BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study.

BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A case report to understand the use of an evidence-based approach of prolonged grief therapy in Chinese culture.

Prolonged grief disorder (PGD) is a new diagnosis that may cause significant functional impairment. Prolonged grief therapy (PGT) is a manualized 16-session intervention, whose efficacy has been demonstrated in studies primarily from Western cultures. The current report aimed to present a case to illustrate the use of PGT in Chinese culture. The client was a bereaved adult suffering from PGD after the death of her mother ten years ago. Additionally, she lost her father three months ago. Questionnaires were completed before and after treatment. In-depth interview was conducted at a 3-month follow-up. The client's scores for grief, functional impairment, grief-related beliefs and avoidance, depression and insomnia all decreased substantially after treatment. The follow-up feedbacks indicated that the beneficial effects of PGT persisted in the client's life. This case report provides preliminary evidence that bereaved people in China could benefit greatly from PGT, with minimal cultural adaptation.

Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial.

Importance: For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

Phase 1b trial of anti-HER2 antibody inetetamab and pan-HER inhibitor pyrotinib in HER2-positive advanced lung cancer.

There remains an unmet need for targeted therapies against advanced non-small-cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti-HER2 agent, this prospective, single-arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti-HER2 antibody inetetamab and pan-HER TKI pyrotinib in HER2-posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose-escalation part, 240 mg, 320 mg; dose-expansion part, 320 mg). Primary endpoints were dose-limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose-escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment-related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4-8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2-mutant NSCLC.

Tribofilm Formation of Zinc Dialkyldithiophosphate as Oil Additives Impregnated in Porous Polyimide under Different Contacts.

To improve the tribological properties of porous polyimide (PPI), ZDDP-mixed PAO4 was impregnated in PPI (denoted as ZPPI), and the tribological properties of ZPPI under single- and double-contacts were investigated. In the single-contact of ZPPI-steel, a rough and thick tribofilm was formed on the steel ball, which could protect the steel surface but resulted in large fluctuations in the friction coefficient. In the double-contact of ZPPI-steel-steel, ZDDP formed a uniform and thinner tribofilm on steel surfaces, leading to a lower friction. ZDDP could inhibit the formation of iron oxides significantly in the double-contact, while the antioxidant effect of ZDDP in the single-contact of ZPPI-steel was not obvious. ZnS and ZnO generated from ZDDP were adsorbed in the ZPPI pores, which aggravated the blackening of the ZPPI worn surface.

Deciphering the critical role of interstitial volume in glassy sulfide superionic conductors.

Sulfide electrolytes represent a crucial category of superionic conductors for all-solid-state lithium metal batteries. Among sulfide electrolytes, glassy sulfide is highly promising due to its long-range disorder and grain-boundary-free nature. However, the lack of comprehension regarding glass formation chemistry has hindered their progress. Herein, we propose interstitial volume as the decisive factor influencing halogen dopant solubility within a glass matrix. We engineer a Li3PS4-Li4SiS4 complex structure within the sulfide glassy network to facilitate the release of interstitial volume. Consequently, we increase the dissolution capacity of LiI to 40 mol% in 75Li2S-25P2S5 glass. The synthesized glass exhibits one of the highest ionic conductivities among reported glass sulfides. Furthermore, we develop a glassy/crystalline composite electrolyte to mitigate the shortcomings of argyrodite-type sulfides by utilizing our synthesized glass as the filler. The composite electrolytes effectively mitigate Li intrusion. This work unveils a protocol for the dissolution of halogen dopants in glass electrolytes.

Multiple approaches to reduce reconstitution time of lyophilized drug products with high protein concentration.

Background: Lyophilized drug products with high protein concentration often perform long reconstitution time, which is inconvenient for clinical use. The objective of this work is to achieve short reconstitution time with multiple and combined strategies. Methods: Here, we describe the following approaches that lead to reduction of reconstitution time, including adding annealing step, decreasing headspace pressure, decreasing protein concentration with reducing diluent volume, increasing high surface-area-to-height ratio of the cakes, increasing frequency of swirling and diluent temperature. Results: Among these strategies, reducing diluent volume to achieve high protein concentration and reducing headspace pressure show markedly reduction of reconstitution time. Moreover, we propose combined strategies to mitigate the reconstitution time, at the same time, to achieve same target dose in clinics. Conclusions: Therefore, this paper provides insights on the application of multiple strategies to accelerate the reconstitution of lyophilized drug products with high concentration, and facilitates their widespread clinical application.

Luminescent Porous Organic Crystals for Adsorptive Separation of Toluene and Methylcyclohexane.

A butterfly-shaped phenothiazine derivative, PTTCN, was synthesized to obtain pure organic porous crystals for the highly efficient absorptive separation of toluene (Tol) and methylcyclohexane (Mcy). Due to the presence of three polar cyano groups and nonplanar conformation, these molecules self-assembled into a hydrogen-bonded organic framework (X-HOF-5) with distinct cavities capable of accommodating Tol molecules through multiple hydrogen-bonding interactions. Upon solvent removal via heating, the activated X-HOF-5 retained its cavity structure albeit with altered stacking arrangements, accompanied by a remarkable fluorescent color change from cyan to green. X-HOF-5a can undergo a phase transformation into X-HOF-5 upon reabsorption of Tol, while exhibiting no accommodation of Mcy due to the weak intermolecular interaction between PTTCN and Mcy. This suggests that the activated HOF material prefers Tol over Mcy. Moreover, X-HOF-5a may selectively accommodate Tol in a Tol/Mcy equimolar mixture, and the purity of Tol can reach 97% after release from the framework. Additionally, it is noteworthy that the HOF material exhibits recyclability without any discernible loss in performance.

QL1706 (anti-PD-1 IgG4/CTLA-4 antibody) plus chemotherapy with or without bevacizumab in advanced non-small cell lung cancer: a multi-cohort, phase II study.

First-line chemoimmunotherapy (with or without bevacizumab) has improved outcomes in advanced non-small cell lung cancer (NSCLC). Here, this open-label, multi-cohort phase II study (NCT05329025) was done to investigate the safety and efficacy of QL1706 (a single bifunctional MabPair product against PD-1 and CTLA-4) and chemotherapy with or without bevacizumab in this population. Patients were enrolled into five different cohorts based on genotype (cohorts 1-4, epidermal growth factor receptor [EGFR] wild-type; cohort 5, EGFR-mutant and progressed on EGFR-tyrosine kinase inhibitors [TKIs]). Between June 11, 2021 and December 29, 2021, 91 patients were enrolled. Most frequent treatment-related adverse events (TRAEs) included decreased appetite (60 [65.9%]), anemia (60 [65.9%]), infusion-related reactions (48 [52.7%]), and pruritus (44 [48.4%]). Grade ≥ 3 TRAEs occurred in 30 (33.0%) patients. Twenty-seven (45%) patients with wild-type EGFR achieved partial response (PR) (objective response rate [ORR] = 45%) and had a median progression-free survival (mPFS) of 6.8 months (95% CI: 5.2-9.7). For 31 patients harboring mutated EGFR, 17 (54.8%) achieved PR (ORR = 54.8%), with an mPFS of 8.5 months (95% CI: 5.72-not evaluable). Overall, QL1706 plus chemotherapy, regardless of having bevacizumab, was generally tolerable and had promising antitumor activity for EGFR wild-type advanced NSCLC in first-line setting. Moreover, QL1706 plus chemotherapy and bevacizumab showed favorable antitumor activity for patients who had EGFR mutated NSCLC but failed in TKI therapy, demonstrating a potential for treating this population.

Photochemical Difluoromethylation of Quinoxalin-2(1H)-ones with Difluoroacetic Anhydride and Pyridine N-Oxide.

A novel photochemical difluoromethylation of quinoxalin-2(1H)-ones under catalyst-free conditions was achieved with difluoroacetic anhydride and pyridine N-oxide. The green and mild reaction conditions as well as readily attainable difluoroacetic anhydride provide a useful protocol to prepare C3-difluoromethylated quinoxalin-2(1H)-ones.

The relationship between sleep disturbance and obsessive- compulsive symptoms: the mediation of repetitive negative thinking and the moderation of experiential avoidance.

Background: Studies have found that sleep disturbance is associated with obsessive-compulsive symptoms. This study aimed to elaborate on the mediating and moderating mechanisms between these two variables. We hypothesized that repetitive negative thinking plays a mediating role in the relationship between sleep disturbance and obsessive-compulsive symptoms, and experiential avoidance plays a moderating role. Method: This study included 639 Chinese adults. A questionnaire survey was used to assess sleep quality, obsessive-compulsive symptoms, experiential avoidance, repetitive negative thinking, and depression symptoms. A moderated mediation model was established. Results: After controlling for depressive symptoms, repetitive negative thinking partially mediated the positive correlation between sleep disturbance and obsessive-compulsive symptoms. This indirect relationship was significant in individuals with lower experiential avoidance levels. Particularly, the relationship between sleep disturbance and repetitive negative thinking was significant among individuals with lower experiential avoidance levels, but not among individuals with higher experiential avoidance levels. Conclusion: This study demonstrated that repetitive negative thinking partially mediated the impact of sleep disturbance on obsessive-compulsive symptoms. The findings suggest that when providing support to individuals with sleep disturbance and obsessive-compulsive symptoms, assessing their level of experiential avoidance is necessary for performing targeted interventions. Individuals with low experiential avoidance may benefit from a clinical intervention targeting repetitive negative thinking to improve sleep quality and obsessive-compulsive symptoms.

The relationship between social acknowledgment and prolonged grief symptoms: a multiple mediation effect of beliefs about the goodness and controllability of grief-related emotions.

Background: Social acknowledgment is a protective factor for survivors of trauma. However, the role of social acknowledgment in association with prolonged grief symptoms has not yet been established.Objectives: The current study aims to explore the relationship between social acknowledgment and prolonged grief via two beliefs foundational to how people think about grief-related emotions (1) goodness (i.e. whether emotions are desirable, useful, or unwanted and harmful), and (2) controllability (i.e. whether emotions are regulated according to our will or involuntary, arising of their own accord). These effects were explored in two different cultural samples of bereaved people.Methods: One hundred and fifty-four German-speaking and two hundred and sixty-two Chinese bereaved people who lost their loved ones completed questionnaires assessing social acknowledgment, beliefs about the goodness and controllability of grief-related emotions, and prolonged grief symptoms.Results: Correlation analyses showed that social acknowledgment was positively linked with stronger beliefs about the goodness and controllability of grief-related emotions and negatively related to prolonged grief symptoms. Beliefs about the goodness and controllability of grief-related emotions correlated negatively with prolonged grief symptoms. Multiple mediation analyses suggested that beliefs about the controllability and goodness of grief-related emotions mediated the link between social acknowledgment and prolonged grief symptoms. Cultural groups did not moderate the above model.Conclusion: Social acknowledgment may be related to bereavement adjustment consequences via the roles of beliefs about the goodness and controllability of grief-related emotions. These effects seem to be consistent cross-culturally.

Social acknowledgment correlated positively with stronger beliefs about the goodness and controllability of grief-related emotions and negatively with prolonged grief symptoms.Beliefs about the goodness and controllability of grief-related emotions were negatively linked with prolonged grief symptoms.Beliefs about the controllability and goodness of grief-related emotions mediated the relationship between social acknowledgment and prolonged grief symptoms. The model presented cross-cultural consistency.

How the bereaved behave: a cross-cultural study of emotional display behaviours and rules.

Cultural norms may dictate how grief is displayed. The present study explores the display behaviours and rules in the bereavement context from a cross-cultural perspective. 86 German-speaking Swiss and 99 Chinese bereaved people who lost their first-degree relative completed the adapted bereavement version of the Display Rules Assessment Inventory. Results indicated that the German-speaking Swiss bereaved displayed more emotions than the Chinese bereaved. The Chinese bereaved, but not the German-speaking Swiss bereaved, thought that bereaved people should display more emotions than they actually did when they were with their close others (but not when they were alone). Bereaved people endorsed more emotional expression "when alone" than "when with close others", demonstrating a social disconnection tendency, which was more evident in the Chinese sample. Bereaved people endorsed more expression of positive emotions (e.g. affection/love) and less expression of powerful negative emotions (e.g. blame/guilt, anger) across cultures. Compared to their Chinese counterparts, the German-speaking Swiss sample indicated more actual expressions for most emotion types (i.e. joy/happiness, affection/love, sadness, anger, and denial) but thought bereaved people should express more joy/happiness and less blame/guilt. The results suggest that bereaved people's display behaviours and rules are influenced by culture, situation, and type of emotion.

Flexible Luminescent Hydrogen-bonded Organic Framework for the Separation of Benzene and Cyclohexane.

A nonplanar phenothiazine derivative with three cyano moieties (PTTCN) is designed and synthesized to achieve functional crystals for absorptive separation of benzene and cyclohexane. PTTCN can crystallize into two kinds of crystals with different fluorescence colors in different solvent systems. The molecules in two crystals are in different stereo isomeric forms of nitrogen, quasi axial (ax), and quasi equatorial (eq). The crystals with blue fluorescence in ax form may selectively adsorb benzene by a single-crystal-to-single-crystal (SCSC) transformation, but separated benzene from a benzene/cyclohexane equimolar mixture with a low purity of 79.6%. Interestingly, PTTCN molecules with eq form and benzene co-assembled to construct a hydrogen-bonded framework (X-HOF-4) with S-type solvent channels and yellow-green fluorescence, and can release benzene to form nonporous guest-free crystal under heating. Such nonporous crystals strongly favor aromatic benzene over cyclohexane and may selectively reabsorb benzene from benzene/cyclohexane equimolar mixture to recover original framework, and the purity of benzene can reach ≈96.5% after release from framework. Moreover, reversible transformation between the nonporous crystals and the guest-containing crystals allows the material to be reused.

m6 A-Dependent Modulation via IGF2BP3/MCM5/Notch Axis Promotes Partial EMT and LUAD Metastasis.

The importance of mRNA N6-methyladenosine (m6 A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m6 A modification is interesting but remains uncharacterized. Here, this work shows that m6 A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial-mesenchymal-transition (EMT) and confers LUAD cells plasticity to metastasize through m6 A-dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m6 A-modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m6 A-dependent IGF2BP3-mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m6 A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD.

Effect of Sowing Date on the Growth Characteristics and Yield of Growth-Constrained Direct-Seeding Rice.

To investigate changes in the yield and physiological characteristics of indica hybrid rice varieties sown on different dates, we evaluated appropriate hybrid rice varieties and their optimal sowing dates in the hilly areas of Sichuan. Three popular indica rice varieties were used as experimental materials, and five sowing dates were set uniformly locally [16 May (SD1), 23 May (SD2), 30 May (SD3), 6 June (SD4), and 13 June (SD5)] to investigate differences in the yield characteristics, growth period, and dry matter accumulation. The results showed that, over the two years, the sowing-to-heading period and overall growth period of the three varieties shortened as the sowing date was delayed, and the difference in yield between the SD1 and SD2 treatments was not significant, owing to higher material accumulation after flowering and higher assimilative material transport capacity. These varieties are both photosensitive and tolerant to low temperatures. Among the three varieties tested, the Huangyouyuehesimiao (V3) cultivar had the highest yield, with 10.75 t ha-1 under the SD2 treatment. The impact of shifting the sowing date on yield components varied. Delaying the sowing date increased and then decreased the number of effective panicles, and the number of grains per panicle and the seed setting rate decreased by differing degrees. In summary, a high yield of indica hybrid rice can be maintained by sowing between 16 and 23 May each year in the study area. It indicated that indica hybrid rice in the hilly rice-producing region of Sichuan is highly adaptable to different sowing dates.

Existential isolation and prolonged grief in bereaved people: The moderating role of culture.

OBJECTIVE: Existential isolation refers to an individual's awareness of the unbridgeable gulf between oneself, other people and the world. This kind of isolation has been found to be higher in individuals with nonnormative experiences, such as racial or sexual minorities. Bereaved individuals may experience a stronger sense of existential isolation and feel that no one shares their feelings or perceptions. However, research on bereaved people's experiences of existential isolation and its effects on post-loss adaptation is scarce. This study aims to validate the German and Chinese versions of the Existential Isolation Scale, investigate cultural and gender differences in existential isolation and explore the associations between existential isolation and prolonged grief symptoms in German-speaking and Chinese bereaved individuals. METHODS: A cross-sectional study with 267 Chinese and 158 German-speaking bereaved participants was conducted. The participants completed self-report questionnaires assessing existential isolation, prolonged grief symptoms, social networks, loneliness and social acknowledgement. RESULTS: The results indicated that the German and Chinese versions of the Existential Isolation Scale demonstrated adequate validity and reliability. No cultural or gender differences (or their interaction) were found for existential isolation. Higher existential isolation was associated with elevated prolonged grief symptoms, which was further moderated by the cultural group. The relationship between existential isolation and prolonged grief symptoms was significant for the German-speaking bereaved people but not significant for those from China. CONCLUSION: The findings highlight the role of existential isolation in the adaptation to bereavement and how different cultural backgrounds moderate the effect of existential isolation on post-loss reactions. Theoretical and practical implications are discussed.

Comprehensive insights into the metabolism characteristics of small RNA Qrr4 in Vibrio alginolyticus.

Vibrio alginolyticus is an important foodborne pathogen that can infect both humans and marine animals and cause massive economic losses in aquaculture. Small noncoding RNAs (sRNAs) are emerging posttranscriptional regulators that affect bacterial physiology and pathological processes. In the present work, a new cell density-dependent sRNA, Qrr4, was characterized in V. alginolyticus based on a previously reported RNA-seq analysis and bioinformatics approach. The effects of Qrr4 actions on the physiology, virulence, and metabolism of V. alginolyticus were comprehensively investigated based on molecular biology and metabolomics approaches. The results showed that qrr4 deletion markedly inhibited growth, motility and extracellular protease activities. Additionally, nontargeted metabolism and lipidomics analyses revealed that qrr4 deletion induced significant disturbance of multiple metabolic pathways. The key metabolic remodelling that occurred in response to qrr4 deletion was found to involve phospholipid, nucleotide, carbohydrate and amino acid metabolic pathways, providing novel clues about a potential mechanism via which mutation of qrr4 could interfere with cellular energy homeostasis, modulate membrane phospholipid composition and inhibit nucleic acid and protein syntheses to regulate the motility, growth and virulence characteristics of V. alginolyticus. Overall, this study provides a comprehensive understanding of the regulatory roles of the new cell density-dependent sRNA Qrr4 in V. alginolyticus. KEY POINTS: • A novel cell density-dependent sRNA, Qrr4, was cloned in V. alginolyticus. •Qrr4 regulated growth and virulence factors of V. alginolyticus. • Phospholipid, nucleotide and energy metabolisms were modulated obviously by Qrr4.

Prognostic value of circulating tumor DNA using target next-generation sequencing in extensive-stage small-cell lung cancer.

BACKGROUND: Chemotherapy remains the mainstay of treatment for small-cell lung cancer (SCLC). Liquid biopsies provide a convenient and non-invasive detection method for monitoring disease progression in patients with SCLC. METHODS: We performed next-generation sequencing of 159 plasma samples from 69 patients with extensive-stage (ES)-SCLC. Circulating tumor (ct)DNA levels were quantified in haploid genome equivalents per mL (hGE/mL). MuTect2 was used to detect single nucleotide variants and short insertions/deletions. The "enrichKEGG" function in the "clusterProfiler" R package was used to enrich the mutated genes that only appeared during disease progression. RESULTS: In our cohort, 66 of 69 (95.7%) plasma samples at the time of diagnosis had detectable somatic mutations; TP53 (89%) and RB1(56%) were the most frequent mutations, as well as copy number variations in some common SCLC-related genes such as RB1. Combination ctDNA and tissue testing improved the overall detection rate of actionable mutations from 19.4% to 26.9% compared with that of tissue detection alone. In addition, ctDNA levels changed dynamically during the course of treatment and were significantly associated with decreased progression-free survival. Notably, actionable mutations were detected at the time of diagnosis and during disease progression. CONCLUSIONS: Our study revealed a dynamic somatic mutation profile through continuous ctDNA detection and confirmed that ctDNA levels can reflect tumor burden and predict PFS in patients with extensive stage-SCLC. Furthermore, we demonstrated that plasma ctDNA assays can provide real-time information on somatic mutations for potential targeted therapies for SCLC.

The maximum tumor growth rate predicts clinical outcomes of patients with small-cell lung cancer undergoing first-line chemotherapy plus immune-checkpoint inhibitor therapy.

BACKGROUND: Currently, no biomarkers can accurately predict survival outcomes in patients with SCLC undergoing treatment. Tumor growth rate (TGR; percent size change per month [%/m]) is suggested as an imaging predictor of response to anti-cancer treatment. We aimed to evaluate the predictive role of the maximum TGR (TGRmax) for outcomes of small-cell lung cancer (SCLC) patients undergoing first-line chemotherapy plus immune-checkpoint inhibitor (ICI) treatment. METHODS: Patients with SCLC receiving first-line chemotherapy plus immunotherapy were analyzed within this retrospective study. The X-tile program was used to identify the cut-off value of TGRmax based on maximum progression-free survival (PFS) stratification. The Kaplan-Meier methods and Cox regression models were used to evaluate the effect of the presence of TGRmax on PFS and overall survival (OS). RESULTS: In total, 104 patients were evaluated. Median (range) TGRmax was -33.9 (-65.2 to 21.6) %/m and the optimal cut-off value of TGRmax was -34.3%/m. Multivariate Cox regression analysis revealed that patients with TGRmax > -34.3%/m was associated with shorter PFS (hazard ratio [HR], 2.81; 95% CI, 1.71-4.63; p < 0.001) and OS (HR, 3.17; 95% CI, 1.41-7.08; p = 0.005). In patients who received partial response (PR), Kaplan-Meier survival analyses showed that superior PFS and OS (p = 0.005 and p = 0.009, respectively) benefit was observed when TGRmax ≤-34.3%/m. CONCLUSIONS: SCLC patients with TGRmax > -34.3%/m had worse PFS and OS in first-line ICI plus platin-based chemotherapy. TGRmax could independently serve as an early biomarker to predict the benefit from chemoimmunotherapy.