Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

Although amplification/overexpression is the predominant mechanism for the oncogenic properties of MDM2, an increasing number of MDM2 somatic missense mutations were identified in cancer patients with the recent advances in sequencing technology. Here, we characterized an MDM2 cancer-associated mutant variant W329G identified from a patient sample that contains a wild-type p53 gene. Trp329 is one of residues that were reported to be critical to MDM2's binding to ribosomal protein L11 (RPL11). We found that the MDM2 W329G mutant was resistant to the inhibitory effect of RPL11 on MDM2-mediated p53 ubiquitination and degradation, in line with its defect on RPL11 binding. Using isogenic U2OS cells with or without endogenous MDM2 W329G mutation, we demonstrated that the expression of classic p53 targets induced by ribosomal stress signals was reduced in mutant cells. RNA-seq analysis revealed that upon 5-FU treatment, the p53 response was significantly impaired. Also, the 5-FU-mediated repression of genes in cell cycle progression and DNA replication was diminished in W329G mutant-containing cells. Physiologically, U2OS W329G cells were more resistant to cell growth inhibition induced by ribosomal stress and exhibited higher glycolytic rates upon 5-FU treatment. Together, our data indicated that cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

Safety and efficacy of multi-target TKI combined with nivolumab in check-point inhibitor-refractory patients with advanced NSCLC: a prospective, single-arm, two-stage study.

BACKGROUND: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. METHODS: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. RESULTS: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. CONCLUSION: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. TRIAL REGISTRATION: NCT04507906 August 11, 2020.

Systematic Transcriptome Profiling of hPSC-derived Osteoblasts Unveils CORIN's Mastery in Governing Osteogenesis Through CEBPD Modulation.

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect hPSC-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide ChIP enrichment and mechanistic studies show that p38 MAPK-mediated CEBPD upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in MSCs exerts a negative regulatory effect on osteogenesis through a similar mechanism. ChIP-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment.

Anti-angiogenic therapy or immunotherapy? A real-world study of patients with advanced non-small cell lung cancer with EGFR/HER2 exon 20 insertion mutations.

Background: For patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation TKIs is still controversial. Immunotherapy research is scarce, and there is an urgent need for more evidence and new treatment options for this group of patients. Methods: We reviewed patients with advanced NSCLC with EGFR/HER2 exon 20 insertion mutations treated in Shanghai Chest Hospital and Shanghai Pulmonary Hospital from 2015 to 2022 and assessed the efficacy of receiving chemotherapy, anti-angiogenic therapy and immunotherapy, including objective response rate (ORR) and disease control rate (DCR), and compared progression-free survival (PFS) and overall survival (OS). Results: Of the 126 patients included in the study, 51 patients had EGFR20ins mutations and 7 5 patients had HER2-20ins mutations. In the first-line treatment, bevacizumab + chemotherapy (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), compared with chemotherapy alone (Chemo), ORR: 40% vs 33.3% vs 15% (p=0.0168); DCR: 84% vs 80.9% vs 67.5% (p=0.1817); median PFS: 8.3 vs 7.0 vs 4.6 months (p=0.0032), ICI+Chemo has a trend of benefiting on OS. Stratified analysis showed that compared with chemotherapy, ICI+Chemo was more effective for EGFR20ins mutation with median PFS: 10.3 vs. 6.3m (P=0.013); Beva+Chemo was more effective for HER2-20ins mutation, with a median PFS: 6.6 vs. 4.3m (p=0.030). In the second-line treatment of EGFR20ins mutation, bevacizumab + chemotherapy has a significant advantage in PFS compared with targeted therapy, median PFS:10.8 vs 4.0 months (P=0.016). Conclusion: For patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.

The influence of induced moods on aging of phonological encoding in spoken word production: an ERP study.

This study investigated the influence of induced mood on the phonological encoding involved in Chinese spoken word production with a picture-word inference task while concurrently recorded electrophysiological signals. In the experiment, young and older participants watched videos for inducing positive, negative, or neutral mood, and then they were instructed to name target picture while ignoring phonologically related or unrelated distractor words. A phonological facilitation effect was observed in young adults but not in older adults, suggesting an age-related decline of phonological encoding. Both groups showed an inhibition effect in negative mood but not in positive mood, suggesting that speakers have different processing styles in different moods. ERP data revealed a phonological effect around the time window of 250-350 ms in both groups. Meanwhile, young adults showed a phonological effect around 350-450 ms in negative mood and positive mood which may reflect self-monitoring in speech production. We suggest that the former effect may reflect phonological encoding while the latter reflects self-monitoring of internal syllables or phonemes. Furthermore, induced moods influence the phonological effect in older and young adults differently. Behavioral and ERP results provide consistent evidence for the aging decline of phonological encoding in spoken word production.

Mapping the global distribution of C4 vegetation using observations and optimality theory.

Plants with the C4 photosynthesis pathway typically respond to climate change differently from more common C3-type plants, due to their distinct anatomical and biochemical characteristics. These different responses are expected to drive changes in global C4 and C3 vegetation distributions. However, current C4 vegetation distribution models may not predict this response as they do not capture multiple interacting factors and often lack observational constraints. Here, we used global observations of plant photosynthetic pathways, satellite remote sensing, and photosynthetic optimality theory to produce an observation-constrained global map of C4 vegetation. We find that global C4 vegetation coverage decreased from 17.7% to 17.1% of the land surface during 2001 to 2019. This was the net result of a reduction in C4 natural grass cover due to elevated CO2 favoring C3-type photosynthesis, and an increase in C4 crop cover, mainly from corn (maize) expansion. Using an emergent constraint approach, we estimated that C4 vegetation contributed 19.5% of global photosynthetic carbon assimilation, a value within the range of previous estimates (18-23%) but higher than the ensemble mean of dynamic global vegetation models (14 ± 13%; mean ± one standard deviation). Our study sheds insight on the critical and underappreciated role of C4 plants in the contemporary global carbon cycle.

EGFR and ERBB2 Exon 20 Insertion Mutations in Chinese Non-small Cell Lung Cancer Patients: Pathological and Molecular Characterization, and First-Line Systemic Treatment Evaluation.

BACKGROUND: Data from studies looking at both EGFR and ERBB2 exon 20 insertion mutations (-20ins) in the same cohort of patients with non-small cell lung cancer (NSCLC) are limited. OBJECTIVE: The purpose of this study was to analyze EGFR/ERBB2-20ins in all-stage NSCLC patients to reveal their histological and molecular features, and to retrospectively evaluate the results of first-line real-world systemic treatments in patients with advanced-stage disease. PATIENTS AND METHODS: We collected 13,920 formalin-fixed paraffin-embedded NSCLC specimens. Clinicopathological features were recorded and DNA-based next-generation sequencing was performed. First-line systemic treatment data were obtained via chart review. RESULTS: In total, 414 (2.97%) EGFR-20ins cases and 666 (4.78%) ERBB2-20ins cases were identified. Both were more common in women, non-smokers, and patients with adenocarcinoma. The incidence of EGFR/ERBB2-20ins in adenocarcinoma is inversely proportional to the degree of invasion; 77 and 26 variants were detected in EGFR-20ins and ERBB2-20ins cases, respectively. The most common concurrently mutated genes were TP53 and RB1. In invasive adenocarcinoma, lepidic components were more common in EGFR/ERBB2-20ins-alone cases than in those with other concurrent mutated genes. In EGFR-/ERBB2-20ins patients, there was no significant difference in progression-free survival (PFS) or treatment response to first-line systemic treatments in this study. There was no significant difference in PFS or treatment response among patients with different EGFR/ERBB2-20ins variants and those with or without concurrent mutated genes. CONCLUSIONS: EGFR/ERBB2-20ins is more common in early lung adenocarcinoma. EGFR-20ins had more variants. In both cohorts, the results for first-line systemic treatments showed no significant difference.

Unraveling the Significance of MET Focal Amplification in Lung Cancer: Integrative NGS, FISH, and IHC Investigation.

MET amplification (METamp) represents a promising therapeutic target in non-small cell lung cancer, but no consensus has been established to identify METamp-dependent tumors that could potentially benefit from MET inhibitors. In this study, an analysis of MET amplification/overexpression status was performed in a retrospectively recruited cohort comprising 231 patients with non-small cell lung cancer from Shanghai Chest Hospital (SCH cohort) using 3 methods: fluorescence in situ hybridization (FISH), hybrid capture-based next-generation sequencing, and immunohistochemistry for c-MET and phospho-MET. The SCH cohort included 130 cases known to be METamp positive by FISH and 101 negative controls. The clinical relevance of these approaches in predicting the efficacy of MET inhibitors was evaluated. Additionally, next-generation sequencing data from another 2 cohorts including 22,010 lung cancer cases were utilized to examine the biological characteristics of different METamp subtypes. Of the 231 cases, 145 showed MET amplification/overexpression using at least 1 method, whereas only half of them could be identified by all 3 methods. METamp can occur as focal amplification or polysomy. Our study revealed that the inconsistency between next-generation sequencing and FISH primarily occurred in the polysomy subtype. Further investigations indicated that compared with polysomy, focal amplification correlated with fewer co-occurring driver mutations, higher protein expressions of c-MET and phospho-MET, and higher incidence in acquired resistance than in de novo setting. Moreover, patients with focal amplification presented a more robust response to MET inhibitors compared with those with polysomy. Notably, a strong correlation was observed between focal amplification and programmed cell death ligand-1 expression, indicating potential therapeutic implications with combined MET inhibitor and immunotherapy for patients with both alterations. Our findings provide insights into the molecular complexity and clinical relevance of METamp in lung cancer, highlighting the role of MET focal amplification as an oncogenic driver and its feasibility as a primary biomarker to further investigate the clinical activity of MET inhibitors in future studies.

The effectiveness of unguided self-help psychological interventions for obsessive-compulsive disorder: A meta-analysis of randomized controlled trials.

BACKGROUND: Evidence-based psychological interventions exist for individuals with obsessive-compulsive disorder (OCD), but many individuals with OCD are unable to access them because of barriers, such as geographical isolation, treatment cost, and stigma etc. Unguided self-help psychological intervention has emerged as a potential solution to this problem. However, there is limited research on its overall effectiveness. This study aimed to address this gap. METHODS: Comprehensive searches from inception to 1st Jan 2023 were conducted in both international (PubMed, Embase, PsycINFO, International clinical trials registry platform of WHO) and Chinese (China National Knowledge Infrastructure, WeiPu, WanFang, Chinese Clinical Trial Registry) databases. The registered protocol is accessible at https://doi.org/10.17605/OSF.IO/FKB5W. We included randomized controlled trials (RCTs) comparing unguided self-help psychological interventions to control groups for individuals with OCD. The primary outcome was OCD symptom severity, with Hedges' g calculated post-intervention. Heterogeneity was deemed to be low, moderate, and high if the I2 value was quantified 25%, 50%, and 75% respectively. Relative Risks (RRs) was calculated for dropout rates post-intervention. Random-effects models were used for all analyses. RESULTS: 12 RCTs comparing unguided self-help psychological interventions to control groups were identified, with a total of 20 comparisons and 769 OCD patients. Overall, unguided self-help psychological interventions demonstrated a significant moderate effect on reducing OCD symptom severity (g = -0.42; 95% CI [-0.69; -0.14]) compared to control groups, with a moderate heterogeneity (I2 = 59%; 95% CI [22.73; 78.38]). This finding remained significant in sensitivity analyses for the self-rated Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; k = 7, g = -0.46; 95% CI [-0.71; -0.2]) and after removing an outlier (g = -0.37; 95% CI [-0.55; -0.19]), but not for the clinician-rated Y-BOCS (k = 4, g = -0.78; 95% CI [-2.75; 1.19]) and Obsessive Compulsive Inventory-Revised (k = 6, g = -0.26; 95% CI [-0.53; 0]). Subgroup analyses revealed a significant difference in effect size between studies conducting intention-to-treat and completers-only analyses (p = .01). The completers-only analyses demonstrated a moderate significant effect (g = -0.65; 95% CI [-1.08; -0.21]), whereas the effect of the intention-to-treat analyses was not significant (g = -0.18; 95% CI [-0.36; 0]). Participants in the unguided self-help groups exhibited a significantly higher dropout rate (RR = 2.08; 95% CI [1.53; 2.81]) compared to control groups. Furthermore, participants recruited from the community had a higher likelihood of dropping out compared to those recruited from clinical settings (p < .001). Additionally, participants who received cognitive-behavioural therapy intervention were more likely to drop out than those who received other types of intervention (p < .001). Most trials (92%) were rated at a high risk of bias. CONCLUSION: Unguided self-help psychological interventions demonstrate potential effectiveness in alleviating OCD symptom severity post-intervention. However, caution should be exercised when interpreting the results due to high risk of bias across trials and the relatively small sample size. And the considerable dropout rate might hinder treatment effects. Future studies with strict methodology should investigate the long-term effectiveness of unguided self-help psychological interventions for OCD, explore the reasons for high dropout rates, and improve intervention adherence.

Looking back on life: An updated meta-analysis of the effect of life review therapy and reminiscence on late-life depression.

BACKGROUND: Twenty years ago, we confirmed the effectiveness of life review therapy and reminiscence (LRT-REM) to treat late-life depression in a meta-analysis. In the current study, we aimed to examine the most updated evidence on the effects of LRT-REM in older adults with depression. METHODS: We systematically searched records in English and Chinese databases up to December 2022 and included randomized controlled studies comparing LRT-REM with control conditions in older adults with depression. Outcomes included depression, anxiety, quality of life, and life satisfaction. Effect sizes (Hedges' g) at post-treatment were pooled with random effects meta-analyses. RESULTS: 42 studies with 3361 depressed older adults (≥60 years) met the selection criteria. We found a significant and large effect of LRT-REM (g = 1.41, p < 0.001) on late-life depression, corresponding to a number-needed-to-treat (NNT) of 1.98. Heterogeneity shrunk from high (I2 = 86.78) to moderate (I2 = 46.87) after excluding eight detected outliers. There were no significant differences between the examined subgroups except for the type of control condition. The effects of LRT-REM were not statistically significant at follow-up when corrected for publication bias. The quality of many included studies was not optimal. LIMITATIONS: The quality of many included studies was not optimal, with a high risk of bias. CONCLUSIONS: LRT-REM may be effective for treating late-life depression, but long-term effects are unclear. More research is needed on the effects of LRT-REM, especially when guided by (para)professional or lay therapists in low- and middle-income countries.

Unveiling the prognostic implications of RPLP1 upregulation in osteosarcoma.

Osteosarcoma, a malignant bone tumor characterized by a high rate of metastasis and poor survival, presents a critical need for identifying novel biomarkers associated with metastasis. In this study, we conducted an extensive analysis utilizing transcriptional and clinical data sourced from databases such as GEO, TCGA, CCLE, R2, and Xena. And we discovered that Ribosomal protein LP1 (RPLP1) ranked among the top upregulated genes in relation to osteosarcoma metastasis. Notably, RPLP1 exhibited significant expression in both osteosarcoma cell lines and patient samples. Moreover, multiple osteosarcoma studies revealed a strong correlation between RPLP1 overexpression and worse metastasis-free survival as well as overall survival. Additionally, we observed a consistent association between dysregulation of RPLP1 and reduced overall survival across various tumor types. Knocking down of RPLP1 led to the down-regulation of MYL5 and functional enrichment toward cell cycle and cellular interaction. Based on these findings, we propose that RPLP1 has the potential to serve as a prognostic biomarker, indicating increased metastasis and worse survival outcomes in osteosarcoma. These insights contribute to a better understanding of the disease and may pave the way for future research and therapeutic approaches.

DLX2 promotes osteosarcoma epithelial-mesenchymal transition and doxorubicin resistance by enhancing HOXC8-CDH2 axis.

Metastasis and doxorubicin resistance are challenges in the clinical diagnosis and treatment of osteosarcoma, the mechanisms underlying these phenomena remain unclear. In this study, we found that DLX2 is highly expressed in metastatic osteosarcoma and is closely related to clinical prognosis. Knockdown of DLX2 inhibited tumor proliferation and migration in vitro and inhibited tumor growth in vivo. Mechanistically, we found that DLX2 enhanced the repression of CDH2 transcription by binding to HOXC8, thereby promoting the epithelial-mesenchymal transition in osteosarcoma cells. Through subsequent exploration, we found that targeting DLX2/HOXC8 signaling significantly restores the sensitivity of osteosarcoma cells to doxorubicin. In conclusion, our findings demonstrate that DLX2 may enhance the transcriptional regulation of CDH2 through interacting with HOXC8, which in turn promotes epithelial-mesenchymal transition and doxorubicin resistance in osteosarcoma. These findings hold great potential for clinical application and may guide the development of novel targeted therapies for osteosarcoma.

Clonal dynamics and Stereo-seq resolve origin and phenotypic plasticity of adenosquamous carcinoma.

The genomic origin and development of the biphasic lung adenosquamous carcinoma (ASC) remain inconclusive. Here, we derived potential evolutionary trajectory of ASC through whole-exome sequencing, Stereo-seq, and patient-derived xenografts. We showed that EGFR and MET activating mutations were the main drivers in ASCs. Phylogenetically, these drivers and passenger mutations found in both components were trunk clonal events, confirming monoclonal origination. Comparison of multiple lesions also revealed closer genomic distance between lymph node metastases and the ASC component with the same phenotype. However, as mutational signatures of EGFR-positive lung squamous carcinomas (LUSCs) were more comparable to EGFR-positive ASCs than to wild-type LUSCs, we postulated different origination of these LUSCs, with ASC being the potential intermediate state of driver-positive LUSCs. Spatial transcriptomic profiling inferred transformation from adenocarcinoma to squamous cell carcinoma, which was then histologically captured in vivo. Together, our results explained the development of ASC and provided insights into future clinical decisions.

Single-cell profiling reveals the trajectory of FOLR2-expressing tumor-associated macrophages to regulatory T cells in the progression of lung adenocarcinoma.

An immunosuppressive microenvironment enriched with regulatory CD4+ T lymphocytes (Tregs) facilitates the progression of lung adenocarcinoma (LUAD). This study aims to investigate the cellular mechanism underlying the formation of the immunosuppressive microenvironment in LUAD. LUAD samples (n = 12) and normal lung samples (n = 3) were obtained from patients with different pathological stages of LUAD. Single-cell RNA sequencing was performed to classify cellular components and analyze the transcriptomes, including transcription factors/targets and chemokine ligands/receptors, followed by bioinformatics study such as pseudotime analysis. Myeloid cells and T cells were the most abundant cell types in tumors and normal lung tissues, while tumor-associated macrophage-folate receptor 2 (TAM-FOLR2) and CD4+ nuclear receptor subfamily 4 group A member 3 (NR4A3) exhibited sharp increases in invasive adenocarcinoma (IA). The enrichment of TAM-FOLR2 in IA might result from alveolar resident macrophage-resistin (ARM-RETN) transformation and recruitment of dendritic cells (DCs) and other TAMs, as evidenced by temporal trajectories and differential expression profiles of chemokine ligands/receptors versus those in the early stages of tumors. High expression of CCL17/19/22 was observed in IA as well as in DCs, along with the strong interaction of TAM-FOLR2 with DCs. The results of pseudotime analysis suggested that CD4+NR4A3 might potentially convert to CD4+FOXP3, further supported by the high expression of NR4A3 target genes in CD4+FOXP3 cells. This study provides a single-cell transcriptome atlas from preinvasive to invasive LUAD and reveals a potential ARM-RETN/TAM-FOLR2/DCs/CD4+NR4A3/CD4+FOXP3 trajectory in shaping the immune suppressive microenvironment along the pathogenesis of LUAD.

Molecular mechanisms of osteosarcoma metastasis and possible treatment opportunities.

In osteosarcoma patients, metastasis of the primary cancer is the leading cause of death. At present, management options to prevent metastasis are limited and non-curative. In this study, we review the current state of knowledge on the molecular mechanisms of metastasis and discuss promising new therapies to combat osteosarcoma metastasis. Genomic and epigenomic changes, metabolic reprogramming, transcription factors, dysregulation of physiologic pathways, and alterations to the tumor microenvironment are some of the changes reportedly involved in the regulation of osteosarcoma metastasis. Key factors within the tumor microenvironment include infiltrating lymphocytes, macrophages, cancer-associated fibroblasts, platelets, and extracellular components such as vesicles, proteins, and other secreted molecules. We conclude by discussing potential osteosarcoma-limiting agents and their clinical studies.

Clinicopathological features and survival of rare primary pulmonary lymphoepithelial carcinoma: A cohort from a single center.

BACKGROUND: Primary pulmonary lymphoepithelial carcinoma (PLEC) is a rare subtype of nonsmall cell lung cancer. This study aimed to investigate the clinicopathological and prognostic characteristics of resected primary PLEC. MATERIALS AND METHODS: In this retrospective study, 95 consecutive patients with primary PLEC, who received radical surgical resection treatment, were examined from October 2009 to January 2022. The clinicopathological features and their association with survival outcomes were analyzed. RESULTS: Primary PLEC predominated in relatively younger patients and nonsmokers, who lacked driver mutations and were always positive for immunohistochemical markers of the squamous cell lineage. Further, 21.1% of patients had abnormally elevated preoperative serum marker fragments of cytokeratin 19 (Cyfra21-1). The median follow-up time was 43.5 months. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96.5%, 81.8%, and 64.3%, respectively. The median RFS time was not reached. Cox univariate survival analysis showed that patients with positive lymph nodes had significantly worse RFS than those with negative ones (p = 0.017). The patients with open surgery experienced significantly worse RFS than those with video-assisted thoracoscopic surgery (p = 0.038). The multivariate survival analysis confirmed that only lymph node involvement (hazard ratio: 2.769; 95% confidence interval: 1.171-6.548, p = 0.020) was an independent prognostic factor. CONCLUSIONS: Primary PLEC is a rare type of lung cancer with a favorable outcome, more common in young and nonsmoking Asian populations. Driver gene mutations are rare. Regional lymph node metastasis is an independent prognostic factor for RFS after radical surgical resection.

Preoperative levels of folate receptor-positive circulating tumor cells in different subtypes of early-stage lung adenocarcinoma: Predictive value for determining extent of surgical resection.

Background: The objective was to measure the correlations of preoperative levels of folate receptor-positive circulating tumor cells (FR+CTCs) with clinical characteristics and histologic subtype in early-stage lung adenocarcinoma, and to determine the predictive value of FR+CTC level in preoperative determination of the extent of surgical resection. Patients and methods: In this retrospective, single-institution, observational study, preoperative FR+CTC levels were measured via ligand-targeted enzyme-linked polymerization in patients with early-stage lung adenocarcinoma. Receiver operating characteristic (ROC) analysis was used to identify the optimal cutoff value of FR+CTC level for prediction of various clinical characteristics and histologic subtypes. Results: No significant difference in FR+CTC level was observed among patients with adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) (P = 0.813). Within the non-mucinous adenocarcinoma group, no difference was observed among patients with tumors whose predominant growth patterns were lepidic, acinar, papillary, micropapillary, solid, and complex gland (P = 0.053). However, significant differences in FR+CTC level were observed between patients with and without the micropapillary subtype [11.21 (8.22-13.61) vs. 9.85 (7.43-12.63), P = 0.017], between those with and without the solid subtype [12.16 (8.27-14.90) vs. 9.87 (7.50-12.49), P = 0.022], and between those with any of the advanced subtypes (micropapillary, solid, or complex glands) vs. none of these [10.48 (7.83-13.67) vs. 9.76 (7.42-12.42), P = 0.032]. FR+CTC level was also correlated with degree of differentiation of lung adenocarcinoma (P = 0.033), presence of visceral pleural invasion (VPI) of lung carcinoma (P = 0.003), and lymph node metastasis of lung carcinoma (P = 0.035). Conclusion: FR+CTC level is of potential predictive value in determining the presence of aggressive histologic patterns (micropapillary, solid, and advanced subtypes), degree of differentiation, and occurrence of VPI and lymph node metastasis in IAC. Measurement of FR+CTC level combined with intraoperative frozen sections may represent a more effective method of guiding resection strategy in cases of cT1N0M0 IAC with high-risk factors.

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027.