Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.

This comprehensive review elucidates the multifaceted roles of paclitaxel, a key chemotherapeutic agent, in cancer therapy, with a focus on its interactions with gap junctions and related kinases. Paclitaxel, with its complex diterpene structure, mediates its anticancer effects predominantly through specific interactions with β-tubulin, instigating cell cycle arrest and triggering various cell death pathways, including apoptosis, pyroptosis, ferroptosis, and necroptosis. The paper systematically delineates the chemical attributes and action mechanisms of paclitaxel and its analogs, underscoring their capacity to disrupt microtubule dynamics, thereby leading to mitotic arrest and subsequent cell death induction. It also scrutinizes the pivotal role of gap junctions, composed of connexin proteins, in the modulation of cancer cell behavior and chemoresistance, especially in the milieu of paclitaxel administration. The review articulates how gap junctions can either suppress tumors or contribute to cancer progression, thereby influencing chemotherapy outcomes. Furthermore, the paper provides an in-depth analysis of how paclitaxel modulates gap junction-associated kinases via phosphorylation, influencing the drug's therapeutic efficacy and resistance profiles. By integrating insights from numerous key studies, the review offers a comprehensive understanding of the interplay between paclitaxel, gap junctions, and kinases, shedding light on potential approaches to augment paclitaxel's anti-tumor effectiveness and counteract chemoresistance in cancer treatment.

The aim of this study was to research the molecular mechanism of lncRNA LINC01963 in pancreatic carcinoma progression.

Total 67 pancreatic cancer patients diagnosed and undergoing pancreatic cancer surgery in our hospital from April 2018 to April 2019 were included in this study. Pancreatic cancer cell lines including PANC-1, CFPAC-1, BxPC-3, SW1990 and AsPC1 were used. Based on bioinformatics information, pIRES2-LINC01963 plasmid, siLINC01963, miRNA mimics, miRNA inhibitor or siTMEFF2 were transfected. qRT-PCR and western blot were used to detect the expression of LINC01963, miR-641 and TMEFF2. CCK8 and Colony formation assay were processed for proliferation. Flow Cytometry Assay was processed to detect cell cycle and apoptosis. Transwell experiment was undertaken for invasion and migration. Luciferase assay and RNA Immunoprecipitation assay were used to verify the binding site among LINC01963, miR-641 and TMEFF2. Tumorigenic experiment was processed to confirm the above mechanisms in vivo.

lncRNA LINC01963 was confirmed to be lower expressed in pancreatic carcinoma tissues and cell lines. By up-regulating the expression of lncRNA LINC01963 in pancreatic carcinoma cell lines, colony number, cell cycle, proliferation and invasion were inhibited, while apoptosis was improved. More importantly, shLINC01963 could improve development of tumor in vivo. Besides, lncRNA LINC01963 negatively regulated the expression of miR-641, while miR-641 negatively targeted TMEFF2. Both miR-641 mimic and siTMEFF2 could reverse the effects of lncRNA LINC01963 overexpression in vitro.

Long non-coding RNA LINC01963 inhibits progression of pancreatic carcinoma by targeting miR-641/TMEFF2.

For the pathogenesis of complex diseases, gene-environment (G-E) interactions have been shown to have important implications. G-E interaction analysis can be challenging with the need to jointly analyze a large number of main effects and interactions and to respect the "main effects, interactions" hierarchical constraint. Extensive methodological developments on G-E interaction analysis have been conducted in recent literature. Despite considerable successes, most of the existing studies are still limited as they cannot accommodate long-tailed distributions/data contamination, make the restricted assumption of linear effects, and cannot effectively accommodate missingness in E variables. To directly tackle these problems, a semiparametric model is assumed to accommodate nonlinear effects, and the Huber loss function and Qn estimator are adopted to accommodate long-tailed distributions/data contamination. A regression-based multiple imputation approach is developed to accommodate missingness in E variables. For model estimation and selection of relevant variables, we adopt an effective sparse boosting approach. The proposed approach is practically well motivated, has intuitive formulations, and can be effectively realized. In extensive simulations, it significantly outperforms multiple direct competitors. The analysis of The Cancer Genome Atlas data on stomach adenocarcinoma and cutaneous melanoma shows that the proposed approach makes sensible discoveries with satisfactory prediction and stability.

Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclinical data, early clinical trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 (FLT3) activating mutations in acute myeloid leukemia (AML) was first recognized. Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM). Through a series of collaborations between industry and academia, midostaurin in combination with standard chemotherapy was evaluated in the Cancer and Leukemia Group B 10603/RATIFY study, a large, phase 3, randomized, placebo-controlled trial in patients with newly diagnosed FLT3-mutated AML. This was the first study to show significant improvements in overall survival and event-free survival with the addition of a targeted therapy to standard chemotherapy in this population. Around the same time, durable responses were also observed in other trials of midostaurin in patients with advanced SM. Collectively, these clinical data led to the approval of midostaurin by the US Food and Drug Administration and the European Medicines Agency for both newly diagnosed FLT3-mutated AML and advanced SM.

The multitargeted protein kinase inhibitor midostaurin is approved for the treatment of both newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and KIT-driven advanced systemic mastocytosis. AML is a heterogeneous malignancy, and investigational drugs targeting FLT3 have shown disparate effects in patients with FLT3-mutated AML, probably as a result of their inhibiting different targets and pathways at the administered doses. However, the efficacy and side effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound but are often comprised of complex cooperative effects between the properties of the parent and active metabolites. Following chronic dosing, two midostaurin metabolites attain steady-state plasma trough levels greater than that of the parent drug. In this study, we characterized these metabolites and determined their profiles as kinase inhibitors using radiometric transphosphorylation assays. Like midostaurin, the metabolites potently inhibit mutant forms of FLT3 and KIT and several additional kinases that either are directly involved in the deregulated signaling pathways or have been implicated as playing a role in AML via stromal support, such as IGF1R, LYN, PDPK1, RET, SYK, TRKA, and VEGFR2. Consequently, a complex interplay between the kinase activities of midostaurin and its metabolites is likely to contribute to the efficacy of midostaurin in AML and helps to engender the distinctive effects of the drug compared to those of other FLT3 inhibitors in this malignancy.

Aplog-1 is a simplified analog of debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (1) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.

Gaining insight into normal cellular signaling and disease biology is a critical goal of proteomic analyses. The ability to perform these studies successfully to extract the maximum value and discovery of biologically relevant candidate biomarkers is therefore of primary importance. Many successful studies in the past have focused on total proteome analysis (changes at the protein level) combined with phosphorylation analysis by metal affinity enrichment (changes at the PTM level). Here, we use the gastric carcinoma cell line MKN-45 treated with the c-Met inhibitor SU11274 and PKC inhibitor staurosporine to investigate the most efficient and most comprehensive strategies for both total protein and PTM analysis. Under the conditions used, total protein analysis yielded few changes in response to either compound, while analysis of phosphorylation identified thousands of sites that changed differentially between the two treatments. Both metal affinity and antibody-based enrichments were used to assess phosphopeptide changes, and the data generated by the two methods was largely complementary (non-overlapping). Label-free quantitation of peptide peak abundances was used to accurately determine fold-changes between control and treated samples. Protein interaction network analysis allowed the data to be placed in a biologically relevant context, and follow-up validation of selected findings confirmed the accuracy of the proteomic data. Together, this study provides a framework for start-to-finish proteomic analysis of any experimental system under investigation to maximize the value of the proteomic study and yield the best chance for uncovering actionable target candidates.

Apoptosis plays an important role during all stages of carcinogenesis and the development of chemoresistance in tumor cells may be due to their selective defects in the intracellular signaling proteins, central to apoptotic pathways. Consequently, many studies have focused on rendering the chemotherapy more effective in order to prevent chemoresistance and pre-clinical and clinical data has suggested that protein kinase C (PKC) may represent an attractive target for cancer therapy. Therefore, a complete understanding of how PKC regulates apoptosis and chemoresistance may lead to obtaining a PKC-based therapy that is able to reduce drug dosages and to prevent the development of chemoresistance.

The role of nonacidic reflux contents on the pathophysiology of Barrett's esophagus remains poorly understood. We hypothesized that esophageal squamous epithelium differs from Barrett's columnar epithelium in response to bile salts with respect to subsequent changes in the cell surface expression of CD95 (Fas/Apo-1) and sensitivity to CD95-mediated apoptosis.

Immortalized esophageal squamous cells (HET-1A) and Barrett's esophagus cells (BAR-T), and esophageal adenocarcinoma cells (Flo-1) were treated with toxic and nontoxic bile salts at concentrations observed in gastroesophageal refluxate. CD95 cell-surface expression and apoptotic response to activating anti-CD95 antibody treatment was determined by FACScan analysis.

Bile salt exposure resulted in a dose-dependent increase in CD95 cell-surface expression in HET-1A cells, but not BAR-T or Flo-1 cells. This response occurred rapidly, within a time-frame inconsistent with de novo protein synthesis and was blocked by protein kinase C (PKC) inhibition. Surprisingly, PKC inhibition in Flo-1 cells resulted in an increase in CD95 cell surface expression. Following bile salt exposure, a corresponding increase in the induction of CD95-mediated apoptosis was observed in HET-1A cells; PKC inhibition sensitized Flo-1 cells to apoptosis.

Our findings suggest that esophageal squamous cells are sensitized to CD95-mediated apoptosis following bile salt exposure. This differential response, compared with columnar epithelial cells, could exert a selection pressure that contributes to the pathophysiology of Barrett's esophagus.

Type I interferons (IFNs) are cytokines with diverse biological properties, including antiviral, growth inhibitory, and immunomodulatory effects. Although several signaling pathways are activated during engagement of the type I IFN receptor and participate in the induction of IFN responses, the mechanisms of generation of specific signals for distinct biological effects remain to be elucidated. We provide evidence that a novel member of the protein kinase C (PKC) family of proteins is rapidly phosphorylated and activated during engagement of the type I IFN receptor. In contrast to other members of the PKC family that are also regulated by IFN receptors, PKCeta does not regulate IFN-inducible transcription of interferon-stimulated genes or generation of antiviral responses. However, its function promotes cell cycle arrest and is essential for the generation of the suppressive effects of IFNalpha on normal and leukemic human myeloid (colony-forming unit-granulocyte macrophage) bone marrow progenitors. Altogether, our studies establish PKCeta as a unique element in IFN signaling that plays a key and essential role in the generation of the regulatory effects of type I IFNs on normal and leukemic hematopoiesis.