravity pendulum device was used to further measure the pulling force that is more than three orders of magnitudes larger than the radiation pressure. This work expands the scope of optical pulling from microscale to macroscale and provides an effective technique approach for macroscopic optical manipulations.

Quantitative evaluation of traditional Chinese medicine development policy: A PMC index model approach.

Background: Traditional Chinese medicine development policies (TCMDPs) are essential in improving the sustainable development of TCM undertakings, of which transmissions of policy information are closely related to the actual policy effectiveness. However, the inherent components of TCMDPs had not been explored from the structural dimension of policy design. Methods: Based on the policy modeling consistency (PMC) index model, we constructed a comprehensive evaluation system, including ten first-level and 40 second-level indicators, and focused on the TCMDPs released by the Chinese central government in the past 42 years (1980-2022) to conduct multi-dimensional inspections to TCMDPs by analyzing the overall policy quality, individual scoring performance, and indicators distribution characteristics. Results: This study pointed out that four policies were rated as "perfect," 35 were rated as "superb," 50 were rated as "excellent," 28 were rated as "good," and four were rated as "acceptable," with total mean values of the PMC index being 7.530 ± 0.835. Although most TCMDPs had appropriate policy structure and consistency, the potential weaknesses in the design of TCMDPs also needed our attention through careful checks on the outlier policy samples. Besides, the existing TCMDPs had room for improvement regarding policy areas, guarantees and incentives, objects included, and issuing agencies. Conclusions: We emphasized that the policy evaluation method used in this current study, the PMC index model, is scarce in the TCMDPs. These findings are helpful for fully understanding the strengths and weaknesses of TCMDPs and provide theoretical references for further studies optimizing TCMDPs.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Prenatal diagnosis identifies compound heterozygous variants in RYR1 that causes ultrasound abnormalities in a fetus.

OBJECTIVE: We presented a non-consanguineous healthy Chinese couple with five pregnancies, three early miscarriages, the fetus II-2 and II-5 with similar abnormal phenotypes of fetal hydrops, scoliosis, fetal akinesia and polyhydramnios. This study aimed to uncover the molecular etiology of this family with a history of multiple adverse pregnancies. MATERIALS AND METHODS: DNA extracted from the fifth fetal umbilical cord and parents' peripheral blood were subjected to SNP-array and whole exome sequencing. The result was verified by Sanger sequencing. Functional characterization of the c.2682G > C (p.Ile860_Pro894del) variant was completed by minigene splicing assay. RESULTS: Trio whole-exome sequencing has identified compound heterozygous variants in RYR1 (c.2682G > C; p.Ile860_Pro894del and c.12572G > A; p.Arg4191His) in fetus II-5. The variant c.2682G > C (p.Ile860_Pro894del) comes from the father and the c.12572G > A (p.Arg4191His) comes from the mother. The c.2682G > C (p.Ile860_Pro894del) affects the splice site resulting in exon 21 skipping, therefore is classified as likely pathogenic. The c.12572G > A (p.Arg4191His) locates in the C-terminal hot spots region of the RYR1, classified as of uncertain significance. CONCLUSIONS: We report the first prenatal case of RYR1-related disorders in Chinese population, expanding the variant spectrum of RYR1 in fetuses.

YouTube as a platform to better understand the treatment of lymphoma using ibrutinib: a cross-sectional study.

Background: Ibrutinib, one Food and Drug Administration-approved, orally available, small-molecule Bruton tyrosine kinase (BTK) inhibitor, is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). YouTube is increasingly used for health purposes. However, videos for ibrutinib on YouTube have not been previously evaluated. This study assessed the accuracy and quality of YouTube videos on ibrutinib, to better understand the information shown on a dominant media platform. Methods: The first 150 video results returned by the YouTube search engine in response to the keyword "ibrutinib" were included (up to June 27, 2022). Typically used predefined inclusion and exclusion criteria were applied to screen the videos based on our needs. A 5-point Global Quality Scale (GQS) determined whether the videos would be useful to patients or not, and the quality of content was analyzed by five content-specific items. The quality of the included videos was classified as "low", "moderate", or "excellent" according to GQS and content score. The median and interquartile range were used to describe the values and Kruskal-Wallis test were used in the analysis. Results: A total of 99 videos with a median of 237 views met the inclusion criteria. The videos were categorized into educational videos (n=6, 6.07%), personal experience and blog (n=3, 3.03%) and interviews videos (n=90, 90.9%). Almost half of the videos were classified as moderate (n=51, 51.51%), followed by excellent (n=25, 25.26%) and low (n=23, 23.23%). Between the groups, no statistically significant differences were observed in the numbers of dislikes, comments, posted days, percentage positivity and viewing rate (P>0.05). There were marked differences in the length, likes, views, viewers' interaction and likeability (P<0.05). Conclusions: YouTube could be an effective source for different groups of people to obtain helpful information about ibrutinib. The physicians, pharmacists, nurses and healthcare organizations should prepare and upload more comprehensible and reliable videos with evidence-based information.

Cost-Utility Analysis of Camrelizumab Plus Chemotherapy Versus Chemotherapy Alone as a First-Line Treatment for Advanced Nonsquamous Non-Small Cell Lung Cancer in China.

Purpose: To evaluate the cost utility of camrelizumab plus standard chemotherapy versus standard chemotherapy alone as a first-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC) from the perspective of the Chinese health care system and to provide a reference for health decision-making. Methods: A Markov model consisting of three health states was designed to evaluate the cost utility of these two treatment regimens for NSCLC patients with the incremental cost-effectiveness ratio (ICER) as the primary output indicator. Clinical data were derived from a published phase III clinical trial (CameL; ClinicalTrials.gov; NCT03134872). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the model uncertainty. Results: Base case analysis showed that the ICER of camrelizumab plus chemotherapy compared with chemotherapy alone was $43,275.43 per QALY. It was higher than the willingness-to-pay (WTP) threshold of $31,510.57 per QALY in China, which has a standard of three times the GDP per capita recommended by the WHO. One-way sensitivity analysis showed that the utility value of PFS had the greatest influence on the results, and the other sensitive parameters were the cost of subsequent second-line therapy in the two group, the pemetrexed price, the cost of adverse event management and the utility value of PD. The probability sensitivity analysis showed that the probabilities of the cost-effectiveness of camrelizumab plus standard chemotherapy were 27.1%, 66.7% and 88.0% when the WTP values were $40,000, $50,000 and $60,000 per QALY, respectively. Conclusions: Taking three times the GDP per capita in China as the WTP threshold, the camrelizumab plus standard chemotherapy regimen does not have a cost-effectiveness advantage compared with the standard chemotherapy regimen alone as a first-line treatment for advanced NSCLC.

Biologically-Inspired Water-Swelling-Driven Fabrication of Centimeter-Level Metallic Nanogaps.

Metallic nanogaps have great values in plasmonics devices. However, large-area and low-cost fabrication of such nanogaps is still a huge obstacle, hindering their practical use. In this work, inspired by the cracking behavior of the tomato skin, a water-swelling-driven fabrication method is developed. An Au thinfilm is deposited on a super absorbent polymer (SAP) layer. Once the SAP layer absorbs water and swells, gaps will be created on the surface of the Au thinfilm at a centimeter-scale. Further experimentation indicates that such Au gaps can enhance the Raman scattering signal. In principle, the water-swelling-driven fabrication route can also create gaps on other metallic film and even nonmetallic film in a low-cost way.

Internal nanocavity based high-resolution and stable structural colours fabricated by laser printing.

Bioinspired structural colors are attracting increasing attention in photonics, display, labeling and so forth. High-resolution and stable coloration is significant but is challenging to be fabricated in a facile and low-cost way. Herein, multilayer architecture containing an internal nanocavity as the structural color unit is obtained conveniently by direct nanosecond laser printing in atmosphere condition. Arbitrary colorful patterns with submicron accuracy can be realized only by a single step. And such structural colors induced by inner structures in the interlayer are antipollutive, antioxidative and easy to clean.

Hyaluronic Acid-Functionalized Hollow Mesoporous Silica Nanoparticles as pH-Sensitive Nanocarriers for Cancer Chemo-Photodynamic Therapy.

Hollow mesoporous silica nanoparticles (HMSNs) served as nanocarriers for transporting doxorubicin hydrochloride (DOX) and indocyanine green (ICG) and were incorporated into a pH-sensitive targeted drug delivery system (DDS). Boronate ester bonds were employed to link HMSNs and dopamine-modified hyaluronic acid (DA-HA), which acted as both the "gatekeeper" and targeting agents (HMSNs-B-HA). Well-dispersed HMSNs-B-HA with a diameter of about 170 nm was successfully constructed. The conclusion was drawn from the in vitro drug release experiment that ICG and DOX (ID) co-loaded nanoparticles (ID@HMSNs-B-HA) with high drug loading efficiency could sustain drug release under acidic conditions. More importantly, in vitro cell experiments perfectly showed that ID@HMSNs-B-HA could well inhibit murine mammary carcinoma (4T1) cells via chemotherapy combined with photodynamic therapy and accurately target 4 T1 cells. In summary, all test results sufficiently demonstrated that the prepared ID@HMSNs-B-HA was a promising nano-DDS for cancer photodynamic combined with chemotherapy.

Two novel BTD mutations causing profound biotinidase deficiency in a Chinese patient.

BACKGROUND: Biotinidase deficiency (OMIM 253260) is an autosomal recessively inherited disorder affecting about 1/60,000 people worldwide. The absence or deficiency of biotinidase impairs free biotin recycling and affects biotin-dependent carboxylase functions. METHODS: A Chinese patient with spontaneous recurrent epilepsy, an eczema-like rash, hair loss, hypotonia, and hearing loss began at three months of age. Her biotinidase activity was 1.0 nmol/ml/min, 9.5% of the mean control activity, which confirmed profound biotinidase deficiency. RESULTS: Compound heterozygous for c.250-1G > C and c.878dupT variants in the BTD gene were identified in this patient. These two variants were novel and absent in the population matched controls and any databases. CONCLUSIONS: This study expanded the mutation spectrum of alterations of the BTD gene. Our patient also emphasized the critical role of biotinidase activity measurement combined with mutation analysis in early diagnosis of biotinidase deficiency.

Quantitative measurement and mechanism analysis of the high-efficiency laser propulsion of a graphene sponge.

Laser propulsion of a graphene sponge shows tremendous potential in propellant-free flight, photoresponsive actuators and micro opto-electro mechanical systems. However, the mechanism is still in dispute and the propulsion force hasn't been accurately measured, seriously hindering its development. This work develops a quantitative method to measure the propulsion force. It is found that the characteristics of the force agree qualitatively with the Knudsen force due to laser-induced thermal nonequilibrium in rarefied gas, which might be another possible mechanism of laser propulsion of a graphene sponge. Also, this kind of laser propulsion is highly efficient, stable and sustainable.

Pharmacokinetics and pharmacogenetics of high-dose methotrexate in Chinese adult patients with non-Hodgkin lymphoma: a population analysis.

PURPOSE: High-dose methotrexate (HD-MTX) is widely used in the treatment of non-Hodgkin lymphoma (NHL), but the pharmacokinetic properties of HD-MTX in Chinese adult patients with NHL have not yet been established through an approach that integrates genetic covariates. The purposes of this study were to identify both physiological and pharmacogenomic covariates that can explain the inter- and intraindividual pharmacokinetic variability of MTX in Chinese adult patients with NHL and to explore a new sampling strategy for predicting delayed MTX elimination. METHODS: A total of 852 MTX concentrations from 91 adult patients with NHL were analyzed using the nonlinear mixed-effects modeling method. FPGS, GGH, SLCO1B1, ABCB1 and MTHFR were genotyped using the Sequenom MassARRAY technology platform and were screened as covariates. The ability of different sampling strategies to predict the MTX concentration at 72 h was assessed through maximum a posteriori Bayesian forecasting using a validation dataset (18 patients). RESULTS: A two-compartment model adequately described the data, and the estimated mean MTX clearance (CL) was 6.03 L/h (9%). Creatinine clearance (CrCL) was identified as a covariate for CL, whereas the intercompartmental clearance (Q) was significantly affected by the body surface area (BSA). However, none of the genotypes exerted a significant effect on the pharmacokinetic properties of MTX. The percentage of patients with concentrations below 0.2 µmol/L at 72 h decreased from 65.6 to 42.6% when the CrCL decreased from 90 to 60 ml/min/1.73 m2 with a scheduled dosing of 3 g/m2, and the same trend was observed with dose regimens of 1 g/m2 and 2 g/m2. Bayesian forecasting using the MTX concentrations at 24 and 42 h provided the best predictive performance for estimating the MTX concentration at 72 h after dosing. CONCLUSIONS: The MTX population pharmacokinetic model developed in this study might provide useful information for establishing personalized therapy involving MTX for the treatment of adult patients with NHL.

Exceptional point-based plasmonic metasurfaces for vortex beam generation.

An exceptional point occurring in a tailor-made lossy optical system has been recently found to alter optical properties in counter-intuitive ways. In the context of tunable plasmonic devices, exceptional points can be useful as a driving mechanism to enhance tunability. Here, we experimentally demonstrate how a plasmonic exceptional point can be incorporated in metasurface Q-plates to have the generated vortex beam tuned through a change of structural parameter. We have observed an orbital rotation in the far-field by 45 degrees in crossing the exceptional point. We expect a new generation of tunable plasmonic devices in polarization control, beam structuring and holograms, which can take advantage of the huge sensitivity from exceptional points.