RITA selectively inhibits proliferation of BAP1-deficient cutaneous melanoma cells in vitro / 南方医科大学学报

OBJECTIVE@#To screen for small molecular compounds with selective inhibitory activity against cutaneous melanoma cells with BAP1 deletion.@*METHODS@#Cutaneous melanoma cells expressing wild-type BAP1 were selected to construct a BAP1 knockout cell model using CRISPR-Cas9 system, and small molecules with selective inhibitory activity against BAP1 knockout cells were screened from a compound library using MTT assay. Rescue experiment was carried out to determine whether the sensitivity of BAP1 knockout cells to the candidate compounds was directly related to BAP1 deletion. The effects of the candidate compounds on cell cycle and apoptosis were detected with flow cytometry, and the protein expressions in the cells were analyzed with Western blotting.@*RESULTS@#The p53 activator RITA from the compound library was shown to selectively inhibit the viability of BAP1 knockout cells. Overexpression of wild-type BAP1 reversed the sensitivity of BAP1 knockout cells to RITA, while overexpression of the mutant BAP1 (C91S) with inactivated ubiquitinase did not produce any rescue effect. Compared with the control cells expressing wild-type BAP1, BAP1 knockout cells were more sensitive to RITA-induced cell cycle arrest and apoptosis (P < 0.0001) and showed an increased expression of p53 protein, which was further increased by RITA treatment (P < 0.0001).@*CONCLUSION@#Loss of BAP1 results in the sensitivity of cutaneous melanoma cells to p53 activator RITA. In melanoma cells, the activity of ubiquitinase in BAP1 is directly related to their sensitivity to RITA. An increased expression of p53 protein induced by BAP1 knockout is probably a key reason for RITA sensitivity of melanoma cells, suggesting the potential of RITA as a targeted therapeutic agent for cutaneous melanoma carrying BAP1-inactivating mutations.

Gene mutation profiling and clinical significances in patients with renal cell carcinoma

Abstract Objectives The pathological mechanisms of patients with Renal Cell Carcinoma (RCC) remain defined. This study aimed to evaluate relationships between the landscape of gene mutations and their clinical significance in RCC patients. Methods Tissue and peripheral blood samples of 42 patients with RCC were collected and performed for the Next Generation Sequencing (NGS) with Geneseeq PrimeTM 425-gene panel probes. Their landscapes of gene mutation were analyzed. We also carried out an evaluation of Tumor-Node-Metastasis (TNM) staging, RENAL nephelometry score, surgery, and targeted drug treatment of patients. Then we compared the correlations of landscape in gene mutations and the prognosis. Results The most common gene alternations, including BAP1, PBRM1, SETD2, CSF1R, NPM1, EGFR, POLE, RB1, and VHL genes, were identified in tissue and blood samples of 75% of patients. EGFR, POLE, and RB1 gene mutations frequently occurred in relapsed and metastatic patients. BAP1, CCND2, KRAS, PTPN11, ERBB2/3, JAK2, and POLE were presented in the patients with > 9 RENAL nephelometry score. Univariable analysis indicated that SETD2, BAP1, and PBRM1 genes were key factors for Disease-Free Survival (DFS). Multivariable analysis confirmed that mutated SETD1, NPM1, and CSF1R were critical factors for the Progression Free Survival (PFS) of RCC patients with target therapy. Conclusions Wild-type PBRM1 and mutated BAP1 in patients with RCC were strongly associated with the outcomes of the patient. The PFS of the patients with SETD2, NPM1, and CSF1R mutations were significantly shorter than those patients without variants.

Quick bioassay test from tillers for detecting ALS herbicide resistance of weedy rice and barnyardgrass

Resistance to acetolactate synthase (ALS) inhibitors have increased recently in South Brazil where the major weeds of flooded rice (barnyardgrass and weedy rice) have evolved resistance to imazapyr+imazapic. The aim of this research was to evaluate a growth medium for tissue regeneration of tillers in barnyardgrass, as well as an agar-based bioassays test (also from tillers) to detect susceptible and resistant biotypes of weedy rice and barnyardgrass to imazapyr+imazapic in vitro. Greenhouse experiments were conducted to detect ALS-resistant (R) and susceptible (S) weedy rice and barnyardgrass biotypes, and bioassays were carried out to evaluate an adequate growth medium for barnyardgrass tiller regeneration and determine the concentration of herbicide to distinguish R and S plants. The culture medium that provided a suitable barnyardgrass growth was MS 50% with the addition of benzylamino-purine. The tissue regeneration in vitro with the growth medium containing imazapyr+imazapic allowed to discriminate between R and S barnyardgrass and weedy rice plants. The concentration required for satisfactory control of susceptible barnyardgrass and weedy rice explants grown in vitro was 0.9 µM and 1.3 µM of imazapyr+imazapic herbicide, respectively. The bioassay in vitro using tiller regeneration provides an opportunity to predict effectively imazapyr+imazapic resistance in barnyardgrass and weedy rice.

Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

PREDICTION OF OUTCOMES IN ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WITH DECAF SCORE AND BAP 65 SCORE

Background: Prognostic research in exacerbations of chronic obstructive pulmonary disease (COPD) requiring hospitalization has been limited and there appears to be little common ground between predictors of mortality in stable disease and during COPD. Furthermore, none of the prognostic tools developed in stable disease have been tested on hospitalised patients so this study was planned. To test dyspnoea, eosinopenia, consolidation, acidaemia, and at Objectives: rial fibrillation (DECAF) and biological assessment profile (BAP) 65 scores on patients in a tertiary care set up and validate the same. Hospital based prospective observational Methods: study was carried out in 80 patients with COPD who were admitted in Government Hospital for Chest and Communicable Diseases. DECAF and BAP-65 Scores were calculated. Data was analysed using SPSS 22 version software. In our study both DECAF score and BAP-65 score Results: performed equally well for prediction of need for Mechanical Ventilation. The AUC for need for Mechanical Ventilation was 0.75 (95% CI=0.67–0.84) for DECAF score and 0.77 (95% CI=0.67–0.85) for BAP-65 score. The AUC for prediction of mortality for DECAF score was 0.81 (95% confidence interval [CI]=0.71–0.88) and for BAP-65 score was 0.79 (95% CI=0.67–0.89). Conclusions: DECAF and BAP-65 are good and also equal in predicting mortality as well as need for mechanical ventilation.

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Decaf Score in Predicting Prognosis of Acute Exacerbation of Copd in Patient Required Hospital and ICU Admission

@#Introduction: Exacerbation refers to deterioration of patient’s respiratory indications and requires a robust scoring tool for subjects suffering from Chronic Obstructive Pulmonary Disease (COPD) undergoing acute exacerbation. The Dyspnoea, Eosinopenia, Consolidation, Acidaemia, and atrial Fibrillation (DECAF) score can be utilized bedside and predicts in-hospital mortality using indices. The study aimed at assessing the prognostic standards (of duration of ICU stay, hospital stay and mortality) and the sensitivity and specificity of acute exacerbation of COPD patients based on DECAF score. Methods: This prospective study was carried out in a tertiary hospital with 84 patients between October 2016 to September 2018. On admission, DECAF score of all patients with acute exacerbation of COPD was noted and admitted to ICU. The mean duration of stay in ICU and hospital were compared. Various components of APACHE II, BAP 65, CURB 65 were also noted on admission. Results: Mean age of population was 68.29±11.80 with male predominance (68%). The study observed mortality in 6% of patients with mean ICU stay of 3.65±2.21 days and mean hospital stay of 6.45±3.28 days. For a score of 5 and 6 mean DECAF score could not be calculated as the mortality rate was 100%. ROC of DECAF score was 0.81 which was more than APACHE II (0.72) and BAP 65 (0.69) (p-value 0.07 and 0.056 suggested significance). Conclusion: The DECAF Score has been observed to be a stronger predictor for hospital mortality. Higher the DECAF score, higher is the in-hospital death rate. The DECAF score also helps in forecasting the duration of ICU stay and hospital stay.

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

Improvement of germination rate and in vitro multiplication of Lavandula angustifolia

Lavender is well-known for its essential oils, which are in high demand and have a very important economicinterest, particularly for the pharmaceutical and cosmetic industries. This work had been done to study seedgermination and in vitro culture of Lavandula angustifolia. The seeds of L. angustifolia had undergonea vernalization followed by two treatments (physical and chemical), in order to increase the percentage ofgermination. Seeds were introduced into tubes containing the culture medium Murashige et Skoog (MS).Untreated seeds were germinated in the same medium supplemented with gibberellic acid at differentconcentrations. The kinetics, the speed, and the final germination rate were retained in order to evaluate theresponse of seeds. The micropropagation of L. angustifolia was performed on MS medium supplemented withdifferent concentrations of 6-Benzylaminopurine (Treatment I) and 6-Benzylaminopurine in combination withNaphthalene Acetic Acid (Treatment II). Multiplication rate, shoots number, nodes number, leaves number, andstem length were determined. Lavandula angustifolia seeds revealed very low germination percentages for allthe treatments used. However, those treated with sand (physical treatment) showed the highest percentage ofgermination (22%) followed by sulfuric acid treatment with a percentage of 14%. Results showed that the 11.11μM concentration of 6-Benzylaminopurine favored the maximum reactivity of the explants. The combinationbetween 6-Benzylaminopurine and Naphthalene Acetic Acid showed that MS supplemented with 8.88 μM6-Benzylaminopurine and 2.68 μM Naphthalene Acetic Acid was the most effective in the development ofvitroplants.

Benign multicystic peritoneal mesothelioma: literature review and update

Benign multicystic peritoneal mesothelioma (BMPM) is a rare peritoneal tumor diagnosed predominantly in pre-menopausal women. Associated risk factors include endometriosis and pelvic inflammatory disease in women, and prior abdominal surgery in both genders. To date, the pathogenesis of this disease remains controversial with possible etiologies, including a neoplastic versus a reactive process. Given the risk factors, some authors believe that this disease is secondary to a reactive process. However, because some studies describe cases where there is no prior surgical history or inflammatory milieu present, and because of this entity's predilection for recurrence, some authors believe the origin to be neoplastic. Some genetic and familial associations have also been reported. Malignant transformation is extremely rare, with only two cases reported in the literature, despite the recurrence potential. Like the etiology, the name of this entity is also controversial. Some authors prefer the term "peritoneal inclusion cyst (PCM)" instead of "benign cystic mesothelioma" and argue that the term mesothelioma should only be used when there is evidence of atypia. Most cases of BMPM are discovered incidentally. Others reflect sequela of tumor mass effect. It appears intra-operatively as large, multi-focal, cystic lesions in the peritoneal and pelvic cavity. Diagnosis is achieved through surgical sampling with histopathological examination. Immunobiologically, BMPM exhibits multiple small cystic spaces with flattened lining containing calretinin positive cells without atypical features, mitotic figures, or tissue invasion. Treatment includes cytoreductive surgery. Here we present a case of BMPM in a 60-year-old male - a rare disease in an uncommon patient population.

Effect of Rhustox on Micropropagation of Scoparia dulcis L. through Leaf Explants Culture

Aim: To investigate the effect of Rhus toxicodendron (30CH) along with different compositions of phytohormones (Auxin and Cytokinin) on the basis of growth and multiplication of explants under optimum temperature under in-vitro conditions. Study Design: To establish and design the standard protocol for the in-vitro propagation through leaf explant of Scoparia dulcis under stress of phytohormones and homeopathic medicine Rhus toxicodendron (30CH). Place and Duration of Study: The plant materials were procured from the Herbal Botanical Garden Patna Science College, Department of Botany, Patna University, Patna, Bihar. The experimental part was carried out in Plant Tissue Culture Laboratory, between December 2017 to August 2018 in Department of Botany P.U. Patna. Methodlogy: The sterilized leaf explants were inoculated into MS media fortified with different phytohormones (Auxin and Cytokinin) and Rhus tox(30CH) under aseptic environmental conditions for the growth and development of callus, embryoids etc. Result: The explants in MS medium supplemented with auxins phytohormones and Rhus tox(30CH) exhibited that IAA (0.10 to 2.0 mg/l) and BAP (0.10 to 2.5 mg/l) induces green and compact calli. Whereas at 0.30mg/l of IAA and 0.50 mg/l BAP induced brown friable calli. 2,4-D (1.5 mg/l) and Kinetin (1.5-6.5mg/l) concentrations induced brown and friable calli. Rhus tox(30CH) (100 µl/100 ml) enhances proliferation with 2,4-D and Kinetin (1.5/1.5 mg/l.). Conclusion: After 42 days of culture initiation and establishment the callus was 520.0±1.12 mg in the mixture of 2,4-D and Kinetin (1.5 mg/l) in Rhus tox free medium. Whereas weight of callus were found to be 1092±0.74 mg after 42 days in the same medium of 2, 4-D and Kinetin (1.5/5.5 mg/l) supplemented with Rhus tox (100 µl/100 ml). Hence, the investigation proponded that the Rhus tox (CH30) has increased the rate of callus development and plantlet regeneration.

Some Chemical Carcinogens for Leukaemia Induction and Their Animal Models

Animal models have been providing invaluable contributions to the better understanding of mechanisms of cancer (including leukaemias) development and effectiveness of most of the treatments. Chemical carcinogens are generally used to study the biology of cancers including leukaemias in many animal models, including rats and mice. The studies in most cases are aimed at the development and evaluation of cancer treatments and preventions. Some of the most common chemical carcinogens used in animal models for leukaemias include N-ethyl-N-nitrosourea (ENU), N-methyl-N-nitrosourea (MNU), dimethyl benz(a)anthracene (DMBA) and benzo(a)pyrene (BaP). This review provides highlights on different animal models of leukaemia induced by the chemical carcinogens mentioned earlier, at the same time discussing the contributions of these models to the leukaemia diagnosis in laboratory animal models for subsequent development of treatment.

Expressions of BAP1 and TET2 proteins in bone marrow of patients with chronic myelomonocytic leukemia and their significances / 白血病·淋巴瘤

Objective To investigate the expressions of BAP1 and TET2 proteins in bone marrow of patients with chronic myelomonocytic leukemia (CMML) and their relationship with the prognosis of CMML. Methods The bone marrow paraffin specimens of 41 cases from 41 adult CMML patients diagnosed by Shanghai Sino-US Joint Leukemia Coordination Group from September 2003 to May 2007 were collected. The immunohistochemistry was used to detect the expressions of BAP1 and TET2 proteins in 41 CMML patients. The expressions of TET2 and BAP1 proteins were also detected by the same method in 40 adult patients with acute myelomonocytic leukemia (AMML) and 20 patients with iron deficiency anemia (IDA) diagnosed at the same time as the comparison. The clinical data of 41 CMML patients were analyzed by using retrospective cohort study. The count data were compared by using chi-square test. The correlation between expressions of BAP1 and TET2 proteins was analyzed by using Pearson correlation analysis. Kaplan-Meier method was used to calculate the survival time, and Log-rank test was used for single factor analysis. Results In 41 CMML patients, the positive expression rate of BAP1 was 31.7％ (13/41), including 28.6％ (8/28) in CMML-1 patients and 38.5％ (5/13) in CMML-2 patients; the positive expression rate of TET2 was 41.5％ (17/41), including 39.3％ (11/28) in CMML-1 patients and 46.2％ (6/13) in CMML-2 patients. In 40 AMML patients, the positive expression rate of BAP1 was 32.5％ (13/40), and the positive expression rate of TET2 was 35.0％ (14/40). In 20 IDA patients, the positive expression rate of BAP1 was 5.0％ (1/20), and TET2 had no positive expression. There was no significant difference in the expressions of BAP1 and TET2 proteins between CMML-1 and CMML-2 patients (χ 2 = 0.40, P = 0.53; χ 2 = 0.17, P = 0.68). There was no significant difference in the expressions of BAP1 and TET2 proteins between CMML and AMML patients (χ 2 = 0.01, P = 0.94; χ 2 = 0.36, P = 0.64). There were significant differences in the positive expression rate of BAP1 and TET2 proteins between hematological neoplastic disease (CMML+AMML) and hematological non-neoplastic disease (IDA) (χ 2 = 6.01, P < 0.05; χ 2 = 11.04, P < 0.01). Pearson correlation analysis showed that there was no correlation between expressions of BAP1 and TET2 proteins (r = 0.35, P = 0.27). Univariate analysis showed that anemia (Hb < 60 g/L), mature monocyte count ≥ 2.0×109/L, neutrophil count (1.5×109/L), abnormal karyotype were associated with poor prognosis for CMML. Protein expressions of BAP1 and TET2 were not related with the prognosis of CMML (χ 2 = 0.28, P = 0.600; χ 2 = 0.53, P = 0.460). Conclusion Both BAP1 and TET2 proteins have high positive expression rates in CMML patients, but the expressions of them are not related to the prognosis.

A Review on In vitro Regeneration of Ginger: Tips and Highlights

Ginger (Zingiber officinale) is one of the oriental spices, widely used worldwide for multiple purposes. It is applied as an important ingredient in Ayurvedic preparations from time immemorial. Tissue culture is a practice that is utilized to propagate plants from cells or tissue under sterile conditions. This study is directed to create a review of the successful and reproducible convention for in vitro recovery of ginger with emphasis on effective initial culture establishment. Furthermore, it has dealt with the appropriate explant size and effectiveness of media quality on micropropagation of ginger. The current study recommends that the medium containing Benzyl Amino Purine (BAP) can be used for inducing shoot development of ginger. Among the diverse explants, shoot tips give the quickest response for starting development and the highest number of multiple shoots are produced. As well, it is demonstrated that a survival rate and proper shoot/root expansion can be obtained through the tissue culture methods. Emphasizing the tips and recommendations, this study would be a route-map towards time and cost saving for producing a better quality of ginger.

Health Risk Impacts of Exposure to Airborne Metals and Benzo(a)Pyrene during Episodes of High PM10 Concentrations in Poland / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To check whether health risk impacts of exposure to airborne metals and Benzo(a) Pyrene during episodes of high PM10 concentrations lead to an increased number of lung cancer cases in Poland.</p><p><b>METHODS</b>In this work, we gathered data from 2002 to 2014 concerning the ambient concentrations of PM10 and PM10-bound carcinogenic Benzo(a)pyrene [B(a)P] and As, Cd, Pb, and Ni. With the use of the criterion of the exceedance in the daily PM10 mass concentration on at least 50% of all the analyzed stations, the PM10 maxima's were selected. Lung cancer occurrences in periods with and without the episodes were further compared.</p><p><b>RESULTS</b>During a 12-year period, 348 large-scale smog episodes occurred in Poland. A total of 307 of these episodes occurred in the winter season, which is characterized by increased emissions from residential heating. The occurrence of episodes significantly (P < 0.05) increased the concentrations of PM10-bound carcinogenic As, Cd, Pb, Ni, and B(a)P. During these events, a significant increase in the overall health risk from those PM10-related compounds was also observed. The highest probability of lung cancer occurrences was found in cities, and the smallest probability was found in the remaining areas outside the cities and agglomerations.</p><p><b>CONCLUSION</b>The link between PM pollution and cancer risk in Poland is a serious public health threat that needs further investigation.</p>

Loss of Nuclear BAP1 Expression Is Associated with High WHO/ISUP Grade in Clear Cell Renal Cell Carcinoma

BACKGROUND: BRCA1-associated protein 1 (BAP1) mutations are frequently reported in clear cell renal cell carcinoma (ccRCC); however, very few studies have evaluated the role of these mutations in other renal cell carcinoma (RCC) subtypes. Therefore, we analyzed BAP1 protein expression using immunohistochemistry in several RCC subtypes and assessed its relationship with clinicopathological characteristics of patients. METHODS: BAP1 expression was immunohistochemically evaluated in tissue microarray blocks constructed from 371 samples of RCC collected from two medical institutions. BAP1 expression was evaluated based on the extent of nuclear staining in tumor cells, and no expression or expression in < 10% of tumor cells was defined as negative. RESULTS: Loss of BAP1 expression was observed in ccRCC (56/300, 18.7%), chromophobe RCC (6/26, 23.1%), and clear cell papillary RCC (1/4, 25%), while we failed to detect BAP1 expression loss in papillary RCC, acquired cystic disease-associated RCC, or collecting duct carcinoma. In ccRCC, loss of BAP1 expression was significantly associated with high World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grade (p = .002); however, no significant correlation was observed between loss of BAP1 expression and survival in ccRCC. Loss of BAP1 expression showed no association with prognostic factors in chromophobe RCC. CONCLUSIONS: Loss of BAP1 nuclear expression was observed in both ccRCC and chromophobe RCC. In addition, BAP1 expression loss was associated with poor prognostic factors such as high WHO/ISUP grade in ccRCC.

Prognoses and Clinical Outcomes of Primary and Recurrent Uveal Melanoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Uveal melanoma has a very poor prognosis despite successful local primary tumor treatment. In this study, we investigated prognostic factors that more accurately reflected the likelihood of recurrence and survival and delineated a prognostic model that could effectively identify different risk groups based on initial clinical parameters. MATERIALS AND METHODS: Prognostic factors associated with distant recurrence, recurrence-free survival (RFS), progression-free survival, and overall survival from distant recurrence to death (OS2) were analyzed in 226 patients with stage I-III uveal melanoma who underwent primary local therapy. RESULTS: Forty-nine patients (21.7%) had distant recurrences, which occurred most frequently in the liver (87.7%). In a multivariate analysis, local radiotherapy improved RFS among patients with multiple recurrence risk factors relative to excision (not reached vs. 19.0 months, p=0.004). Patients with BRCA1-associated protein-1 (BAP1)–negative primary tumors showed a longer RFS duration after primary treatments, while those with BAP1-negative metastatic tissues had a shorter OS2 compared to those with BAP1-positive tumors, both not statistically insignificance (RFS: not reached vs. 82.0 months, p=0.258; OS2: 15.7 vs. 24.4 months, p=0.216). Male sex (hazard ratio [HR], 3.79; p=0.012), a short RFS (HR, 4.89; p=0.014), and a largest metastatic tumor linear diameter ≥ 45 mm (HR, 5.48; p=0.017) were found to correlate with worse post-recurrence survival. CONCLUSION: Risk factors could be used to classify uveal melanoma cases and subsequently direct individual treatment strategies. Furthermore, metastasectomy appears to contribute to improved survival outcomes.

Ras oncogene and Hypoxia-inducible factor-1 alpha (hif-1α) expression in the Amazon fish Colossoma macropomum (Cuvier, 1818) exposed to benzo[a]pyrene

Abstract Benzo[a]pyrene (B[a]P) is a petroleum derivative capable of inducing cancer in human and animals. In this work, under laboratory conditions, we analyzed the responses of Colossoma macropomum to B[a]P acute exposure through intraperitoneal injection of four different B[a]P concentrations (4, 8, 16 and 32 μmol/kg) or corn oil (control group). We analyzed expression of the ras oncogene and the Hypoxia-inducible factor-1 alpha (hif-1α) gene using quantitative real-time PCR. Additionally, liver histopathological changes and genotoxic effects were evaluated through the comet assay. Ras oncogene was overexpressed in fish exposed to 4, 8 of 16 μmol/kg B[a]P, showing 4.96, 7.10 and 6.78-fold increases, respectively. Overexpression also occurred in hif-1α in fish injected with 4 and 8 μmol/kg B[a]P, showing 8.82 and 4.64-fold increases, respectively. Histopathological damage in fish liver was classified as irreparable in fish exposed to 8, 16 and 32 μmol/kg μM B[a]P. The genotoxic damage increased in fish injected with 8 and 16 μmol/kg in comparison with the control group. Acute exposure of B[a]P was capable to interrupt the expression of ras oncogene and hif-1α, and increase DNA breaks due to tissue damage.

A prospective validation of NEWS, CREWS and BAP-65 among patients with AECOPD / 中华护理杂志

Objective To compare the efficiency of National Early Warning Score (NEWS),Chronic Respiratory Early Warning Score(CREWS) and BAP-65(elevated Blood urea nitrogen,Altered mental status,Pulse＞109bpm,age＞65 years)among patients with AECOPD (acute exacerbations of chronic obstructive pulmonary disease).Methods Totally 181 patients with AECOPD were investigated by these three scales,and the efficiency of NEWS,CREWS and BAP-65 was compared.Results The scores of NEWS,CREWS and BAP-65 in the death group were higher than those in the survival group and the general ward group(P＜0.01).Regarding the predicted results of hospital death,the area under the ROC curve of NEWS,CREWS and BAP-65 was 0.878,0.836 and 0.774,respectively,and the differences were not statistically significant(P＞0.05);for predicted results of ICU admission,the area under the ROC curve of NEWS,CREWS and BAP-65 was 0.826,0.813 and 0.716,respectively,and the differences were not statistically significant (P＞0.05).Conclusion NEWS,CREWS and BAP-65 have satisfied predictive efficiency for prognosis,and NEWS and CREWS are much easier and faster to use.