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(1) Introduction: Claudin-9 (CLDN9) is a member of the claudin protein family, a critical transmembrane protein family for tight junctions that are implemented in the progression of numerous cancer types. The present study investigated the role that CLDN9, along with the subcoat proteins, Zonula Occludens (ZOs), plays in clinical breast cancer and subsequent impact on drug response of patients. (2) Methods: CLDN9 protein and CLDN9 transcript were determined and correlated with clinical and pathological indicators, together with the status of hormonal receptors. The levels of CLDN9 transcript were also assessed against the therapeutic responses of the patients to chemotherapies by using a dataset from the TCGA database. Breast cancer cell models, representing different molecular subtypes of breast cancer, with differential expression of CLDN9 were created and used to assess the biological impact and response to chemotherapeutic drugs. (3) Results: Breast cancer tissues expressed significantly higher levels of the CLDN9, with the high levels being associated with shorter survival. CLDN9 was significantly correlated with its anchorage proteins ZO-1 and ZO-3. Integrated expression of CLDN9, ZO-1 and ZO-3 formed a signature that was significantly linked to overall survival (OS) (p = 0.013) and relapse-free survival (RFS) (p = 0.024) in an independent matter. CLDN9 transcript was significantly higher in patients who were resistant to chemotherapies (p < 0.000001). CLDN9 connection to chemoresistance was particularly prominent in patients of ER-positive (ER(+)), Her-2-negative((Her-2(−)), ER(+)/Her-2(−) and triple-negative breast cancers (TNBCs), but not in patients with HER-2-positive tumors. In Her-2-negative MCF7 and MDA-MB-231 cancer cells, loss of CLDN9 significantly increased sensitivity to several chemotherapeutic drugs including paclitaxel, gemcitabine and methotrexate, which was not seen in Her-2(+) SKBR3 cells. However, suppressing Her-2 using neratinib, a permanent Her-2 inhibitor, sensitized cellular response to these chemodrugs in cells with CLDN9 knockdown. (4) Conclusions: CLDN9 is an important prognostic indicator for patients with breast cancer and also a pivotal factor in assessing patient responses to chemotherapies. Her-2 is a negating factor for the treatment response prediction value by CLDN9 and negating Her-2 and CLDN9 may enhance breast cancer cellular response to chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Leukemia stem cells (LSCs) constitute the critical barrier to the cure of acute myeloid leukemia (AML) due to their chemoresistance and immune evasion property. Herein, the role of anlotinib, a multiple tyrosine kinase inhibitor, in killing LSCs and regulating chemoresistance and immune evasion was explored. Anlotinib treatment induced apoptosis of LSC-like cells as well as primary AML LSCs, while sparing the normal mononuclear cells in vitro. Moreover, anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib inhibited phosphorylation of c-kit, JAK2/STAT3, and STAT5, and downregulated STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic proteins Bcl-2 and Bcl-xL, and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. Intriguingly, anlotinib could also partially rescue the interferon-g production of T cells cocultured with LSCs by downregulating PD-L1 expression. In conclusion, anlotinib showed anti-LSC activity and the potential to enhance the sensitivity to idarubicin and inhibit the immunosuppressive feature of LSCs via JAK2/STAT signaling pathway downregulation in the preclinical study. Our results provided a rational basis for combinatory strategies involving anlotinib and chemotherapy or immunotherapy. [ABSTRACT FROM AUTHOR]

The anomalous enrichment of the rare earth elements and yttrium (REY), U, Mo, As, Se, and V in the coal-bearing intervals intercalated within the carbonate successions in South China has attracted much attention due to the highly promising recovery potential for these elements. This study investigates the mineralogical and geochemical characteristics of the late Permian coal-bearing intervals (layers A–F) intercalated in marine carbonate strata in the Xian'an Coalfield in Guangxi Province to elucidate the mode of occurrence and enrichment process of highly elevated elements. There are two mineralogical assemblages, including quartz-albite-kaolinite-carbonates assemblage in layers D–F and quartz-illite-kaolinite-carbonates assemblage in layers A–C. Compared to the upper continental crust composition (UCC), the REY, U, Mo, As, Se, and V are predominantly enriched in layers A and B, of which layer A displays the REY–V–Se–As assemblage while layer B shows the Mo–U–V assemblage. The elevated REY contents in layer B are primarily hosted by clay minerals, zircon, and monazite; Mo, U, and V show organic association; and As and Se primarily display Fe-sulfide association. Three geological factors are most likely responsible for geochemical anomaly: (1) the more intensive seawater invasion gives rise to higher sulfur, Co, Ni, As, and Se contents, as well as higher Sr/Ba ratio in layers A–C than in layers D–F; (2) both the input of alkaline pyroclastic materials and the solution/rock interaction jointly govern the anomalous enrichment of REY; and (3) the influx of syngenetic or early diagenetic hydrothermal fluids is the predominant source of U, Mo, V, Se, and As. [ABSTRACT FROM AUTHOR]

During the Late Paleozoic, West Junggar (Xinjiang, NW China) experienced a shift in tectonic setting from compression to extension. Ha'erjiao is an important area for investigating collisional structures, post–collisional structures, and magmatic activities. Based on the petrological and geochemical characteristics of pyroclastic and other volcanic rocks in the Permian Kalagang Formation from the borehole ZKH1205 in the Jimunai Basin, the main types of source rock for the pyroclastic rocks deposited in the basin are identified and their implications for the Early Permian tectonic setting examined. The abundance of basalt and andesite lithic fragments in the pyroclastic rocks, together with the REE characteristics and the contents of transition and high field strength elements show that the source rocks were chiefly intermediate–basic volcanic rocks. High ICV values, low CIA values, low Rb/Sr ratios, low Th/U ratios and the mineralogical features suggest weak chemical weathering of the source rocks; the geochemical patterns of the pyroclastic rocks might not only have been impacted by crustal contamination but also might be related to the nature of the magma from the source area. The geochemical properties of the pyroclastic rocks distinguish them from arc‐related ones, and such samples plot in the within‐plate basalt (WPB) field in some diagrams. This is consistent with the formation background of the Early Permian volcanic rocks in this region. [ABSTRACT FROM AUTHOR]