Integrative analysis of single-cell and bulk RNA-sequencing data revealed disulfidptosis genes-based molecular subtypes and a prognostic signature in lung adenocarcinoma.

BACKGROUND: Disulfidoptosis is an unconventional form of programmed cell death that distinguishes itself from well-established cell death pathways like ferroptosis, pyroptosis, and necroptosis. METHODS: Initially, we conducted a single-cell analysis of the GSE131907 dataset from the GEO database to identify disulfidoptosis-related genes (DRGs). We utilized differentially expressed DRGs to classify TCGA samples with an unsupervised clustering algorithm. Prognostic models were built using Cox regression and LASSO regression. RESULTS: Two DRG-related clusters (C1 and C2) were identified based on the DEGs from single-cell sequencing data analysis. In comparison to C1, C2 exhibited significantly worse overall prognosis, along with lower expression levels of immune checkpoint genes (ICGs) and chemoradiotherapy sensitivity-related genes (CRSGs). Furthermore, C2 displayed a notable enrichment in metabolic pathways and cell cycle-associated mechanisms. C2 was also linked to the development and spread of tumors. We created a prognostic risk model known as the DRG score, which relies on the expression levels of five DRGs. Patients were categorized into high-risk and low-risk groups depending on their DRG score, with the former group being linked to a poorer prognosis and higher TMB score. Moreover, the DRG score displayed significant correlations with CRSGs, ICGs, the tumor immune dysfunction and exclusion (TIDE) score, and chemotherapeutic sensitivity. Subsequently, we identified a significant correlation between the DRG score and monocyte macrophages. Additionally, crucial DRGs were additionally validated using qRT-PCR. CONCLUSIONS: Our new DRG score can predict the immune landscape and prognosis of LUAD, serving as a reference for immunotherapy and chemotherapy.

A phase I study of FCN-411, a pan-HER inhibitor, in EGFR-mutated advanced NSCLC after progression on EGFR tyrosine kinase inhibitors.

BACKGROUND: There are no approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC) without EGFR T790M mutation after progression on first- or second-generation EGFR-TKIs. METHODS: We conducted this phase I, open-label, multicenter, dose-escalation/dose-expansion study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of FCN-411, a TKI targeting EGFR, HER2, and HER4, in patients with EGFR-mutated advanced NSCLC whose disease had progressed during treatment of EGFR-TKIs. Adult patients with stage IIIB-IV NSCLC harboring EGFR mutations (exon 18/19/20/21) who had progressed on prior EGFR-TKIs were enrolled. In the dose-escalation phase, patients received 4 mg, 8 mg, 12 mg, and 16 mg FCN-411 once daily until the maximum tolerated dose (MTD). In the dose-expansion phase, patients received FCN-411 at the recommended phase II dose (RP2D) continuously in 21-day cycles. The primary endpoints were safety, tolerability, MTD, and RP2D. RESULTS: From July 23, 2018 to September 29, 2020, 77 patients were enrolled, including 30 with EGFR T790M mutation in tumor tissues. The cut-off date was February 1, 2021. No dose-limiting toxicities were observed. The most common grade ≥ 3 treatment-emergent adverse events among all patients were diarrhea (8; 10.4%) and dermatitis acneiform (7; 9.1%). Ten of 67 evaluable patients achieved confirmed partial response, with an objective response rate (ORR) of 14.9% (95% confidence interval [CI], 8.3-24.0); the ORR was 33.3%, 14.0%, 0, and 25.0% at 4 mg, 8 mg, 12 mg, and 16 mg, respectively. Besides, the ORR in patients without and with EGFR T790M mutation was 20.5% and 7.4%, respectively. Moreover, 39 patients achieved stable disease across all doses, and the disease control rate was 73.1% (95% CI, 60.9-83.2). Median progression-free survival was 4.1 (95% CI, 2.9-5.3) months. Median duration of response and overall survival have not been reached. CONCLUSIONS: FCN-411 was well tolerated and demonstrated preliminary antitumor activity in patients with EGFR-mutated NSCLC after progression on EGFR-TKIs, especially in those without EGFR T790M mutation. The RP2D was defined as 8 mg once daily. Future studies are warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03420079.

Establishment of a Lung Cancer Discriminative Model Based on an Optimized Support Vector Machine Algorithm and Study of Key Targets of Wogonin in Lung Cancer.

An optimized support vector machine model was used to construct a lung cancer diagnosis model based on serological indicators, and a molecular regulation model of Wogonin, a component of Scutellaria baicalensis, was established. Serological indexes of patients were collected, the grid search method was used to identify the optimal penalty coefficient C and parameter g of the support vector machine model, and the benign and malignant auxiliary diagnosis model of isolated pulmonary nodules based on serological indicators was established. The regulatory network and key targets of Wogonin in lung cancer were analyzed by network pharmacology, and key targets were detected by western blot. The relationship between serological susceptibility genes and key targets of Wogonin was established, and the signaling pathway of Wogonin regulating lung cancer was constructed. After support vector machine parameter optimization (C = 90.597, g = 32), the accuracy of the model was 90.8333%, with nine false positives and two false negative cases. Ontology functional analysis of 67 common genes between Wogonin targets and lung cancer-related genes showed that the targets were associated with biological processes involved in peptidye-serine modification and regulation of protein kinase B signaling; cell components in the membrane raft and chromosomal region; and molecular function in protein serine/threonine kinase activity and heme binding. Kyoto Encyclopedia of Genes and Genomes analysis showed that the regulation pathways involved the PI3K-Akt signaling pathway, ERBB signaling pathway, and EGFR tyrosine kinase inhibitor resistance. In vitro analyses using lung cancer cells showed that Wogonin led to significantly increased levels of cleaved caspase-3 and Bad and significantly decreased Bcl-2 expression in a concentration-dependent manner. ErbB4 expression also significantly decreased in lung cancer cells after treatment with Wogonin. A regulatory network of Wogonin regulating lung cancer cell apoptosis was constructed, including the participation of serological susceptibility genes. There is a certain regulatory effect between the serological indexes that can be used in the diagnosis of lung cancer and the key targets of Chinese herbal medicine treatment of lung cancer, which provides a new idea for the diagnosis, treatment and prognosis of clinical lung cancer.

Comparison of Combination Stereotactic Body Radiotherapy Plus High-Intensity Focused Ultrasound Ablation Versus Stereotactic Body Radiotherapy Alone for Massive Hepatocellular Carcinoma.

BACKGROUND Thermal high-intensity focused ultrasound ablation is a non-invasive treatment of massive hepatocellular carcinomas. In stereotactic body radiotherapy, ablative radiotherapy is administered to tumors in targeted, limited doses to minimize damage to nearby tissues. We evaluated the outcomes and survival of patients receiving stereotactic body radiotherapy (singular therapy) versus those receiving combination thermal high-intensity focused ultrasound ablation plus stereotactic body radiotherapy (combination therapy). MATERIAL AND METHODS We compared data of 160 patients with massive hepatocellular carcinomas (12.5-18 cm) who were treated with combination therapy to those treated with singular therapy between January 2009 and February 2016. RESULTS Eighty-four patients were treated with single therapy while 76 were treated with combination therapy. Comparison of short-term outcomes and long-term survival between the groups revealed no significant differences in adverse events. In the combination group, the proportions of patients with complete response, partial response, stable disease, and progressive disease were 52.6%, 21.1%, 21.1%, and 5.3%, respectively; in the single therapy group, the corresponding rates were 0%, 23.8%, 50%, and 26.2%, respectively (P<0.0001). The 1-year, 3-year, and 5-year survival rates in the combination group were 33%, 20%, and 13%, respectively, while those in the single therapy group were 21%, 14%, and 1%, respectively. These data indicated no differences in complications between the groups except for a significantly higher level of skin edema in the combination group (P=0.015). CONCLUSIONS Combination therapy is more effective than single therapy for the treatment of massive hepatocellular carcinomas, although rates of most complications appear to be similar.

Establishment of apoptotic regulatory network for genetic markers of colorectal cancer.

Our purpose is to screen out genetic markers applicable to early diagnosis for colorectal cancer and to establish apoptotic regulatory network model for colorectal cancer, thereby providing theoretical evidence and targeted therapy for early diagnosis of colorectal cancer. Taking databases including CNKI, VIP, Wanfang data, Pub Med, and MEDLINE as main sources of literature retrieval, literatures associated with genetic markers applied to early diagnosis of colorectal cancer were searched to perform comprehensive and quantitative analysis by Meta analysis, hence screening genetic markers used in early diagnosis of colorectal cancer. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed to establish apoptotic regulatory network model based on screened genetic markers, and then verification experiment was conducted. Through Meta analysis, seven genetic markers were screened out, including WWOX, K-ras, COX-2, p53, APC, DCC and PTEN, among which DCC shows highest diagnostic efficiency. GO analysis of genetic markers found that six genetic markers played role in biological process, molecular function and cellular component. It was indicated in apoptotic regulatory network built by KEGG analysis and verification experiment that WWOX could promote tumor cell apoptotic in colorectal cancer and elevate expression level of p53. The apoptotic regulatory model of colorectal cancer established in this study provides clinically theoretical evidence and targeted therapy for early diagnosis of colorectal cancer.

Establishment of optimal regulatory network of colorectal cancer based on p42.3 protein.

Objective: to establish regulatory network of colorectal cancer involving p42.3 protein and to provide theoretical evidence for deep functional exploration of p42.3 protein in the onset and development of colorectal cancer. Methods: with protein similarity algorithm, reference protein set of p42.3 cell apoptosis was built according to structural features of p42.3. GO and KEGG databases were used to establish regulatory network of tumor cell apoptosis involving p42.3; meanwhile, the largest possible working pathway that involves p42.3 protein was screened out based on Bayesian network theory. Besides, GO and KEGG were used to build regulatory network on early diagnosis gene markers for colorectal cancer including WWOX, K-ras, COX-2, p53, APC, DCC and PTEN, at the same time, a regulatory network of colorectal cancer cell apoptosis which involves p42.3 was established. Results: cell apoptotic regulatory network that p42.3 participates in primarily consists of Bcl-2 family genes and the largest possible pathway is p42.3 → FKBP → Bcl-2 centered as FKBP protein. Combined with colorectal cancer regulatory network that involves early diagnosis gene markers, it can be predicted that p42.3 is most likely to regulate the colorectal cancer cell apoptosis through FKBP → Bcl-2 → Bax → caspase-9 → caspase-3 pathway. Conclusion: the colorectal cancer apoptosis network based on p42.3 established in the study provides theoretical evidence for deep exploration of p42.3 regulatory mechanism and molecular targeting treatment of colorectal cancer.

Clinical evaluation of oral Fructus bruceae oil combined with radiotherapy for the treatment of esophageal cancer.

OBJECTIVE: To evaluate the therapeutic efficacy and side effects of oral Fructus bruceae oil combined with radiotherapy in the treatment of esophageal cancer. METHODS: A total of 80 patients with esophageal cancer were equally and randomly divided into two groups. The patients in Group A were treated with radiotherapy (60-65 Gy, 6-7 weeks) and oral Fructus bruceae oil (20 mL, 3 times per day for 12 weeks), while the patients in Group B were treated with radiotherapy alone. The short-term effect was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) and quality of life (QOL) was evaluated by the Karnofsky scoring (KFS). The outcome measures included complete remission (CR) rate, partial remission (PR) rate, effective rate as CR+PR, patients' QOL and adverse effects. RESULTS: After 12-week treatment, the CR and CR+PR were significantly higher in Group A than those in Group B (P <0.05). There was an improvement in esophageal obstruction of 87.5% and 60.0%, respectively, and in KFS of 84.6% and 43.9%, respectively, in Groups A and B. CONCLUSION: Oral medication with oral Fructus bruceae oil could effectively improve the efficacy of radiotherapy in esophageal cancer, including a reduction in esophageal obstruction, and also reduce the side effects of radiotherapy; thus it would be very promising for clinical application.

Current gamma knife treatment for ophthalmic branch of primary trigeminal neuralgia.

AIM: To probe into problems existing in gamma knife treatment of ophthalmic branch of primary trigeminal neuralgia (TN), and propose a safe and effective solution to the problem. METHODS: Through sorting the literature reporting gamma knife treatment of refractory TN in recent years, this article analyzed the advantages and problems of gamma knife treatment of primary TN, and proposed reasonable assessment for existing problems and the possible solution. RESULTS: Gamma knife treatment of TN has drawn increasing attention of clinicians due to its unique non-invasion, safety and effectiveness, but there are three related issues to be considered. The first one is the uncertainty of the optimal dose (70-90GY); the second one is the difference in radiotherapy target selection (using a single isocenter or two isocenters); and the third one is the big difference of recurrent pains (specific treatment methods need to be summarized and improved). CONCLUSION: For patients with refractory TN, gamma knife treatment can be selected when the medical treatment fails or drug side effects emerge. The analysis of a large number of TN patients receiving gamma knife treatment has shown that this is a safe and effective treatment method.