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Biomarkers in the diagnosis and treatment of malignant pleural disease: an integrative review
Fiamma Buttitta1,2,3, Alessia Di Lorito2,3, Emanuela D'Angelo1,2
1Department of Medical and Oral Sciences and Biotechnologies, 2Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, Chieti, Italy; 3Department of Pathology, SS Annunziata Clinical Hospital, Chieti, Italy
Contributions: (I) Conception and design: F Buttitta; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV)Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Fiamma Buttitta, MD, PhD. Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST), University of Chieti-Pescara, via L. Polacchi, 13, 66100, Chieti, Italy; Department of Medical and Oral Sciences and Biotechnologies, University of Chieti-Pescara, Chieti, Italy. Email: fbuttitta@unich.it.
Abstract: Pleural mesothelioma (PM) is deemed an uncommon tumor, resistant to chemotherapy with little chance of radical surgery and low survival rates. This review summarizes the latest advances in biomarker selection for diagnosis and drug treatment, based on search in Medline database carried out in the period between 1992 and 2020. The main prognostic and predictive biomarker is the histological subtype. The epithelioid neoplastic form is less aggressive than the sarcomatoid subtype and has a high sensitivity to chemotherapy, resulting in longer survival than sarcomatoid or biphasic subtypes of PM. Several biomarkers have been identified for the diagnosis of mesothelioma, but no mesothelial marker has a sensitivity of 100%. Therefore, panels of different biomarkers are needed, with positive and negative predictive value. New biomarkers emerging from the literature may be useful in differentiating reactive pleural processes from malignant ones and PMs from other neoplastic forms. In particular, the role of loss of expression of BAP1, MTAP and CDKN2A must be highlighted. The presence of frequent inactivating homozygous mutations of the BAP1 locus and the CDKN2A gene has been demonstrated by parallel massive sequencing in approximately 60% and 62% of cases respectively If simultaneous loss of BAP1 expression and homozygous deletion of CDKN2A or loss of expression of BAP1 and MTAP are present, sensitivity is much higher (92–100%). The new perspectives on therapy derive from studies conducted on BAP1 and other homologous recombination genes and from trials conducted on patients treated with immunotherapy. The inactivation of BAP1 could be used therapeutically, similarly to what has been shown in clinical studies conducted on patients with ovarian and prostate cancer with mutations in the DNA repair genes. In ongoing clinical trials, the recruitment of MPM patients will allow to assess the relationship between BAP1 genotype status and response to PARP inhibitors such as olaparib and niraparib. In addition, mesothelial cancer cells can express PDL1 especially in the epithelioid form and this expression is associated with a worse prognosis. PDL1 has also been evaluated in other tumor forms as an indicator of immunotherapy efficacy and seems to allow the best selection of patients affected by mesothelioma.
Keywords: Mesothelioma; BAP1; CDKN2; MTAP; PDL1
Received: 01 July 2020; Accepted: 20 August 2020; Published: 25 December 2020.
Mesothelioma is an aggressive tumor arising from the mesothelial surface. Mesothelioma occurs in the pleural cavity (PM) and peritoneum in approximately 90% and 10% of cases, respectively. Primary paratesticular and pericardial mesothelioma are very rare (1-3). It is considered a relatively rare neoplasia, accounting of 0.2% of all tumors, with an incidence of 3.4/100,000 patients. Occupational exposure to asbestos is considered the main risk factor in adult patients, since more than 90% of the cases have a history of asbestos exposure. In the last 10 years, the incidence of PM has increased slightly, mainly due to the 30–50 years delay between exposure to asbestos and development of malignant cell growth. Asbestos fibers, alone or with other risk factors, such as a particular genetic background and/or viral infections can cause genetic alterations responsible for the transformation of normal mesothelial cells (4-6). In most cases, mesothelioma is a sporadic neoplasm, but familial neoplastic forms, characterized by germline mutations of the BAP1 gene have been described. In addition to mesothelioma, germline BAP1 mutations confer increased susceptibility for the development of several other tumors including uveal melanoma, cutaneous melanoma, and renal cell cancers (7,8).
Patients typically experience weight loss, pain and shortness of breath. Unilateral serum effusions are also often present on clinical examination. These signs and symptoms can manifest themselves for many months. Diagnosis is based on clinical and radiological characteristics, although it is necessary to have a detailed professional history. Samples for diagnosis can be obtained from pleural effusions by thoracentesis.
However, tissue samples obtained by ultrasound-guided biopsies, video-assisted thoracic surgery (VATS) or debulking samples should be examined whenever clinically possible (4-6,9).
Prognosis is poor due to the limited therapeutic options and difficulty in complete surgical removal. According to Global Cancer Observatory (World Health Organization) data [2018], 25,576 patients died for PM. The patients not treated have a median survival time of 6 months and most patients die within 24 months of diagnosis (10).
However, the progress of the last years in the knowledge of genetic and immunophenotype characteristics of mesothelioma could be useful for innovative pharmacological treatments in the next future. With this aim, we made a selection of the most reliable and recent data emerging from the literature, by searching original articles published in indexed journals in MEDLINE in the period between 1992 and 2020, to propose an updated state of the art. Several other sources have also been considered, including some most-viewed Web sites (http://www.pathologyoutlines.com/; http://med.stanford.edu/pathology.html; www.clinicaltrials.gov) and the latest guidelines [College of American Pathologists (CAP) guidelines 2017; American Society of Clinical Oncology (ASCO) 2018; ERS/ESTS/EACTS/ESTRO guidelines 2020]. We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/jxym-20-79).
Pathological diagnosis and prognosis
Pathological diagnosis of PM, according to the 2015 classification of the World Health Organization, can sometimes be very complicated, due to the heterogeneity of neoplastic cells and the propensity of mesothelioma cells to mimic other forms of cancer. For this reason, it generally requires a multidisciplinary approach through a correlation of cytological and histological characteristics with clinical and radiological data. The "epithelioid" is the main histotype, accounting for 60–75% of all cases. It is the variant with the largest number of cytoarchitectural patterns often mixed together (trabecular, microcystic, papillary, tubulo-papillary, micropapillary, solid, with clear cells, ring with bezel or small cells) which mimic an epithelial neoplasm, a lymphoma or a lymphoepithelial-like carcinoma (Figure 1). Often it causes pleural serum effusions and is related to a good prognosis (12–27 months after diagnosis) (11). Sarcomatoid histotype accounts for 10–15% of all cases of mesotheliomas. It is characterized by the presence of a proliferation of spindle cells arranged in short bundles with a history form or disordered pattern that infiltrates the parietal pleura or the pulmonary parenchyma. The nuclear atypia and mitosis can be of varying degrees, from absent to prominent (Figure 2). The presence of tumor necrosis is relevant for the diagnosis. A variant of sarcomatoid PM is mentioned as desmoplastic if >50% of the tumor shows desmoplastic pattern. The desmoplastic variant is usually the most difficult form to diagnose. It is a mild proliferation of spindle elements arranged in a disordered manner, in a hyalinized collagen stroma. Invasion of soft tissue or lung parenchyma is sometimes difficult to demonstrate, as immunohistochemical testing for the mesothelium are often negative. Sarcomatoid phenotype and its desmoplastic variant are related to an unfavorable prognosis, with an overall survival of 4-18 months after diagnosis (11).
Figure 1 Common morphological aspects of epithelioid mesothelioma in 75-year-old patient. (A) Epithelioid mesothelioma with high dense cellularity and stromal invasion by trabecular structured cells (hematoxyilin-eosin; magnification 10×). (B) Epithelioid mesothelioma showing atypical cells (hematoxyilin-eosin; magnification 20×).
Figure 2 Conventional morphological features of sarcomatoid mesothelioma in a 70-year-old patient. (A) Sarcomatoid mesothelioma showing atypical spindle cells in fascicular pattern (hematoxyilin-eosin; magnification 10×). (B) Sarcomatoid mesothelioma with spindle atypical cells and high mitotic rate (hematoxyilin-eosin; magnification 20×).
The Biphasic form of PM, 10–25% of all cases, is a combination of the epithelioid and sarcomatoid pattern: each component should represent at least 10% of the tumor for the diagnosis of this variant and it is recommended to indicate the percentages of the respective components in the report (11). The overall survival of biphasic subtype varies from 8 to 21 months.
Often, the first biological material available for pathological diagnosis is the cytological sample, particularly for patients with epithelioid mesothelioma which have a serous pleural effusion in up to 90% of cases. Sarcomatoid and biphasic mesotheliomas rarely cause large pleural effusions and, when this occurs, these subtypes do not present a large exfoliate neoplastic cellular component, the neoplastic cells are rare and difficult to evaluate (12,13). Diagnosis on cytological material is reliable but requires the presence of both cytological characteristics of malignancy and evidence of the expression of mesothelial biomarkers (14).
The first clinical question for the pathologist is the origin of the atypical cells and, once the mesothelial origin has been ascertained, when necessary, it is essential to distinguish between benign pleural serous effusions, which can present mesothelial reactive cells, and malignant pleural effusions. The presence of tumor cells in pleural effusions may also depend on a metastatic localization of a known primary tumor at another site, but also when patients are affected by other known malignancies, the possibility of a coexisting mesothelial neoplasms must be taken into consideration (12-15). It should also be noted that three-dimensional aggregates of atypical mesothelial cells may be present in benign effusions related to heart failure, cirrhosis or benign ovarian pathology (12).
However, cytopathological diagnosis should be confirmed on tissue obtained by guided ultrasound biopsies, VATS or debulking surgery. Indeed, the evaluation of vascular or stromal invasions is necessary for a differential diagnosis with the pleurisy. To distinguish mesothelioma from pleurisy, a full-thickness biopsy is required in order to visualize neoplastic growth from the pleural surface towards the underlying areas because only in this way it is possible to recognize the stromal invasion (12,16-18). On the other hand, invasion can be difficult to recognize when tissue sample is small. In this case, the presence of infiltrating neoplastic cells may not be evident due to the difficulties related to the orientation of small biopsy in paraffin block. In case of proliferation of atypical mesothelial cells, early invasive PM should be suspected and if there is no clear sign of stromal invasion, the diagnosis of "atypical mesothelial proliferation" should be made and further sampling should be suggested (16). On the contrary, cell growth sometimes mimics neoplastic infiltration. This is the case of the "fake fat" in the pleuritis, a very common diagnostic pitfall due to a traction artifact caused by biopsy procedure. "Fake fat" is a pattern characterized by round or elongated spaces in fibrotic tissue, parallel to the pleural surface with mesothelial cells in the middle (19).
For the diagnosis of mesothelioma major and minor criteria are required. The main criteria are hypercellularity, solid or diffuse cell growth and a zonation. The so-called zonation is referred to a pattern characterized by hypercellularity at the surface while a reduced cellularity is observed in deep. Cellular atypia, mitoses and the presence of necrosis are considered to be minor criteria because they are also present in mesothelial reactive hyperplasia. However, severe atypia and numerous atypical mitotic figures are in favor of PM (17-20).
Old and new biomarkers for the diagnosis and prognosis of mesothelioma
The diagnosis of PM must be based both on morphology and on an appropriate immunophenotypic characterization of neoplastic cells. This allows to carry out a differential histological diagnosis of PM versus primary lung cancer or epithelioid/biphasic mesothelioma versus reactive mesothelial proliferations and sarcomatoid PM versus fibrinoid pleuritis. Several specific biomarkers for mesothelial and epithelial cells can be searched on large tissue resections, small biopsies and cell blocks. Therefore, an adequate amount of tissue or cells is a crucial parameter in order to be able to test all needed biomarkers, and a small biopsy may not be representative of the tumor (12,21).
Malignant mesothelioma vs. malignant epithelial cell proliferations
The differential diagnosis between mesothelioma and malignant epithelial neoplasia is sometimes difficult. For this reason, analysis of multiple biomarkers can allow a more accurate diagnosis. In some particular cases, it is advisable to proceed with a multi-step algorithm, based on the morphological aspect of the neoplasm (22,23). The first biomarkers to be used are those dedicated to the identification of the mesothelial cell line. Broadly speaking, mesothelial neoplastic cells have been reported to overexpress some proteins and in particular calretinin, Wilms tumor 1 (WT1) and-cytokeratins 5 and 6 (Ck5/6) (Figure 3). Calretinin exhibits immunoreactivity in the cytoplasm and nucleus of mesothelial cells, while WT1 protein shows only nuclear expression and the immunoreactivity for CK5 and CK6 is evident only in the cytoplasm. These characteristics must be considered to recognize tissue artifacts or methodological defects (24-27). However, the loss of expression of the aforementioned proteins, does not exclude the diagnosis of PM because about 30% of mesothelial malignancies have a "null phenotype" (21). Other markers that are useful for establishing the mesothelial cell line include epithelial membrane antigen (EMA), podoplanin (D2-40), thrombomodulin and more recently HEG1 (28-30). In recent studies, HEG1 has proven to be the most sensitive and specific marker in the different variants of mesothelioma and in the differential diagnosis with pulmonary adenocarcinoma. EMA is a mucin-like transmembrane glycoprotein with membrane immunoreactivity. Thrombomodulin (CD141) is an endothelial transmembrane glycoprotein localized on the surface of endothelial cells, while mesothelin is a glycoprotein of the surface of normal mesothelial cells. Since 2005, several studies reported, in mesothelial neoplastic cells, the expression of podoplanin, a transmembrane mucoprotein recognized by the D2–40 monoclonal antibody (31-33). Specificity and sensitivity for these biomarkers are summarized in Table 1. Unfortunately, some markers are not so specific for mesothelial cells. Calretinin and CK5/6 well recognize breast and squamous cell carcinomas (34). Mesothelin protein can be expressed in pancreatic adenocarcinoma.
Table 1 Sensitivity and specificity of main mesothelioma biomarkers in clinical practice
In clinical practice, when in doubt, it is mandatory to consider other primary sites and distinguish mesothelioma from lung carcinoma or pleural metastasis from other sites (kidney, breast, ovary etc.) (Table 2). To rule out the possibility of epithelial neoplasia, a variety of biomarkers such as CEA, MOC-31, B72.3 and BER-EP4 must be tested (35). In particular, to exclude lung primitivity the most common biomarkers are TTF1 and Napsin A, which show immunoreactivity in lung adenocarcinoma, and p40 expressed in squamous cell carcinoma (35-38) (Figure 3). Based on MESOPATH studies, TTF1 and calretinin biomarkers allow to differentiate lung adenocarcinoma from epithelioid mesothelioma which is positive for calretinin and negative for TTF1 (39-43). In differential diagnosis with breast cancer, the expression of estrogen (ER) and progesterone receptors (PR) is useful, considering that over 75% of breast carcinomas show immunoreactivity for ER/PR.
Table 2 Biomarkers (listed in first line) with positive and negative immunoreactivity in mesothelioma (second line) and in other malignancies (third line)
Figure 3 Epithelioid mesothelioma. Diffuse and strong immunoreactivity for pan-cytocheratins (A) (magnification 10×), WT1 (B) (magnification 10×), Calretinin (C) (magnification 10×) and absence of immunoreaction of Napsin A (D) (magnification 10×). See the text for more details.
Some biomarkers, such as CD15, PAX8 and PAX2, allow to identify an epithelial kidney cancer (44). Gastrointestinal tract adenocarcinomas can be recognized for the CDX2 expression, while prostate carcinoma for the prostate- specific antigen (PSA) (12,21,45).
Recently, the International Mesothelioma Interest Group reported recommendations on relevant biomarkers and suggested to use at least 2 positive biomarkers in neoplastic mesothelial cells such as calretinin, WT1 protein, keratin 5/6 or podoplanin and 2 positive biomarkers in epithelial malignancies among TTF1, MOC-31, B72.3, CEA, BER-EP4, CD115 and ER-a (see below). Therefore, no specific panel is proposed, but the International Mesothelioma Group recommends that each laboratory should choose antibodies with a sensitivity and specificity of at least 80% for immunohistochemical evaluation (18). In addition, the selected markers should be supplemented with other biomarkers for addressing the differential diagnosis in particular situations (Table 2).
Epithelioid mesothelioma vs. reactive mesothelial proliferation
Reactive mesothelial proliferation can be difficult to distinguish from mesothelioma because it often shows necrosis, cytological atypia, high proliferation rate, high cellularity and entrapment of mesothelial cells within fibrosis with histological aspects that can mimic neoplastic invasion. The real invasion can be demonstrated by the expression of pan-cytokeratin and in epithelioid mesothelioma also by calretinin expression. Indeed, as described above, a very common diagnostic pitfall is the "fake fat" due to a traction artifact. This morphological aspect mimics neoplastic invasion and in difficult cases, the EMA expression with an accentuated reactivity at the cell membrane level and the absence of desmin immunoreactivity have been reported as useful biomarkers for mesothelioma diagnosis. International studies recommended the combined use of desmin/EMA staining to overcome difficulties (46).
In addition, recent studies suggested that BRCA-associated protein-1 (BAP1) and ciclin-dependent kinase inhibitor 2 (CDKN 2, p16) are very useful in differentiating benign from malignant mesothelial proliferation. The absence of BAP1 expression has been associated with malignant mesothelial proliferations and represents the most reliable and specific diagnostic marker (when negative) even on cytological samples, since all reactive mesothelial processes are positive for the expression of BAP1 (47).
The BAP1 gene is located on the chromosome band 3p21, and encodes BAP1 protein that is a deubiquitinase, involved in the removal of ubiquitin from H3a (mono-ubiquitin) and from targets as BRCA1, BARD1 and HCF1, a transcription co-factor. BAP1 is involved in cellular growth, regulation of DNA transcription and cell cycle, response to DNA damage and chromatin remodeling (48).
Indeed, germline BAP1 mutations have been associated with a familial syndrome characterized by increased risks to develop different cancer types as skin basal cell carcinoma, uveal and cutaneous melanoma, breast and renal cell carcinoma, sarcomas, brain tumors and malignant mesothelioma. Somatic mutations in the BAP1 gene occur in up to 50% of sporadic mesotheliomas (7,8,48). The most common gene alterations are point mutations and bi-allelic inactivating deletions that cause the truncated protein. The result is a degradation of the BAP1 protein with loss of expression, easily documented by loss of immunoreactivity which shows a high concordance with the presence of the BAP1 mutation. A subset of cases can only have cytoplasmic staining resulting from the loss of the BAP1 autodeubiquitination function and this type of altered expression should also be considered positive. Loss of BAP1 expression is reported in 60% of epithelioid and biphasic mesothelioma and in 20% of sarcomatoid type, Therefore, in clinical practice, BAP1 is an important biomarker as it allows to distinguish, by immunostaining of tumor sections, between malignant (loss of BAP1expression) and benign (presence of expression) mesothelial proliferations (49-55).
The homozygous deletion of the CDKN2A gene is reported in half of the cases of mesothelioma. P16 plays a very important role in the regulation of the cell cycle and is recently described in aging. Therefore, the high mutation frequency could be caused by oxidative stress and inflammatory background, both induced by exposure to asbestos. The analysis of CDKN2a can be performed by fluorescence in situ hybridization (FISH) and a homozygous deletion is reported in up to 70% of primary epithelioid and 90% to 100% of sarcomatoid PM. It is important to highlight that benign mesothelial reactive proliferation is not characterized by CDKN2A deletion with a specificity of 100%.
Some studies have revealed frequent co-deletion of the MTAP gene (which encodes methylthioadenosine phosphorylase) and CDKN2A at the 9p21 locus. The loss of MTAP protein expression has been described as a surrogate for CDKN2A deletion and is relatively easy to diagnose, considering the excellent inter-observer reproducibility (47,56-58). Loss of cytoplasmic MTAP immunostaining shows a sensitivity of 65–88% and a specificity of 96–100% for CDKN2A homozygous deletion. In addition, BAP1 and MTAP expression are documented in PM but not in mesothelial reactive proliferations with a specificity of 100% and sensitivity of 60% and 40%, respectively. If BAP1 and MTAP are evaluated simultaneously, the sensitivity is higher (77%). Indeed, the recent literature does not report MTAP loss in benign mesothelial lesions (59,60).
Recently, 5-hmC is described for mesothelioma diagnosis. It is a modified nucleotide, produced from 5-methylcytosine by the TET family of DNA hydroxylases, that is the first step for DNA demethylation. Decreased levels of 5-hmC with loss of staining in greater than 50% of tumor cells have demonstrated high sensitive (92%) and 100% of specificity for malignancies. Until now, there are few studies published and a larger multi-institutional study will be necessary to confirm these data (60,61).
Finally, enhancer of zeste homolog 2 (EZH2) that is a component of polycomb repressive complex 2 (PRC2) has a central role in epigenetic suppression of gene expression through trimethylation of a critical lysine residue in histone 3 (H3K27). EZH2 overexpression is reported in a range of malignancies, and a link between BAP1 loss and overexpression of EZH2 has been described. The first work showed significantly higher EZH2 expression levels in malignant mesothelioma compared to reactive mesothelial pleuritis. Today EZH2 is considered a promising marker of malignant mesothelioma, however it needs validation in larger multi-institutional studies (62,63).
Sarcomatoid mesothelioma versus fibrous pleuritis
When there is a proliferation of spindle cells, the stromal invasion can sometimes be difficult to recognize, but reactive fibrous pleurisy can be highlighted with pancytokeratin staining. It is important to note that CK7 is more expressed in sarcomatoid mesothelioma compared to reactive spindle cell proliferations. In these cases, it is really important to identify where pancytokeratin positive cells are localized. If the immunoreactive cells are present in adipose tissue or skeletal muscle tissue or lung tissue, it is possible to formulate a diagnosis of mesothelioma (64).
In some cases of organizing pleuritis, cytokeratin positive cells, horizontally oriented, may be present around the fat like spaces. Additional biomarkers such as S100 protein, laminin and collagen IV may help to differentiate sarcomatoid mesothelioma from "fake fat" which shows no expression of these biomarkers (12,21,65).
Sarcomatoid mesothelioma versus other malignancies
The heaviest diagnostic difficulties are encountered with sarcomatoid/desmoplastic mesothelioma forms because most sarcomatoid mesotheliomas tend to lose the expression of the classic mesothelial markers and maintain only the positivity for cytokeratins (CAM5.2 low molecular weight cytokeratin cocktail or other cocktails such as AE1/AE3 and MNF116). For this reason, these biomarkers have been included in CAP guidelines. The positive immunoreactivity for cytokeratins can be particular useful for detecting neoplastic cells and infiltration of these cells into soft tissues. The other biomarkers previously described in epithelioid mesothelioma as CK5/6, WT1, claudin 4, CEA, Ber-EP4 and MOC31 are not useful because they are completely negative in the sarcomatoid subtype. Sarcomatoid mesothelioma can exhibit calretinin expression in around 30% of the cases and podoplanin in a variable percentage of the cases (21).
The differential diagnosis with other malignant tumors includes mainly the sarcomatoid carcinoma of lung and kidney, synovial sarcoma, angiosarcoma and melanoma. For sarcomatoid lung carcinoma, a panel of biomarkers including TTF1, napsin-A and p40/p63 can be used (66). In addition, GATA-3 may be useful in the differential diagnosis between sarcomatoid or desmoplastic mesothelioma, both positive in most cases, and sarcomatoid carcinoma of the lung, generally negative for GATA-3 expression (67,68). Renal sarcomatoid lesions can exhibit the expression of PAX2 and PAX8 genes, but not CK5/6 protein expression (21). Synovial sarcoma is characterized by the cromosomal traslocation (X;18) and CD99 immunoreactivity (69). Indeed, other biomarkers have been tested for other sarcomas including CD31, ERG, FLI1 (angiosarcoma), CD34, STAT6 (solitary fibrous malignant tumor), desmin, myoglobin (myogenic sarcoma), S100 (liposarcoma) and SOX10 (neurogenic tumors). Muscle specific actin can be expressed in sarcomatoid mesothelioma. On the contrary, desmin expression is very rare in sarcomatoid mesothelioma but it is present in reactive mesothelial cells (21,70). Regarding the utility of BAP1 and p16 in sarcomatoid mesothelioma, the literature data are discordant and need yet to be confirmed. However, in sarcomatoid lesion, few cases have shown the loss of BAP1 expression, while homozygous deletion in the 9p21 region is seen in around 90-100% of cases (54,56,60).
Prognostic biomarkers
Some markers are studied for their prognostic value, as BAP1, P16, RTK-AXL, c-MET, p16, MDM2, WT1, p53 and EZH2 (60). Patients with BAP1 inactivation by mutation and copy number variation are younger, with epithelioid mesotheliomas and better prognosis. Multiple studies have shown that homozygous deletion of CDKN2A is associated with shorter survival in both pleural and peritoneal mesothelioma, but it is linked with increased survival post-chemotherapy. A similar prognostic value for MTAP has been assumed but has not yet been validated (60,71-73).
c-MET is an important receptor tyrosine kinase (RTK), overexpressed in some cancer types, also including PM. In a MESOPATH study, a higher c-MET expression and its localization to the membrane, compared to exclusively cytoplasmic localization or co-expression at the membrane and cytoplasm, were found to be linked with longer overall survival (74). Other biomarkers significantly associated with good prognosis, increased survival and epithelioid morphology, if overexpressed, are Axl and Syndecan-1. Axl is a RTK which is involved in cell survival and in epithelial-to-mesenchymal transition (EMT) (75). On the other hand, Syndecan acts as tumor inhibitor, preventing cellular proliferation of tumor cell, and play a role in cell adhesion and cytoskeletal organization (76). Other studies reported that neurotensin, CD9 and aquaporin are biomarkers of good prognosis, whilst increased expression of caveolin is associated with poor prognosis. In addition, diagnostic biomarkers as WT1 and calretinin, are also linked with good prognosis (60,77).
MDM2, E3 ubiquitin ligase, is an important regulator of P53 activity and stability. Overexpression of MDM2 can lead to degradation of P53 with a loss of its function and this is common in some tumors as lung, breast, colon, stomach and hepatocellular carcinomas. It is described that approximately 20% of all PM show strong nuclear MDM2 expression, especially epithelioid PM or the epithelioid component of biphasic PM. MDM2 positivity in PM is significantly associated with decreased overall survival. P14/ ARF is the physiological inhibitor of MDM2. If P14/ARF activity is lost, it may have a similar effect as loss of P53. P14/ARF is recognized as a tumor suppressor inducing cell cycle arrest in a both P53-dependent and independent manner. A recent study indicates that MDM2 mRNA and protein expression correlated significantly with overall and progression-free survival in PM, showing a poor prognosis for patients with elevated MDM2 expression. In this study, MDM2 has been indicated as a prognostic and predictive marker for a platin-pemetrexed therapy of patients with PM; at the same time, downregulation of P14/ARF expression seems to contribute to MDM2 overexpression-mediated P53 inactivation in such patients (78).
In 8% of PM it is described the loss of P53, that is important for cell protection against oxidative stress, caused by chronic inflammation related to asbestos exposure (79).
The prognostic role of EZH2 in relation to protein expression levels was examined in a study in which patients with high EZH2 expression had poorer survival (60,63). This correlation has not been confirmed by other studies (80). Therefore, more solid data on larger case histories are needed to establish the prognostic role of EZH2 (60).
New perspectives: targeted therapies and immunotherapies
The therapeutic approach for mesothelioma patients is unsatisfactory for several reasons: the diagnosis is often delayed, the tumor unresectable and the available pharmacological options are limited (4,9,81). At present, the strategies include surgery, chemotherapy and radiotherapy or a combination of them based on the clinical characteristics and stage. In patients with inoperable advanced PM, and candidates for systemic treatment, chemotherapy represents the cardinal treatment. The Food and Drug Administration (FDA) has approved cisplatin and pemetrexed for pharmacological approach with or without the addition of anti-VEGF (vascular endothelial growth factor) drugs, such as bevacizumab or nintedanib, as reported in MAPS and LUME-Meso trials respectively (82,83). As an alternative to cisplatin, carboplatin is indicated, above all, in the elderly population for the better tolerability. Generally, the epithelioid neoplastic form is less aggressive than sarcomatoid subtype, highly sensitive to chemotherapy and with a longer survival than the sarcomatoid or biphasic subtypes of PM (81,84,85).
Regarding new therapeutic options offered by molecular target therapy, phase I and phase II trials, which tested tyrosine kinase receptor inhibitors (RTK) in PM patients, with impaired regulation of EGFR and VEGFR pathways, have given poor results (86). To date, the best results are achieved with the combination of bevacizumab and chemotherapy with an increase in survival of 2.6 months compared to patients who have not received bevacizumab (87).
Deep-sequencing analysis, of 216 biopsies with PM diagnosis, has let to identify frequent gene fusions and splicing alterations causing inactivation of BAP1, NF2 and SETD2 and genetic mutations in Hippo, mTOR, p53 signaling, histone methylation and RNA helicase (88). These alterations could be new targets in the future and are being investigated. Recently, it has been demonstrated, by next-generation sequencing, high frequent homozygous inactivating mutations of the BAP1 locus in approximately 60% of mesothelioma patients (89). BAP1 gene codes for a protein binding to the breast cancer type 1 susceptibility protein (BRCA1) and the BRCA1-associated RING domain protein 1 (BARD1) (90). BAP1 is involved in many pathways including cell death, DNA damage response, homologous recombination and repair of defective DNA (91). It has been demonstrated in cell lines with loss of function of BAP1 that, by inducing synthetic lethality of alternate DNA repair pathways, poly-ADP ribose polymerase (PARP) inhibitors can cause cell death (92). The role of BAP1 in homologous recombination could be used therapeutically in a wide PM setting, similarly to what has been shown in clinical studies conducted on patients affected by ovarian or prostate cancer with mutations in the DNA repair genes. In clinical trials, the recruitment of PM patients is ongoing to examine the relationship between BAP1 genotype and response to PARP inhibitors such as olaparib (NCT03531840) and niraparib (NCT03207347) (93). The latter study is recruiting cancer patients, including those with mesothelioma, with alterations in the BAP1 gene and other deficiencies in the DNA damage response (DDR) pathway. On the contrary with what already observed in ovarian and breast cancer patients with inherited mutations in BRCA1 and BRCA2, BAP1 mutant mesothelioma cell lines resulted significantly less sensitive than BAP1 wild type cells to gemcitabine (91).
An improvement of the therapeutic possibilities comes from immunotherapy which is based on the use of checkpoint inhibitor anticancer drugs that are emerging as a front-line treatment for several types of malignancies. The most studied mechanism of checkpoint signaling is the one involving the programmed cell death-1 (PD1) receptor and its programmed cell death-1 ligand-1 (PDL1) ligand, which normally limits the activity of T lymphocytes in the tissues, subsequently to an inflammatory or autoimmune response. It is now recognized that this pathway is used in tumors to block the immune response to cancer growth since the PD1-PDL1 binding blocks the proliferation of activated T lymphocytes causing a "T-cell exhaustion" (94,95).
Recently, it has emerged that neoplastic cells, in mesothelioma, can express PDL1 protein especially in the epithelioid form and this expression is associated with a worse prognosis. In contrast, sarcomatoid mesotheliomas show PDL1 expression in a low percentage of cases that is around 30%.
Phase II clinical trials investigated PD1 and PDL1 inhibitor drugs such as pembrolizumab (already approved for NSCLC and melanoma), nivolumab, avelumab, durvalumab and CTLA4 inhibitors such as tremelimumab.
The main phase II clinical studies include the PROMISE-meso study (pembrolizumab versus second-line chemotherapy) and MAPS2 (nivolumab versus nivolumab plus ipilimumab). In monotherapy, the efficacy of pembrolizumab in unresectable patients is being analyzed in the phase Ib study, KEYNOTE-028, while the efficacy of nivolumab is being evaluated in the MERIT study. The first emerging data report a clinical benefit in a subset of patients in which there is an average increase in survival of 5–6 months (96,97). Further studies are also underway in patients with recurrence of mesothelioma.
The phase II MESOT-TREM-2008 and MESOT-TREM2012 trials have shown encouraging results and for this reason a larger randomized controlled trial, DETERMINE, has been designed with high doses of tremelimumab (98-100). The first results have been promising, as a trend has emerged in the group of sarcomatoid mesothelioma patients treated with tremelimumab. This therapeutic approach could be important for these patients characterized by a very poor prognosis. Other information comes from trials based on combined therapies such as the MAPS-II trial (nivolumab alone or nivolumab and ipilimumab) and tremelimumab with durvalumab (anti PDL1), tested on the first and second lines in the NIBT trial (101). We are waiting for the results of durvalumab together with standard chemotherapy in the phase II DREAM study (102).
Currently there are several phase III trials which have to evaluate the efficacy of immunotherapeutic approach in the first line, as Checkmate 743, IND-227 (NCT02784171) and ETOP BEAT-meso trial (NCT03762018) (93-103).
The final results of the studies mentioned above will help us to know which biomarkers will be useful to select patients with mesothelioma for immunotherapy treatment. At the present time, PDL1 is the only biomarker evaluated with an immunohistochemical assay in other neoplastic forms, and seems to allow the best selection of patients for immunotherapy. Literature data report that PDL1 is expressed in about 40-60% of mesotheliomas and when expressed it is associated with a worse prognosis. In many studies, the expression of PDL1 correlates with the response to PDL1 inhibitors with or without CTLA inhibitors (104-106). Patients treated with pembrolizumab and tumoral expression of PDL1 >1%, had response rates between 19% and 44%, while tumors with PDL1 expression <1% show clinical responses around 10% of cases (107).
However, in literature there are other studies reporting different data regarding the category of patients with PDL1 <1% which show an ORR of 27–33% or even response rates similar to those of patients with PDL1 expression >1% if treated with a combination of immunotherapy drugs (108). These data could be explained by the presence of a low number of tumor infiltrating CD8 + lymphocytes (TIL) in patients with poor response. Mesotheliomas with a high number of TILs show tumor cell apoptosis, low clinical stage and increased survival. A greater number of cases with PDL1 >1% and CD8 positive TILs are reported in the subset of sarcomatoid mesothelioma patients and this observation would explain the best response of patients with this type of mesothelioma to checkpoint inhibitor therapy (109). In conclusion, immunotherapy could represent in the near future a therapeutic option in selected groups of patients with mesothelioma, although it is necessary to identify one or more biomarkers for a wider selection of patients to be treated (110,111).
Mesothelioma currently remains a serious disease, not sensitive to chemotherapy, with little chance of surgical radicality which results in a low overall survival rate. The various morphological patterns require the analysis of multiple biomarkers for an accurate diagnosis. Recent and important advances in the molecular field allow the pathologist to better characterize the lesion both morphologically and genetically for address patients towards new clinical trials for innovative therapeutic possibilities.
Provenance and Peer Review: This article was commissioned by the Guest Editors (Duilio Divisi, Roberto Crisci) for the series "Malignant Pleural Effusion" published in Journal of Xiangya Medicine. The article was sent for external peer review organized by the Guest Editors and the editorial office.
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/jxym-20-79
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jxym-20-79). The series "Malignant Pleural Effusion" was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Cite this article as: Buttitta F, Di Lorito A, D'Angelo E. Biomarkers in the diagnosis and treatment of malignant pleural disease: an integrative review. J Xiangya Med 2020;5:40.
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VR Tourviewer is dedicated software to watch tours created with Pano2VR on various VR headsets. Currently supports Oculus Go & Rift, Samsung Gear VR and Google Cardboard. This includes support for their respective controllers as a laser pointer. Google Daydream support is added soon.
VR Tourviewer uses the extra sensors of the headsets and low latency of the Unity implementation, this results in a much smoother and more immersive experience than with a webview/browser workaround to watch tours on these devices.The app can work with locally stored tours (also in offline mode) or load them from an URL.
It supports monoscopic and stereoscopic tours, node hotspot navigation, surround audio, lensflares, image and video overlays, single & multi resolution panoramas and panoramic videos up to 4K. Skins (incl. tour maps), animation, and scripts aren't supported.
Environmental effects like falling rain, snow and leaves can be easily added to a panorama by simply adding a user tag in Pano2VR.
A remote viewer for Windows has been released too, to be able to see what a VR user is seeing on a laptop or big screen. With normal screencasting applications, a videostream of the screen has to be transmitted. Due to the high CPU/GPU and traffic intensity of this technique, this results in lag in both the VR experience and the casted result. I strongly advise not to use such apps to avoid ruining the VR experience.
With VR Remote Tourviewer this has been solved by running an identical (non-VR) tour on a Windows computer, and only synchronizing the camera movement and user interaction. This results in a very high quality, low latency, synchronized view of the tour on a big screen, fullscreen ie: without the 'binoculor vision' of a screen casting app.
The free version of VR Tourviewer contains a watermark, a version without watermark can be ordered for € 75 per device. This includes free updates up to a year after purchase. Reduced pricing available for purchasing of 5 or more licenses at once.
A white label (bespoke) version can be ordered with the offline 'Storage' section. Impress your clients! Use your own business or project logo, app name, splash screen, launcher icon, hotspot colors and even your own panorama for the background of the menu area. It's possible to automatically start a tour on startup without using the menu area, and use a soundtrack/music to play uninterupted during the entire tour. Pricing is € 300 for a white label version for offline use (using storage on device) including a license to use the app on two devices. Addtional customization is also possible of course.
VR Tourviewer has no subscription or monthly fees, and no costs per tour.
Note that VR Tourviewer is developed independently by 3DV (Netherlands) and 3DV is not affiliated with Garden Gnome.
So if you have any questions or remarks please use the VR Tourviewer support (FAQ, knowledge base and forum) : https://www.vrtourviewer.com or email.
Last edited by 3DV on Sat Sep 08, 2018 4:31 pm, edited 3 times in total.
Is this only for Android and Windows?
A lot of my clients just use iPhone and Apple Mac !
Is there an online desktop demo i can see without using the app?
Today I've had a little play with VR Tour Viewer, viewing an older tour I did on my Oculus Go. Felt like a lot less hassle than on the Gear VR, however, it feels extremely limiting to only be able to export tours with the Stare, or Cardboard skins and because of this I feel reluctant to move on from the free version, despite VR Tour Viewer working really well on the Go.
Has anyone designed a more feature-rich skin, or one that's more visually appealing, that works well with VR Tour Viewer, and if not, what might I have to bear in mind if I build one myself? My main priorities are mixed media hotspots with HTML content, and nice looking animated icons to access them and navigate about. Cheers!!!
An update for VR Tourviewer and VR Tourviewer Remote (for live view) is now available!


Us at Quote Roller our always looking for new ways to improve our product and service, and what's great is that our clients feel the same way. Today we're talking with Jason Blumer of Blumer & Associates CPAs, which has worked to turn his company digital and to change the way the industry does pricing.
Jennifer Riggins: Could you please briefly introduce yourself and tell us what your business is about?
Jason Blumer: I am the owner of Blumer & Associates CPAs. Our goal as a firm is to equip creative people to become mature business owners. We do this through all the traditional services of accounting, tax, payroll. etc. We also do business coaching, retreats, and consulting.
Jen: Why did you start it? What makes it unique?
Jason: I took over the firm in 2003, but my dad started it in 1997. We are unique because we are virtual. Our team of seven all works from home. Most of us are in South Carolina, but we have one team member in Colorado. We also don't track time or bill by the hour like most in our profession. All pricing is agreed upon upfront so our customers never have to worry about a surprise bill from us. Speaking of our customers, we only work with those in creative professions; primarily web and mobile designers, developers, and agencies.
Jen: What do you love about being an entrepreneur?
Jason: I love that, even though I work more than I ever did, it's on my own terms. I have the freedom to set my own schedule. I love seeing ideas become real, tangible services or products. I love seeing customers learn and grow their businesses too.
Jen: How do you envision success?
Jason: You have to know why you do what to do to know when you have achieved success. Knowing that our purpose is to equip business owners helps us know when we're successful. Our processes can confuse them or clarify for them. We're shooting for clarity. And, of course, being profitable is a sign that we got something right.
Jen: How did you hear about Quote Roller? Why did you decide to try our app?
Jason: Our customer, The Honey Agency, told us about Quote Roller.
Jen: How does Quote Roller help your business?
Jason: Quote Roller made our process for creating contracts more efficient. What used to take a few hours may take about 20 or 30 minutes now.
Jen: What would you tell your friends about Quote Roller?
Jason: I would tell them it is easy to set up and that the templates are the way to go. Templates have made our lives so much easier! Quote Roller makes searching for past proposals easy.
Jen: Have you seen any winning rate increases?
Jason: Any other delightful numbers? (Note: we use Quote Roller to send contracts, but not proposals.) We really like the dashboard at the top.
Do you have any questions for this Client Tale? Ask away!


text:
Climate Change Act 2008
The target for 2050
Blaenorol: Introduction
Nesaf: Crossheading
Dangos Graddfa Ddaearyddol(e.e. Lloegr, Cymru, Yr Alban a Gogledd Iwerddon)
Dangos Llinell Amser Newidiadau
Newidiadau dros amser i: Cross Heading: The target for 2050
Newidiadau i ddeddfwriaeth:
Climate Change Act 2008, Cross Heading: The target for 2050 is up to date with all changes known to be in force on or before 17 July 2019. There are changes that may be brought into force at a future date. Changes that have been made appear in the content and are referenced with annotations.
Revised legislation carried on this site may not be fully up to date. Changes and effects are recorded by our editorial team in lists which can be found in the 'Changes to Legislation' area. Where those effects have yet to be applied to the text of the legislation by the editorial team they are also listed alongside the legislation in the affected provisions. Use the 'more' link to open the changes and effects relevant to the provision you are viewing.
View outstanding changes
Changes and effects yet to be applied to the whole Act associated Parts and Chapters:
Whole provisions yet to be inserted into this Act (including any effects on those provisions):
s. 86(1)(a) words renumbered as s. 86(1)(a) by 2016 c. 22 s. 211(2)(a)
s. 86(1)(b) and word inserted by 2016 c. 22 s. 211(2)(b)
s. 86(7A)(7B) inserted by 2016 c. 22 s. 211(5)
The target for 2050U.K.
1The target for 2050U.K.
(1)It is the duty of the Secretary of State to ensure that the net UK carbon account for the year 2050 is at least 80% lower than the 1990 baseline.
(2)"The 1990 baseline" means the aggregate amount of—
(a)net UK emissions of carbon dioxide for that year, and
(b)net UK emissions of each of the other targeted greenhouse gases for the year that is the base year for that gas.
2Amendment of 2050 target or baseline yearU.K.
(1)The Secretary of State may by order—
(a)amend the percentage specified in section 1(1);
(b)amend section 1 to provide for a different year to be the baseline year.
(2)The power in subsection (1)(a) may only be exercised—
(a)if it appears to the Secretary of State that there have been significant developments in—
(i)scientific knowledge about climate change, or
(ii)European or international law or policy,
that make it appropriate to do so, or
(b)in connection with the making of—
(i)an order under section 24 (designation of further greenhouse gases as targeted greenhouse gases), or
(ii)regulations under section 30 (emissions from international aviation or international shipping).
(3)The developments in scientific knowledge referred to in subsection (2) are—
(a)in relation to the first exercise of the power in subsection (1)(a), developments since the passing of this Act;
(b)in relation to a subsequent exercise of that power, developments since the evidential basis for the previous exercise was established.
(4)The power in subsection (1)(b) may only be exercised if it appears to the Secretary of State that there have been significant developments in European or international law or policy that make it appropriate to do so.
(5)An order under subsection (1)(b) may make consequential amendments of other references in this Act to the baseline year.
(6)An order under this section is subject to affirmative resolution procedure.
3Consultation on order amending 2050 target or baseline yearU.K.
(1)Before laying before Parliament a draft of a statutory instrument containing an order under section 2 (order amending the 2050 target or the baseline year), the Secretary of State must—
(a)obtain, and take into account, the advice of the Committee on Climate Change, and
(b)take into account any representations made by the other national authorities.
(2)The Committee must, at the time it gives its advice to the Secretary of State, send a copy to the other national authorities.
(3)As soon as is reasonably practicable after giving its advice to the Secretary of State, the Committee must publish that advice in such manner as it considers appropriate.
(4)The Secretary of State may proceed to lay such a draft statutory instrument before Parliament without having received a national authority's representations if the authority does not provide them before the end of the period of three months beginning with the date the Committee's advice was sent to the authority.
(5)At the same time as laying such a draft statutory instrument before Parliament, the Secretary of State must publish a statement setting out whether and how the order takes account of any representations made by the other national authorities.
(6)If the order makes provision different from that recommended by the Committee, the Secretary of State must also publish a statement setting out the reasons for that decision.
(7)A statement under this section may be published in such manner as the Secretary of State thinks fit.
PrintThis Cross Heading only
PDF This Cross Heading only
Tudalen we This Cross Heading only
Rhychwant ddaearyddol: Indicates the geographical area that this provision applies to. For further information see 'Frequently Asked Questions'.
Dangos Llinell Amser Newidiadau: See how this legislation has or could change over time. Turning this feature on will show extra navigation options to go to these specific points in time. Return to the latest available version by using the controls above in the What Version box.
Testun a grëwyd gan yr adran o'r llywodraeth oedd yn gyfrifol am destun y Ddeddf i esbonio beth mae'r Ddeddf yn ceisio ei wneud ac i wneud y Ddeddf yn hygyrch i ddarllenwyr nad oes ganddynt gymhwyster cyfreithiol. Cyflwynwyd Nodiadau Esboniadol ym 1999 ac maent yn cyd-fynd â phob Deddf Gyhoeddus ac eithrio Deddfau Adfeddiannu, Cronfa Gyfunol, Cyllid a Chyfnerthiad.
Llinell Amser Newidiadau

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: OCI -22303: type not "OE". "CUST_ADDRESS_TYPE" I have created Virtual Private Database (VPD) policy to oe.customers table that if the customer service department users login to the database as an Account Managers they only will be able to see information related to the customers attached to their account and not all customers information (i.e. if the account manager executes following SQL statement select * from customers; he/she will be able to see only customers who are attached to his/her account.
after completion of my VPD if I login as a account manager and search for
Select * from oe.customers

I am getting error message

OCI -22303: type not "OE". "CUST_ADDRESS_TYPE" not found.

however if I search like
select (column) from oe.customer

query successfully returns my values.
below I have given all my sql command which I used for creating my VPD.
Please help me how can I get result for
Select * from oe.customers

as a account manager such as Account1/passowrd
Connect sys/oracle as sysdba
GRANT CREATE SESSION, CREATE ANY CONTEXT, CREATE PROCEDURE, CREATE TRIGGER, ADMINISTER DATABASE TRIGGER TO sysadmin_vpd IDENTIFIED BY password;
GRANT EXECUTE ON DBMS_SESSION TO sysadmin_vpd;
GRANT EXECUTE ON DBMS_RLS TO sysadmin_vpd;

GRANT CREATE SESSION TO Account1 IDENTIFIED BY password;
GRANT CREATE SESSION TO Account2 IDENTIFIED BY password;
GRANT CREATE SESSION TO Account3 IDENTIFIED BY password;
GRANT CREATE SESSION TO Account4 IDENTIFIED BY password;

CONNECT oe/oe

CREATE TABLE oe.Account_mgr (
 account_mgr_id    NUMBER(6),
 account_name  VARCHAR2(20));

INSERT INTO oe.Account_mgr VALUES (145, 'Account1');
INSERT INTO oe.Account_mgr VALUES (147, 'Account2');
INSERT INTO oe.Account_mgr VALUES (148, 'Account3');
INSERT INTO oe.Account_mgr VALUES (149, 'Account4');

GRANT SELECT ON oe.customers TO sysadmin_vpd;

GRANT SELECT ON oe.customers TO Account1;
GRANT SELECT ON oe.customers TO Account2;
GRANT SELECT ON oe.customers TO Account3;
GRANT SELECT ON oe.customers TO Account4;

Connect sysadmin_vpd/password

CREATE OR REPLACE CONTEXT CUSTOMER_CTX USING CUSTOMER_CTX _PKG;

CREATE OR REPLACE PACKAGE CUSTOMER_CTX _PKG IS
  PROCEDURE SET_ACCNUM;
 END;
/
CREATE OR REPLACE PACKAGE BODY CUSTOMER_CTX _PKG IS
  PROCEDURE SET_ACCNUM
  AS
    ACCNUM NUMBER;
  BEGIN
     SELECT ACCOUNT_MGR_ID INTO ACCNUM FROM OE.ACCOUNT_MGR
        WHERE ACCOUNT_NAME = SYS_CONTEXT('USERENV', 'SESSION_USER');
     DBMS_SESSION.SET_CONTEXT('CUSTOMER_CTX ', 'ACCOUNT_MGR_ID', ACCNUM);
  EXCEPTION
   WHEN NO_DATA_FOUND THEN NULL;
  END SET_ACCNUM;
END;
/

CREATE TRIGGER SET_ACCNUM_CTX_TRIG AFTER LOGON ON DATABASE
 BEGIN
  SYSADMIN_VPD.CUSTOMER_CTX _PKG.SET_ACCNUM;
 END;
/

SELECT SYS_CONTEXT('CUSTOMER_CTX ', 'ACCOUNT_MGR_ID') ACCNUM FROM DUAL;

CREATE OR REPLACE FUNCTION ACC_MGR (
  schema_p   IN VARCHAR2,
  table_p    IN VARCHAR2)
 RETURN VARCHAR2
 AS
  CUSTOMER_PREDICATE VARCHAR2 (400);
 BEGIN
  CUSTOMER_PREDICATE:= 'account_mgr_id = SYS_CONTEXT(''CUSTOMER_CTX '', ''ACCOUNT_MGR_ID'')';
 RETURN CUSTOMER_PREDICATE;
END;
/

BEGIN
 DBMS_RLS.ADD_POLICY (
  object_schema    => 'OE',
  object_name      => 'CUSTOMERS',
  policy_name      => 'CUSTOMERS_POLICY',
  function_schema  => 'SYSADMIN_VPD',
  policy_function  => 'ACC_MGR',
  statement_types  => 'SELECT');
END;
/

A: The type CUST_ADDRESS_TYPE  in customers table needs to be given grant separately
GRANT EXECUTE ON CUST_ADDRESS_TYPE TO  Account1;
GRANT EXECUTE ON CUST_ADDRESS_TYPE TO  Account2;
GRANT EXECUTE ON CUST_ADDRESS_TYPE TO  Account3;
GRANT EXECUTE ON CUST_ADDRESS_TYPE TO  Account4;

Update1:- In order for other accounts to view details of the oe.customer table we can use the  predicate which if null returns all the rows in oe.customer
CREATE OR REPLACE FUNCTION ACC_MGR (
schema_p   IN VARCHAR2,
table_p    IN VARCHAR2)
RETURN VARCHAR2
  AS
CUSTOMER_PREDICATE VARCHAR2 (400);
BEGIN
  IF SYS_CONTEXT('CUSTOMER_CTX', 'ACCOUNT_MGR_ID') IS NOT NULL
  THEN
  CUSTOMER_PREDICATE:= 'account_mgr_id = SYS_CONTEXT(''CUSTOMER_CTX '', ''ACCOUNT_MGR_ID'')';
  END IF;
  RETURN CUSTOMER_PREDICATE;
END;
/

redpajama_set_name: RedPajamaStackExchange


Marble tile option is becoming more and more popular among homeowners, frequently trending for floors in kitchens, bathrooms, and entryways. Marble is a luxurious addition and an upgrade to your home. With its refined sophistication and elegant beauty, the marble flooring really shines, but few seem to know the proper maintenance and care to ensure it lasts in optimal condition and looks incredible. Having a variety of colors and unique patterns, marble is a soft stone that offers strength and durability and when polished, it has a mirror-like finish. When it makes contact with acidic compounds, it can etch the surface and grit can cause scratches though marble is resistant to erosion and fire. Professional maintenance and the care of homeowners given on a consistent basis impacts the longevity, condition, and overall appearance. We at CA Carpet Cleaning & Water Damage Cleanup would like to discuss the maintenance of marble tile.
1) Frequently Sweep. The surface of marble flooring should be cleaned daily whenever possible with a soft bristled broom, a dust mop, or a vacuum. Hard floor vacuums are ideal but if you have a standard vacuum ensure the rotator bar is not rotating or it can damage the marble. Though marble is durable, it is still a soft stone, so the grit and grime can cause etches and scratches, especially if the sealant has worn away. The removal of dust and debris should be done a minimum of 2 days a week, but ultimately it should be done daily. The marble should be kept dust free to allow it shine. Keep in mind that daily traffic is causes friction and the dirt, mud, and debris are natural abrasives that causes scratches that contributes to the marble tile looking lifeless dull, and filthy.
2) Spot Clean and Mop. Keeping the floor clean is recommended; immediately wiping up any spills and spot mopping the marble floor is essential. To wash marble floors for a more intensive clean, use commercial store bought cleaners that are specifically formulated to marble floors. Read the label carefully and follow the directions, even if it is a product you routinely use as you never know when manufacturers reformulate their products. Many DIY cleaning concoctions call for vinegar but it is important you avoid vinegar at all costs from making contact with your marble tile as well as other acidic compounds that abrasive, causing damage to the marble surface. Other acidic cleaners as wells as mild soaps are included in agents to avoid. If you are ever in doubt, just use plain warm water to clean the marble tile.
3) Professional Marble Maintenance Service. As a part of the regular care of your marble flooring in addition to your efforts, professional cleaning and sealing services are essential. Experts use quality products and equipment to reach the maximum level of clean and marble tile should be sealed, as it acts as a barrier to protect it from harmful agents. Marble tile should never be neglected and it is equally important that professional maintenance one – two times a year is scheduled.
When your tile and grout are in need of cleaning, call the professionals of CA Carpet Cleaning & Water Damage Cleanup and let our experts take care of the rest.


- Tulsi Gabbard jumped into the race during an interview with Van Jones, which we learned about on January 11 – but has not yet formally announced.
- Julián Castro officially announced on January 12 and is full steam ahead.
- Kirsten Gillibrand formed an exploratory committee, but basically told us she was running this past Tuesday on the Colbert Show.
With two woman and a Latino man joining the field, we're starting to see some of the rich diversity in the Democratic Party – one of the biggest reasons I'm proud to be a member.
- Alright, Kamala Harris is basicallyin the race. We're just waiting for a final announcement. Rumor is, it'll come on MLK Day.
- Pete Buttigeig told the South Bend Tribune that he plans to make a decision in the next few weeks.
- Sherrod Brown is going on a listening tour around Ohio, Iowa, Nevada, New Hampshire, and South Carolina. Hmmmmm…..
- A campaign logo for Amy Klobuchar leaked on Twitter after someone found sketches at a DC coffee shop. She's called them fake, but continues to keep the door open for a run.
- Beto O'Rourke can't help but be an enigma. An interview with the Washington Post this week led to criticism about his lack of substance; meanwhile, his live-blog from his solo road trip has left everyone utterly stumped about what's going on in his head.
- Still no word from Joe Biden– but he can afford to wait as long as he'd like.
- Bernie Sanders met with women who experienced sexual harassment and discrimination on his campaign in 2016 – but no other news on the 2020 front.
- Has anyone seen Cory Booker? For someone consistently mentioned as a potential candidate, he's been fairly quiet. This could mean he's about to make a splash in the race – or he's trying to disappear from the conversation.
I never had strong feelings about Kirsten Gillibrand as a senator – but she's grown on me as a 2020 candidate.
She entered the national political scene as a congresswoman from New York, gaining household name recognition after her appointment to fill Hillary Clinton's senate seat after the 2008 presidential election cycle. Since then, she's developed a strong brand as a reliable progressive – advocating for gun control, gender equality, and immigration reform. She even passes the new liberal litmus test of rejecting corporate PAC money.
But it's worth noting that many of these were not her original policy positions. While in Congress, she maintained an A rating from the NRA and endorsed stronger border control measures – but now flouts an F rating and echoes calls to abolish ICE. She also has been accused of being cozy with Wall Street (though somewhat understandably, considering they're her constituents). This has drawn significant media attention and could challenge her candidacy moving forward.
With that said, I don't think this disqualifies her from a fair shot at the Democratic nomination. Obviously, we shouldn't allow a free pass to those who claim to have "evolved" from hateful, prejudiced views that are antithetical to our values – but shouldn't we, as Democrats, encourage our leaders to move left over time on important challenges like gun safety and economic equality? Not doing so would box out a number of candidates with great potential.
Her lane in this race is, according to FiveThirtyEight, courting female voters – which make up roughly 60% of the party. By focusing on gender equality issues and supporting female candidates down the ballot through her "Off the Sidelines" PAC, it's clear that this – smartly – is her play to carve out a chunk of the primary electorate. And she has the credibility to lead in this space, too.
Her campaign is pushing dual messages: her record of legislative achievement and her image as a fighter against "systems of power that do not want Americans to have … opportunity." In this sense, she sounds a lot like Elizabeth Warren – who has an advantage because she jumped into the race first.
Unlike Warren, however, I feel like we're missing a compelling story around Gillibrand. I still have questions like: Why is she the right one for this moment? What's her vision for this country? How will she fare against Trump? These are questions she'll have in answer – but I'm more than willing to give her the chance.
Impeachment has been a hot topic in the liberal world this week. A growing drumbeat from the Russia investigation – culminating in this week's bombshell report from BuzzFeed Newsthat the president instructed Michael Cohen to lie to Congress about the Trump Tower project in Moscow – has more and more Democrats speaking out about possible impeachment proceedings.
So, while we wait for the Mueller report to play itself out, I'm looking forward to seeing how Democrats on the 2020 trail talk about Trump – and whether or not they make the case about his fitness for office as they begin the journey to remove him from office themselves.


The Co2 boost bucket is a Co2 generator that is affordable and easy to use. This Co2 system will help your plants grow at a much faster rate than tradition or hydroponic gardening. Co2 Boost Bucket - Co2 Generator Grow up to 50% faster with a Co2 Boost. This Co2 generator is affordable and easy to use. Using a Co2 boost bucket for your plants means your plants will grow faster due to the absorption of pure Co2 and other ingredients. The Co2 Boost will last 6 months at which time you can purchase a refill pack at a discounted price.


text:
description("Trivial animVal testcase, to see wheter we support it at all. Should result in a 200x200 rect and only PASS messages");
createSVGTestCase();

// Setup test document
var rect = createSVGElement("rect");
rect.setAttribute("id", "rect");
rect.setAttribute("width", "200");
rect.setAttribute("height", "200");
rect.setAttribute("fill", "green");
rect.setAttribute("onclick", "executeTest()");

var animate = createSVGElement("animate");
animate.setAttribute("id", "animation");
animate.setAttribute("attributeName", "width");
animate.setAttribute("from", "200");
animate.setAttribute("to", "100");
animate.setAttribute("begin", "click");
animate.setAttribute("dur", "4s");
rect.appendChild(animate);
rootSVGElement.appendChild(rect);

// Setup animation test
function sample1() {
    // Check initial/end conditions
    shouldBeCloseEnough("rect.width.animVal.value", "200");
    shouldBe("rect.width.baseVal.value", "200");
}

function sample2() {
    // Check half-time conditions
    shouldBeCloseEnough("rect.width.animVal.value", "150");
    shouldBe("rect.width.baseVal.value", "200");
}

function sample3() {
    // Check just before-end conditions
    shouldBeCloseEnough("rect.width.animVal.value", "100");
    shouldBe("rect.width.baseVal.value", "200");
}

function executeTest() {
    const expectedValues = [
        // [animationId, time, sampleCallback]
        ["animation", 0.0,   sample1],
        ["animation", 2.0,   sample2],
        ["animation", 3.999, sample3],
        ["animation", 4.001, sample1]
    ];

    runAnimationTest(expectedValues);
}

var successfullyParsed = true;

redpajama_set_name: RedPajamaGithub