The Ribonuclease ZC3H12A is required for self-inflicted DNA breaks after DNA damage in small cell lung cancer cells.

Radiotherapy is the first line treatment for small cell lung cancer (SCLC); However, radio-resistance accompanies with the treatment and hampers the prognosis for SCLC patients. The underlying mechanisms remains elusive. Here we discovered that self-inflicted DNA breaks exist in SCLC cells after radiation. Moreover, using nuclease siRNA screening combined with high-content ArrayScan™ cell analyzer, we identified that Ribonuclease ZC3H12A is required for the self-inflicted DNA breaks after radiation and for SCLC cell survival after DNA damage. ZC3H12A expression was increased in response to DNA damage and when ZC3H12A was knocked down, the DNA repair ability of the cells was impaired, as evidenced by decreased expression of the DNA damage repair protein BRCA1, and increased γH2AX at DNA damage sites. Colony formation assay demonstrates that ZC3H12A knocked down sensitized small cell lung cancer radiotherapy. Therefore, the Ribonuclease ZC3H12A regulates endogenous secondary breaks in small cell lung cancer and affects DNA damage repair. ZC3H12A may act as an important radiotherapy target in small cell lung cancer.

The artificial intelligence and machine learning in lung cancer immunotherapy.

Since the past decades, more lung cancer patients have been experiencing lasting benefits from immunotherapy. It is imperative to accurately and intelligently select appropriate patients for immunotherapy or predict the immunotherapy efficacy. In recent years, machine learning (ML)-based artificial intelligence (AI) was developed in the area of medical-industrial convergence. AI can help model and predict medical information. A growing number of studies have combined radiology, pathology, genomics, proteomics data in order to predict the expression levels of programmed death-ligand 1 (PD-L1), tumor mutation burden (TMB) and tumor microenvironment (TME) in cancer patients or predict the likelihood of immunotherapy benefits and side effects. Finally, with the advancement of AI and ML, it is believed that "digital biopsy" can replace the traditional single assessment method to benefit more cancer patients and help clinical decision-making in the future. In this review, the applications of AI in PD-L1/TMB prediction, TME prediction and lung cancer immunotherapy are discussed.

Immunotherapy efficacy predictive tool for lung adenocarcinoma based on neural network.

Background: Remarkably, the anti-cancer efficacy of immunotherapy in lung adenocarcinoma (LUAD) has been demonstrated. However, predicting the beneficiaries of this expensive treatment is still a challenge. Materials and methods: A group of patients (N = 250) diagnosed with LUAD and receiving immunotherapy were retrospectively studied. They were randomly divided into a training dataset (80%) and a test dataset (20%). The training dataset was utilized to train neural network models to predict patients' objective response rate (ORR), disease control rate (DCR), responders (progression-free survival time > 6 months), and overall survival (OS) possibility, which were validated by both the training and test datasets and packaged into a tool later. Results: In the training dataset, the tool scored 0.9016 area under the receiver operating characteristic (AUC) curve on ORR judgment, 0.8570 on DCR, and 0.8395 on responder prediction. In the test dataset, the tool scored 0.8173 AUC on ORR, 0.8244 on DCR, and 0.8214 on responder determination. As for OS prediction, the tool scored 0.6627 AUC in the training dataset and 0.6357 in the test dataset. Conclusions: This immunotherapy efficacy predictive tool for LUAD patients based on neural networks could predict their ORR, DCR, and responder well.

The intersection molecule MDA5 in Cancer and COVID-19.

The connections between pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) constitutes the crucial signaling pathways in the innate immune system. Cytoplasmic nucleic acid sensor melanoma differentiation-associated gene 5 (MDA5) serves as an important pattern recognition receptor in the innate immune system by recognizing viral RNA. MDA5 also plays a role in identifying the cytoplasmic RNA from damaged, dead cancer cells or autoimmune diseases. MDA5's recognition of RNA triggers innate immune responses, induces interferon (IFN) response and a series of subsequent signaling pathways to produce immunomodulatory factors and inflammatory cytokines. Here we review the latest progress of MDA5 functions in triggering anti-tumor immunity by sensing cytoplasmic dsRNA, and recognizing SARS-CoV-2 virus infection for antiviral response, in which the virus utilizes multiple ways to evade the host defense mechanism.

Long-Read Sequencing Annotation of the Transcriptome in DNA-PK Inactivated Cells.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) with a Ku70/Ku80 heterodimer constitutes the intact DNA-PK kinase, which is an upstream component of the DNA repair machinery that signals the DNA damage, orchestrates the DNA repair, and serves to maintain genome integrity. Beyond its role in DNA damage repair, the DNA-PK kinase is also implicated in transcriptional regulation and RNA metabolism, with an illuminated impact on tumor progression and therapeutic responses. However, the efforts to identify DNA-PK regulated transcriptomes are limited by short-read sequencing to resolve the full complexity of the transcriptome. Therefore, we leveraged the PacBio Single Molecule, Real-Time (SMRT) Sequencing platform to study the transcriptome after DNA-PK inactivation to further underscore the importance of its role in diseases. Our analysis revealed additional novel transcriptome and complex gene structures in the DNA-PK inactivated cells, identifying 8,355 high-confidence new isoforms from 3,197 annotated genes and 523 novel genes. Among them, 380 lncRNAs were identified. We validated these findings using computational approaches and confirmatory transcript quantification with short-read sequencing. Several novel isoforms representing distinct splicing events have been validated through PCR experiments. Our analyses provide novel insights into DNA-PK function in transcriptome regulation and RNA metabolism.

[Analysis of the Efficacy of Immunotherapy in Elderly Patients with Lung Cancer].

BACKGROUND: Immunotherapy represented by immune checkpoint inhibitors (ICIs) has become the standard treatment for patients with non-oncogenic advanced non-small cell lung cancer (NSCLC). While lung cancer is most prevalent in elderly patients, these patients are rarely included in pivotal clinical trial studies. We aimed to describe the efficacy and safety of immunotherapy for elderly patients in the "real-world". METHODS: The data of older NSCLC patients and younger patients who received immunotherapy between July 2018 to October 2021 were retrospectively analyzed and the objective response rate (ORR) and progression-free survival (PFS) in different age groups (less than 60 years old was defined as the young group, 60 years-74 years old was the young old group, 75 years old and above was the old old group) were compared. And the impact of different clinical characteristics on treatment response and prognosis were analyzed in each age subgroup. RESULTS: A total of 21 young patients, 70 young old patients and 15 old old patients were included in this study, with ORR of 33.3%, 52.8% and 53.3%, respectively, without statistically significant difference (P=0.284). The median PFS was 9.1 mon, 7.6 mon and 10.9 mon, respectively, without statistically significant difference (P=0.654). Further analysis of the predictors of immunotherapy in each subgroup revealed that patients in the young old group and young group who received immunotherapy in the first line had a longer PFS. The difference of the incidence of adverse events was not statistically significant among the three groups (P>0.05). CONCLUSIONS: The efficacy and safety of immunotherapy in elderly patients were similar to those in younger patients, and PFS was superior in the first-line immunotherapy. Further prospective studies are still needed to explore predictors of immunotherapy in elderly NSCLC patients.

Subsegmentectomy versus segmentectomy resection for the treatment of operable patients with stage IA non-small cell lung cancer: A meta-analysis.

Background: There were new points of interest in performing subsegmentectomy and segmentectomy for patients with early stage non-small cell lung cancer (NSCLC). However, whether patients who underwent subsegmentectomy could obtain satisfactory clinical outcomes remains unclear. The present study aimed to compare the clinical outcomes and security of surgical procedures between subsegmentectomy and segmentectomy. Methods: A systematic review and meta-analysis was performed through five online databases to identify the included literatures which presented intact clinical outcome data among different surgical procedures. The included studies were evaluated based on precise and predefined inclusion criteria. Results: There were 4 published studies identified in this meta-analysis. A total of 325 patients who underwent subsegmentectomy and 904 patients who underwent segmentectomy were involved in this analysis. The duration of drainage [MD -0.19; 95%CI (-0.36, -0.02), p = 0.03] and postoperative hospital stay [MD -0.30; 95%CI (-0.58, -0.02), p = 0.009] of subsegmentectomy were significantly less than that of segmentectomy. There was no statistically significant difference among recurrence rate [OR 0.85; 95%CI (0.21, 3.42), p = 0.82], operation time, blood loss, incidence of complications [OR 0.83; 95%CI (0.58, 1.20), p = 0.33] between subsegmentectomy and segmentectomy in patients with stage IA NSCLC. Conclusion: The meta-analysis was firstly performed to compare perioperative outcomes among surgical procedures. The perioperative outcomes were comparable between subsegmentectomy and segmentectomy. Subsegmentectomy might be an alternative treatment for the deep tumor with size less than 1.5 cm and mainly composed of Ground Glass Opacity (GGO).