Serum extracellular vesicle-derived miR-21-5p and miR-26a-5p as non-invasive diagnostic potential biomarkers for gastric cancer: A preliminary study.

PURPOSE: Gastric cancer is the most common malignancy worldwide and is the third leading cause of cancer-related deaths, urgently requiring an early and non-invasive diagnosis. Circulating extracellular vesicles may emerge as promising biomarkers for the rapid diagnosis in a non-invasive manner. METHODS: Using high-throughput small RNA sequencing, we profiled the small RNA population of serum-derived extracellular vesicles from healthy controls and gastric cancer patients. Differentially expressed microRNAs (miRNAs) were randomly selected and validated by reverse transcription-quantitative real-time polymerase chain reaction. Receiver operating characteristic curves were employed to assess the predictive value of miRNAs for gastric cancer. RESULTS: In this study, 193 differentially expressed miRNAs were identified, of which 152 were upregulated and 41 were significantly downregulated. Among the differently expressed miRNA, the expression levels of miR-21-5p, miR-26a-5p, and miR-27a-3p were significantly elevated in serum-derived extracellular vesicles of gastric cancer patients. The miR-21-5p and miR-27a-3p were closely correlated with the tumor size. Moreover, the expression levels of serum miR-21-5p and miR-26a-5p were significantly decreased in gastric cancer patients after surgery. CONCLUSIONS: The present study discovered the potential of serum miR-21-5p and miR-26a-5p as promising candidates for the diagnostic and prognostic markers of gastric cancer.

Characterization of the Nucleus Pulposus Progenitor Cells via Spatial Transcriptomics.

Loss of refreshment in nucleus pulposus (NP) cellularity leads to intervertebral disc (IVD) degeneration. Nevertheless, the cellular sequence of NP cell differentiation remains unclear, although an increasing body of literature has identified markers of NP progenitor cells (NPPCs). Notably, due to their fragility, the physical enrichment of NP-derived cells has limited conventional transcriptomic approaches in multiple studies. To overcome this limitation, a spatially resolved transcriptional atlas of the mouse IVD is generated via the 10x Genomics Visium platform dividing NP spots into two clusters. Based on this, most reported NPPC-markers, including Cathepsin K (Ctsk), are rare and predominantly located within the NP-outer subset. Cell lineage tracing further evidence that a small number of Ctsk-expressing cells generate the entire adult NP tissue. In contrast, Tie2, which has long suggested labeling NPPCs, is actually neither expressed in NP subsets nor labels NPPCs and their descendants in mouse models; consistent with this, an in situ sequencing (ISS) analysis validated the absence of Tie2 in NP tissue. Similarly, no Tie2-cre-mediated labeling of NPPCs is observed in an IVD degenerative mouse model. Altogether, in this study, the first spatial transcriptomic map of the IVD is established, thereby providing a public resource for bone biology.

Amplifying "eat me signal" by immunogenic cell death for potentiating cancer immunotherapy.

Immunogenic cell death (ICD) is a unique mode of cell death, which can release immunogenic damage-associated molecular patterns (DAMPs) and tumor-associated antigens to trigger long-term protective antitumor immune responses. Thus, amplifying "eat me signal" during tumor ICD cascade is critical for cancer immunotherapy. Some therapies (radiotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), etc.) and inducers (chemotherapeutic agents, etc.) have enabled to initiate and/or facilitate ICD and activate antitumor immune responses. Recently, nanostructure-based drug delivery systems have been synthesized for inducing ICD through combining treatment of chemotherapeutic agents, photosensitizers for PDT, photothermal transformation agents for PTT, radiosensitizers for radiotherapy, etc., which can release loaded agents at an appropriate dosage in the designated place at the appropriate time, contributing to higher efficiency and lower toxicity. Also, immunotherapeutic agents in combination with nanostructure-based drug delivery systems can produce synergetic antitumor effects, thus potentiating immunotherapy. Overall, our review outlines the emerging ICD inducers, and nanostructure drug delivery systems loading diverse agents to evoke ICD through chemoradiotherapy, PDT, and PTT or combining immunotherapeutic agents. Moreover, we discuss the prospects and challenges of harnessing ICD induction-based immunotherapy, and highlight the significance of multidisciplinary and interprofessional collaboration to promote the optimal translation of this treatment strategy.

Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling.

Esophageal carcinoma is among the most fatal malignancies with increasing incidence globally. Tumor onset and progression can be driven by metabolic reprogramming, especially during esophageal carcinoma development. Exosomes, a subset of extracellular vesicles, display an average size of ∼100 nanometers, containing multifarious components (nucleic acids, proteins, lipids, etc.). An increasing number of studies have shown that exosomes are capable of transferring molecules with biological functions into recipient cells, which play crucial roles in esophageal carcinoma progression and tumor microenvironment that is a highly heterogeneous ecosystem through rewriting the metabolic processes in tumor cells and environmental stromal cells. The review introduces the reprogramming of glucose, lipid, amino acid, mitochondrial metabolism in esophageal carcinoma, and summarize current pharmaceutical agents targeting such aberrant metabolism rewiring. We also comprehensively overview the biogenesis and release of exosomes, and recent advances of exosomal cargoes and functions in esophageal carcinoma and their promising clinical application. Moreover, we discuss how exosomes trigger tumor growth, metastasis, drug resistance, and immunosuppression as well as tumor microenvironment remodeling through focusing on their capacity to transfer materials between cells or between cells and tissues and modulate metabolic reprogramming, thus providing a theoretical reference for the design potential pharmaceutical agents targeting these mechanisms. Altogether, our review attempts to fully understand the significance of exosome-based metabolic rewriting in esophageal carcinoma progression and remodeling of the tumor microenvironment, bringing novel insights into the prevention and treatment of esophageal carcinoma in the future.

Tunnel lining crack expansion and maintenance strategy optimization considering train loads: A case study.

Cracks in concrete tunnel linings are inevitable during service life. It is necessary to keep abreast of the cracking condition of the lining and formulate reasonable inspection and maintenance measures to ensure operational safety. Considering the influence of train loads on the safety and service performance of cracked linings, the expansion process of lining cracks and the maintenance strategy of tunnels during the service period was investigated. The impact of detection probability and maintenance measures on the service life of tunnel lining and the cost of detection and maintenance of cracked lining in the whole life cycle was analyzed; the optimization calculation model of tunnel lining crack detection and maintenance strategy based on genetic algorithm was established with the multi-objective optimization function of maximizing the service life of detection and maintenance and minimizing the total cost of detection and maintenance of fatigue cracks. The optimization analysis of lining crack expansion, detection, and maintenance was carried out for an operational railroad tunnel. Finally, an optimization analysis of lining crack expansion and maintenance was carried out in a railway tunnel. The results show that the stress intensity factor at the tip of the lining cracks is the same as the train load waveform; the magnitude of the stress intensity factor approximately satisfies the exponential function relationship with the depth of cracks; the fatigue service life of cracked lining is positively correlated with the cost of inspection and maintenance; the adoption of the necessary maintenance and the increase in the number of inspections and maintenance have a better economy while meeting the expectation of the service life. According to the Pareto solution set, the management can formulate the inspection and maintenance strategy based on the tunnel's expected life and maintenance budget.

Assessment of geothermal resource potential in Changbaishan utilizing high-precision gravity-based man-machine interactive inversion technology.

As one of the clean energy sources, geothermal resources have no negative impact in changing the climate. However, the accurate assessment and precise identification of the potential geothermal resource is still complex and dynamic. In this paper, ~2,000 large-scale high-precision gravity survey points are conducted in the north of the Tianchi caldera, Changbaishan. Advanced data processing technologies can provide straightforward information on deep geothermal resources (Hot source, caprock, geothermal reservoir and geothermal migration pathway). Upwards continuation and the technologies decode two dome shaped low and gentle anomalies (-48 × 10-5 m/s2-65 m/s2) and a positive gravity gradient anomaly (0.4 × 10-7 m/s2-1.6 × 10-5 m/s2) in large-scale high-precision gravity planar. According to two point five dimensional man-machine interactive inversion technology and the research on petrophysical parameters, the density of the shied-forming basalts in the two orthogonal gravity sections is 2.58 g/cm3. The relatively intermediate to high density (2.60-2.75 g/cm3) represents geothermal reservoir, and low density (low to 2.58 g/cm3) is the geothermal migration pathway. In addition, large-scale high-precision gravity planar with a solution of about 1/50,000 indicate that the north of the Tianchi caldera exits the sedimentary basin and uplift mountain geothermal system.

Synergistic pathogenicity of avian orthoreovirus and Staphylococcus aureus on SPF chickens.

Avian arthritis is a relatively common disease in the poultry industry, the cause of which is complex. Bacterial arthritis is often caused by infection of Staphylococcus aureus (S. aureus), whereas viral arthritis is caused by avian orthoreovirus (ARV). To investigate the infection of S. aureus and ARV in cases of avian arthritis, a total of 77 samples characterized by arthritis were collected and detection. The results showed that 68.83% of the samples were positive for ARV, and 66.23% were positive for S. aureus. Among them, the ARV mono-infection rate was 22.08%, the S. aureus mono-infection rate was 19.48%, and ARV and S. aureus co-infection rate was 45.45%, indicating that ARV and S. aureus co-infection is common in arthritis cases. To further investigate the synergistic pathogenicity of ARV and S. aureus, ARV and S. aureus were used to mono-infect, co-infect, and (or) sequential infect SPF chickens and the clinical indications, pathologic changes, ARV load, S. aureus bacterial distribution, and cytokine level of the challenged chickens were evaluated. Decreased weight gain, increased mortality, and difficulties in standing were observed in all dual-infected groups and the singular-infected group. There were significantly more severe macroscopic and microscopic hock lesions, and larger amounts of a wider range of tissue distribution of ARV antigens and S. aureus bacterial distribution in the dual-infected groups compared to the single-infected and control groups. Cytokine detection showed a significant change in IFN-γ, IL-1ß, and IL-6 levels in the infected groups, especially in the ARV-S. aureus co-infection, and (or) sequential infection groups, compared with the control group. Hence, ARV and S. aureus synergistically increased mortality in infected chickens, potentiated the severity of arthritis, and increased the amount of ARV RNA in tendons.

Pathogenicity of goose astrovirus genotype 2 in chickens.

Goose astrovirus genotype 2 (GAstV-2) is the causative agent causing severe visceral gout and joint gout in goslings, with mortality rates of affected flocks up to 50%. To date, continuous GAstV-2 outbreaks still pose a great threat to goose industry in China. Although most researches on GAstV-2 have focused on its pathogenicity to geese and ducks, limited studies have been performed on chickens. Herein, we inoculated 1-day-old specific pathogen-free (SPF) White Leghorn line chickens with 0.6 mL of GAstV-2 culture supernatant (TCID50 10-5.14/0.1 mL) via orally, subcutaneously and intramuscularly, and then assessed the pathogenicity. The results revealed that the infected chickens presented depression, anorexia, diarrhea, and weight loss. The infected chickens also suffered from extensive organ damage and had histopathological changes in the heart, liver, spleen, kidney, and thymuses. The infected chickens also had high viral load in tissues and shed virus after the challenge. Overall, our research demonstrates that GAstV-2 can infect chickens and adversely affect the productivity of animals. And the viruses shed by infected chickens can pose a potential risk to the same or other domestic landfowls.

Co-circulation of multiple genotypes of ARV in poultry in Anhui, China.

ABSTRACTPoultry production in China has been experiencing a high incidence of broiler arthritis /tenosynovitis caused by avian orthoreovirus (ARV) since 2013. In the spring of 2020 severe arthritis cases from broiler flocks were identified in a large-scale commercial poultry company in Anhui Province, China. Diseased organs from dead birds were sent for diagnosis to our laboratory. ARVs, including seven broiler-isolates and two breeder-isolates, were successfully harvested and sequenced. Interestingly, the genotypes of ARVs isolated from infected chickens were inconsistent between different flocks, or even between different houses on the same flocks. Pathogenicity testing in chicks confirmed that the seven broiler-isolates were pathogenic strains, which could cause arthritis in infected chickens. Subsequently, a total of 89.66% serum samples collected from apparently healthy adult broiler flocks not vaccinated against ARV tested positive for ARV antibodies, suggesting that low and high virulence reovirus strains may be co-circulating in the farm. To this end, we collected dead embryos of unhatched chicken eggs for pathogen tracing, and the two ARV breeder-isolates isolated indicated that vertical transmission from breeders to progeny should not be underestimated for the prevalence of ARV within broiler flocks. The findings have implications for the evidenced-based formulation of prevention and control strategies.

Application of artificial intelligence for improving early detection and prediction of therapeutic outcomes for gastric cancer in the era of precision oncology.

Gastric cancer is a leading contributor to cancer incidence and mortality globally. Recently, artificial intelligence approaches, particularly machine learning and deep learning, are rapidly reshaping the full spectrum of clinical management for gastric cancer. Machine learning is formed from computers running repeated iterative models for progressively improving performance on a particular task. Deep learning is a subtype of machine learning on the basis of multilayered neural networks inspired by the human brain. This review summarizes the application of artificial intelligence algorithms to multi-dimensional data including clinical and follow-up information, conventional images (endoscope, histopathology, and computed tomography (CT)), molecular biomarkers, etc. to improve the risk surveillance of gastric cancer with established risk factors; the accuracy of diagnosis, and survival prediction among established gastric cancer patients; and the prediction of treatment outcomes for assisting clinical decision making. Therefore, artificial intelligence makes a profound impact on almost all aspects of gastric cancer from improving diagnosis to precision medicine. Despite this, most established artificial intelligence-based models are in a research-based format and often have limited value in real-world clinical practice. With the increasing adoption of artificial intelligence in clinical use, we anticipate the arrival of artificial intelligence-powered gastric cancer care.

Knowledge mapping of research on the mitochondrial unfolded protein response: a bibliometric and visual analysis.

Background: The mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which exerts a crucial role in maintaining mitochondrial proteostasis during stress. However, there is no bibliometric analyses systematically studied this field which could comprehensively review research trends, evaluate publication performances and provide future perspectives. Methods: Articles investigating UPRmt published between 1994 and 2021 were downloaded from the Core Collection of the Web of Science (WOS). CiteSpace and VOSviewer bibliometric software were applied for bibliometric and visual analyses. Results: A total of 2,073 papers researching UPRmt were retrieved. According to the published number of papers, the field of UPRmt research has gone through its infancy (after 2000) and rapid growth (after 2021) phases. The United States and China contributed the most to UPRmt research. Regarding the distribution of institutions, Harvard University was the most influential institution. The most prolific authors are Johan Auwerx and CM Haynes. PLoS One is the most extensive journal in the field of UPRmt research, while the Cell Death and Differentiation journal had the greatest impact among the most-authored journals. Moreover, biochemistry/molecular biology, and cell biology are the largest subject areas. UPRmt research is mainly categorized as UPRmt, transcription, endoplasmic reticulum (ER) stress, lipotoxicity, mitophagy, inflammation, skeletal muscle, hypoxia, apoptosis, mitochondrial dysfunction, neurodegeneration, mitochondrial permeability transition, and integrated stress response. Conclusions: At present, research on UPRmt is booming. Further strengthening the cooperation and exchanges between countries, institutions, and authors in the future will surely promote the development of this field.

Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma.

BACKGROUND: Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m6A regulators in hepatocellular carcinoma (HCC). METHODS: Pan-cancer genomic analysis of the crosstalk between 5mC and m6A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m6A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications. RESULTS: 5mC and m6A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients' clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m6A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME. CONCLUSIONS: Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m6A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape.

Spillover effect analysis of home-purchase limit policy on housing prices in large and medium-sized cities: Evidence from China.

Home-purchase limit is a unique administrative housing policy of China and has non-negligible influences on the housing price. The objective of this study is to analyze the spillover effect of home-purchase limit policy on housing prices in 35 large and medium-sized cities. The panel data of these cities and the spatial Durbin model are employed in this study. The results indicate that the spillover effect of home-purchase limit policy is positive and significant in all of 35 cities. However, when we categorize these cities into high-risk, medium-risk, and low-risk based on housing price characteristics, the spillover effect of home-purchase limit policy is different. It is not significant in high-risk cities, is negatively significant in medium-risk cities, and is positively significant in low-risk cities. This paper suggests that local governments can pay more attention to the precise design and implementation of home-purchase limit policy, and maintain policy continuity to avoid further spillover fluctuations in housing prices.

Application of nanomaterials in diagnosis and treatment of glioblastoma.

Diagnosing and treating glioblastoma patients is currently hindered by several obstacles, such as tumor heterogeneity, the blood-brain barrier, tumor complexity, drug efflux pumps, and tumor immune escape mechanisms. Combining multiple methods can increase benefits against these challenges. For example, nanomaterials can improve the curative effect of glioblastoma treatments, and the synergistic combination of different drugs can markedly reduce their side effects. In this review, we discuss the progression and main issues regarding glioblastoma diagnosis and treatment, the classification of nanomaterials, and the delivery mechanisms of nanomedicines. We also examine tumor targeting and promising nano-diagnosis or treatment principles based on nanomedicine. We also summarize the progress made on the advanced application of combined nanomaterial-based diagnosis and treatment tools and discuss their clinical prospects. This review aims to provide a better understanding of nano-drug combinations, nano-diagnosis, and treatment options for glioblastoma, as well as insights for developing new tools.

Mitochondrial unfolded protein response in ischemia-reperfusion injury.

Mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that activates the transcriptional program of mitochondrial chaperone proteins and proteases to keep protein homeostasis in mitochondria. Ischemia-reperfusion injury results in multiple severe clinical issues linked to high morbidity and mortality in various disorders. The pathophysiology and pathogenesis of ischemia-reperfusion injury are complex and multifactorial. Emerging evidence showed the roles of UPRmt signaling in ischemia-reperfusion injury. Herein, we discuss the regulatory mechanisms underlying UPRmt signaling in C. elegans and mammals. Furthermore, we review the recent studies into the roles and mechanisms of UPRmt signaling in ischemia-reperfusion injury of the heart, brain, kidney, and liver. Further research of UPRmt signaling will potentially develop novel therapeutic strategies against ischemia-reperfusion injury.

Definition of a Novel Cuproptosis-Relevant lncRNA Signature for Uncovering Distinct Survival, Genomic Alterations, and Treatment Implications in Lung Adenocarcinoma.

Objective: Cuproptosis is a newly discovered copper-independent cell death modality, and limited evidence suggests the critical implications in human cancers. Nonetheless, the clinical impacts of cuproptosis-relevant lncRNAs in lung adenocarcinoma (LUAD) remain largely ill-defined. The present study was aimed at defining a cuproptosis-relevant lncRNA signature for LUAD and discuss the clinical utility. Methods: We collected transcriptome expression profiling, clinical information, somatic mutation, and copy number variations from TCGA-LUAD cohort retrospectively. The genetic alterations of cuproptosis genes were systematically assessed across LUAD, and cuproptosis-relevant lncRNAs were screened for defining a LASSO prognostic model. Genomic alterations, immunological and stemness features, and therapeutic sensitivity were studied with a series of computational approaches. Results: Cuproptosis genes displayed aberrant expression and widespread genomic alterations across LUAD, potentially modulated by m6A/m5C/m1A RNA modification mechanisms. We defined a cuproptosis-relevant lncRNA signature, with a reliable efficacy in predicting clinical outcomes. High-risk subset displayed higher somatic mutations, CNVs, TMB, SNV neoantigens, aneuploidy score, CTA score, homologous recombination defects, and intratumor heterogeneity, cytolytic activity, CD8+ T effector, and antigen processing machinery, proving that this subset might benefit from immunotherapy. Increased stemness indexes and activity of oncogenic pathways might contribute to undesirable prognostic outcomes for high-risk subset. Additionally, high-risk patients generally exhibited higher response to chemotherapeutic agents (cisplatin, etc.). We also predicted several small molecule compounds (GSK461364, KX2-391, etc.) for treating this subset. Conclusion: Accordingly, this cuproptosis-relevant lncRNA signature offers an efficient approach to identify and characterize diverse prognosis, genomic alterations, and treatment outcomes in LUAD, thus potentially assisting personalized therapy.

Application of Extracorporeal Membrane Oxygenation in Patients With Severe Acute Respiratory Distress Syndrome Caused by Pneumocystis jirovecii Pneumonia Following Kidney Transplantation: A Case Series.

Objective: To investigate the application effect of extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome (ARDS) caused by Pneumocystis jirovecii pneumonia (PJP) after kidney transplantation. Methods: This is a case series on 10 kidney transplant recipients with severe ARDS caused by PJP at the People's Hospital of Zhengzhou, who were enrolled as the case group. A total of 17 cases of PJP diagnosed with severe ARDS without ECMO were selected as the control group. The timing and mode of ECMO support and treatment complications were summarized. The primary aim of this study was mortality and secondary was imaging and complications. Results: The enrolled patients' oxygenation index before the start of ECMO ranged from 25 to 92, and the time from admission to the start of ECMO was 1-17 days, with an average of 5.56 days. In the case group, one patient died of hemorrhagic shock due to abdominal hemorrhage, but the other nine patients were successfully weaned from ECMO. Of these patients, one died due to sepsis following weaning. The survival rate in the case group was 80.0% (8/10), and the survival rate in the control group was 35.29% (6/17). The vein-vein ECMO support time in the nine successfully weaned patients in the case group ranged from 131 to 288 h, with an average of 215.5 h. Of the eight patients who survived, deterioration of renal function after transplantation occurred in two patients, but no fatal complications occurred. Conclusion: Overall, Patients with severe ARDS caused by postoperative PJP infection following kidney transplantation have a poor prognosis. The mortality was lower in patients who were treated with ECMO compared to standard care.

Ferroptosis, necroptosis, and pyroptosis in the tumor microenvironment: Perspectives for immunotherapy of SCLC.

Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by dismal prognosis. Although SCLC may initially respond well to platinum-based chemotherapy, it ultimately relapses and is almost universally resistant to this treatment. Immune checkpoint inhibitors (ICIs) have been approved as the first- and third-line therapeutic regimens for extensive-stage or relapsed SCLC, respectively. Despite this, only a minority of patients with SCLC respond to ICIs partly due to a lack of tumor-infiltrating lymphocytes (TILs). Transforming the immune "cold" tumors into "hot" tumors that are more likely to respond to ICIs is the main challenge for SCLC therapy. Ferroptosis, necroptosis, and pyroptosis represent the newly discovered immunogenic cell death (ICD) forms. Promoting ICD may alter the tumor microenvironment (TME) and the influx of TILs, and combination of their inducers and ICIs plays a synergistical role in enhancing antitumor effects. Nevertheless, the combination of the above two modalities has not been systematically discussed in SCLC therapy. In the present review, we summarize the roles of distinct ICD mechanisms on antitumor immunity and recent advances of ferroptosis-, necroptosis- and pyroptosis-inducing agents, and present perspectives on these cell death mechanisms in immunotherapy of SCLC.