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Burkitt lymphoma (BL), which is characterized by high invasiveness, is a subgroup of non-Hodgkin lymphoma. Although BL is regarded as a highly curable disease, especially for children, some patients unfortunately still do not respond adequately. The understanding of the etiology and molecular mechanisms of BL is still limited, and targeted therapies are still lacking. Here, we found that T-LAK cell-derived protein kinase (TOPK) and phosphorylated Janus kinase 2 (p-JAK2) are highly expressed in the tissues of BL patients. We report that TOPK directly binds to and is phosphorylated at Tyr74 by JAK2. Histone H3, one of the downstream targets of TOPK, is also phosphorylated in vivo and in vitro. Furthermore, we report that the phosphorylation of TOPK at Tyr74 by JAK2 plays a vital role in the proliferation of BL cells and promotes BL tumorigenesis in vivo. Phosphorylation of TOPK at Tyr74 by JAK2 enhances the stability of TOPK. Collectively, our results suggest that the JAK2/TOPK/histone H3 axis plays a key role in the proliferation of BL cells and BL tumorigenesis in vivo. [ABSTRACT FROM AUTHOR]

This research focuses on exploring RSK4 protein expression within Clear Cell Renal Cell Carcinoma (ccRCC), based on these investigations on level of expressions coupled with the relevance to clinicopathologic features and clinical outcomes. The expression of RSK4 in 48 ccRCC and 20 hydronephrosis samples were under the detection of immunohistochemistry; besides, its relevance to the combination of clinicopathologic features with prognosis was committed in virtue of statistical approaches. The 48 ccRCC samples included 36 (75%, 36/48) positive for RSK4, while the positive rate in hydronephrosis samples were 5 (25%, 5/20). Statistical analysis showed that RSK4 in ccRCC samples express higher expression the hydronephrosis samples (P < 0.05). Furthermore, the expression of RSK4 in ccRCC samples weren't correlated with ages and genders (P > 0.05), while WHO/ISUP nucleolar grade harboured relevance to low survival rate (P = 0.018). Molecular researches demonstrated that over-expression of RSK4 was able to upgrade the proliferation capability of ccRCC cell lines. According to the expression pattern and molecular systems featured RSK4 in ccRCCs, it performed the function of a latent independent prognostic factor performing the function of a newly built latent therapeutic aim oriented with the patients undergoing RCC. Moreover, the specific mechanism of action is expected to be revealed in the future research. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) has a high probability of relapse and poor overall survival. Neoadjuvant chemotherapy (NACT) is currently a routine treatment strategy for TNBC, but some patients do not respond well. T-LAK cell-originated protein kinase (TOPK) is highly expressed in breast cancer cells and contributes to cancer cell proliferation. The present study aimed to investigate the correlation of TOPK expression with NACT treatment response and prognosis in TNBC. We collected 66 pairs of TNBC samples before and after NACT with docetaxel + epirubicin + cyclophosphamide (TEC). The Miller-Payne (MP) system was used to assess the therapeutic response to NACT in TNBC patients. Immunohistochemistry analysis showed that TNBC patients with high TOPK expression before NACT had a poor treatment response and a poor prognosis. The expression of TOPK after NACT was significantly higher than that before NACT in patients with MP grade 1–3. In contrast, patients with MP grade 4–5 had significantly lower TOPK expression after NACT than before NACT, and the expression change in Ki-67 in patients with MP grade 4–5 exhibited the same trend. Survival analysis revealed that patients with TNBC accompanied by elevated TOPK expression before NACT had a worse prognosis than those with lower TOPK expression. TOPK may be a novel predictor for the therapeutic response to NACT and prognosis for patients with TNBC. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is a multifactorial disease and the sixth leading cause of death from cancer worldwide. Patients with ESCC usually have a short survival period due to the late stage at diagnosis. Incidence rates of ESCC remain high among the elderly. With recent advances, it has been demonstrated that ESCC tumors display a unique genetic profile. This study aimed to examine the possible function of OTX1 in ESCC. We collected paraffin-embedded tumor tissues from 107 patients originally diagnosed with ESCC at Xijing Hospital and fresh-harvested and paired adjacent normal esophageal tissues from 15 ESCC patients undergoing curative resection. The expression level of OTX1 was evaluated through immunohistochemistry and western blot. Prognostic and survival analyses were conducted using univariate/multivariate analysis and log-rank analysis with SPSS 23.0. Cell models and xenograft models were used to examine the overexpression of OTX1 in vivo and in vitro. OTX1 was overexpressed in ESCC tissues compared with normal esophageal tissues. Both the mRNA expression level and protein level of OTX1 were higher than they were in paired normal tissue. Prognostic and OS analyses showed that the OTX1 expression level was an individual prognostic factor in ESCC patients. Cell viability was significantly promoted when OTX1 was overexpressed in ESCC cell, Furthermore, downregulating OTX1 in EC109 cell significantly attenuated the cell proliferation migration and invasion. Flow cytometric detection showed that cells overexpressing OTX1 were predominantly in the S and G2&M phases. In the xenograft model, both tumor size and weight in the OTX1 overexpression group were significantly larger than those in the control group. OTX1 is an independent prognostic factor of ESCC and contributes to tumorigenesis both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

RSK4 refers to one Ser/Thr protein kinase functioning downstream pertaining to the signaling channel of protein kinase (MAPK) stimulated by Ras/mitogen. RSK4 can regulate numerous substrates impacting cells' surviving state, growing processes and proliferating process. Thus, dysregulated RSK4 active state display a relationship to several carcinoma categories, covering breast carcinoma, esophageal squamous cell carcinoma, glioma, colorectal carcinoma, lung carcinoma, ovarian carcinoma, leukemia, endometrial carcinoma, and kidney carcinoma. Whether RSK4 is a tumor suppressor gene or one oncogene remains controversial. No specific inhibiting elements for RSK4 have been found. This review briefs the existing information regarding RSK4 activating process, the function and mechanism of RSK4 in different tumors, and the research progress and limitations of existing RSK inhibitors. RSK4 may be a potential target of molecular therapy medicine in the future. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is characterized by nonsuppurative destructive cholangitis and is thought to be an autoimmune disorder. Currently, ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to nearly one-third of patients do not achieve a complete response to this treatment. Adaptive immune cells, including T cells and B cells, have been found in the portal tracts and the bile duct epithelium and play a role in the pathogenesis of PBC, but the importance of these cells for evaluating the therapeutic response to UDCA in PBC has not yet been studied. In this study, we collected liver puncture biopsy specimens from 34 matched patients with PBC before and after UDCA treatment and investigated the relationship between the infiltration of adaptive immune cells and the treatment response to UDCA. The extent of immune cell infiltration was determined by immunohistochemical analysis. Responses were defined based on Paris-I criteria. After 1 year of treatment, 25/34 patients responded to UDCA treatment according to Paris-I criteria (responders), and 9/34 patients were nonresponders. Immunohistochemical analysis showed that UDCA responders exhibited significantly less CD4+ T cell infiltration after UDCA treatment than before (50.4 ± 7.5/HPF vs 30.0 ± 7.9/HPF, P = 0.002). In contrast, UDCA nonresponders exhibited significantly more CD4+ T cell infiltration after UDCA treatment than before (32.2 ± 8.0/HPF vs 75.0 ± 13.9/HPF, P = 0.045). Moreover, patients who exhibited a reduction in CD4+ T cell infiltration after UDCA treatment had a higher response rate than those that exhibited an increase in CD4+ T cell infiltration (85.7 % vs 53.8 %, P = 0.041). However, CD3+ T cell, CD8+ T cell, and CD20+ B cell infiltration was not significantly different before and after treatment in either UDCA responders or nonresponders. Furthermore, we found that the number of infiltrating T-bet+ Th1 cells was much lower after UDCA treatment than before in responders (10.5 ± 5.7/HPF vs. 5.16 ± 4.0/HPF, P = 0.0214) but much higher in nonresponders after treatment than before (1.89±1.2/HPF vs. 12.3±5.4/HPF, P = 0.043). However, there was no difference in the extent of GATA3+ Th2 or FOXP3+ Treg infiltration before and after treatment in either UDCA responders or nonresponders. Collectively, our results suggest that a decrease in the number of liver-infiltrating CD4+ Th1 cells is associated with a good response of PBC patients to UDCA treatment. Immunohistochemical analysis of CD4 and T-bet in PBC liver specimens may be a potential approach for evaluating the therapeutic response to UDCA. [ABSTRACT FROM AUTHOR]

• The amino acid position 200 in HA1 of H9N2 AIVs is a newly identified multi-functional site. • The D200N substitution of HA1 changed antigenicity of H9N2 AIVs. • D200N increased the HA cleavage efficiency and reduced acid and thermal stability of HA protein. • Residue 200N increased the replication of H9N2 viruses in both chicken embryo fibroblast cells and chicken embryonated eggs. Influenza virus hemagglutinin (HA) plays an important role in viral antigenicity, replication and host range. However, few amino acid positions in HA were reported to play multiple functions in both viral antigenicity and replication. In the present study, through analyzing the amino acid sequences of H9N2 avian influenza viruses (AIVs) isolated from China, we identified a multi-functional substitution of D200N in HA1 protein. Firstly, the substitution of D200N changed the antigenicity of H9N2 AIVs. Secondly, the D200N increased the HA cleavage efficiency and reduced acid and thermal stability of HA protein, which triggered viral-endosomal membrane fusion whereby promoted the release of viral genome into the host cytoplasm. Finally, residue 200-N increased the replication of H9N2 viruses in both chicken embryo fibroblast (CEF) cells and chicken embryonated eggs. In summary, the D200N substitution is a newly identified antigenicity and replication determinant of H9N2 AIVs, which should be paid more attention during surveillance. [ABSTRACT FROM AUTHOR]

Triple-negative breast carcinoma (TNBC) is a subtype of breast carcinoma defined by negativity for estrogen receptor (ER) or progesterone receptor (PR) by immunohistochemical analysis and negativity for human epidermal growth factor receptor (Her2) by immunohistochemistry or in situ hybridization. TNBC is clinically marked by its high aggressiveness, particularly poor outcomes including a low survival rate, and the lack of specific and effective treatments. Therefore, new potential targets for the treatment of TNBC must be identified. This review summarizes recent evidence supporting novel targets and possible therapeutic regimens in the treatment of TNBC. [ABSTRACT FROM AUTHOR]