Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial.

BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS: This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS: Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION: Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.

Immune protection of grass carp by oral vaccination with recombinant Bacillus methylotrophicus expressing the heterologous tolC gene.

In the field of aquaculture, the enhancement of animal health and disease prevention is progressively being tackled using alternatives to antibiotics, including vaccines and probiotics. This study was designed to evaluate the potential of a recombinant Bacillus methylotrophicus, engineered to express the outer membrane channel protein TolC of Aeromonas hydrophila AH3 and the green fluorescent protein GFP, as an oral vaccine. Initially, the genes encoding tolC and GFP were cloned into a prokaryotic expression system, and anti-TolC mouse antiserum was generated. Subsequently, the tolC gene was subcloned into a modified pMDGFP plasmid, which was transformed into B. methylotrophicus WM-1 for protein expression. The recombinant B. methylotrophicus BmT was then administered to grass carp via co-feeding, and its efficacy as an oral vaccine was assessed. Our findings demonstrated successful expression of the 55 kDa TolC and 28 kDa GFP proteins, and the preparation of polyclonal antibodies with high specificity. The BmT exhibited stable expression of the GFP-TolC fusion protein and excellent genetic stability. Following oral immunization, significant elevations were observed in serum-specific IgM levels and the activities of acid phosphatase (ACP), alkaline phosphatase (AKP), superoxide dismutase (SOD), and lysozyme (LZM) in grass carp. Concurrently, significant upregulation of immune-related genes, including IFN-I, IL-10, IL-1ß, TNF-α, and IgT, was noted in the intestines, head kidney, and spleen of the grass carp. Colonization tests further revealed that the BmT persisted in the gut of immunized fish even after a fasting period of 7 days. Notably, oral administration of BmT enhanced the survival rate of grass carp following A. hydrophila infection. These results suggest that the oral BmT vaccine developed in this study holds promise for future applications in aquaculture.

Telehealth With Comprehensive Live-Fed Real-World Data as a Patient Care Platform for Lung Cancer: Implementation and Evaluation Study.

BACKGROUND: Telehealth has emerged as a popular channel for providing outpatient services in many countries. However, the majority of telehealth systems focus on operational functions and offer only a sectional patient journey at most. Experiences with incorporating longitudinal real-world medical record data into telehealth are valuable but have not been widely shared. The feasibility and usability of such a telehealth platform, with comprehensive, real-world data via a live feed, for cancer patient care are yet to be studied. OBJECTIVE: The primary purpose of this study is to understand the feasibility and usability of cancer patient care using a telehealth platform with longitudinal, real-world data via a live feed as a supplement to hospital electronic medical record systems specifically from physician's perspective. METHODS: A telehealth platform was constructed and launched for both physicians and patients. Real-world data were collected and curated using a comprehensive data model. Physician activities on the platform were recorded as system logs and analyzed. In February 2023, a survey was conducted among the platform's registered physicians to assess the specific areas of patient care and to quantify their before and after experiences, including the number of patients managed, time spent, dropout rate, visit rate, and follow-up data. Descriptive and inferential statistical analyses were performed on the data sets. RESULTS: Over a period of 15 months, 16,035 unique users (13,888 patients, 1539 friends and family members, and 174 physician groups with 608 individuals) registered on the platform. More than 382,000 messages including text, reminders, and pictures were generated by physicians when communicating with patients. The survey was completed by 78 group leaders (45% of the 174 physician groups). Of the participants, 84% (65.6/78; SD 8.7) reported a positive experience, with efficient communication, remote supervision, quicker response to questions, adverse event prevention, more complete follow-up data, patient risk reduction, cross-organization collaboration, and a reduction in in-person visits. The majority of the participants (59/78, 76% to 76/78, 97.4%) estimated improvements in time spent, number of patients managed, the drop-off rate, and access to medical history, with the average ranging from 57% to 105%. When compared with prior platforms, responses from physicians indicated better experiences in terms of time spent, the drop-off rate, and medical history, while the number of patients managed did not significantly change. CONCLUSIONS: This study suggests that a telehealth platform, equipped with comprehensive, real-world data via a live feed, is feasible and effective for cancer patient care. It enhances inpatient management by improving time efficiencies, reducing drop-off rates, and providing easy access to medical history. Moreover, it fosters a positive experience in physician-patient interactions.

[Preparation of magnetic carbon nitride composite toward phosphopeptide enrichment].

Protein phosphorylation plays an important role in cellular signaling and disease development. Advances in mass spectrometry-based proteomics have enabled qualitative and quantitative phosphorylation studies as well as in-depth biological explorations for biomarker discovery and signaling pathway analysis. However, the dynamic changes that occur during phosphorylation and the low abundance of target analytes render direct analysis difficult because mass spectral detection offers no selectivity, unlike immunoassays such as Western blot and enzyme-linked immunosorbent assay (ELISA). The present study aimed to solve one of the key problems in the specific and efficient isolation of phosphorylated peptides. A method based on a magnetic carbon nitride composite coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was developed for the enrichment and analysis of phosphopeptides with low abundance in complex samples. Magnetic carbon nitride composite was synthesized and characterized by electron microscopy, infrared spectroscopy, and X-ray diffractometry. The composite showed a well-distributed two-dimensional layered structure and functional groups with excellent paramagnetic performance. Two classical phosphoproteins, namely, α- and ß-caseins, were selected as model phosphorylated samples to assess the performance of the proposed enrichment technique. The magnetic carbon nitride composite exhibited high selectivity and sensitivity for phosphopeptide enrichment. The limit of detection was determined by MALDI-TOF-MS analysis to be 0.1 fmol. The selectivity of the method was investigated using the digest mixtures of α-casein, ß-casein, and bovine serum albumin (BSA) with different mass ratios (1∶1∶1000, 1∶1∶2000, and 1∶1∶5000). Direct analysis of the samples revealed the dominance of spectral signals from the abundant peptides in BSA. After enrichment with the magnetic carbon nitride composite, the high concentration of background proteins was washed away and only the signals of the phosphopeptides were captured. The signals from the casein proteins were clearly observed with little background noise, indicating the high selectivity of the composite material. The robustness of the method was tested by assessing the reusability of the same batch of magnetic carbon nitride materials over 20 cycles of enrichment. The composite showed nearly the same enrichment ability even after several cycles of reuse, demonstrating its potential applicability for a large number of clinical samples. Finally, the method was applied to the analysis of phosphopeptides from several commonly used phosphoprotein-containing samples, including skimmed milk digest, human serum, and human saliva; these samples are significant in the analysis of food quality, disease biomarkers, and liquid biopsies for cancer. Without enrichment, no phosphopeptide was detected because of the high abundance of nonphosphopeptide materials dominating the spectral signals obtained. After pretreatment with the developed magnetic carbon nitride composite, most of the phosphosites were identified with high selectivity and sensitivity via MALDI-TOF-MS. These results revealed the practicality of the developed approach for clinical applications. In addition, our method may potentially be employed for phosphoproteomics with real complex biological samples.

Garsorasib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRASG12C inhibitor, has shown promising antitumour activity in patients with KRASG12C-mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRASG12C-mutated NSCLC. METHODS: This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRASG12C-mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting. FINDINGS: From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed. INTERPRETATION: The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. FUNDING: InventisBio.

IMpower210: A phase III study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer.

Objective: IMpower210 (NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs. docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC) in East Asian patients. Methods: Key eligibility criteria for this phase III, open-label, randomized study included age ≥18 years; histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system (7th edition); Eastern Cooperative Oncology Group performance status of 0 or 1; and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab (1,200 mg) or docetaxel (75 mg/m2). The primary study endpoint was overall survival (OS) in the intention-to-treat (ITT) population with wild-type epidermal growth factor receptor expression (ITT EGFR-WT) and in the overall ITT population. Results: Median OS in the ITT EGFR-WT population (n=467) was 12.3 [95% confidence interval (95% CI), 10.3-13.8] months in the atezolizumab arm (n=312) and 9.9 (95% CI, 7.8-13.9) months in the docetaxel arm [n=155; stratified hazard ratio (HR), 0.82; 95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5 (95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1 (95% CI, 8.4-14.2) months (n=377) with docetaxel treatment (n=188; stratified HR, 0.87; 95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm. Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade 3/4 TRAEs.

Patient-derived tumor-like cell clusters for personalized chemo- and immunotherapies in non-small cell lung cancer.

Many patient-derived tumor models have emerged recently. However, their potential to guide personalized drug selection remains unclear. Here, we report patient-derived tumor-like cell clusters (PTCs) for non-small cell lung cancer (NSCLC), capable of conducting 100-5,000 drug tests within 10 days. We have established 283 PTC models with an 81% success rate. PTCs contain primary tumor epithelium self-assembled with endogenous stromal and immune cells and show a high degree of similarity to the original tumors in phenotypic and genotypic features. Utilizing standardized culture and drug-response assessment protocols, PTC drug-testing assays reveal 89% overall consistency in prospectively predicting clinical outcomes, with 98.1% accuracy distinguishing complete/partial response from progressive disease. Notably, PTCs enable accurate prediction of clinical outcomes for patients undergoing anti-PD1 therapy by combining cell viability and IFN-γ value assessments. These findings suggest that PTCs could serve as a valuable preclinical model for personalized medicine and basic research in NSCLC.

The use of blockchain technology in enterprise financial accounting information sharing.

This work intends to comprehensively analyze the application of blockchain technology in enterprise financial accounting information sharing and address prevalent issues such as information opacity, data tampering, and data security in the current practices. Therefore, it writes smart contracts based on the Ethereum platform to achieve the secure sharing of financial accounting information between enterprises. This work employs a randomized experimental design approach, using a computer-generated random number program to divide 100 enterprises into experimental and control groups, each comprising 50 enterprises. Enterprises in the experimental group share financial accounting information using smart contracts on the Ethereum platform during the experiment. The financial personnel of these enterprises upload reconciled data to the corresponding smart contracts using the enterprise's digital signatures after each month's accounting process. Enterprises in the control group continue to use traditional methods of financial accounting information sharing (such as email and web platforms) to share financial data files directly. Quantitative analysis is performed to compare the data between the experimental and control groups. Empirical results reveal a notable enhancement in information-sharing efficiency by 25.7%, a 19.8% improvement in data accuracy, and a 13.6% reduction in financial information-sharing costs within the experimental group compared to the control group. This work provides compelling evidence that adopting blockchain-based information-sharing methods can effectively elevate data trustworthiness and security. Supported by systematic empirical findings, this work validates the significant potential of blockchain technology in the realm of enterprise financial accounting information sharing.

(De)carboxylation mechanisms of heteroaromatic substrates catalyzed by prenylated FMN-dependent UbiD decarboxylases: An in-silico study.

The UbiD enzymes are proposed to catalyze reversible (de)carboxylation reaction of unsaturated carboxylic acids using prenylated flavin mononucleotide (prFMN) as a cofactor. This positions UbiD enzymes as promising candidates for converting CO2 into valuable chemicals. However, their industrial-scale biotransformation is currently constrained by low conversion rates attributed to thermodynamic limitations. To enhance the carboxylation activity of UbiD enzymes, a molecular-level understanding of the (de)carboxylation mechanisms is necessary. In this study, we investigated the reaction mechanisms of heteroaromatic substrates catalyzed by PtHmfF, PaHudA, and AnlnD enzymes using molecular dynamics (MD) simulations and free energy calculations. Our extensive mechanistic study elucidates the mechanisms involved in the formation of the initial prFMN-substrate intermediate. Specifically, we observed nucleophilic attack during decarboxylation, while carboxylation reactions involving furoic acid, pyrrole, and indole tend to favor a 1,3-dipolar cycloaddition mechanism. Furthermore, we identified proton transfer as the rate-limiting step in the carboxylation reaction. In addition, we considered the perspectives of reaction energies and electron transfer to understand the distinct mechanisms underlying decarboxylation and carboxylation. Our calculated free energies are consistent with available experimental kinetics data. Finally, we explored how different rotamers of catalytic residues influence the efficiency of the initial intermediate formation.

Dexamethasone Suppresses IL-33-exacerbated Malignant Phenotype of U87MG Glioblastoma Cells via NF-κB and MAPK Signaling Pathways.

BACKGROUND: Interleukin (IL)-33 is highly expressed in glioblastoma (GBM) and promotes tumor progression. Targeting IL-33 may be an effective strategy for the treatment of GBM. Dexamethasone (DEX) is a controversial drug routinely used clinically in GBM therapy. Whether DEX has an effect on IL-33 is unknown. This study aimed to investigate the effect of DEX on IL-33 and the molecular mechanisms involved. METHODS: U87MG cells were induced by tumor necrosis factor (TNF)-α to express IL-33 and then treated with DEX. The mRNA levels of IL-33, NF-κB p65, ERK1/2, and p38 were determined by real-time quantitative PCR. The expression of IL-33, IkBα (a specific inhibitor of NF-κB) and MKP-1 (a negative regulator of MAPK), as well as the phosphorylation of NF-κB, ERK1/2 and p38 MAPK, were detected by Western blotting. The secretion of IL-33 was measured by ELISA. The proliferation, migration and invasion of U87MG cells were detected by CCK8 and transwell assays, respectively. RESULTS: DEX significantly reduced TNF-α-induced production of IL-33 in U87MG cells, which was dependent on inhibiting the activation of the NF-κB, ERK1/2 and p38 MAPK signaling pathways, and was accompanied by the increased expression of IkBα but not MKP-1. Furthermore, the proliferation, migration and invasion of U87MG cells exacerbated by IL-33 were suppressed by DEX. CONCLUSION: DEX inhibited the production and tumor-promoting function of IL-33. Whether DEX can benefit GBM patients remains controversial. Our results suggest that GBM patients with high IL-33 expression may benefit from DEX treatment and deserve further investigation.

Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study.

INTRODUCTION: Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer. METHODS: This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2. RESULTS: Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline. CONCLUSIONS: Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

Determination of organic and inorganic Cl in gaseous ethylene based on gas-liquid equal mass response followed by automatic quick furnace-ion chromatography.

Herein, a practical method for the determination of organic and inorganic Cl in gaseous ethylene by liquid standard samples was established; and then, the effects of various speciation and matrices on results were investigated followed by automatic quick furnace-ion chromatography (AQF-IC) analysis. From the evaluation of speciation and matrices, unified equation was explored and the method for accurately determining trace HCl with strong adsorption was also developed. First, summarize regularity that the light oil liquid standards themselves conformed to equal Cl mass response by AQF-IC (R2=0.99993). Then, the actual Cl mass in standard gas at 4 levels with different speciation and matrices were calculated by the same regularity based on the assumption of not affected by speciation or matrix change. The gas mass was accurately calculated based on Van der Waals' Equation. As a result, combined with the theoretical Cl mass calculated by equation, the recoveries of the organic and inorganic Cl were in the range of 93.0%-101.4% [2.0 µmol/mol of CH3Cl/(N2+ethylene)], 93.4%-104.9% (10.1 µmol/mol of CH3Cl/N2), 101.6%-111.2% (20.2 µmol/mol of CH3Cl/ethylene) and 95.3%-101.0% (11.0 mg/m3 of HCl/N2), respectively, indicating the successful verification of above assumption rather than applying more exploration to rebuild relationships between different systems. As proof of principle and for more verification, system of CH2Cl2/He gas standard sample was prepared to explore the quantitative accuracy in more speciation with recoveries in the range of 91.3%-98.5%. In addition, the detection limit of Cl content based on S/N = 3 for ethylene was 0.06 mg/kg. Intra-day and inter-day relative standard devations (RSDs) were in the range of 9.3%-12.0% (≤1.0 mg/kg) and 2.5%-4.4% (>1.0 mg/kg). Finally, the developed method based on gas-liquid equal mass response was successfully applied in the actual samples of light olefins such as ethylene and propylene.

Correction to: Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis.

[This corrects the article DOI: 10.1093/nsr/nwab232.].

International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

Microbiome data analysis via machine learning models: Exploring vital players to optimize kitchen waste composting system.

Composting, reliant on microorganisms, effectively treats kitchen waste. However, it is difficult to precisely understand the specific role of key microorganisms in the composting process by relying solely on experimental research. This study aims to employ machine learning models to explore key microbial genera and to optimize composting systems. After introducing a novel microbiome preprocessing approach, Stacking models were constructed (R2 is about 0.8). The SHAP method (SHapley Additive exPlanations) identified Bacillus, Acinetobacter, Thermobacillus, Pseudomonas, Psychrobacter, and Thermobifida as prominent microbial genera (Shapley values ranging from 3.84 to 1.24). Additionally, microbial agents were prepared to target the identified key genera, and experiments demonstrated that the composting quality score was 76.06 for the treatment and 70.96 for the control. The exogenous agents enhanced decomposition and improved compost quality in later stages. In summary, this study opens up a new avenue to identifying key microorganisms and optimizing the biological treatment process.

High-Throughput Phytochemical Unscrambling of Flowers Originating from Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) P. K. Hsiao and Astragalus membranaceus (Fisch.) Bug. by Applying the Intagretive Plant Metabolomics Method Using UHPLC-Q-TOF-MS/MS.

Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) P. K. Hsiao (MO) and Astragalus membranaceus (Fisch.) Bug. (ME) are two primary sources of the Astragalus herb, also known as "Huangqi" in China, which is widely applied to treat hypertension, glomerulonephritis, ischemic heart disease, and diabetes mellitus. As two different sources of the Astragalus herb, the chemical profiles of MO and ME may be different. Previous studies showed abundant differences in chemical composition between MO and ME. Therefore, the by-products of MO and ME, such as Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) P. K. Hsiao flower (MOF) and Astragalus membranaceus (Fisch.) Bug. flower (MEF), may have different phytochemical profiles. In this paper, a metabolomics method combined with ultra-high-performance liquid chromatography and electrospray ionization/quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was employed to analyze the components of MOF and MEF. Consequently, the results of principal component analysis (PCA) showed that MOF and MEF could be separated clearly. In total, 31 chemical markers differentiating MOF and MEF were successfully identified, including 22 flavonoids, 8 isoflavones and 1 benzopyran. Among them, the contents of 18 components, including Calycosin, Cyanidin-3-O-glucoside, Quercetin, Rutin, Kaempferol, Formononetin, Isomucronulatol and Prim-O-glucosylcimifugin in MEF, were significantly higher than in MOF. In turn, the contents of another 13 components, covering Biochanin A, Tectoridin, Isomucronulatol-7-O-glucoside, Liquiritin, Rhamnetin, etc., were lower in the MEF group than that in the MOF group. It is worth noting that flavonoids, especially flavonoid glycosides, were the primary active chemical ingredients in MOF and MEF. The 18 ingredients in MEF with a higher level carried out diverse activities, like anti-oxidant, anti-inflammatory, anti-bacterial and anti-tumor activities, which led us to speculate that MEF may have greater pharmacological effects and potential development prospects than MOF. The present results displayed that the contents of ingredients in the two different species of plants were radically different, and there was significant uniqueness to the components of MOF and MEF. Our study not only provides helpful chemical information for further quality assessment and active mechanism research of MOF and MEF but also offers scientific support for the resource utilization of MOF and MEF.

miR-32-5p induces hepatic steatosis and hyperlipidemia by triggering de novo lipogenesis.

BACKGROUND AND OBJECTIVES: MicroRNA-dependent regulation of hepatic lipid metabolism has been recognized recently as a key pathological mechanism contributing to the development of NAFLD. However, whether miR-32-5p (miR-32) plays a role in lipid metabolism or contributes to NAFLD remains unclear. METHODS AND RESULTS: A marked increase in miR-32 expression was observed in liver samples from patients and mice with NAFLD, as well as in palmitate-induced hepatocytes. Hepatocyte-specific miR-32 knockout (miR-32-HKO) dramatically ameliorated hepatic steatosis and metabolic disorders in high-fat diet-fed mice. Conversely, hepatic miR-32 overexpression markedly exacerbated the progression of these abnormalities. Further, combinational analysis of transcriptomics and lipidomics suggested that miR-32 was a key trigger for de novo lipogenesis in the liver. Mechanistically, RNA sequencing, luciferase assay and adenovirus-mediated downstream gene rescue assay demonstrated that miR-32 directly bound to insulin-induced gene 1 (INSIG1) and subsequently activated sterol regulatory element binding protein-mediated lipogenic gene programs, thereby promoting hepatic lipid accumulation and metabolic disorders. Notably, pharmacological administration of miR-32 antagonist significantly inhibited palmitate-induced triglyceride deposition in hepatocytes and markedly mitigated hepatic steatosis and metabolic abnormalities in obesity-associated NAFLD mice. CONCLUSION: miR-32 is an important checkpoint for lipogenesis in the liver, and targeting miR-32 could be a promising therapeutic approach for NAFLD treatment.