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1.
Open Med (Wars) ; 18(1): 20230690, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37786776

RESUMO

Acquired resistance to chemotherapeutic drugs in gallbladder cancer (GBC) results in therapy failure. This study is aimed to establish oxaliplatin (OXA)-resistant GBC cell lines and uncover their gene expression profiles. First, two OXA-resistant GBC cell lines (GBC-SD/OXA and SGC996/OXA) were established by gradually increasing the drug concentration, and the resistance index was 4-5. The two resistant cell lines showed slower proliferation and higher stemness, colony formation, and migration abilities. Epithelial mesenchymal transformation and increased levels of P-glycoprotein were also detected. Next RNA-sequence analysis identified 4,675 dysregulated genes (DGs) in resistant cells, and most of the 12 randomly selected DGs were verified to be consistent with the sequence results. Kyoto Encyclopedia of Genes and Genomes analysis indicated that several DGs were involved in resistance- and phenotype-related pathways, of which the activations of PD-L1 and ERK1/2 were both verified in resistant cell lines. In conclusion, this study is the first to report the gene expression profile of OXA-resistant GBC cells and provides a useful database for target development.

2.
Cancer Lett ; 544: 215812, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35780928

RESUMO

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.


Assuntos
Linfoma de Burkitt , Linfoma de Burkitt/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Criança , Histonas/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação
3.
BMC Cancer ; 22(1): 833, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35907820

RESUMO

BACKGROUND: The amino acid transporter SLC6A14, which transports 18 of the 20 proteinogenic amino acids, is too low to be detected in healthy normal tissues but is significantly increased in some solid cancers. However, little is known about the roles of SLC6A14 in colorectal cancer (CRC). METHODS: The mRNA and protein levels of SLC6A14 were detected using TCGA database, real-time polymerase chain reaction, western blot, and tissue microarrays, respectively. Amino acids concentration was determined by LC-MS/MS. Cell proliferation and apoptosis were determined using MTT assay and flow cytometry. Transwell invasion assay and wound healing assay were employed to analyze cell migration and invasion. The protein levels of Akt-mTOR signaling pathway and MMPs proteins were detected by western blot. RESULTS: Both of the mRNA and protein levels of SLC6A14 were upregulated in CRC tissues, and the protein levels of SLC6A14 were closely related to the tumor cells differentiation: the higher the expression of SLC6A14 was, the poorer the differentiation of the tumor cells was. Further knockdown SLC6A14 with siRNA or treatment with α-MT in CRC cell lines reduced cell proliferation and migration in vitro and inhibited xenograft tumor growth in vivo. Mechanistically, SLC6A14 was demonstrated to regulate the expression and phosphorylation of Akt-mTOR, which mediates the promoting tumor growth function of SLC6A14. Blockade of SLC6A14 with α-MT inhibited the activation of mTOR signaling. CONCLUSION: SLC6A14 was upregulated in CRC and could promote tumor progression by activating the Akt-mTOR signaling pathway, which may serve as an effective molecular target for the treatment of CRC.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas c-akt , Sistemas de Transporte de Aminoácidos , Aminoácidos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Cromatografia Líquida , Neoplasias Colorretais/patologia , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro , Serina-Treonina Quinases TOR/metabolismo , Espectrometria de Massas em Tandem
4.
Pathol Res Pract ; 232: 153841, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35303522

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: OTX1 is an independent prognostic factor of ESCC and contributes to tumorigenesis both in vivo and in vitro.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Idoso , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição Otx/genética , Fatores de Transcrição Otx/metabolismo , Prognóstico
5.
Front Oncol ; 11: 771528, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790580

RESUMO

Emerging evidence suggests that hypermethylation of HOXD10 plays an important role in human cancers. However, the biological and clinical impacts of HOXD10 overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of HOXD10 in paired cancer and normal tissues (n = 42) by using pyrosequencing, followed by validation of the methylation status of HOXD10 from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of HOXD10 was characterized in cell lines. We further evaluated the effects of HOXD10 and its targets on chemoresistance in our established resistant cell lines and clinical cohort (n = 66). HOXD10 was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, HOXD10 acts as a tumor suppressor gene, in which HOXD10-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the HOXD10 promoter, and demethylation by 5-Aza-2'-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce HOXD10 expression. HOXD10 regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of HOXD10 in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that HOXD10 is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of HOXD10 activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).

6.
Pathol Res Pract ; 227: 153642, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34649054

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/enzimologia , Neoplasias Renais/enzimologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Carga Tumoral , Regulação para Cima
7.
Cell Death Discov ; 7(1): 234, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34489426

RESUMO

TRIM22 is involved in tumorigenesis and development, but its mechanism is not clear. In this study, we investigated the expression and biological role of TRIM22 in gastric cancer. We found that TRIM22 mRNA and protein expression was abnormally low in gastric cancer tissues and cells and correlated with tumor size and depth of invasion. Overexpression of TRIM22 significantly inhibited the proliferation, colony formation, and migration of gastric cancer cells and downregulated the expression of HSPA6. However, the HSPA6-siRNA complementation test showed that TRIM22 did not regulate cell proliferation through HSPA6. Furthermore, overexpression of TRIM22 downregulated the phosphorylation of Smad2 and Smad3. In addition, TRIM22 directly binds to Smad2, and overexpression of Smad2 can reverse the inhibition of cell proliferation and migration induced by TRIM22. In vivo, overexpression of TRIM22 significantly inhibited the growth of subcutaneous xenografts in nude mice. Our study indicates that TRIM22 has an important role in the development of gastric cancer and may inhibit the proliferation of gastric cancer cells through Smad2.

8.
Pathol Res Pract ; 226: 153603, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34500374

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: TOPK may be a novel predictor for the therapeutic response to NACT and prognosis for patients with TNBC.


Assuntos
Biomarcadores Tumorais/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico
9.
Mol Ther Nucleic Acids ; 26: 280-294, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34513310

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal cancers and is projected to be the second leading cause of cancer deaths in the United States by 2030. The lack of effective treatment and increased incidence in PDAC encourage a deeper knowledge of PDAC progression. By analyzing a long noncoding RNA (lncRNA) dataset, we found that increased LINC00941 expression led to poor outcomes in PDAC patients. Furthermore, in vitro and in vivo experiments revealed that LINC00941 promoted PDAC cancer cell growth by enhancing aerobic glycolysis. Mechanistically, LINC00941 was found to interact with mammalian STE20-like protein kinase 1 (MST1), which facilitated the protein phosphatase 2A (PP2A)-mediated dephosphorylation of MST1, resulting in Hippo pathway activation and consequently, enhanced glycolysis in PDAC. These results suggest that LINC00941 plays a key role in regulating PDAC tumorigenesis, potentially highlighting novel avenues for PDAC therapy.

10.
Front Oncol ; 11: 638154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34221962

RESUMO

BACKGROUND: Anaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear. METHODS: Thirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis. RESULTS: Patients with A-DLBCL presented higher expression of PD-L1 (40% vs 10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3% vs 4.0%, P=0.001). The numbers of PD-1+ TILs (tumor infiltrating lymphocytes) and CD8+T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3+ Th2 cells, FOXP3+ Tregs and CD33+ myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1+ TILs was lower and the number of CD33+ MDSCs was higher in patients with mutated TP53 compared to those with wild-type TP53. The number of FOXP3+ Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8+ T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1+, mPD-L1+(PD-L1+ nonmalignant stromal cells) or mPD-L1+ status had a significantly poorer overall survival (OS) than those with PD-L1- status. An increase in the number of CD3+ T cells, FOXP3+ Treg cells and T-bet+ Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL. CONCLUSION: Our study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.

11.
Onco Targets Ther ; 14: 1605-1611, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688207

RESUMO

PURPOSE: Colorectal cancer (CRC) is one of the most common types of malignancies, and radiochemotherapy (RCT) followed by surgery is the recommended approach for CRC treatment. However, some cases do not respond to first-line conventional chemotherapy or even progress further after treatment. Moreover, there is a risk of severe side effects, such as radiodermatitis. Therefore, identifying predictors for RCT sensitivity is an essential step toward predicting and eventually overcoming resistance. MATERIALS AND METHODS: We used integrative bioinformatics analysis and experimental validation to show that regenerating family member 4 (REG4) may be a potential biomarker for RCT sensitivity in CRC. RESULTS: REG4, whose expression is upregulated in some CRC tissues and downregulated in RCT-sensitive CRC cells, was identified as a potential genetic marker for RCT sensitivity in CRC. Immunohistochemistry-based tissue microarray of human CRC was used to experimentally validate REG4 data obtained from the bioinformatics analysis. CONCLUSION: Collectively, these results indicate that REG4 may be a potential biomarker for RCT sensitivity in CRC.

12.
Front Oncol ; 11: 622648, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33747936

RESUMO

Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79-382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.

13.
Pathol Res Pract ; 219: 153374, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33621918

RESUMO

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.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Neoplasias da Mama/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Esofágicas/genética , Humanos
14.
Asian J Surg ; 44(1): 164-168, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32513636

RESUMO

BACKGROUND: A few factors influence the feasibility of transrectal natural orifice specimen extraction (NOSE) surgery for colorectal cancers. However, little is known about the underlying factors of NOSE surgery. METHODS: Consecutive patients with rectal and sigmoid colon cancers treated laparoscopically between January 2014 and April 2017 were enrolled in this study. The transrectal NOSE performed laparoscopically was the first choice of all patients. When NOSE failed, the specimen was removed through a midline abdominal wall incision. Univariate and multivariate logistic regression analyses were performed to identify challenging factors influencing the intraoperative specimen extraction. RESULTS: Overall, 412 consecutive patients were included. NOSE performed laparoscopically was successful in 278 patients (75.5%) and unsuccessful in 90 patients (24.5%). The multivariate analyses indicated that body mass index (BMI; odds ratio [OR] = 3.510, 95% confidence interval [CI]: 1.333-9.243, p = 0.011), mesenteric thickness (OR = 1.069, 95% CI: 1.032-1.107, p < 0.001), maximum tumor diameter (OR = 2.827, 95% CI: 1.094-7.302, p = 0.032), and tumor T stage (OR = 2.831, 95% CI: 1.258-6.369, p = 0.012) were the factors influencing the feasibility of NOSE surgery. CONCLUSION: A successful transrectal NOSE surgery was associated with a lower BMI, thinner mesentery, lesser tumor diameter, and earlier tumor T stage.


Assuntos
Endoscopia Gastrointestinal/métodos , Laparoscopia/métodos , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Neoplasias do Colo Sigmoide/patologia , Neoplasias do Colo Sigmoide/cirurgia , Manejo de Espécimes/métodos , Adulto , Índice de Massa Corporal , Estudos de Viabilidade , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos
15.
Pathol Res Pract ; 217: 153291, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33249399

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Fígado/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Biomarcadores/análise , Contagem de Linfócito CD4 , Feminino , Humanos , Imuno-Histoquímica , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Proteínas com Domínio T/análise , Células Th1/imunologia , Células Th1/metabolismo , Fatores de Tempo , Resultado do Tratamento
16.
Mod Pathol ; 34(5): 922-933, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32973328

RESUMO

We report 17 cases of sinusoidal large B-cell lymphoma (SLBCL). Clinical, morphologic, immunophenotypic, and molecular features were detected and analyzed. All cases showed an obvious sinusoidal growth pattern, usually associated with residual atrophic lymphoid tissue. All tumors contained large pleomorphic lymphoid cells and one or more prominent nucleoli, with abundant amphophilic cytoplasms; 15/17 cases showed anaplastic morphologic features. The patient age ranged from 43 to 80 years (median 57 years), and 7 males and 10 females were included. Eleven of 15 (73.3%) patients had Ann Arbor stage III or IV disease, and 10/15 (66.6%) patients had an International Prognostic Index (IPI) score ≥3. Immunophenotypically, 16/17 (94.1%) cases displayed a nongerminal center B-cell (non-GCB) immunophenotype. Furthermore, 16/17 (94.1%) cases were positive for CD30, and p53 was expressed in 10/16 (62.5%) cases. In total, 12/14 (85.7%) cases expressed BCL2 and MYC simultaneously (double expression), and 11/14 (78.6%) cases showed PD-L1 positivity (6/11 had a PD-L1 tumor proportion score ≥50%). Cytogenetically, concurrent MYC and BCL2 and/or BCL6 abnormalities (break-apart or extra copy) were detected in 10/15 cases, and 7/13 (53.8%) cases harbored a PD-L1/L2 amplification. TP53 mutation was found in 7/13 (53.8%) cases by Sanger sequencing. Whole-exome and large-panel sequencing results revealed high mutation frequencies of TP53 (4/7), MYD88 (3/7), KMT2D (3/7), CREBBP (3/7), and PIM1 (3/7). Among the 13 patients with SLBCL treated with aggressive chemotherapy regimens, the median overall survival (OS) was 18 months, and the 2-year OS rate was 34.6%. The OS of patients with SLBCL was markedly worse than that of 35 control group patients with common diffuse large B-cell lymphoma (DLBCL) without sinusoidal features (P < 0.001). SLBCL may represent a specific type of DLBCL that has characteristic pathologic features. The cancer is aggressive in most clinical cases, and outcomes are poor. SLBCL and anaplastic DLBCL (A-DLBCL) have many overlapping clinicopathological and molecular features.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Linfoma de Células B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Humanos , Imunofenotipagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Taxa de Sobrevida , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
17.
J Gastrointest Oncol ; 11(2): 260-268, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32399267

RESUMO

BACKGROUND: Laparoscopic anterior resection with natural orifice specimen extraction (NOSE) avoids extra abdominal extraction incision during colorectal surgery. Some surgeons realized the benefits of NOSE on clinical efficacy. We compared the clinical efficacy of laparoscopic NOSE, laparoscopic non-NOSE and open surgery (OS) for short-term recovery and quality of life (QoL). METHODS: A single randomized controlled trial of NOSE for middle and upper rectal cancer between April 2014 and February 2018. Preoperative and postoperative clinical variables were analyzed and compared between the groups. Preoperative and 6 months postoperative QoL was assessed with the SF-36 QoL questionnaire. RESULTS: A total of 378 patients were enrolled, 334 patients randomly divided into NOSE group (n=104), non-NOSE group (n=119), OS group (n=111). The NOSE group was superior to the other two groups on the QoL after surgery. The NOSE group had the lowest postoperative VAS score between three groups. The postoperative time for bowel function recovery and the length of hospital stay was statistically significantly different among the three groups, with the NOSE group having the shortest time. The incidence of postoperative complications was lower in the NOSE group (12/104, 11.5%) than in the non-NOSE group (20/119, 16.8%), the difference was statistically significant. The Kaplan-Meier (K-M) survival curve showed no statistically significant difference in the disease-free survival (DFS) rate between the three groups. CONCLUSIONS: Comparing NOSE to non-NOSE and OS, the NOSE had significantly better functional recovery and better QoL. The NOSE group had a significant lower surgical complication rate than the non-NOSE group.

18.
J Surg Res ; 254: 16-22, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32402832

RESUMO

BACKGROUND: In the present paper, we introduce our experience with the novel method during laparoscopic anterior resection of upper rectal or sigmoid colon cancer by transrectal natural orifice specimen extraction (NOSE). METHODS: A prospective randomized controlled trial was performed from June 2016 to May 2019. Patients with upper rectal or sigmoid colon cancer were randomized in a 1:1 ratio to the NOSE group and the non-NOSE group. Preoperative and postoperative clinical variables were analyzed and compared between groups. Postoperative pain was analyzed utilizing a visual analog scale. Postoperative overall survival was analyzed using a Kaplan-Meier curve. RESULTS: A total of 276 patients were enrolled, of whom 254 were randomly divided into the NOSE group (n = 122) and the conventional laparoscopic group (n = 119). NOSE failed in 22 cases, which were converted to transabdominal specimen extraction. Intention-to-treat analysis was performed, and these 22 cases were included in the NOSE group. The incidence of postoperative complications was significantly lower in the NOSE group (11/122, 9%) than in the non-NOSE group (25/119, 21%). The NOSE group had a longer operation time, less blood loss, and a lower postoperative visual analog scale score than the non-NOSE group. The time for intestinal function recovery (ventilation) and the length of hospital stay were significantly longer in the non-NOSE group. The Kaplan-Meier survival curve showed no statistically significant difference in the disease-free survival rate between the NOSE group and the non-NOSE group. CONCLUSIONS: The novel NOSE method is safe and feasible to use in patients having colorectal cancer. Compared with traditional laparoscopic surgery, the postoperative complication rates of NOSE surgery were lower with an improved short-term clinical recovery.


Assuntos
Cirurgia Endoscópica por Orifício Natural/efeitos adversos , Cirurgia Endoscópica por Orifício Natural/métodos , Neoplasias Retais/cirurgia , Neoplasias do Colo Sigmoide/cirurgia , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Humanos , Laparoscopia/métodos , Tempo de Internação , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Resultado do Tratamento
19.
Diagn Pathol ; 15(1): 28, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209138

RESUMO

BACKGROUND: To investigate the expression and function of RSK4, MMP-9 and CD44 in primary clear cell renal cell carcinoma (primary ccRCC) and metastatic clear cell renal cell carcinoma (metastatic ccRCC), as well as the correlation with clinicopathological features of patients. METHOD: The expression levels of RSK4, CD44 and MMP-9 in 52 primary ccRCC samples and 48 metastatic ccRCC samples were detected by immunohistochemistry, and the relationship between RSK4, CD44 and MMP-9 expression and clinicopathological features as well as prognosis of metastatic ccRCC patients was statistically analysed. Ectopic RSK4 expression in ccRCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability. RESULTS: The positive rates of RSK4, MMP-9 and CD44 expression in metastatic ccRCC tissues were 75, 68.75 and 91.7%, respectively, while the rates in primary ccRCC tissues were 44.2, 34.6 and 69.2%, respectively. Thus, the positive rates in metastatic ccRCC were higher than those in primary ccRCC (PRSK4 = 0. 002; PMMP-9 = 0. 002; PCD44 = 0. 001). However, the expression of RSK4, CD44 and MMP-9 was unrelated to age, gender, or metastatic sites (P > 0.05) but was related to WHO/ISUP nucleolar grade (PRSK4 = 0.019; PCD44 = 0.026; PMMP-9 = 0.049). In metastatic ccRCC, expression among the three proteins showed a positive correlation (P = 0.008). Moreover, expression between RSK4 and CD44 (P = 0.019) and MMP-9 and CD44 (P = 0.05) also showed positive correlations, whereas RSK4 and MMP-9 showed no significant correlation (P = 1.00). Molecular studies showed that overexpression of RSK4 could enhance the invasive and migratory abilities of ccRCC cell lines through the regulation of CD44 and MMP-9 expression and vice versa. CONCLUSIONS: The overexpression of RSK4, MMP-9 and CD44 is associated with the invasion and metastasis of ccRCC, indicating that they could be potential prognostic factors and serve as new potential therapeutic targets for ccRCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Renais/patologia , Receptores de Hialuronatos/biossíntese , Neoplasias Renais/patologia , Metaloproteinase 9 da Matriz/biossíntese , Proteínas Quinases S6 Ribossômicas 90-kDa/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Adulto Jovem
20.
Pathol Res Pract ; 216(4): 152874, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32088086

RESUMO

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.


Assuntos
Neoplasias de Mama Triplo Negativas/fisiopatologia , Feminino , Humanos
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