Molecular cluster, transmission characteristics, origin and dynamics analysis of HIV-1 CRF59_01B in China: a molecular epidemiology study.

PURPOSE: This study investigated for the HIV-1 CRF59_01B epidemic's spatiotemporal dynamics and its transmission networks in China. METHODS: Between 2007 and 2020, a total of 250 partial pol gene sequences of HIV-1 CRF59_01B were collected from four regions (10 Chinese provinces). Phylogenetic tree construction and cluster identification were then performed. The Bayesian skyline and birth-death susceptible-infected-removed models were employed for the phylodynamic analyses of subtypes and large clusters, respectively. Phylogenetic analyses and trait diffusion of these sequences were performed using Bayesian phylogenetic methods (beast-classic package). Distance-based molecular network analyses were performed to identify putative relationships. RESULTS: Using a genetic distance threshold of 1.3%, We identified 45 clusters that included 62.40% (156/250) of the sequences. Three clusters (6.67%, 3/45) had 10 or more sequences, and were considered "large clusters". Six clusters (13.33%) included sequences from different regions (Southeast, Northeast, Southeast, and Central China). Thirteen clusters (28.89%) included sequences of men who had sex with men only, three clusters (6.67%) included sequences of heterosexuals only, and 12 clusters (26.67%) included sequences of both groups. The substitution rate of CRF59_01B was 1.91  × 10-3 substitutions per site per year [95% highest posterior density (HPD) interval: 1.39 × 10-3-2.49 × 10-3)], the time to the most recent common ancestor of CRF59_01B was to be 1992.83 (95% HPD: 1977.97-2002.81). A Bayesian skyline plot revealed that the effective population size of CRF59_01B increased from 2000 to 2015 and remained stable after 2015. The large clusters showed continuous growth from 2013-2020. Phylogeographic analysis showed that CRF59_01B B most likely originated in Southeast China, with a posterior probability of 97.44 %, and then spread to other regions. CONCLUSIONS: Our study revealed the temporal and geographical origins of HIV-1 CRF59_01B as well as the process of transmission among various regions and risk groups in China, which can help develop targeted HIV prevention strategies.

Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer.

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

Coherence sidelobe suppression of laser diode by white-noise-current modulation and external cavity feedback.

A coherence sidelobe suppression method for a laser diode (LD) is proposed, based on the white-noise-current modulation and external cavity feedback. The theoretical model of the coherence of the white-noise-current-modulated external cavity laser (WECL) is established, which details the spectrum broadening mechanism and the coherence sidelobe suppression. At the noise current modulation, the coherence sidelobe induced by the internal cavity is lowered by the external cavity feedback, and the position of the coherence sidelobe induced by the external cavity is controlled with the cavity length, which can extend the coherence range without the sidelobes. The experimental results demonstrate that the 98.4% sidelobe suppression ratio (SLSR) of the WECL is achieved in dynamic interferometry, which is about 20% higher than that of the laser diode only with the white-noise-current modulation. This new, to the best of our knowledge, method can avoid the stray fringe cross talk caused by the multiple coherence sidelobes in the surface error measurements of parallel plates.

Evolving molecular HIV clusters revealed genotype-specific dynamics in Guangzhou, China (2008-2020).

OBJECTIVES: This study investigated the genotype-specific dynamics of molecular HIV clusters (MHCs) in Guangzhou, China, aiming to enhance HIV control. METHODS: HIV pol sequences from people with HIV (PWH) in Guangzhou (2008-2020) were obtained for genotyping and molecular network creation. MHCs were identified and categorized into three types: emerging, growing, or stable. Clustering rates, proportions of cluster types, and members within each type were calculated and their trends were assessed using joinpoint regression. RESULTS: Among 8395 PWH, the most prevalent HIV-1 genotypes were CRF07_BC (39.7%) and CRF01_AE (32.6%). The genotype composition has been stable since 2012 (Ps > 0.05). The overall clustering rate was 43.3%, with significant variations across genotypes (P < 0.001), indicating genotype-specific transmission fitness. Significant declines in overall and genotype-specific clustering rates toward the end of 2020 (Ps < 0.05), potentially offer support for HIV control efforts in reducing local infections. The continuously increasing proportions of stable clusters and the gradually decreasing proportions of emerging and growing clusters (either Ps < 0.05 or Ps > 0.05) suggest a trend toward stable molecular network structure. However, growing clusters exhibited CRF55_01B, CRF07_BC, and CRF59_01B dominance that indicate their priority for interventions. CONCLUSION: The evolving MHCs highlight the genotype-specific cluster dynamics, providing fresh insights for enhanced prevention and control strategies.

Impact of Awareness of Sexual Partners' HIV Serostatus on the HIV Acquisition among Men Who Have Sex with Men in Guangzhou, China: A Nested Case-Control Study.

This study aimed to investigate the impact of sexual partners' HIV serostatus awareness on the HIV acquisition among men who have sex with men (MSM) in Guangzhou, China. A nested case-control study was conducted based on a prospective cohort of MSM in Guangzhou. Within the cohort, individuals who underwent HIV seroconversion were identified as the case group, and each case was matched with four controls from the non-seroconverted participants. Information regarding the awareness of sexual partners' HIV serostatus over the preceding 6 months was gathered. Of the 161 participants, 36.0% were aware of the HIV serostatus of all their sexual partners. The practice of engaging in condomless anal sex with partners of unknown HIV serostatus and being aware of the HIV serostatus of only some casual partners were positively correlated with an elevated risk of acquiring HIV. Conversely, being fully aware of the HIV serostatus of all sexual partners, including regular ones, was associated with a diminished risk of HIV incidence. Regular communication with sexual partners regarding HIV testing outcomes, honest disclosure of one's own HIV serostatus, and refusal of sexual contact with partners of unknown HIV serostatus can potentially mitigate the risk of acquiring HIV among MSM.

The global burden of disease attributable to high body mass index in 204 countries and territories: Findings from 1990 to 2019 and predictions to 2035.

AIM: Our study aims to provide an updated estimate of age- and sex-specific deaths and disability-adjusted life years (DALYs) associated with high body mass index (BMI) from 1990 to 2019 at the global, regional and national levels, and to forecast the global burden of disease attributed to high BMI from 2020 to 2035. METHODS: We used the data for the number of deaths, DALYs, age-standardized rate (per 100 000 population), percentage change and population attributable fraction from the Global Burden of Disease Study 2019 (GBD 2019) to examine the disease burden attributable to high BMI. We further applied an autoregressive integrated moving average (ARIMA) model to predict the disease burden for the period 2020-2035. RESULTS: From 1990 to 2019, the deaths and DALYs attributable to high BMI increased by 148% and 155.86% for men, and by 111.67% and 121.78% for women, respectively. In 2019, high BMI directly accounted for 8.52% [95% uncertainty intervals (UI) 0.05, 0.12] of all-cause deaths and 5.89% (95% UI 0.04, 0.08) of global DALYs. The highest death rates were observed in men aged 65-69 and women aged 75-79. The highest DALY rates were observed in the age group of 60-64 for both sexes. In 2019, the highest age-standardized deaths and DALY rates were observed in the Central Asia region [163.15 (95% UI 107.72, 223.58) per 100 000 people] and the Oceania region [4643.33 (95% UI 2835.66, 6902.6) per 100 000 people], respectively. Fiji [319.08 (95% UI 213.77, 444.96) per 100 000 people] and Kiribati [10 000.58 (95% UI 6266.55, 14159.2) per 100 000 people] had the highest age-standardized deaths and DALY rates, respectively. In 2019, the highest age-standardized rates of high BMI-related deaths and DALYs were observed in the middle-high socio-demographic index quintile and in the middle socio-demographic index quintile. The age-standardized deaths and DALY rates attributable to high BMI are projected to increase in both sexes from 2020 to 2035. The death rates are projected to rise from 62.79 to 64.31 per 100 000 people, while the DALY rates are projected to rise from 1946 to 2099.54 per 100 000 people. CONCLUSIONS: High BMIs significantly contribute to the global disease burden. The projected rise in deaths and DALY rates attributable to high BMI by 2035 highlights the critical need to address the impact of obesity on public health. Our study provides policymakers with up-to-date and comprehensive information.

The origin and spread of HIV-1 CRF59_01B epidemic in China: A molecular network and phylogeographic analysis.

Human immunodeficiency virus type 1 CRF59_01B, identified in China in 2013, has been detected nationwide, exhibiting notably high prevalence in Guangzhou and its vicinity. This study aimed to unravel its origin and migration. A data set was established, incorporating all available CRF59_01B pol gene sequences and their metadata from Guangzhou and the public database. Bayesian phylogeographic analysis demonstrated that CRF59_01B originated in Shenzhen, the neighboring city of Guangzhou, around 1998 with posterior probability of 0.937. Molecular network analysis detected 1131 transmission links and showed a remarkably high clustering rate (78.9%). Substantial inter-city transmissions (26.5%, 300/1131) were observed between Shenzhen and Guangzhou while inter-region transmissions linked Guangzhou with South (46) and Southwest (64) China. The centre of Guangzhou was the hub of CRF59_01B transmission, including the inflow from Shenzhen (3.57 events/year) and outflow to the outskirts of Guangzhou (>2 events/year). The large-scale analysis revealed significant migration from Shenzhen to Guangzhou (5.08 events/year) and North China (0.59 events/year), and spread from Guangzhou to Central (0.47 events/year), East (0.42 events/year), South (0.76 events/year), Southwest China (0.76 events/year) and Shenzhen (1.89 events/year). Shenzhen and Guangzhou served as the origin and the hub of CRF59_01B circulation, emphasizing inter-city cooperation and data sharing to confine its nationwide diffusion.

Accumulation mechanism of metabolite markers identified by machine learning between Qingyuan and Xiushui counties in Polygonatum cyrtonema Hua.

Polygonatum cyrtonema Hua is a traditional Chinese medicinal plant acclaimed for its therapeutic potential in diabetes and various chronic diseases. Its rhizomes are the main functional parts rich in secondary metabolites, such as flavonoids and saponins. But their quality varies by region, posing challenges for industrial and medicinal application of P. cyrtonema. In this study, 482 metabolites were identified in P. cyrtonema rhizome from Qingyuan and Xiushui counties. Cluster analysis showed that samples between these two regions had distinct secondary metabolite profiles. Machine learning methods, specifically support vector machine-recursive feature elimination and random forest, were utilized to further identify metabolite markers including flavonoids, phenolic acids, and lignans. Comparative transcriptomics and weighted gene co-expression analysis were performed to uncover potential candidate genes including CHI, UGT1, and PcOMT10/11/12/13 associated with these compounds. Functional assays using tobacco transient expression system revealed that PcOMT10/11/12/13 indeed impacted metabolic fluxes of the phenylpropanoid pathway and phenylpropanoid-related metabolites such as chrysoeriol-6,8-di-C-glucoside, syringaresinol-4'-O-glucopyranosid, and 1-O-Sinapoyl-D-glucose. These findings identified metabolite markers between these two regions and provided valuable genetic insights for engineering the biosynthesis of these compounds.

Co-expressed network analysis based on 289 transcriptome samples reveals methyl jasmonate-mediated gene regulatory mechanism of flavonoid compounds in Dendrobium catenatum.

Flavonoids are momentous bioactive ingredients in orchid plant Dendrobium catenatum (D. catenatum), which are bioactive compounds with great medical and commercial potential. However, the accurate dissection of flavonoids profiling and their accumulation mechanism are largely unknown. In this study, methyl jasmonate (MeJA) treatment was used to investigate the change of flavonoids content and transcripts in two D. catenatum clones (A6 and B1). We identified 40 flavonoids using liquid chromatograph mass spectrometer (LC-MS). By weighted gene co-expressed network analysis (WGCNA) of flavonoids content and transcript expression of MeJA-treated samples, 37 hub genes were identified. Among them, DcCHIL, DcFLS, and DcDFR were highly correlation with two key transcription factors DcWRKY3/4 by correlation analysis of large-scale transcriptome data and above hub genes expression. Furthermore, transient overexpression of DcWRKY3/4 in tobacco leaves significantly increased the content of flavonoids. This study identified flavonoid profiling and built a new approach to mine regulatory mechanism of flavonoids in D. catenatum. These valuable flavonoids and gene resources will be key for understanding and harnessing natural flavonoids products in pharmaceuticals and foods industry of D. catenatum.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial.

BACKGROUND: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. METHODS: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. FINDINGS: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). INTERPRETATION: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). FUNDING: Dizal Pharmaceutical.

Effect of natural gums on pasting, rheological, structural and hydrolysis properties of kudzu starch.

Hydrocolloids have been widely used to adjust properties of natural starches, but related research on kudzu starch is still rare. In this study, we investigated the effects of gum arabic (AG), sodium alginate (SA), locust bean gum (LG), and guar gum (GG) on kudzu starch from the perspective of its particle size, pasting, texture, rheology, dehydration rate, thermal properties, microstructure, and sensitivity to amyloglucosidase. Results showed that GG significantly increased the particle size of starch. Addition of AG led to lower peak-, final- and holding-viscosity. SA increased the retention viscosity of kudzu starch, while LG and GG increased its peak viscosity. Addition of hydrocolloids increased the hardness, chewiness, and cohesiveness of starch-hydrocolloid complexes, and reduced the dehydration rate of complex gels. Dynamic rheological data showed that the energy storage modulus (G') was significantly higher than the loss modulus (G″). The magnitude of modulus increased with frequency, and elastic properties were better than viscous properties. Thermal analysis showed that hydrocolloids increased the starting temperature (To), and the final temperature (Tc). With addition of each of these four hydrocolloids, a more regular and porous thick-wall dense structure was formed, which effectively lowered kudzu starch's sensitivity to amyloglucosidase. It indicated that the binding of hydrocolloid to starch may slow down glucose release into blood during digestion. These results will help understand effects of natural hydrocolloid on kudzu starch, as well as expanding its application in food industry.

Plant fructans: Recent advances in metabolism, evolution aspects and applications for human health.

Fructans, fructose polymers, are one of the three major reserve carbohydrate in plants. The nutritional and therapeutic benefits of natural fructans in plants have attracted increasing interest by consumers and food industry. In the course of evolution, many plants have developed the ability of regulating plant fructans metabolism to produce fructans with different structures and chain lengths, which are strongly correlated with their survival in harsh environments. Exploring these evolution-related genes in fructans biosynthesis and de novo domestication of fructans-rich plants based on genome editing is a viable and promising approach to improve human dietary quality and reduce the risk of chronic disease. These advances will greatly facilitate breeding and production of tailor-made fructans as a healthy food ingredient from wild plants such as huangjing (Polygonatum cyrtonema). The purpose of this review is to broaden our knowledge on plant fructans biosynthesis, evolution and benefits to human health.

Interactions between endophytic fungus Pestalotiopsis sp. DO14 and Dendrobium catenatum: Deciphering plant polysaccharide and flavonoid accumulation and underlying mechanisms by comparative transcriptome and metabolome analyses.

Dendrobium catenatum, which belongs to the Orchidaceae family, has been used as a traditional medicine and healthy food in China for over 2000 years, and is of enormous economic value. Polysaccharides and flavonoids are two major functional ingredients in D. catenatum stems that contribute to its health benefits. D. catenatum lives in close association with endophytic fungi, but the literature regarding the further relations between them, especially the fungal-induced accumulation of metabolites in the host plant, is sparse. Our previous study showed that Pestalotiopsis sp. DO14 isolated from D. catenatum improved the host plant growth and metabolite accumulation. This study was performed to investigate dynamic variations of the growth traits, key metabolites (polysaccharides and flavonoids), and expression of key genes of D. catenatum under conditions of the DO14 colonization. Colonization with DO14 promoted D. catenatum growth as indicated by increased leaf area, mid-stem thickness, and plant height. The content of polysaccharides, mannose, and sucrose increased even without DO14 entering the host cells or forming a mature symbiotic relationship concurrent with improved photosynthesis rate. Furthermore, DO14 induced upregulation of genes involved in sugar and flavonoid metabolism, especially phosphoenolpyruvate carboxykinase (PCKA), chalcone synthase (CHS) and UDP-glycose flavonoid glycosyltransferase (UFGT). These observations suggested that endophytic fungi induce the accumulation of polysaccharides and flavonoids by plants, increasing the efficiency of carbon assimilation and carbon turnover. The findings of this study provide insight into the mechanisms underlying Orchidaceae-endophyte interactions, and suggest potential novel applications of endophytic fungi in D. catenatum breeding to improved plant quality.

Functional analysis of WOX family genes in Dendrobium catenatum during growth and development.

The WUSCHEL-Related Homeobox (WOX) family is a group of transcription factors unique to plants that play an important role in regulating key developmental processes such as stem cell maintenance and organ morphogenesis. As a rare and valuable Chinese herb, Dendrobium catenatum has a unique epiphytic lifestyle and growth and developmental characteristics, and a functional investigation of its WOX family genes can help to further understand the conserved and specific development of D. catenatum. In this study, we analyzed the phylogeny, spatio-temporal expression pattern and heterologous expression function of D. catenatum WOX family genes (DcWOX). The results showed that members of the D. catenatum WOX gene family could be divided into three evolutionary branches with significantly different tissue expression profiles. In transgenic Arabidopsis, overexpression of DcWOX4 resulted in significant dwarfism, pinnately leaf margins, and delayed flowering for 2 weeks; overexpression of DcWOX9 resulted in plant dwarfing, serrated leaf margin, delayed flowering for 1 week, and even male and female sterility in strong phenotype plants; overexpression of DcWOX11 caused curl downward leaf. The abnormal morphogenesis of DcWOX4/9/11 overexpression Arabidopsis leaves are related to the down-regulation of TCP family genes, CUC family genes and the up-regulation of KNOX family genes; Postponement of flowering is related to down-regulation of early flowering genes such as FT, SOC1 and CO. Therefore, this study showed that D. catenatum WOX family genes have important functions in regulating plant morphogenesis, leaf development, flowering time and fertility, further expanding the understanding of the WOX gene family function, and providing clues for the conservation and specificity during orchid development and evolution.

Machine learning uncovers accumulation mechanism of flavonoid compounds in Polygonatum cyrtonema Hua.

The compositions and yield of flavonoid compounds of Polygonatum cyrtonema Hua (PC) are important indices of the quality of medicinal materials. However, the flavonoids compositions and accumulation mechanism are still unclear in PC. Here, we identified 22 flavonoids using widely-targeted metabolome analysis in 15 genotypes of PC. Then weighted gene co-expression network analysis based on 45 transcriptome samples was performed to construct 12 co-expressed modules, in which blue module highly correlated with flavonoids was identified. Furthermore, 4 feature genes including PcCHS1, PcCHI, PcCHS2 and PcCHR5 were identified from 94 hub genes in blue module via machine learning methods support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF), and their functions on metabolic flux of flavonoids pathway were confirmed by tobacco transient expression system. Our findings identified representative flavonoids and key enzymes in PC that provided new insight for elite breeding rich in flavonoids, and thus will be beneficial for rapid development of great potential economic and medicinal value of PC.

Whole-genome sequencing analysis of Klebsiella aerogenes among men who have sex with men in Guangzhou, China.

Klebsiella aerogenes is a common infectious bacterium that poses a threat to human health. Nevertheless, there are limited data on the population structure, genetic diversity, and pathogenicity of K. aerogenes, especially among men who have sex with men (MSM). The present study aimed to clarify the sequence types (STs), clonal complexes (CCs), resistance genes, and virulence factors of popular strains. Multilocus sequence typing was used to describe the population structure of K. aerogenes. The Virulence Factor Database and Comprehensive Antibiotic Resistance Database were used to assess the virulence and resistance profiles. In this study, next-generation sequencing was performed on nasal swabs specimens collected in an HIV Voluntary Counseling Testing outpatient department in Guangzhou, China, from April to August 2019. The identification results showed that a total of 258 K. aerogenes isolates were collected from 911 participants. We found that the isolates were most resistant to furantoin (89.53%, 231/258) and ampicillin (89.15%, 230/258), followed by imipenem (24.81%, 64/258) and cefotaxime (18.22%, 47/258). The most common STs in carbapenem-resistant K. aerogenes were ST4, ST93, and ST14. The population has at least 14 CCs, including several novel ones identified in this study (CC11-CC16). The main mechanism of drug resistance genes was antibiotic efflux. Based on the presence of the iron carrier production genes irp and ybt, we identified two clusters according to virulence profiles. In cluster A, CC3 and CC4 carry the clb operator encoding the toxin. Increased monitoring is needed for the three main ST type strains carried by MSM. The main clone group CC4 has a large number of toxin genes, and it spreads among MSM. Caution is needed to prevent further spread of this clone group in this population. In sum, our results may provide a foundation for the development of new therapeutic and surveillance strategies for treating MSM.

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here. METHODS: Eligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated. RESULTS: 355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6-40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0-50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4-81.8%) and 100% (45/45; 95% CI: 92.1-100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: -55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months. CONCLUSIONS: Rezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases.

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study.

BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

All-fiber orthogonal-polarized white-noise-modulated laser for short-coherence dynamic interferometry.

An all-fiber orthogonal-polarized white-noise-modulated laser (AOWL) for short-coherence dynamic interferometry is proposed. Short-coherence laser is achieved by current modulating of a laser diode with the band-limited white noise. A pair of orthogonal-polarized lights with adjustable delay for short-coherence dynamic interferometry are output by the all-fiber structure. In the non-common-path interferometry, the AOWL can significantly suppress the interference signal clutter with 73% side lobe suppression ratio, that improves the positioning accuracy of zero optical path difference. The wavefront aberrations of a parallel plate are measured with the AOWL in the common-path dynamic interferometers, avoiding the fringe crosstalk.

Theoretical and experimental studies on intermodal nonlinear effects of a high-power near-single-mode CW Yb-doped fiber laser.

An intermodal-nonlinearity-induced time-frequency evolution model of high-power near-single-mode continuous-wave fiber lasers (NSM-CWHPFLs) was proposed to simulate the evolution of spectral characteristics and beam quality under the combined action of intermodal and intramodal nonlinear effects. The influence of fiber laser parameters on intermodal nonlinearities was analyzed, and a suppression method involving fiber coiling and seed mode characteristic optimization was proposed. Verification experiments were conducted with 20/400, 25/400, and 30/600 fiber-based NSM-CWHPFLs. The results demonstrate the accuracy of the theoretical model, clarify the physical mechanisms of nonlinear spectral sidebands, and demonstrate the comprehensive optimization of intermodal-nonlinearity-induced spectral distortion and mode degradation.