Immune checkpoint inhibitors for RET fusion non-small cell lung cancer: hopes and challenges.

Immune ch eckpoint inhibitors (ICIs) represent a milestone in advanced nonsmall cell lung cancer (NSCLC). Nevertheless, NSCLC with known oncogenic drivers has been overlooked in most studies evaluating anti-programmed death-1/programmed death ligand 1. Rearranged during transfection proto-oncogene (RET) gene fusion was identified in 1-2% of NSCLC patients. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy and good tolerability. In contrast, the activity of ICIs in RET fusion NSCLC has not been well characterized. Here, we analyzed the clinical data of ICIs and discussed the suitable time to introduce ICIs in RET fusion NSCLC. Finally, we put forward future strategies to adequately maximize the efficacy of ICIs treatment in patients with RET fusion NSCLC in the upcoming era of combination immunotherapies.

Full-Length Transcriptome Survey and Expression Analysis of Cassia obtusifolia to Discover Putative Genes Related to Aurantio-Obtusin Biosynthesis, Seed Formation and Development, and Stress Response.

The seed is the pharmaceutical and breeding organ of Cassia obtusifolia, a well-known medical herb containing aurantio-obtusin (a kind of anthraquinone), food, and landscape. In order to understand the molecular mechanism of the biosynthesis of aurantio-obtusin, seed formation and development, and stress response of C. obtusifolia, it is necessary to understand the genomics information. Although previous seed transcriptome of C. obtusifolia has been carried out by short-read next-generation sequencing (NGS) technology, the vast majority of the resulting unigenes did not represent full-length cDNA sequences and supply enough gene expression profile information of the various organs or tissues. In this study, fifteen cDNA libraries, which were constructed from the seed, root, stem, leaf, and flower (three repetitions with each organ) of C. obtusifolia, were sequenced using hybrid approach combining single-molecule real-time (SMRT) and NGS platform. More than 4,315,774 long reads with 9.66 Gb sequencing data and 361,427,021 short reads with 108.13 Gb sequencing data were generated by SMRT and NGS platform, respectively. 67,222 consensus isoforms were clustered from the reads and 81.73% (61,016) of which were longer than 1000 bp. Furthermore, the 67,222 consensus isoforms represented 58,106 nonredundant transcripts, 98.25% (57,092) of which were annotated and 25,573 of which were assigned to specific metabolic pathways by KEGG. CoDXS and CoDXR genes were directly used for functional characterization to validate the accuracy of sequences obtained from transcriptome. A total of 658 seed-specific transcripts indicated their special roles in physiological processes in seed. Analysis of transcripts which were involved in the early stage of anthraquinone biosynthesis suggested that the aurantio-obtusin in C. obtusifolia was mainly generated from isochorismate and Mevalonate/methylerythritol phosphate (MVA/MEP) pathway, and three reactions catalyzed by Menaquinone-specific isochorismate synthase (ICS), 1-deoxy-d-xylulose-5-phosphate synthase (DXS) and isopentenyl diphosphate (IPPS) might be the limited steps. Several seed-specific CYPs, SAM-dependent methyltransferase, and UDP-glycosyltransferase (UDPG) supplied promising candidate genes in the late stage of anthraquinone biosynthesis. In addition, four seed-specific transcriptional factors including three MYB Transcription Factor (MYB) and one MADS-box Transcription Factor (MADS) transcriptional factors) and alternative splicing might be involved with seed formation and development. Meanwhile, most members of Hsp20 genes showed high expression level in seed and flower; seven of which might have chaperon activities under various abiotic stresses. Finally, the expressional patterns of genes with particular interests showed similar trends in both transcriptome assay and qRT-PCR. In conclusion, this is the first full-length transcriptome sequencing reported in Caesalpiniaceae family, and thus providing a more complete insight into aurantio-obtusin biosynthesis, seed formation and development, and stress response as well in C. obtusifolia.

Identification and analysis of prognostic immune cell homeostasis characteristics in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most invasive malignant tumor of the respiratory system. It is also the common pathological type leading to the death of LUAD. Maintaining the homeostasis of immune cells is an important way for anti-tumor immunotherapy. However, the biological significance of maintaining immune homeostasis and immune therapeutic effect has not been well studied. METHODS: We constructed a diagnostic and prognostic model for LUAD based on B and T cells homeostasis-related genes. Minimum absolute contraction and selection operator (LASSO) analysis and multivariate Cox regression are used to identify the prognostic gene signatures. Based on the overall survival time and survival status of LUAD patients, a 10-gene prognostic model composed of ABL1, BAK1, IKBKB, PPP2R3C, CCNB2, CORO1A, FADD, P2RX7, TNFSF14, and ZC3H8 was subsequently identified as prognostic markers from The Cancer Genome Atlas (TCGA)-LUAD to develop a prognostic signature. This study constructed a gene prognosis model based on gene expression profiles and corresponding survival information through survival analysis, as well as 1-year, 3-year, and 5-year ROC curve analysis. Enrichment analysis attempted to reveal the potential mechanism of action and molecular pathway of prognostic genes. The CIBERSORT algorithm calculated the infiltration degree of 22 immune cells in each sample and compared the difference of immune cell infiltration between high-risk group and low-risk group. At the cellular level, PCR and CKK8 experiments were used to verify the differences in the expression of the constructed 10-gene model and its effects on cell viability, respectively. The experimental results supported the significant biological significance and potential application value of the molecular model in the prognosis of lung cancer. Enrichment analyses showed that these genes were mainly related to lymphocyte homeostasis. CONCLUSION: We identified a novel immune cell homeostasis prognostic signature. Targeting these immune cell homeostasis prognostic genes may be an alternative for LUAD treatment. The reliability of the prediction model was confirmed at bioinformatics level, cellular level, and gene level.

Ferroptosis in renal fibrosis: a mini-review.

Ferroptosis is a novel form of programmed cell death that is iron-dependent and distinct from autophagy, apoptosis, and necroptosis. It is primarily characterised by a decrease in glutathione peroxidase 4 (GPX4) activity, or by the accumulation of lipid peroxidation and reactive oxygen species (ROS). Renal fibrosis is a common pathological change in the progression of various primary and secondary renal diseases to end-stage renal disease and poses a serious threat to human health with high morbidity and mortality. Multiple pathways contribute to the development of renal fibrosis, with ferroptosis playing a crucial role in renal fibrosis pathogenesis due to its involvement in the production of ROS. Ferroptosis is related to several signalling pathways, including System Xc-/GPX4, abnormal iron metabolism and lipid peroxidation. A number of studies have indicated that ferroptosis is closely involved in the process of renal fibrosis caused by various kidney diseases such as glomerulonephritis, renal ischaemia-reperfusion injury, diabetic nephropathy and renal calculus. Identifying the underlying molecular mechanisms that determine cell death would open up new insights to address a therapeutic strategy to renal fibrosis. The review aimed to browse and summarise the known mechanisms of ferroptosis that may be associated with biological reactions of renal fibrosis.

ADCY4 promotes brain metastasis in small cell lung cancer and is associated with energy metabolism.

Brain metastasis (BMs) in small cell lung cancer (SCLC) has a very poor prognosis. This study combined WGCNA with the mfuzz algorithm to identify potential biomarkers in the peripheral blood of patients with BMs. By comparing the significantly differentially expressed genes present in BMs samples, we identified ADCY4 as a target for further study. Expression of ADCY4 was used to cluster mfuzz expression pattern, and 28 hub genes for functional enrichment. PPI network analysis were obtained by comparing with differentially expressed genes in BMs. GABRE, NFE4 and LMOD2 are highly expressed in patients with BMs and have a good diagnostic effect. Immunoinfiltration analysis showed that SCLC patients with BMs may be associated with memory B cells, Tregs, NK cell activation, macrophage M0 and dendritic cell activation. prophytic was used to investigate the ADCY4-mediated anti-tumor drug response. In conclusion, ADCY4 can be used as a promising candidate biomarker for predicting BMs, molecular and immune features in SCLC. PCR showed that ADCY4 expression was increased in NCI-H209 and NCI-H526 SCLC cell lines. In vitro experiments confirmed that the expression of ADCY4 was significantly decreased after anti-PD1 antibody treatment, while the expression of energy metabolism factors were significantly different. This study reveals a potential mechanism by which ADCY4 mediates poor prognosis through energy metabolism -related pathways in SCLC.

Can Patients with HER2-Low Breast Cancer Benefit from Anti-HER2 Therapies? A Review.

Breast cancer (BC) poses a severe threat to the health of women worldwide. Currently, different therapeutic regimens are used for BC according to the pathological classification of HER2-positive or HER2-negative. Clinical reports of HER2-low expression indicate that the condition is HER2-negative, which was ineligible for HER2-targeted therapy. In contrast to HER2-zero tumors, however, HER2-low BC is a heterogeneous disease with unique genetic characteristics, prognoses, and different therapeutic responses. Clinical efficacy has been demonstrated by numerous potent and innovative anti-HER2 medications, particularly antibody-drug conjugates (ADCs). Certain ADCs, including T-DXd, have demonstrated good efficacy in some trials either used alone or in conjunction with other medications. To enhance outcomes in individuals with HER2-low BC, immunotherapy and other treatments are frequently combined with HER2-targeted therapy. There are also alternative strategies that target both HER2 and HER3 or other antigenic sites. We hope more individuals with HER2-low BC will benefit from more precise treatment regimens in the future. This article provides a review of existing research and clinical trials.

Traditional Chinese medicines for non-small cell lung cancer: Therapies and mechanisms.

The most common subtype of lung cancer is non-small cell lung cancer (NSCLC), which has a poor prognosis and seriously threatens the health of human beings. The multidisciplinary comprehensive treatment model has gradually become the mainstream of NSCLC treatment. Traditional Chinese medicine (TCM) can be used effectively either as an adjunctive therapy or alone throughout the NSCLC therapy, which has a significant impact on survival, quality of life, and reduction of toxicity. Therefore, this paper reviewed the theoretical basis, the latest clinical application, and combined treatment mechanisms in order to explore the advantage stage of TCM treatment and the synergistic therapeutic mechanisms.

Maintenance anlotinib improves the survival prognosis of extensive-stage small cell lung cancer: a single-arm, prospective, phase II study.

The extent to which anlotinib provides survival benefits in the maintenance therapy of extensive-stage small cell lung cancer (ES-SCLC) remains unclear. Thus, this study aimed to assess the efficacy and safety of anlotinib monotherapy as maintenance therapy following induction chemotherapy in ES-SCLC patients. 27 ES-SCLC patients registered at the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine were screened from February 2022 to October 2022, of which 3 were not eligible. Eligible patients in stable status after first-line chemotherapy would subsequently accept oral anlotinib (12 mg, p.o., qd. on d1-d14, every 21 days). The maintenance method was continued until disease progression or unmanageable toxicity occurred. The primary endpoint is median progression-free survival (mPFS). The second endpoints include median duration of response (mDOR), median overall survival (mOS) and safety. The mPFS and mDOR have been determined (mPFS: 252 days, 95% CI: 217.782-286.218 days; mDOR: 126 days, 95% CI: 98.899-153.101 days). The mOS was not reached; only 7 patients were reached while 20 patients survived. The primary treatment-related adverse events included hypertension (n=7, 25.9%), fatigue (n=5, 18.5%), poor appetite (n=5, 18.5%), and others. Notably, no patients required a dose reduction due to the severity of adverse events. Patients were generally able to tolerate treatment with anlotinib and exhibited a favorable prognosis. Anlotinib achieved prospective efficacy and manageable safety in the maintenance treatment of ES-SCLC.

Advances in Antibody-Drug Conjugates in the Treatment of HER2-Positive Breast Cancer.

Although targeted drugs improved the therapeutic effect of HER2-positive breast cancer, the long-term prognosis was still poor. In this regard, the research and development of antibody-drug conjugates (ADCs) came into being and made a lot of progress. ADCs had the characteristics of both chemotherapeutic agents and targeted agents by combining chemotherapeutic agents and targeted agents through a linker. It not only had a strong anti-tumor effect on HER2-positive breast cancer, but also had certain anti-tumor effects on HER2-low and even HER2-negative patients. In addition, the clinical researches of ADCs combined with immune checkpoint inhibitors (ICIs) therapy had also made a great breakthrough. This review aimed to summarize the clinical progress of ADCs, in particular the two drugs approved by the US Food and Drug Administration (FDA) for HER2-positive metastatic breast cancer as well as to summarize the current status of ADCs in combination with ICIs.

Research Progress on RET Fusion in Non-Small-Cell Lung Cancer.

Great progress has been made in the treatment of driver gene-positive Non- Small Cell Lung Cancer (NSCLC) in recent years. RET fusion was seen in 0.7% to 2% of NSCLC and was associated with younger age and never-smoker status. The pralsetinib and selpercatinib for RET fusion NSCLC was recommended by the 2021 NSCLC treatment guidelines. This review outlines the research progress in the treatment of RET fusion NSCLC, identifies current challenges and describes proposals for improving the outlook for these patients.

Research Progress of Antibody-Drug Conjugate Therapy for Advanced Gastric Cancer.

Gastric cancer is an intractable malignant tumor that has the fifth highest morbidity and the third highest mortality in the world. Even though various treatment options did much to ameliorate the prognosis of advanced gastric cancer, the survival time remained unsatisfactory. It is significant to develop new therapeutic agents to improve the long-term outcome. Antibody-drug conjugate is an innovative and potent antineoplastic drug composed of a specifically targeted monoclonal antibody, a chemical linker, and a small molecule cytotoxic payload. Powerful therapeutic efficacy and moderate toxicity are its preponderant advantages, which imply the inevitable pharmaceutical developments to meet the demand for individualized precision therapy. Nevertheless, it is unavoidable that there is a phenomenon of drug resistance in this agent. This article systematically reviewed the recent progress of antibody-drug conjugates in advanced gastric cancer therapy.

Non-Small Cell Lung Cancer: Challenge and Improvement of Immune Drug Resistance.

Lung cancer is the leading cause of cancer deaths in the world. At present, immunotherapy has made a great breakthrough in lung cancer treatment. A variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4. However, in the actual clinical process, about 30%-50% of patients still do not receive long-term benefits. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the immune mechanism of immune checkpoint inhibitor resistance, various combination strategies, and prediction of biomarkers to overcome resistance in order to accurately screen out the advantageous population, expand the beneficiary population, and enable precise and individualized medicine.

Advances in Immunotherapy of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) represents the uncommon cancer originating from pleural mesothelial cells, which is associated with dismal prognostic outcome. According to CheckMate-743 results, nivolumab plus ipilimumab has been approved to treat the unresectable MPM in treatment-naive patients as a first-line therapy by the FDA in October 2020. Immunotherapy is expected to be the best choice for MPM treatment. In the following article, the past treatment plan and the progress of immunotherapy for MPM will be reviewed.

Elevated CA125 in primary peritoneal serous psammocarcinoma: a case report and review of the literature.

Psammocarcinoma is a rare form of serous carcinoma of the ovary or peritoneum, and it is characterised by extensive psammoma body formation and invasion of surrounding structures. This report describes the case of a 42-year-old woman who presented with large ascites and raised CA125 level. Following a full staging laparotomy, she was made stable in stage IIIC. Despite the limited number of cases reported, the clinical prognosis of carcinomas resembling the serous borderline lesions seems much more favourable than the common serous carcinomas. A summary of all the reported cases is provided to highlight the clinical and prognostic features of this scarce tumour.