Lung cancer is one of the most common causes of cancer-related deaths, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Kirsten rat sarcoma virus ...(KRAS), one of the three subtypes of the RAS family, is the most common oncogene involved in human cancers and encodes the key signaling proteins in tumors. Oncogenic KRAS mutations are considered the initiating factors in 30% of NSCLC cases, accounting for the largest proportion of NSCLC cases associated with driver mutations. Because effective inhibition of the related functions of KRAS with traditional small-molecule inhibitors is difficult, the KRAS protein is called an “undruggable target.” However, in recent years, the discovery of a common mutation in the KRAS gene, glycine 12 mutated to cysteine (G12C), has led to the design and synthesis of covalent inhibitors that offer novel strategies for effective targeting of KRAS. In this review, we have summarized the structure, function, and signal transduction pathways of KRAS and discussed the available treatment strategies and potential treatment prospects of KRAS mutation subtypes (especially G12C, G12V, and G12D) in NSCLC, thus providing a reference for selecting KRAS mutation subtypes for the treatment of NSCLC.
Cholangiocarcinoma (CCA) is a type of aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, and is usually diagnosed at an advanced stage. The standard first-line ...systemic therapy for patients with advanced CCA is a combination of gemcitabine and cisplatin; targeted therapies and angiogenesis inhibitors are not widely used clinically at present. However, with the development of precision medicine, immunotherapy has started to play a more important role. Programmed cell death protein 1 inhibitors are now considered a good therapeutic option for CCA. Treatments using chimeric antigen receptor T cells, bispecific antibodies, oncolytic viruses and cancer vaccines have also achieved satisfactory results. In addition, combinations of immunotherapy with a variety of conventional therapies have shown some efficacy, and several studies have provided insights into their use in antitumor therapy. Although there are numerous challenges in the treatment of advanced CCA, immunotherapy remains a noteworthy breakthrough. The current evidence on the immunotherapy of CCA is discussed in the present review.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
More recently, microbiota was detected in several tumorous tissues including multiple myeloma (MM), but the roles of which is still under-studied as paucity of research on tumor biology. Moreover, we ...also detected the presence of microbiota in the bone marrow of patients with MM by 2bRAD-M sequencing technology, which is an incurable hematological malignancy characterized by accumulation of abnormal plasma cells in the bone marrow. However, the roles of intratumor microbiota in tumor disease remains poorly understood. In this manuscript, we critically reviewed recent literature about microbiota in the tumorigenesis and progression of MM. Importantly, we proposed the emergence of microbiota in the microenvironment of multiple myeloma may be attributed to microbial dysbiosis and impaired intestinal barrier, due to the increased prevalence of MM in patients with obesity and diabetes, of which the characteristic phenotype is gut microbial dysbiosis and impaired intestinal barrier. When the intestinal barrier is damaged, dysbiotic microbiota and their metabolites, as well as dysregulated immune cells, may participate in the reshaping of the local immune microenvironment, and play pivotal roles in the tumorigenesis and development of multiple myeloma, probably by migrating to the bone marrow microenvironment from intestine. We also discuss the emerging microbiological manipulation strategies to improve long-term outcomes of MM, as well as the prospective of the state-of-the-art techniques to advance our knowledge about the biological implication in the microbiome in MM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The prognostic value of plasma cell CD56 expression of patients with multiple myeloma (MM) has been reported in many studies, but the results are controversial. This study aimed to examine the ...prognostic significance of CD56 in MM patients. Eighty seven patients with newly diagnosed MM were enrolled in this study, and their clinical characteristics, immunophenotypes, and cytogenetics were retrospectively analyzed to explore the prognostic significance of CD56 expression. Multiparameter flow cytometry was used to detect MM in bone marrow samples from all patients. Patients were divided into 2 groups based on whether they expressed CD56: CD56 + group and CD56 - group. After 4 cycles of chemotherapy, the overall response rate of the CD56 - patients was lower than that of the CD56 + patients (60.0% vs 81.1%, P = .036). Survival analysis showed that the median progression-free survival (PFS) was 10 months for the CD56 - group and 27 months for the CD56 + group (P = .007). The median overall survival (OS) of patients for the CD56 - group was 25 months versus not reached in the CD56 + group (P = .010). In addition, among the high-risk patients detected by fluorescence in situ hybridization (FISH), the median PFS was 4 months for the CD56 - group and 16 months for the CD56 + group (P = .012). The median OS of the CD56 + group and CD56 - group was 36 months and 15 months, respectively, with statistically significant differences (P = .017). Our study confirmed that CD56 - patients with MM had a worse prognosis than that of CD56 + patients with MM. Among the patients with ≥ 2 high-risk cytogenetics, the existence of the CD56 negativity can further identify MM patients with poor PFS and OS.
AIM: To investigate the immune function of dendritic cells from both peripheral blood and operated tissues of esophageal carcinoma patients in order to find the relationship between the immune ...function of dendritic cells and the pathogenesis of esophageal carcinoma. METHODS: The expression of CD83, CD80, and CD86 on the surface of dendritic cells cultured from the peripheral blood of patients was detected compared with that from health donors using flow cytometry. The ability of dendritic cells to induce T lymphocyte proliferation was evaluated by a liquid scintillation counter. The expression of CD80, CD86, CD83, and S-100 proteins was assessed in esophageal carcinoma tissues using immunohistochemical method. RESULTS: Compared with those from healthy donors, dendirtic cells cultured from the peripheral blood of patients expressed lower CDS0 and CD86. Furthermore, the ability of dendritic cells in patients to induce T lymphocyte proliferation was significantly lower than that of the control group. Compared with the control group, the positive expression ratio and frequencies of CDS0, CD86, and S100 in esophageal carcinoma tissues were significantly down regulated. The expression of CD83 was up-regulated in the pericancerous tissues, but no expression was found in the cancerous nodules. CONCLUSION: The impaired immune function and the decreased number of dendritic cells cause pathogenesis and progression of esophageal carcinoma.
A sequential quadratic programming numerical method is proposed for American option pricing based on the variational inequality formulation. The variational inequality is discretized using the ...θ-method in time and the finite element method in space. The resulting system of algebraic inequalities at each time step is solved through a sequence of box-constrained quadratic programming problems, with the latter being solved by a globally and quadratically convergent, large-scale suitable reflective Newton method. It is proved that the sequence of quadratic programming problems converges with a constant rate under a mild condition on the time step size. The method is general in solving the variational inequalities for the option pricing with many styles of optimal stopping and complex underlying asset models. In particular, swing options and stochastic volatility and jump diffusion models are studied. Numerical examples are presented to confirm the effectiveness of the method.
•A fast sequential quadratic programming method (SQPM) is developed.•The convergence of the SQPM is proved.•The SQPM can solve non-symmetric variational inequalities.•The SQPM is efficient for solving general classes of American and swing options.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the ...description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.
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