Therapeutic management of small cell lung cancer (SCLC) remains a major challenge for clinicians, with few treatment options significantly impacting patient survival. One of the barriers to advancing the treatment of patients with SCLC has been identified as the lack of detailed molecular characterization. A recent large real-world data reveals genomic characterization of predominantly Caucasian SCLC patients. However, little is known about that in Chinese SCLC patients. Here, we analyzed whole-exome sequencing data based on 178 Chinese SCLC patients to understand the genomic characteristics of Chinese patients, and compare them with those of Caucasian patients. Univariate Cox regression analysis was performed to figure out the correlation between gene mutation and prognosis. CCLE database was used to predict drug responses in SCLC cells with different mutation status. The top ten frequently mutated genes in Chinese SCLC patients were TP53, TTN, RB1 MUC16, USH2A, FSIP2, ZFHX4, SYNE1 CSMD3 and OBSCN. And the top ten frequently genes with copy number amplifications/deletions were SDHA, NKX2-1, PSIP1, SRSF2, CALR PTPN6, SUZ16, PABPC1, MAP2K4, and MSI2. PKD1L1 mutation was found to be associated with worse prognosis in both Chinese and Caucasian SCLC patients, and analyses based on the CCLE dataset found that SCLC cell lines with PKD1L1 mutation were more sensitive to small molecular inhibitors targeting the MYC and mTOR signaling pathways. Compared with Caucasian, the genetic alterations of Chinese SCLC patients presented different patterns, and we identified a common gene, PKD1L1, associated with poor prognosis in patients from different populations, and this gene may be a predictive marker of drug reactivity targeting the MYC and/or mTOR signaling pathways.

Savolitinib is a potent and highly selective oral MET tyrosine-kinase inhibitor, approved in China for the treatment of NSCLC patients (pts) that have progressed following prior systemic therapy or are unable to receive chemotherapy with MET exon 14 mutation (METex14) based on the phase II study (NCT02897479). Here we report the primary analysis results from a phase IIIb confirmatory study (NCT04923945; data cut: Oct 20, 2023; follow-up: treatment-naïve ≥12 months, previously treated ≥6 months). Previously treated (≥2L) or treatment-naive (1L) pts with advanced or metastatic METex14 NSCLC were enrolled. Pts received savolitinib QD at 600 mg (≥50 kg) or 400 mg (<50 kg). The primary endpoint was ORR assessed by BIRC per RECIST 1.1. Secondary endpoints mainly included DCR, DoR, TTR, PFS and OS. For treatment-naïve pts (n=87; median age: 70 yrs; male: 58.6%; ECOG PS of 1: 81.6%; adenocarcinoma: 80.5%; PSC: 8.0%; brain metastasis: 11.5%), as assessed by BIRC, ORR was 62.1%, DCR was 92.0%; mPFS was 13.7 months and mOS was not reached with median follow-up 18.0 and 20.8 months, respectively. For previous treated pts (n=79; median age: 68.8 yrs; male: 57.0%; ECOG PS of 1: 87.3%; adenocarcinoma: 78.5%; PSC: 5.1%; brain metastasis: 26.6%), ORR was 39.2%, DCR was 92.4%; mPFS was 11.0 months and mOS was also immature with median follow-up 11.0 and 12.5 months, respectively (see details in Table). Study drug-related treatment-emergent adverse events of Grade ≥3 occurred in 100 pts (60.2%) from total 166 pts. The most common ones (≥5%) were hepatic function abnormal (16.9%), alanine aminotransferase increased (14.5%), aspartate aminotransferase increased (12.0%), gamma-glutamyltransferase increased (6.0%), and oedema peripheral (6.0%). Table: 1MOBIRC assessedTreatment-naïve n=87Previously treated n=79ORR, % (95% CI)62.1 (51.0, 72.3)39.2 (28.4, 50.9)DCR, % (95% CI)92.0 (84.1, 96.7)92.4 (84.2, 97.2)mDoR, mos (95% CI)12.5 (8.3, 15.2)11.1 (6.6, -)mTTR, mos (95% CI)1.4 (1.4, 1.5)1.6 (1.4, 2.7)mPFS, mos (95% CI)13.7 (8.5, 16.6)11.0 (8.3, 16.6) Open table in a new tab The data showed an encouraging efficacy and a tolerable safety profile of savolitinib in treatment for METex14-mutated NSCLC, offering a new standard treatment option for naïve and treated pts for this population.

AIMS:Transformed small cell lung cancer (T-SCLC) is a highly aggressive clinical disease with a notably poor prognosis. It most often arises from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) following treatment. To date, no standard treatment has been established for T-SCLC. Platinum-etoposide was the most commonly used regimen, but progression-free survival remains unsatisfactory. Therefore, there is an urgent unmet need to develop novel and effective strategies for this population. Our study, a multicentre, open-label, single-arm phase II clinical trial (NCT05957510), aims to evaluate the efficacy and safety of serplulimab plus chemotherapy in untreated T-SCLC patients after histological transformation.MATERIALS AND METHODS:In total, 36 eligible participants experiencing SCLC transformation from EGFR-mutant NSCLC will be enrolled to receive combination therapy of serplulimab, etoposide and carboplatin for four to six cycles, followed by maintenance therapy with serplulimab for up to 2 years. The primary endpoint is progression-free survival; secondary endpoints include objective response rate, overall survival and safety.RESULTS:Enrolment started in July 2023 and is ongoing, with an estimated completion date of December 2025.CONCLUSIONS:This study aims to provide valuable insights into the efficacy and safety of combining serplulimab with chemotherapy for treating patients with T-SCLC originating from EGFR-mutant NSCLC.

Long non-coding RNAs play critical roles in the development of lung cancer by functioning as tumor suppressors or oncogenes. Changes in the expression of LINC01279 have been associated with cell differentiation and human diseases. However, the mechanism underlying LINC01279 activity in tumorigenesis is not clear.

Recombinant human endostatin (Rh-endostatin), in combination with chemotherapy has been recommended by Chinese Society of Clinical Oncology (CSCO) guideline as the first-line treatment for advanced non-small cell lung cancer (NSCLC). However, clinical evidences of Rh-endostatin plus PD-1 inhibitors as the first-line therapy for EGFR/ALK-negative, advanced or metastatic, non-squamous NSCLC has still been insufficient, which greatly limited the application of evidence-based medicine in medical practice.

A previous study, based on human single-cell RNA sequencing data and cellular and mice models, has shown that HES1 and KLF6 are driver genes of skin aging, exerting geroprotective effects. To evaluate whether there are genetic and epigenetic risk factors linked to skin aging mediated by HES1 and KLF6 in the real world, we conducted a large-scale population cohort study in China comprising 3,375 participants. We used the validated skin aging score SCINEXATMto evaluate skin aging and collected data on genotype, DNA methylation, and lifestyle questionnaire. We then analyzed 332 SNPs and 368 CpGs located near HES1 and KLF6, or regulating their expression (eQTL and eQTM), to investigate their association with the skin aging phenotypes. We found 9 SNPs located 10-23kb downstream of HES1 can downregulate HES1 and alleviate solar elastosis, while 5 SNPs can decrease HES1 expression and increase the number of pigment spots on the cheek. Furthermore, cg10480300 and cg06048750 located on KLF6 are associated with skin aging traits, including solar elastosis and evenness of pigment spots on the forearm, as well as lifestyle factors such as BMI and food deficiency. Mediation analysis showed that cg06048750 mediates the association between BMI, food deficiency, and evenness of pigment spots on the forearm (indirect effect of -0.001 and 0.007 respectively, both P<0.05), while cg10480300 mediates the association between BMI and solar elastosis (indirect effect=-0.001, P<0.05). In summary, our findings shed light on the potential genetic and epigenetic regulatory role of HES1 and KLF6 in the manifestation of skin aging.

Abstract Objective Long non-coding RNAs (lncRNAs) are involved in tumorigenesis. The telomerase RNA component (TERC) is an lncRNA that functions as an essential template for the addition of the telomere repeat.The aims of our study were to determine the biological function and mechanism of TERC in lung adenocarcinoma. Methods RNA-seq analyses were used to compare the expression levels of TERC in cancerous and adjacent normal lung tissues. Functional assays of TERC in LUAD cell lines were performed by siRNA-mediated knockdown. Cell proliferation, migration and invasion were evaluated by WST-1 and transwell assays. Reactive oxygen species (ROS) levels were determined by flow cytometry and examined by fluorescence microscopy, and the morphology of mitochondria was observed using transmission electron microscopy. Protein expression was analyzed by western blot. The formation of autophagosomes was monitored by fluorescence microscopy following expression of fluorescent-tagged LC3. Results RNA-seq analyses show that the expression of TERC is upregulated in lung cancer tissues. Knockdown of TERC inhibits migration and invasion of LUAD cells. Mechanistic analyses indicate that silencing of TERC increases the expression of autophagy-related proteins LC3B, Beclin-1 and AMP-activated protein kinase (AMPK) meanwhile the expression of p62 protein, as well as ferroptosis-regulated proteins GPX4 and SLC7A11 were diminished. Importantly, inhibition of AMPK function counterbalances the effects of TERC knockdown on autophagy and ferroptosis in LUAD cells. Conclusions These findings reveal that suppression of TERC in lung cancer promotes autophagy and ferroptosis via regulation of AMPK. They help to understand the mechanism underlying TERC activity in tumorigenesis.

Objective: To analyze the clinical presentation and progression risk factors of patients with monoclonal gammopathy of undetermined significance (MGUS) in China. Methods: We retrospectively assessed the clinical features and disease progression of 1 037 patients with monoclonal gammopathy of undetermined significance between January 2004 and January 2022 at Peking Union Medical College Hospital. Results: A total of 1 037 patients were recruited in the study, including 636 males (63.6%) , with a median age of 58 (18-94) years. The median concentration of serum monoclonal protein was 2.7 (0-29.4) g/L. The monoclonal immunoglobulin type was IgG in 380 patients (59.7%) , IgA in 143 patients (22.5%) , IgM in 103 patients (16.2%) , IgD in 4 patients (0.6%) , and light chain in 6 patients (0.9%) . 171 patients (31.9%) had an abnormal serum-free light chain ratio (sFLCr) . According to the Mayo Clinic model for risk of progression, the proportion of patients in the low-risk, medium-low-risk, medium-high risk, and high-risk groups were 254 (59.5%) , 126 (29.5%) , 43 (10.1%) , and 4 (0.9%) , respectively. With a median follow-up of 47 (1-204) months, 34 of 795 patients (4.3%) had disease progression, and 22 (2.8%) died. The overall progression rate was 1.06 (0.99-1.13) /100 person-years. Patients with non-IgM MGUS have a markedly higher disease progression rate per 100 person-years than IgM-MGUS (2.87/100 person-years vs 0.99/100 person-years, P=0.002) . The disease progression rate per 100 person-years in non-IgM-MGUS patients of Mayo classification low-risk, medium-low risk and medium-high risk groups were 0.32 (0.25-0.39) /100 person-years, 1.82 (1.55-2.09) /100 person-years, and2.71 (1.93-3.49) /100 person-years, which had statistically difference (P=0.005) . Conclusion: In comparison to non-IgM-MGUS, IgM-MGUS has a greater risk of disease progression. The Mayo Clinic progression risk model applies to non-IgM-MGUS patients in China.

Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes. Their dysregulation has been closely associated with tumorigenesis. LINC00265 is upregulated in lung adenocarcinoma and is a prognostic biomarker of this cancer. However, the mechanism underlying its function in cancer progression remains poorly understood.

Objective: The study investigated the efficacy and safety of daratumumab in the treatment of cardiac light chain (AL) amyloidosis. Methods: We retrospectively analyzed the clinical characteristics, hematologic response, organ response, long-term survival, and adverse events of 20 patients with newly diagnosed or relapsed/refractory cardiac AL amyloidosis treated with daratumumab in Peking Union Medical College Hospitalo from January 2017 to March 2021. Results: The overall median age of 20 patients was 62 (range, 45-73) yeas, with a male to female ratio of 2.3:1. Nine patients were newly diagnosed, while 11 patients had relapsed or refractory disease. Based on Mayo 2004 cardiac AL staging system, stages Ⅱ and Ⅲ diseases were present in 20 patients respectively. Four patients died during the first cycle of daratumumab, and the remaining 16 patients completed a median of 3 (range, 1-10) cycles of treatment. Overall hematologic response rates were 80% each at 1, 3, and 6 months after treatment initiation, and 45% , 60% , and 60% of the patients achieved at least a very good partial response at 1, 3, and 6 months respectively. The median duration to hematologic response was 13 (range, 6-28) days. At 3, 6, and 12 months, 20% , 30% , and 40% of the patients respectively achieved a cardiac response, and the median days to response was 91 (range, 30-216) days. As of the last follow-up, 9 (45% ) patients died. The 1-month mortality rate of all the patients and stage IIIb patients was 25% and 40% , respectively. The 1-year overall survival rate was 48.4% . Lymphocytopenia was the most common hematological adverse event (above grade 3) . Non-hematological adverse events were mainly infusion-related reactions and infections. Conclusion: Daratumumab could induce deep and rapid hematologic response in newly diagnosed and previously treated cardiac AL amyloidosis patients. However, daratumumab was not effective in preventing the high and early mortality rate in stage Ⅲb patients.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved clinical outcomes for patients with EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC); however, patients will inevitably progress often due to acquired resistance mutations. Coexisting MET overexpression is known to be associated with resistance to EGFR TKIs. Savolitinib is a potent and highly selective oral MET TKI that has shown encouraging antitumor activity and a favorable safety profile in patients with pulmonary sarcomatoid carcinoma and other NSCLC with MET exon 14 skipping alterations in a phase 2 study (NCT02897479).

Objective: To investigate the prognostic value of translocation t(11;14) in newly-diagnosed primary light-chain (AL) amyloidosis patients treated with bortezomib-based regimen. Method: Clinical information of newly-diagnosed AL amyloidosis patients in Peking Union Medical College Hospital who had baseline t(11;14) data and accepted bortezomib-combined therapies from September, 2015 to September, 2021 was collected. The relationships between t(11;14) status and baseline characteristics, hematological response, organ response and prognosis were analyzed. Results: A total of 152 patients were included, aged (59.5±9.1) years and 93 cases were male (61.2%). Forty-six patients carried t(11;14) (30.3%). There was no statistical difference in the proportion of organ involved, distribution of Mayo 2004 and 2012 stages and laboratory indexes between patients with and without t(11;14) (all P>0.05). For hematological response, the difference in the rates of ≥very good partial response (VGPR) between those with t(11;14) and without after the first cycle [28.2%(11/39) vs 37.4%(34/91), P>0.05] was not statistically significant. After 3 cycles, the difference in the rates of ≥VGPR between two groups was not statistically significant [35.9%(14/39) vs 51.1%(46/90), P>0.05]. The difference in the ratio of the best hematological response reaching ≥VGPR between two groups during the first-line treatment was not statistically significant [52.2%(24/46) vs 64.2%(68/106), P>0.05]. But patients with t(11;14) had lower cardiac response rate at 3 months [15.2%(5/33) vs 34.6%(28/81), P=0.038] and 6 months [19.4%(6/31) vs 50.6%(42/83),P=0.003] than those without, but the difference in cardiac response rates at 12 months was not statistically significant [41.7%(10/24) vs 53.5%(38/71),P>0.05]. For survival, the differences in overall survival (not reached vs 50.1 months, P>0.05) and hematological event-free survival (36.2 months vs 39.9 months, P>0.05) between patients carrying t(11;14) and those without were not statistically significant. Conclusion: Patients with t(11;14) had lower cardiac response rate than those without, but their hematological response and survival are not significantly different from those free from t(11;14).

At present, there are few researches on the structural design of integrated circuit vibration fixture, and the fixture structure selected by the empirical method lacks theoretical analysis and research. Based on integrated circuit fixture on the natural frequency and vibration response to demand higher characteristic, selection method of vibration fixture structure in the fixture design research, the maximum number of installation location is used to simulate assembly fixture structure. Considering the characteristics of vibration test sample number of integrated circuits and the influence of the natural frequency of the fixture structure, we choose the hexahedral H-shaped and Tshaped fixture structure with the most installation stations, respectively on the quality of the aluminum alloy material with the three fixture structure modal simulation and acceleration response analysis. Also, installation to test the sample tooling to fixture is analyzed on the structure natural frequency and the influence of the acceleration transfer response, selected suitable fixture structure. This work provides selection basis for integrated circuit fixture structure design and lays a solid foundation for subsequent fixture optimization design.