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Back to Journals » Cancer Management and Research » Volume 10
Advances in antitumor effects of NSAIDs
Authors Zhang Z, Chen FL, Shang L
Received 24 May 2018
Accepted for publication 13 July 2018
Published 15 October 2018 Volume 2018:10 Pages 4631—4640
DOI https://doi.org/10.2147/CMAR.S175212
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Professor Harikrishna Nakshatri
Download Article [PDF]
Zhen Zhang,1,2 Fulin Chen,1,2 Lijun Shang1–3
1Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi'an, Shaanxi Province 710069, People's Republic of China; 2Provincial Key Laboratory of Biotechnology of Shaanxi, Northwest University, Xi'an, Shaanxi Province 710069, People's Republic of China; 3School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford, UK
Abstract: In recent years, the reports on using nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer prevention and treatment have been on the rise. In 2017, the US Preventive Services Working Group issued primary prevention guidelines on the use of NSAIDs, especially aspirin, for cardiovascular disease and colorectal cancer, and formally established the role and status of aspirin in cancer prevention. However, the mechanism of NSAIDs on preventing cancer is still not clear. In this paper, the progress of the application of NSAIDs, especially aspirin, in the prevention and treatment of tumors in recent years is summarized, and new ideas and directions for the follow-up study are also discussed.
Keywords: NSAIDs, aspirin, platelets, cancer
In 1897, German chemist Felix Hoffmann successfully applied salicylic acid and acetic anhydride to synthesize acetyl salicylic acid (acetylated salicylic acid) and obtained excellent effects in the treatment of rheumatoid arthritis for his father. This drug was named aspirin. Since then, this anti-inflammatory drug has been officially accepted in clinical practice, making it the most widely used antipyretic, analgesic and anti-inflammatory drug in the world. In addition to treatment, aspirin has been utilized as a standard preparation for the evaluation of other drugs. The molecular structure of aspirin is simple but used in vivo aspirin has shown a variety of effects over the years. It has been used as analgesic, antipyretic, anti-inflammatory and antirheumatic treatment in cardiovascular and cerebrovascular thrombosis. While its side effects cannot be ignored, especially long-term use of aspirin can lead to increased risk of gastrointestinal bleeding, increased uric acid, allergic asthma, coagulation inhibition amongst others.1 In recent years, different types of NSAIDs have been developed and applied to clinical treatment, but among all NSAIDs, aspirin still seems to be the best and first choice.2
Some large epidemiological studies have displayed that aspirin shows great effect in the primary and secondary prevention of cancer and in a variety of malignant tumor treatments (especially in colon cancer, stomach cancer etc.).3–6 In May 2009, a meta-analysis of aspirin in the prevention of colorectal cancer (CRC) and other cancers in recent years7 reported that regular administration of aspirin is associated with the reduction of the incidence of cancer. This attracted scientific interest and posed the question: could anti-inflammatory drugs be used for the prevention and treatment of the tumor? There are some problems raised in this hypothesis, such as how to avoid the gastrointestinal bleeding caused by long-term use of aspirin and the optimal dosage of aspirin. Therefore using aspirin in cancer prevention and treatment is still very controversial. In 2012, Rothwell8 indicated that regular administration of aspirin (≥75 mg/daily) could reduce the incidence of adenocarcinoma, CRC, and lung cancer, inhibit tumor metastases, and improve the survival rate of cancer patients. Additionally, they hypothesized that aspirin could inhibit tumor metastasis by eliminating platelet aggregation.
Early theories indicated that anti-inflammatory drugs could remove inflammatory factors in the surrounding inflammatory microenvironment of the tumor, so that the tumor cells can be directly exposed to immune cells, and then immune cells can function through immune recognition to achieve the role of cleaning up tumor cells. It is known that the body can self-recover after short-term inflammatory response, and this is a normal body self-protection mechanism, but long-term chronic inflammation may lead to cancer. Colotta et al9 proposed that tumors are caused by inflammation factors (IL-1, IL-6, IL-12, IL-17, TNF-α, TGF-β, etc.) assembling and the reactive oxygen species (ROS) produced by inflammatory infiltrating cells in the inflammatory microenvironment causing DNA damage (such as P53 gene mutation) and further induce normal cell carcinogenesis. Based on this, Okada et al10 created gp91phox gene knockout mouse implanted with or without degenerated fibro sarcoma cells (QR cells) and wild-type mouse macrophages. Compared to the gene knockout mouse, mouse implanted with wild-type mouse macrophages increased frequency of tumor development, and showed macrophage-driven ROS participated in the development of tumors. Amino guanidine is a broad inhibitor of inducible nitric oxide synthase, and its regulation can partially and significantly inhibit the transformation of degenerating QR cells into fibrosarcoma cells, therefore Futoshi Okada et al10 speculated that in addition to ROS there was nitrous oxide (NO) involved in the process of tumor deterioration. In addition, the inflammatory cytokines, chemokines (IL family) and NK cells can accumulate in the surrounding microenvironment of the tumor, and mediate the growth and metastasis of tumor cells (related to the upregulation of the expression of vascular growth factor in the surrounding tumor microenvironment).11,12 Additionally, the inflammatory factor and histamine can increase the permeability of the vessel wall and the lymphatic wall, and assist the distal metastasis of the tumor.13 This article was therefore regarded as the cornerstone of the researches.
Aspirin used in primary tumor prevention
A great number of large epidemiological studies found that long-term use of low-dose aspirin (75–300 mg/daily) can effectively inhibit a variety of cancer incidence, malignant cancer metastasis rate, and provide patients with a high survival rate. In 2012, Rothwell et al14 conducted a meta-analysis of the six trials of daily low-dose aspirin in primary prevention (35,535 participants) and pointed out that the regular administration of low-dose aspirin (75–300 mg/daily) for more than 3 years can reduce cancer risk by 24% (324 vs 421 cases; OR = 0.76, 95% CI 0.66–0.88, P=0.0003). In addition, the aspirin group reduced the risk of CRC within 20 years in six randomized trials and 26 case–control studies. At the same time, the risk of esophageal cancer, gastric cancer, cholangiocarcinoma and breast cancer in the aspirin group was significantly decreased. Rothwell et al15 analyzed five large randomized clinical trials which examined the effects of aspirin (75 mg/daily or more) on tumors. The results of the analysis showed that aspirin could reduce the incidence of distant metastases by 36% and reduce the risk of cancer-specific mortality by 50% compared with the control group. For patients with adenocarcinoma, the risk of morbidity can be reduced by 46%. In patients with no metastatic adenocarcinoma at the time of initial diagnosis, the use of aspirin in the subsequent long-term observation can reduce the associated cancer metastasis rate by 70%. In 2014, Cuzick et al16 also concluded that taking low doses of aspirin (30–100 mg/daily) for 10 years can reduce the risks of gastric cancer, esophageal cancer, and CRC by 30%. Liao et al17 found regular use of aspirin (twice a week or more, standard dose of 325 mg aspirin tablets) after diagnosis, compared with wild-type PIK3CA cancer patients, mutant PIK3CA CRC patients can obtain more benefits, and this once again determined the value of aspirin in primary prevention of CRC. A prospective study showed that among the registered 130,251 healthy subjects, after a 32-year follow-up survey, 27,985 people had cancer (20,414 women).18 Those who regularly take aspirin (0.5–1.5 standard aspirin tablets/week, 163 mg to 488 mg) for at least 6 years would reduce the overall risk of cancer by 3%, gastrointestinal cancer incidences reduce, including CRC (19% lower risk) and gastroesophageal cancer, but the risks of non-gastrointestinal cancer (such as breast cancer, advanced prostate cancer, lung cancer, etc.) were not significantly reduced. Importantly, retrospective epidemiological studies have shown that low-dose aspirin (75 mg/day) is more effective in reducing morbidity and mortality associated with CRC than high-dose aspirin (325–1200 mg/day).8
In April 2016, the USPSTF19 reviewed a number of large randomized controlled trials (RCTs) in the use of aspirin to prevent cancer, and found that taking aspirin for 3.6–10.1 years showed no significant difference in the overall cancer mortality and incidence between the aspirin group and the normal control group. The 20-year mortality rate of CRC was significantly lower in the aspirin group (four RCTs, RR=0.67), and the incidence of CRC was reduced for those taking aspirin for 10–19 years (three RCTs, total number of cases 47464, relative risk [RR]=0.60). In view of this, the USPSTF eventually issued aspirin as a guide for cardiovascular disease (CVD) and primary prevention of CRC, and ultimately recommended that: adults aged 50–69 years, 10% or greater 10-year CVD risk, are not at increased risk of bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin (75 mg/daily) for at least 10 years, should consider taking low-dose aspirin to prevent CVD and CRC. The working group here considered the benefits of the various protocols that have been demonstrated in primary prevention trials, including doses of 75 and 100 mg per day and doses of 100 and 325 mg aspirin every day. The daily dose of 75 mg seems to be as effective as the higher dose (325 mg). However, the risk of gastrointestinal bleeding may increase with the increased doses. Comprehensive consideration is given that aspirin should be taken at 50–325 mg/day. Meanwhile, the guidelines also emphasize the need for trade-offs and individualization of aspirin-induced bleeding and other risks and benefits. It is worth mentioning that in the USA, the most commonly prescribed dose is 81 mg per day. In addition, we have summarized the main recommendations of the USPSTF in Table 1.
Table 1 Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer in the USA: clinical summary19
Abbreviations: CVD, cardiovascular disease; CRC, colorectal cancer; GI, gastrointestinal.
Antitumor mechanism of non-steroidal anti-inflammatory drugs (NSAIDs)
Inhibition of COX-2
Most of the NSAIDs are thought to act as tumor suppressors by inhibiting cyclooxygenase-COX.20 COX is known to convert arachidonic acid to prostaglandins (PGs), and the PGs overexpression are thought to be early events in a variety of oncogenic events. COX has three structural subtypes, structural COX-1 and inducible COX-2 (selectivity), COX-3 (found in the nervous system appears late in the inflammatory response).21,22 COX-1 is mainly present in normal tissue cells and catalyzes the production of PGs that maintain normal physiological function. COX-2 is a membrane-bound protein. In normal physiological status, the majority of tissue cells do not express COX-2; but in inflammation, tumor and other pathological conditions, due to inflammatory substances and carcinogenic substances such as the inflammatory mediators induced, COX-2 shows an increasing expression, and participates in a variety of pathophysiological processes, causing canceration (large number of COX-2-dependent genes are involved in this tumorigenesis process).23,24 Krysan et al25 found that COX-2 is usually upregulated in carcinoma in situ and non-small-cell lung cancer. Chen et al26 showed that the high expression of COX-2 in tumor tissue upregulated the expression of bcl-2 and thus played the role of an antiapoptotic effect of tumor cells. In addition, COX-2 and PG overexpression in chronic inflammation suggest that PGs produced by COX-2 catalysis can induce neovascularization to a certain extent and provide nutrition for tumor survival and proliferation.27 Finally, the COX-2 can affect upregulation of matrix metalloproteinase-2 expression which then promotes tumor invasion and metastasis.28 Recent studies have shown that the specific COX-2 enzyme inhibitor celecoxib (a NSAID) can effectively inhibit a variety of tumor cell proliferation and promote apoptosis on Raji cells, SK-N-SH cells and K562 cells in vitro.29–31 In addition, Harris et al32 conducted a case–control study of NSAID in 489 lung cancer patients and 978 control subjects. The results showed that a daily intake of aspirin or ibuprofen for at least 2 years reduces the relative risk of lung cancer by 68% (P<0.01). The detection of COX-2 in patients also suggested that patients taking NSAID significantly reduced the content. These results, with molecular evidence suggested that NSAID intake may prevent cancer by blocking COX-2 expression.
Induced tumor cell apoptosis
Bcl-2 gene inhibits apoptosis predominantly in the following three ways: 1) Bcl-2 can change the mitochondrial thiol reduction state to control the membrane potential and regulate apoptosis; 2) Bcl-2 can regulate the mitochondrial membrane permeability of some apoptotic protein precursors; 3) Bcl-2 can locate the apoptotic protein precursor Apaf-1 to the mitochondrial membrane so that it cannot play a role in apoptosis.
Yang et al and Xu et al33,34 used aspirin to treat human small cell lung cancer A549 cells, ovarian cancer SK-OV-3 cells and showed the expression of bcl-2 gene decreased and the expression of bax gene increased. Kim35 found that strong NSAIDs such as naproxen used on culture bladder cancer cells caused significant cell apoptosis, which was mainly due to the downregulation of bcl-2 gene and the upregulation of bax gene. In addition, Bank et al36 found that NSAIDs sulindac acid can degrade antiapoptotic protein bcl-XL, block bcl-XL antagonism of bax, make pro-apoptotic protein bax activation caspase cascade reaction, then activate the cell apoptosis program. Raza et al37 found that amino salicylic acid can increase the production of intracellular ROS, reduce intracellular glutathione storage, and inhibit mitochondrial respiratory chain enzyme complex, electron transport chain complex Body I, electron transport chain complex IV, mitochondrial matrix enzyme, cis-aconitase and other enzyme activity. The mitochondrial permeability changes can then lead to the synthesis of ATP being blocked, bcl-2 expression downregulated, and the release of cytochrome C will eventually trigger apoptosis. Furthermore, celecoxib can increase the wild-type p53 gene cancer overexpressing the p53 protein.38 The upregulation of p53 protein expression could further upregulate the expression of p53up-regulated modulator of apoptosis (PUMA) protein, which is the p53 gene downstream positive regulator. PUMA encodes the BH3-only protein of the bcl-2 family, whereas the BH3-only protein is a key factor in the initiation of apoptosis by the p53 pathway.
Downregulation of EGFR expression
Recently, Dong et al39 found that in 80% of patients with colorectal cancer EGFR overexpression occurred, but it can be downregulated by regular use of aspirin. Similarly, they noted that EGFR and COX-2 were co-located in patients with familial multiple adenomas and that COX-2 overexpression triggers proto-oncogene c-Jun-dependent transcription factors which bind to the EGFR promoter activation of protein-1 and can further promote the accumulation of EGFR cells in cells and promote their transformation to malignant.
Protect and repair DNA damage
Oxidative stress plays an important role in the development of various diseases such as cancer, cardiovascular disease, etc40,41 and can damage nucleic acid, protein, membrane and other cell elements. Banti et al42 mentioned that aspirin counteracts exogenous bacterial infections by inhibiting the production of peroxides, and oxygen radicals produced by bacteria, and can therefore cause great damage to cellular DNA. Chen et al43 confirmed that aspirin can inhibit the formation of nucleic acid cleavage and hydroxyl radicals caused by peroxynitrite, which play a role in protecting DNA. Goel et al44 found that aspirin could induce high expression of DNA mismatch repair proteins hMLH1, hMSH2, hMSH6 and hPMS2 in colon cancer cells, and the high expression of hMLH1 and hMSH2 could induce tumor cell apoptosis. Dibra et al45 found that aspirin can induce X-ray repair of cross-complementary gene 3 (XRCC3) and its protein expression, thus promoting DNA self-healing.
The general antitumor mechanism of NSAIDs is summarized in Table 2.
Table 2 Traditional pathway of NSAIDs inhibiting tumors
Abbreviations: COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs; XRCC3, X-ray repair of cross-complementary gene 3.
The new thinking on the apparent phenomenon
Individual differences bring non-universality
A recent study in 2012 set out aspirin as a research boom in CRC secondary prevention. Liao et al17 retrospectively analyzed 964 patients with CRC and found that CRC-related mortality was significantly reduced (RR=0.18) and the overall survival extended (RR =0.54) in patients with CRC who had been diagnosed with aspirin-treated PIK3CA mutations. In contrast, in PIK3CA wild-type patients, regular aspirin administration (twice a week or more, standard dose of 325 mg aspirin tablets) after diagnosis did not improve CRC patients specific survival (RR=0.96) or overall survival (RR=0.94). In addition, some studies46,47 have shown that patients with 15-PGDH (15-hydroxyprogesterone dehydrogenase) and antigen-specific HLA-1 high expression in colon cancer can achieve more benefits in aspirin therapy (twice a week or more, standard dose of 325 mg aspirin tablets). Based on this, whether PIK3CA, 15-PGDH and HLA-1 can be used as key molecular biomarkers in the treatment of CRC is worthy of consideration.
NSAIDs prevents cancer from escaping immune surveillance
In 2015, Zelenay et al48 demonstrated that skin cancer, breast cancer and CRC cells often produce large amounts of PG E2 (PGE2), which can attenuate the immune system's normal response to diseased cells and help cancer cells to hide. This process allows the tumor to grow rapidly, and therefore explains why some immunotherapy has difficulty in achieving the desired effect. Aspirin is a kind of COX inhibitor, which can inhibit the synthesis of PGE2 to achieve the effect of re-awakening the immune system. Therefore, compared with the use of immunotherapy alone, the combination of immunotherapy with aspirin or other COX inhibitors can significantly reduce the growth of CRC or melanoma in mice. In addition, a study showed that platelets can also help tumor cells escape the immune system.49 In vivo platelet-specific Glycoprotein A Repetitions Predominant (GARP) can activate platelet-derived or non-platelet-derived TGFβ, and GARP-TGFβ complex can effectively reduce the activity of T-cell activity at the physiological level. Thus most tumor cells can escape the clearance of the immune system, and the use of platelet antagonists will significantly improve the killing of tumor cells by the immune system. Therefore, the administration of COX inhibitor or platelet antagonists simultaneously with the patient's immunotherapy can make cancer immunotherapy more effective and may become a new treatment with great potential.
Aspirin, platelet, tumor
Recent reports show that patients with a high blood platelet count are significantly more likely to develop cancer than those with a low blood platelet count, suggesting that tumor development may be associated with platelets.50 It is known that platelets, in addition to coagulation, play a role in the formation of new blood vessels.51 This effect is usually beneficial, such as the formation of a new clot after injury, and the need for new blood vessels to regulate blood flow. However, the same effect will also help the tumor growth. Platelets can enhance the invasiveness of cancer cells,49 promote epithelial-mesenchymal transition (EMT) transformation,52 and contribute to the deterioration of cancer to a large extent. In addition, cancer as a long-term chronic injury process will inevitably produce various mechanical damage etc. and promote the self-aggregation of platelets in the cancer site. There is already evidence that platelets can be spontaneously recruited to colon cancer cells in patients with colon cancer,53 which will undoubtedly greatly increase the progression of cancer. So we speculate that use of platelet antagonists can effectively slow down the progression of cancer. Lichtenberger et al54 indicated that aspirin can inhibit the activity of COX-1 enzyme, control the number of circulating platelets and their activity levels, and therefore block the interaction between platelets and cancer cells. They used platelet co-culture of human and murine colon cancer cell layers with two different aspirin preparations (normal aspirin and combination of phosphatidylcholine-specific aspirin) and found that platelets can significantly promote tumor cell proliferation and enhance its ability to migrate, while the use of aspirin can significantly decline the effect, and the effect of special aspirin (aspirin and phosphatidylcholine mixture) had increased efficacy. Other previous studies55 used platelets as a carrier to deliver PD-L1 antibody to the tumor site to achieve targeted killing of tumor cells and suggested that the role of platelets in the development of tumors is not absolute. Therefore, changing the traditional thoughts on cancer treatment would make us gain more benefits in the fight against tumors.
Aspirin against cancer by slowing up the mutation accumulates
It is known that tumorigenesis is caused by long-term accumulation of genetic mutations. Kostadinov et al56 suggested that aspirin can prevent cancer by slowing the accumulation of DNA mutations in abnormal cells in precancerous lesions. They analyzed 13 biopsy samples from patients with Barrett's esophagus and conducted a 6–19 years follow-up studies. In the "observational crossover" studied, some patients began taking aspirin daily initially for several years and then stopped taking it, while others took aspirin until the end of the observation. The biopsy results showed that patients who did not use aspirin showed more than 10 times faster accumulations of gene mutations than those who used aspirin long term.
Different forms of NSAIDs may have different effects
In addition to traditional formulations of NSAIDs for the prevention and treatment of tumor, various forms of NSAIDs become available for tumor prevention or treatment either in vivo or in vitro. One example is the use of aspirin-phosphatidylcholine in vitro achieved better results in human or murine colon cancer cell lines at the cellular level compared to traditional aspirin.54 In addition, another study57 showed that the use of nano-forms of aspirin and ibuprofen to treat lung cancer patient's whole blood in vitro could effectively reduce the DNA damage of white blood cells, which suggested that the nano-form of NSAIDs is more likely to enter the cell membrane and bind to DNA. It is worth mentioning that the use of metal complexes could also enhance the affinity of the complex for DNA binding.42 Therefore, NSAIDs and metal complexes should be taken into consideration in the treatment of cancer. Compared with traditional NSAIDs, NSAIDs with bio-metals show better pharmacological activity,58 and lower gastrointestinal toxicity.59 In addition, different metal and NSAIDs complexes are selective for different cell lines, for example, the platinum complexes of the NSAIDs tomeidine and indomethacin have the higher selectivity on non-cancerous cells BHK21 and L929.42 This suggests that we can choose different metal complexes as ligands to modify NSAIDs and to achieve selective killing of tumor cells.
In addition, as early as 2013, Liu et al60 conducted a meta-analysis of 10 studies between 2003 and 2013 and concluded that the use of aspirin and other NSAIDs did not significantly affect the incidence of brain tumors and was not associated with special subtypes of brain tumor. However, Simms et al61 showed that in vivo the liquid containing aspirin may be able to extend the life of thousands of patients with brain cancer. This is a breakthrough result in which they found that liquid aspirin can pass through the blood–brain barrier (known in the treatment of brain tumor, the blood–brain barrier can prevent chemotherapy drugs passing into the brain to kill brain tumor cells), and early tests showed that compared to existing chemotherapy drugs, liquid aspirin can kill brain cancer cells to improve the efficiency ten-fold. Therefore, we speculate that the role of aspirin in tumor treatment may be associated with the use of drug forms.
Enhance the effect of antitumor therapy
Some NSAIDs can enhance the sensitivity of the tumor to chemotherapy drugs, thus antitumor drugs and NSAIDs combination can produce a better prognosis in tumor therapy. Huang et al62 found that for in vitro culture of glioma cells, the use of indomethacin and adriamycin can significantly inhibit tumor cell growth than indomethacin use only. The result of QT-PCR and Western blot showed that indomethacin could downregulate the expression of ABCG2, MDR1 and MRP1, which were colloidal tumor-associated resistance genes, so that the antitumor effect of chemotherapeutic drugs was significantly improved. In addition, indomethacin does not only downregulate the resistance genes, but also enhances the sensitivity of colon cancer cells to chemotherapy drugs. 5-fluorouracil (5Fu) is known as a common cancer chemotherapy drug. Réti et al63 found that in patient body 80% 5Fu could metabolize into 5, 6-dihydro-5-fluorouracil by dihydropyrimidine dehydrogenase and lost the activity. And taking indomethacin could increase the concentration of 5Fu in vivo by inhibiting the activity of dihydropyrimidine dehydrogenase; thereby the increasing concentration of 5Fu can enhance the toxicity to tumor cells. Cheng et al64 demonstrated a new technique by using nucleophilic substitution to combine tumor chemotherapeutic drug cisplatin and aspirin which can significantly reduce the drug resistance of cisplatin in tumor therapy. Finally, in a recent study,49 the researchers found that when using combination of aspirin and clopidogrel (antiplatelet drugs) to treat melanoma-bearing mice, the mice obtained longer survival and fewer relapses when receiving adoptive T-cell therapy, suggesting that antiplatelet drugs could attenuate the ability of platelets to help tumor cells escape immune clearance. It is fair to say that the combination of NSAIDs and traditional cancer therapies or adoptive T cell therapy therefore could lead to a further breakthrough in cancer therapy with "1+1>2."
All the above new thoughts are summarized in Table 3.
Table 3 The new thinking about NSAIDs inhibiting tumors
Abbrevations: GARP, Glycoprotein A Repetitions Predominant; NSAIDs, nonsteroidal anti-inflammatory drugs; PGE2, prostaglandin E2.
Based on a large amount of clinical data, NSAIDs, especially aspirin chemical prophylaxis has been gradually extended to clinical cancer treatment. The National Comprehensive Cancer Network colorectal cancer guide (2017 version) established the role of aspirin in the secondary prevention of cancer. However, taking into account the side effects of long-term use of aspirin, the large-scale use of aspirin as a cancer chemical prophylaxis still needs to weigh up the pros and cons for individual patients. The US "Guidelines for the Use of Preventive Drugs" clearly state that daily intake of "low-dose" aspirin has anticancer effects; here "low-dose" means 75–100 mg per day. But it is worth noting that the mechanism of anti-inflammatory drugs in tumor prevention and control is still not clear, future studies need to focus on the precise molecular classification and reasonable choice of population and dose, to achieve the largest anticancer benefits. As the body's own platelets are linked to tumor growth and metastasis during tumorigenesis,54 our in vitro study found that platelets promote the proliferation of tumor cells and this effect can be inhibited by aspirin (unpublished data). In addition, a prospective cohort study50 showed that thrombocytosis is positively associated with tumor incidence. Of all the 9,435 male thrombocythemia patients, 1,098 were diagnosed with cancer (11.6%; 95% CI=11.0–12.3), however, only 106 out of 2,599 men without thrombocytosis had cancer (4.1%; 95% CI=3.4–4.9). Similarly, a total of 1,355 out of 21,826 females with thrombocytosis developed cancer (6.2%; 95% CI=5.9–6.5), compared with 119 of 5,370 females without (2.2%; 95% CI=1.8–2.6). Our previous in vitro studies also showed that the effect of platelets on adenoma cells is two-sided, but this effect can be attenuated by the platelet antagonist aspirin (unpublished data). Furthermore, our in vivo experiments have shown that aspirin has a certain effect on inhibiting tumor metastasis and both the duration and varying time periods of drug use could affect the survival of tumor-bearing mice (unpublished data). Further research work should focus on exploring the relationship between platelet, cancer and aspirin, clarifying the role of platelets in tumorigenesis and development, evaluating which stage of aspirin intervention could gain more benefits, proposing potential molecular mechanisms and new ideas for aspirin in clinical cancer prevention and treatment.
The authors report no conflicts of interest in this work.
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Liu HF, Hsiao PW, Chao JI. Celecoxib induces p53-PUMA pathway for apoptosis in human colorectal cancer cells. Chem Biol Interact. 2008;176(1):48–57.
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Chen W, Zhu H, Jia Z, et al. Inhibition of peroxynitrite-mediated DNA strand cleavage and hydroxyl radical formation by aspirin at pharmacologically relevant concentrations: implications for cancer intervention. Biochem Biophys Res Commun. 2009;390(1):142–147.
Goel A, Chang DK, Ricciardiello L, Gasche C, Boland CR. A novel mechanism for aspirin-mediated growth inhibition of human colon cancer cells. Clin Cancer Res. 2003;9(1):383–390.
Dibra HK, Brown JE, Hooley P, Nicholl ID. Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line. Oncol Rep. 2010;24(1):37–46.
Fink SP, Yamauchi M, Nishihara R, et al. Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD). Sci Transl Med. 2014;6(233):233re2.
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B2B: Unauthorized Construction — To Be Demolished Without a Court Decision?
The ongoing reform of Russian civil law has distracted many of us from giving enough consideration to a new law that came into force September 1, 2015. Although it changes only one Article of the Russian Civil Code (Article 222 of the Russian Civil Code), it is likely to have a great impact on the rules for the demolition and recognition of title to an unauthorized construction (Federal Law No. 258-FZ of the Russian Federation dated 13 July 2015 "On amending Article 222 of Part One of the Russian Civil Code and the law "On bringing Part One of the Russian Civil Code into force" ("Law No. 258").
Russian law has always contained a general provision that buildings, structures and other immovable property should be demolished if they are (1) erected on a land plot that was allocated for purposes other than construction and/or (2) without the requisite permits having been obtained or (3) found in material breach of town planning and construction rules and regulations (Article 222 of the Russian Civil Code). Law No. 258 has changed the general definition to exclude the reference to immovable property, which signifies that the regulation, which was always designed to combat unlawful construction of permanent buildings and facilities, may now theoretically be applied to any construction, including temporary or non-permanent structures.
Article 222 initially envisaged rules enabling the title holder of the land to obtain, in certain exceptional cases, rights to such unauthorized construction, and court practice has built on this. Based on the developments in court practice, Law No. 258 has introduced certain changes to clarify these rules. The criteria that have to be met for the court to be able to acknowledge title to an unauthorized construction are now expressed more explicitly: not only should an applicant be the title holder to the land (the owner of the land plot or a person possessing another proprietary right to it), but (i) the title to the land plot must generally envisage the right to construct; (ii) the unauthorized construction must comply with all the land planning and land use development rules, and (iii) the unauthorized construction must not infringe the legitimate interests of other persons and must pose no threat to an individual's life or health.
Most importantly, Russian law in general, and Article 222 in particular, has always rested on a fundamental principle that only a court may decide whether a certain building or structure is unauthorized, and therefore needs to be demolished. Law No. 258 has made a huge change to that principle, introducing a procedure for an administrative order to specify that a building or structure is an unauthorized construction. Starting from September 1, 2015, a local governmental authority may pass the relevant decision ordering a structure to be demolished if (i) the land plot in question was not allocated for construction purposes; and (ii) such land plot is located in the use-restricted zone (save for buffer zones of national heritage sites), in public areas or in the easement areas of federal, regional or local utility networks. It is evident that a significant proportion of unauthorized constructions may meet these criteria.
The administrative procedure prescribes that the order to demolish a structure must be delivered within 7 days to the developer which erected the structure in question. The order must also set a deadline of no more than 12 months by which the structure must be demolished. It is also possible for the local government administration to arrange for demolition by its own efforts should the respective developer have not been found, notwithstanding the local authority making public announcements about the demolition.
It appears that the new changes introduced by Law No. 258 in fact substitute a fair court trial in which every party is given a full opportunity to defend its position. Of course, the new administrative order does not exclude the option of going to court to challenge an order for demolition, but the limitation period for the developer to do this is only 3 months, which is an extremely tight deadline.


A divorce can be termed as the dissolution of marriage in a lawful manner. There is no doubt that divorce is a long-winded and costly affair in China if it is contested. Partners that mutually agree to the divorce, however, should prove that they have been separated for more than a year. The number of divorces in China is rising. According to the Ministry of Civil Affairs, the number of couples who filed for divorce in 2013 raised up to 12.8 percent to 3.5 million. Hence, there is a huge demand for the best divorce lawyer in China. Prior to the current surge in divorces, China witnessed two other waves of speedily rising rates of divorce, the first case happened in the 1950s when returning victorious Communist soldiers deserted their farms and rural wives to move to the city. And, the second came after the Cultural Revolution, between 1966 and 1980.
Here is the list of divorce rules in China.
1. After a divorce, the ex-husband usually gets custody of the children and the ex-wife is not accepted and has trouble getting a job. Talking about the case of bad marriages, women usually put up with them rather than tolerate hardships caused by a divorce. In the earlier time, there were even fewer divorces as men used to take a concubine and ignored the wife.
2. Some Chinese people think that it is too easy to get a divorce now. Once upon a time, a 56-year-old man told the china daily that "we treated marriage as something blessed. Divorce was measured as a shame, so the divorce rate was little. This meant there was no need for any such agreement." With an increasing rate of divorce, people tend to look for the best divorce lawyer in China.
3. There is a book called "How to Divorce," which describes unhappy couple everything they need to know about getting a divorce, is available in China today. Coming to the Question №160 reads, "if one face is sold into marriage, and wants a divorce, how does the court manage this?" Answer: "Selling spouses is against the law. Plaintiff has clear grounds for separation. The purchase price will be removed by the state".
Talking about the reasons for divorce in China. The list is endless. Here is the list of reasons for the increasing number of divorce cases in China.
1. In the earlier time, there was a considerable amount of embarrassment attached to being divorced. If they were depressed and had extramarital affairs couples stayed together even went on for years. The reason behind that is married couples didn't want to hurt their children or lose face with their parents.
2. Feminist hotlines support women who want to have a divorce to look for other alternatives. One hotline planner told the Los Angeles Times she tells women they have to be practical and sensible. "Women can't expect too much from their husbands," she said, "the more they expect the more they will get hurt".
3. As far as other reasons for seeking divorce include lack of capital, one-girl families, crowded households, arguments with in-laws, and so on. Several marriages break up because of physical and verbal abuse by wives.


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Q: Ubuntu 16.04 New Install screen icon not functioning properly New install of Ubuntu 16.04 on an older Dell Optiplex 760.
The issues that needs to be addressed is screen flicker and lack of functionality. After install use CLI to update the system and got this problem
Could not get lock /var/lib/apt/lists/lock - open (11: Resource temporarily unavailable)

Fixed that with:
sudo rm /var/lib/apt/lists/* -vf

Followed with:
sudo apt-get update
sudo apt-get upgrade

After that was completed the system was rebooted and that is when the issues started.
The Issue
I can log in but not all menu icons work. When clicking on the Firefox icon all items on the screen disappear for no more than a flicker but eventually Firefox does start. This routine repeats for for the other 'productivity' type program icons.
The top icon the Ubuntu swirl a click there will cause the screen to flicker but nothing happens. This same thing happens for the setting icon the software icon and so on down the list. But wait there is more when clicking the top right power icon the drop-down menu appears with no screen flicker but when I click on "Shut Down.." the screen flickers goes but the menu to actually shut down the computer does not appear.
But wait there's more. Just hovering the mouse over the menu icon on the left will cause the screen to flicker.
Here screen 'flicker' is that all apps and menu icons, everything on the screen, disappears and just the wallpaper is left on the screen and then screen goes back to normal. There is a pattern to this sequence, first the top menu showing the time and the speaker icon disapears, then the left side icon menu disapears, if there is an app on the fore-front it shifts up and left to fill the space from the recently disappeared top and left menu icons before is disappears showing just the wallpaper.
Any help on addressing this issue would be appreciated.

A: The problem appears to have something to do with the video drivers per this bug report
https://bugs.launchpad.net/ubuntu/+source/mesa/+bug/1735594
The solution offered in comment #39 worked. Upon reading the complete bug report I will reinstall Ubuntu and follow the remedy that is suggested in comment #69 and forward. #39 seems to be the fix to see if it works while #69 seem to be the more permanent solution.
I will do a re-install in the near future and report back my results.

redpajama_set_name: RedPajamaStackExchange


As a Christian school, Bishop Rawstorne note the importance of educating the whole child. The values and ethos of our school are central to our teaching of both PSHEe and Citizenship which are integrated into all aspects of life at Bishop Rawstorne including in classroom teaching, tutor group time, worship and games.
Personal, social, health and economic education is delivered to years 7-10 which allows our young people to grow and develop as individuals, as members of families and of social and economic communities. Taught in form groups, PSHEe is designed to allow students to discuss challenging material sensitively and as part of their form group community. It is a subject that we regard as invaluable as it equips our students with the knowledge, understanding, attitudes and practical skills to live healthy, safe, productive, fulfilled, capable and responsible lives. PSHE education enables our students to reflect on and clarify their own values and attitudes, and explore the complex and sometimes conflicting range of values and attitudes they encounter now and in the future.
Citizenship allows students to consider how we live together in our communities and about how we 'get on' locally, nationally and globally. It is about ensuring that everyone has the knowledge and skills to understand, engage with and challenge the main pillars of our democratic society - politics, the economy and the law. Our aim through Citizenship is to develop well-informed, educated citizens with the confidence and appetite to take part in society; to question injustice and to drive change. In essence, the best way to guarantee a brighter future for all is to create a society in which we all understand our rights and responsibilities and in which everyone is equipped, and ready, to play an active part.


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Contributions on new topics are welcome. To be considered, contributions must be signed, sent from a valid email address and provide a phone number which ActonForum may use to contact you to confirm that the contribution is genuine. Source information should be included for all factual contributions or corrections.
For Insider's Guide pieces, we are looking for the unique perspective of someone who has "been there and done that." If you have served on a town board or committee, or have a special expertise in a particular area of interest, and would like to give the facts plus some commentary, this section of the ActonForum is for you! Your contribution, if published, will be credited to you unless you request that your name not be published (it will then be listed as "contributed by a reader").
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You can find more Unity Christian Hudsonville, MI alumni who participated in activities at Classmates.com®. Click here to join Classmates.com® for free and to view UCHS profiles.
Choose an activity that students at UCHS could particpate during their time in high school in Hudsonville to view the names of the students who participated in that sport or activity. You can also add yourself to the list.	The main activities at Unity Christian Hudsonville, MI that have members on this site were Band, Baseball, Basketball, Cheerleading, Drama, Music, Softball, Swimming, Tennis, Track, Volleyball, Wrestling and Yearbook.


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For John Bolton, war is the answer
John Bolton speaks in 2011 at the Conservative Principles Conference in Des Moines. (Charlie Neibergall/AP)
By Dana Milbank
Opinion columnist covering national politics
After the horrors of the Iraq war, some former Bush administration officials pursued healing activities. Donald Rumsfeld set up a foundation, and White House chief of staff Josh Bolten has done philanthropic work overseas. Iraq viceroy Jerry Bremer took up painting, as did his old boss, George W. Bush.
But John Bolton's avocation is exactly what his vocation was: He makes war.
The former Bush State Department official, U.N. ambassador and champion of the Iraq war is exceptionally good at his hobby. At the moment, the Obama administration is trying to nail down a nuclear agreement with Iran, and hawks in Congress are pushing instead for tougher sanctions. But Bolton, now at the conservative American Enterprise Institute, is leading the charge for a third alternative: immediate bombing.
For the mustachioed man of war, force is the option of first resort. The military option isn't just on the table — it's the only thing on the menu.
"The inescapable conclusion is that Iran will not negotiate away its nuclear program," Bolton wrote last week in a New York Times op-ed. "Nor will sanctions block its building a broad and deep weapons infrastructure. The inconvenient truth is that only military action" like Israel's previous strikes on reactors in Iraq and Syria "can accomplish what is required."
He suggested that "the United States could do a thorough job of destruction, but Israel alone can do what's necessary." That could buy three to five years to work on "regime change in Tehran."
Bombs and regime change? It sounds so 2003. But there's something refreshing and honest about Bolton's assessment of the situation. Even if one doesn't share his skepticism that a diplomatic solution in Iran is possible, he is almost certainly correct that the alternative to a negotiated settlement is not stronger sanctions — it's war.
On Wednesday, I went over to AEI to hear Bolton expand on his views at a forum asking "Is Iran the new North Korea?" The answer, from Bolton's perspective, was obvious: Iran should be the next Iraq — a war Bolton evidently is still fighting.
"Now, what about the case of Iraq?" Bolton asked rhetorically after discussing North Korea. "The sanctions have been imposed in light of Security Council decisions by the European Union and others —"
Fellow panelist George Perkovich of the Carnegie Endowment for International Peace interrupted Bolton. "You mean Iran," he said. "You said Iraq."
"Thank you. Appreciate it," Bolton, an architect of that earlier war, responded. "In the case of Iran . . ."
Other than Perkovich, the other panelists, AEI's Nicholas Eberstadt and Michael Rubin, were as dismissive as Bolton was of the Obama administration's negotiations with Tehran. Eberstadt, borrowing some imagery from last week's Germanwings crash, said Obama was trying to "lock the Congress out of the cockpit in the negotiations that are ongoing now."
But Bolton, his trademark bushy mustache now white, had no use for that conservative complaint, pointing out that at least 90 percent of international agreements since World War II have not been subject to Senate ratification. "I don't think it's so important that the Senate actually gets a shot at this," he said. "I think in many respects it's a diversion from where I think [attention] should be, which is what a wretched deal this is."
Also wretched, he argued, was the call in Congress for new sanctions. "Many people who oppose the Obama administration's negotiations with the ayatollahs over the nuclear weapons issue have said that economic sanctions can solve the problem of a nuclear Iran. This is fundamentally false," he said.
That leaves one violent alternative — a conclusion Bolton's AEI colleague Rubin didn't share. Rubin said it would just delay Iran's nuclear ambitions. "Without having a policy in place to take advantage of that delay, it's an irresponsible use of the U.S. military to kick the can down the road," he said.
During the question time, I noted their different views on bombing, and Bolton interrupted. "So you can write a story about disagreement at AEI — congratulations," he retorted, before letting me finish.
"What is the solution — if negotiations don't work and sanctions don't work and maybe even military power doesn't work — other than hide under our desks?" I asked.
Rubin gave a thoughtful answer about a comprehensive effort to undermine the Iranian regime. Bolton didn't answer — and when the session ended, he bolted from the room, two steps ahead of a pursuing camera crew.
It probably didn't matter what the question was. For Bolton, war is the answer.
Twitter: @Milbank
Read more from Dana Milbank's archive, follow him on Twitter or subscribe to his updates on Facebook.
David Ignatius: Deal or no deal, the Iran talks have borne fruit
Joshua Muravchik: War with Iran is probably the only choice
Hans Binnendijk: Don't sugarcoat the costs of war
Ali Alfoneh and Reuel Marc Gerecht: What else is Iran hiding?
Dana Milbank Dana Milbank is an opinion columnist for The Washington Post. He sketches the foolish, the fallacious and the felonious in politics. His new book is "The Destructionists: The 25-Year Crackup of the Republican Party" (Doubleday). Follow

redpajama_set_name: RedPajamaCommonCrawl


How to Remove Eegookiz.com Pop Up Ads from your Browser?
Home Browser hijacker How to Remove Eegookiz.com Pop Up Ads from your Browser?
eegookiz.com is a fake search engine that aims to generate improved search results. It may seem legitimate but acts as a browser hijacking application that keeps a track on your browsing activity.
It infiltrates the browser with ads and changes the default homepage with browser hijacker's fake home page. Also, cause frequent redirections to unknown web URLs. eegookiz.com pop up ads play an important role because whenever the users click such ads they are directed to fake and malicious web pages.
What is eegookiz.com browser hijacker?
Whenever a users access fake search website, the site promotes adware via malicious pop-ups and advertisements. The search results are not genuine and the hijacker adds extensions in the most widely used browsers like Google Chrome and Mozilla Firefox.
If this fake engine starts appearing as your homepage in your default browser, then your browser is infected from eegookiz.com push notification. You must take action before it causes damage to your computers.
The browser hijackers are malicious and cause various high-risk computer infections. They have an attractive user interface but most of their connection to the internet is unsecured.
A point must be taken care: If a website doesn't have HTTPS (secured connection), then you must not access it because it might become a gateway for viruses, adware, and many more other hijackers.
Once eegookiz.com browser virus infiltrates itself in your system, it hijacks the popular web browsers and replaces new tab, web URL and default search homepage with the hijacker's homepage.
Once the page opens, it becomes impossible for the users to revert the changes. Moreover, research results show that the hijacker continuously changes the extension whenever a user tries to get back the default settings.
Due to these unintentional changes, web browsing quality significantly decreases. Third parties (Developers who display malicious adverts) run an ad-supported campaign on your browser, entice you to click those ads and generate revenue for themselves via PPC.
While the attackers or developer of such browser hijackers keeps track of your browsing activity to steal information like banking details, emails, login IDs, passwords, geolocations, social media accounts and IP address. However, there is a solution to it!
We highly recommend to remove this hijacker from your browser and scan your computer with eegookiz.com pop up virus removal tool Malware Crusher to create a strong and secure firewall.
Without the user's consent or knowledge, such browser hijacker changes the browser settings or modify the internet browsing settings. They are a type of malware that ultimately aims at harming and infecting the machine.
It displays advertising banners on the web pages you are visiting.
It installs other adware programs without the user's knowledge.
It causes the occurrence of fake alert messages and notifications.
It posses the ability to modify the 'new tab' functionality to process the changed search portal page.
Via this browser hijacker, ads load into the web browser.
Is eegookiz.com safe to visit?
No, it is not safe to visit because it is a browser hijacker - a form of an unwanted program which without your permission changes all browser settings and spy your whole internet activities to record your personal sensitive information.
Always pay attention before installing software as it comes with additional installs (optional) eegookiz.com.
Watch out carefully when you agree to install.
Always opt for custom installation and deselect everything that isn't familiar (Especially, that software which you never intentionally download).
Do not install any software that you don't trust.
The instructions given below are purely for Windows computer users.
Since this browser virus is an intrusive threat, it is important to remove it. For this purpose, we have prepared a detailed removal guide which easily briefs you about all the necessary methods to remove any browser hijacker.
Note: The guide first helps you to clear unwanted eegookiz.com extension, then after suggests you to install antimalware strongly capable in preventing and removing browser hijacker.
Delete eegookiz.com virus from Google Chrome and Mozilla Firefox.
Make Sure: Once you delete the extensions, clear your browsing history and set your browser to default.
Important: Malware Crusher is free and is recommended as the most impactful tool when it comes to fighting against malware, viruses, trojans and browser hijackers.
Follow the mentioned steps to scan and Delete eegookiz.com Pop up from the browser and other malicious programs from your computer completely.
'Download' Malware Crusher by clicking on the link given below.
This link will open a new tab from where you can download Malware Crusher.
Now install the downloaded Malware Crusher setup by double-clicking on the downloaded file.
Install Malware Crusher setup. Once the installation process is complete, it will start downloading and installing the updates from the server.
Once the update is finished, it will start scanning your computer from the detection of eegookiz.com and other malicious programs.
Once the scan is completed the found threats will appear on your screen as shown below. You can also view the log of the detected items.
Click on the Remove Now button to get rid of all the malicious programs.
A system reboot might be required once the scan is complete. Finally, click on the Okay, I understand button to initiate the cleaning.
Malware Crusher will create a restore point before cleaning the found threats (in case you need to reverse the actions).
Malware Crusher has successfully scanned and removed all the malicious programs on your computer. Click the Finish Button to close Malware Crusher and make sure that you scan your system once a week with Malware Crusher to Keep it Safe.
6. Restore The Removed Items.
You can restore the cleaned items by selecting desired items and clicking the Restore button. In case if you click on the Delete button, the backup will be deleted.
We believe now your system is free from the browser hijacker. In case, if you are still facing any issues, repeat the above-given steps to make sure your system is clean and free of infections.
A malware program that modified the web browser without the permission of a user is known as a browser hijacker. It changes the browser settings and redirects the user to some other unintended websites. These websites are usually are infectious and malicious. Hence, browser hijacking is pursued through a browser hijacker.
Always pay attention while installing software because they might come with additional installs(optional) such as eegookiz.com browser hijacker.
Opt for custom installation always and deselect everything that doesn't appear to be familiar. Especially, an optional software that you never intended to download.


Many have thought that the law of GOD was given as a means of keeping men in check, but the truth is that unless GOD constrains a man to follow HIS law he will disregard it regardless of the extent to which that law is published. That man who is spiritually awakened sees the law of GOD as that which reveals the innate sin of his heart and can grant him no comfort in the thought of thinking that he possesses the ability to keep it.
Paul said, "For I was alive without the law once: but when the commandment came, sin revived, and I died. And the commandment, which was ordained to life, I found to be unto death. For sin, taking occasion by the commandment, deceived me, and by it slew me. Wherefore the law is holy, and the commandment holy, and just, and good. Was then that which is good made death unto me? God forbid. But sin, that it might appear sin, working death in me by that which is good; that sin by the commandment might become exceeding sinful. For we know that the law is spiritual: but I am carnal, sold under sin." (Rom 7:9-14) Now what Paul is saying is that whenever the spiritual nature of the law was revealed to him, he was slain by it. He despaired of keeping it and it was the law which revealed his inborn love of sin.
In the Muslim law if a man is caught stealing they chop his hand off. But GOD never taught the Israelites to do such because HE would teach them that the law is spiritual in nature and that the problem with man's sin is not his hand that steals but his heart which moves him to sin. Paul said, "For though we walk in the flesh, we do not war after the flesh: (For the weapons of our warfare are not carnal, but mighty through God to the pulling down of strongholds;) Casting down imaginations, and every high thing that exalteth itself against the knowledge of God, and bringing into captivity every thought to the obedience of Christ;"(2Co 10:3-5) We are not sent into the world to conduct a moral crusade and try to get men to alter their behavior by declaring to them the law of GOD. Rather that message we are sent with is mighty in power (as it is indicted by the HOLY GHOST) to pierce the very hearts of those whom HE sends it to. HE changes men's hearts and turns them from darkness to light. As a result of this "power" their very thoughts are made captives of CHRIST.
In the midst of the chaos around us, the people of GOD have found a place of refuge in JESUS CHRIST. "So that we may boldly say, The Lord is my helper, and I will not fear what man shall do unto me." (Heb 13:6) The Psalmist said, "he shall hide me in his pavilion".
This PAVILION is not of this world. The LORD did not come to deliver us out of the world but rather to be our DELIVERER in the world. "These things I have spoken unto you, that in me ye might have peace. In the world ye shall have tribulation: but be of good cheer; I have overcome the world." (John 16:33) We are not hidden from the sorrows and trials which befall all men. We are however kept from the power of those trials to destroy us. "There hath no temptation (i.e.; trial) taken you but such as is common to man: but God is faithful, who will not suffer you to be tempted above that ye are able; but will with the temptation also make a way to escape, that ye may be able to bear it." (1Cor. 10:13) Sickness and disease may invade this house of clay, yea even the skin-worms ultimately eat our flesh but we cannot be destroyed because HE has undertaken our cause and will be our PORTION forever for we are hidden in HIM from the foundation of the world.
This PAVILION is the only place of comfort for the sons of GOD. David said, "One thing have I desired of the LORD, that will I seek after; that I may dwell in the house of the LORD all the days of my life, to behold the beauty of the LORD, and to inquire in his temple." (Psa 27:4) The men of this world seek comfort and safety in a variety of means (see Eccl.7:29) but there is only one place wherein the awakened sons of GOD have sought refuge. Job said, "Though he slay me, yet will I trust in him: " (Job 13:15) Peter said, "Lord, to whom shall we go? thou hast the words of eternal life. And we believe and are sure that thou art that Christ, the Son of the living God." (John 6:68-69) Many men have sought out help in religion of one type or other, assurances of men, or even acts of "righteousness" which are supposed to salve the conscience, but none of these things can give any aid to that man who is awakened by the SPIRIT of GOD and enabled to see and hear spiritual things.


text:
Q: How to handle error when a field is not available in the Firestore database? I have a model data class with a few attributes. I have added some data into the Firestore and read them using this model class. Later, I decided to add a few more attributes in the model class but I have not added new fields in the Firestore database. When I read the data like before, my app crashes. This is obvious that as we go further we would add more details but we may or may not add these new details to old items that are already added to the database. How can I handle this situation?
This is how I am reading from the `Firestore'
mFireStore.collection("product_details")
                .get()
                .addOnCompleteListener {
                    if (it.isSuccessful) {
                        for (document in it.result) {
                            val product = document.toObject(ProductDetails::class.java)
                            product.product_id = document.id
                            productsList.add(product)

                        }
                    } else {
                    }
                    tempProductsList.addAll(productsList)
                    listProducts()
                }
                .addOnFailureListener {
                }

and this is where I am getting the error.
val product = document.toObject(ProductDetails::class.java)
Edit:
A sample of my model class is provided below. It has a lot of fields but I copied only a few here. 'min_order_quantity' and 'max_order_quantity' are the two that I newly added in this model class and the items already in the Firestore doesn't have these fields.
@Parcelize
data class ProductDetails(
    var product_id: String? = "",
    val title: String = "",
    val mrp: String= "0.00",
    val price: String = "0.00",
    val description: String = "",
    var min_order_quantity: String="",
    var max_order_quantity: String="",
) : Parcelable

Logcat:
Process: com.abc.xyz, PID: 19223
java.lang.VerifyError: Verifier rejected class com.abc.xyz.models.ProductDetails: void com.abc.xyz.models.ProductDetails.<init>() failed to verify: void com.abc.xyz.models.ProductDetails.<init>(): [0x1FB] Rejecting invocation, expected 1 argument registers, method signature has 2 or more (declaration of 'com.abc.xyz.models.ProductDetails' appears in /data/data/com.abc.xyz/code_cache/.overlay/base.apk/classes5.dex)
    at java.lang.reflect.Constructor.newInstance0(Native Method)
    at java.lang.reflect.Constructor.newInstance(Constructor.java:343)
    at com.google.firebase.firestore.util.ApiUtil.newInstance(ApiUtil.java:43)
    at com.google.firebase.firestore.util.CustomClassMapper$BeanMapper.deserialize(CustomClassMapper.java:757)
    at com.google.firebase.firestore.util.CustomClassMapper$BeanMapper.deserialize(CustomClassMapper.java:741)
    at com.google.firebase.firestore.util.CustomClassMapper.convertBean(CustomClassMapper.java:542)
    at com.google.firebase.firestore.util.CustomClassMapper.deserializeToClass(CustomClassMapper.java:253)
    at com.google.firebase.firestore.util.CustomClassMapper.convertToCustomClass(CustomClassMapper.java:100)
    at com.google.firebase.firestore.DocumentSnapshot.toObject(DocumentSnapshot.java:183)
    at com.google.firebase.firestore.QueryDocumentSnapshot.toObject(QueryDocumentSnapshot.java:116)
    at com.google.firebase.firestore.DocumentSnapshot.toObject(DocumentSnapshot.java:161)
    at com.google.firebase.firestore.QueryDocumentSnapshot.toObject(QueryDocumentSnapshot.java:97)
    at com.abc.xyz.ui.fragments.HomeFragment.getProductList$lambda-7(HomeFragment.kt:431)
    at com.abc.xyz.ui.fragments.HomeFragment.lambda$QeVGu-lWsXTqkddk(Unknown Source:0)
    at com.abc.xyz.ui.fragments.-$$Lambda$HomeFragment$QeVGu-lWsXTqkddk.onComplete(Unknown Source:2)
    at com.google.android.gms.tasks.zzj.run(com.google.android.gms:play-services-tasks@@17.2.0:4)
    at android.os.Handler.handleCallback(Handler.java:938)
    at android.os.Handler.dispatchMessage(Handler.java:99)
    at android.os.Looper.loop(Looper.java:246)
    at android.app.ActivityThread.main(ActivityThread.java:8633)
    at java.lang.reflect.Method.invoke(Native Method)
    at com.android.internal.os.RuntimeInit$MethodAndArgsCaller.run(RuntimeInit.java:602)
    at com.android.internal.os.ZygoteInit.main(ZygoteInit.java:1130)

A: This isn't a problem with firebase fields. Try clearing your caches and restarting your computer. Please see this related question for more information:
java.lang.VerifyError: Verifier rejected class on Lollipop when using release APK
If you have a field in your model that isn't in the Firestore, it will be initialized to its default value. (in your case, "").
Additionally, if a field in the firestore does not exist in your model, it will be skipped during deserialization.
A data class can only have a certain number of parameters, which probably is 245.

A: As I understand, there is a limit to the number of parameters a data class can have and I think it's 245. I already had 245 and when I add another two the issue started. When I removed any two parameters, it works. Thanks for your insights


Today is an exciting day at the office!
Jean-Paul Calderone (exarkun from Twisted arrived in our office this morning to give our development team an in-depth training on Twisted.
For now, the schedule is two days of Twisted training, one day of code sprinting on Twisted, and two days of consulting on our platform and various issues and projects we have.
For us it's exciting to get a training from one of the top hackers in Twisted, and I hope it is exciting for him to see a commercially successful use of the project he worked on.
But mainly I'm looking forward to a bunch of days of high-level technology talk.
As we are deluding ourselves here into thinking it's snowing in Barcelona, I thought it appropriate to post some videos from the past few snowboarding trips.
Coincidentally, this is my first foray into the HTML5 video world – more on that later.
(Also notice the cool new orange snowboard pants that I settled on. Snowboard fashion was really boring this year, mostly grey and black only, with some ugly flashy colours as exceptions. I leave it to you to judge whether orange is one of them).
We spent eight full days in Tignes, France, with only about three days of sunny weather, and the rest filled with clouds and snow.
My goal this year was to learn how to do a 180. With the help of an instructor, that's exactly what I did! Here's an admittedly simple one – all the good ones are not caught on video.
A few weeks before our snowboard trip, we also had a business planning weekend which included one day of skiing. Xavier risked life and limb following me around with his iPhone to record this. It's not the most exciting descent in the world, and he ended up missing my one fall in it, but I was surprised to see how short the whole descent really is if you don't take any time to stop!
there is an enormous difference in colour between playing Ogg in Firefox, MP4 in Safari, and MP4 in Quicktime, on the same MacBook. My pants range from a soft orange to a bright red. Something is obviously up!
I configured our transcoding platform to generate the three types of output file needed to support HTML5: the thumbnail, Ogg/Theora/Vorbis, and .mp4 with H264 and AAC.
The embedded video should work fine in Firefox/Safari/Chrome/iPhone/Opera (except in Aitor's "I plug mplayer into Opera" case), and work fine in Explorer too where it falls back to Flash.
I couldn't get this to work in Android. 2.0 is rumoured to support the video tag, but so far no dice, and I couldn't find a single HTML5 video page online that the Android phones over here can play. If you can see these videos embedded in Android, or know what I should to fix them, please do let me know!
Since a few weeks my Facebook sharing has stopped working. At first it only seemed like a missing icon and broken config. But I had a really really hard time to figure out the problem, much harder than it should have been for a mostly open platform. Of course, for some reason this sharing part is closed, which doesn't make much sense at all. What secrets can Nokia possibly have invested in some code that pushes photos to flickr or Facebook.
At first I thought I had some login details problems, so I went to Settings > Sharing accounts and clicked on the Facebook account. That didn't do anything at all, no dialog popped up. Since the Delete button is in that popup, I also couldn't use the UI to recreate my Facebook sharing account.
I moved this file around to force recreation of data, which seemed to work after a reboot, since my Flickr data was now gone, as well as the Facebook one. I was able to click Flickr in Settings > Sharing accounts, but the Facebook still didn't pop up a dialog. At least this narrows down the problem I should solve for now: I can't even configure the service from scratch even when deleted, so let's focus on that first.
I reinstalled the package that contained the facebook sharing plugin. This restored the icon, but the popup still didn't work.
Usually I would just strace the relevant binary, but I considered the friction too high at first since there is no strace in fremantle, and I would have to set up a chroot for this.
But what binary ? I didn't even know what program handles the settings. After comparing a few ps listings, I figured out the program was controlpanel.
" which I wrongly took to mean that adding a facebook account was failing because it was still somehow present in the config. This is when I figured out that this code is closed, because I wasn't able to figure out where to get accountstore.c and look at what it is doing. I'm pretty sure it's not storing its settings in gconf (at least I couldn't find anything related to facebook sharing when walking the gconf tree), and it doesn't seem to be in any dot folders in my home dir. Anyone know ?
Finally, I gave up, set up the chroot, and straced that binary. And I should have known this would have led me to the right solution. Among all the noise, there were some calls trying to open a library. It's normal for a bunch of calls to fail as it searches the whole LD_LIBRARY_PATH, but usually the last one of those in an strace log should succeed. But they weren't; apparently /usr/lib/libfacebookcommon.so.0 was missing!
Looking for that file on disk confirmed that it wasn't there, and doing dpkg -L feedservice-plugin-fb-common showed that it should in fact be there. This reminded me of a pet peeve I have with those people who claim Debian's packaging system to be far superior to rpm – apparently dpkg doesn't have any equivalent of rpm -qv which allows you to verify that the files that should be installed by a package are indeed on disk. This would have saved me *a lot* of time figuring out this problem, and is typically the first thing I do on an rpm-based system where things act funny.
Using dpkg -S to figure out what package this belonged to, I apt-get remove'd that package, then reinstalled it and dependencies.
Still didn't work, so repeated the process, this time libfeeserviceutils.so.0 was missing, so reinstall feedservice-utils and dependencies.
For the record, I didn't tinker with any package files by hand (anyone who knows me a little knows my stance on packages and /usr), and I have no idea what I did to get into a situation where files that should be on disk aren't. And I'm worried about what else is missing, so if anyone can point me to some resources explaining how to verify installed package manifests, that would be awesome.


A major manufacturing company in Northwest Ohio has announced significant expansion plans for its Williams County-facility.
20/20 Custom Molded Plastics stated its intention to double production capacity through a $15.5 million investment which is expected to create at least 100 new jobs. The company will construct a 140,000 square-foot plant to go alongside its existing facility, while adding new injection molded machinery and equipment.
20/20 manufactures plastics products, specializing in structural foam molding. Founded in 1999 in Holiday City, located in the northwestern corner of Ohio, the company will be adding to its current workforce of 220 employees.
Ohio faced serious competition for this project from across the country, but in the end, Ernsberger credited the favorable utility rates and direct access to the Ohio Turnpike as key factors for his company choosing Holiday City.
Local, regional and state partners worked together in moving this project forward, including the Williams County Economic Development Corporation (WEDCO).
In addition, the Regional Growth Partnership and JobsOhio helped in providing a grant for the purchase of new machinery and equipment.


text:
Home » Colleges » Tata Institute of Fundamental Research
Tata Institute of Fundamental Research
Homi Bhabha Road , Mumbai, Maharashtra, India - 400005
+91 22 - 22782000
webmaster @tifr.res.in
http://www.tifr.res.in
About Tata Institute of Fundamental Research
Tata Institute of Fundamental Research (TIFR), Mumbai was established in 1945.
TIFR is a National Centre of the Government of India, under the umbrella of the Department of Atomic Energy, as well as a deemed University awarding degrees for master's and doctoral programs.
At TIFR, they carry out basic research in physics, chemistry, biology, mathematics, computer science and science education.
The institute first began functioning within the cosmic ray research unit on the campus of the Indian Institute of Science, Bangalore and later moved to Bombay.
All Bachelor P.hd
Bachelor Of Science in (Hons) Mathematics Full Time 3 Years
Bachelor Of Science in (Hons) Physics Full Time 3 Years
Bachelor of Science in Computer Science Full Time 3 Years 10+2
Doctor Of Philosophy in Computer Science Full Time 1 Year


There was a threat of rain Saturday night, but it didn't stop a good number of bluegrass fans from attending our Groundhog Day Show at the Santa Ynez Valley Grange Hall in downtown Los Olivos. We honored the ground hog with a foot-tall stuffed example (battery-operated), dug up by bassist Tom Lee and stuck in front of the main microphone all night. Peter brought along a fretless banjo, made by Frank Proffitt of Reese, NC. It sported a groundhog skin head which, as Frank told Peter in 1961, "is almost as good as cat skin for a banjer head." Peter, of course, performed a solo version Groundhog, learned from a version by Vester Jones of Carrol County, Virginia. The Very Lonesome Boys were joined by Ms. Francine, who sang a couple of her own songs and helped out with Jesse James to round out the evening.


Have you wondered about SOLIDWORKS User Groups and how you can get involved in one close to you? This Q&A features James Adkins, Computer Aided Drafting department head at Almanac Community College and group leader for the BACoN SWUG.
1. When you started using CAD software in your classroom in 2014, what made you choose to use SOLIDWORKS instead of another CAD program?
My introduction to SOLIDWORKS began out of necessity to support my students. While I did not teach SOLIDWORKS, my students were taking a class in it and asked me questions about their projects. I realized I would be a more effective educator if I were better able to assist them and provide more thorough answers. Up to that point, all of my solid modeling had been done in AutoCad 3D. Once I started using SOLIDWORKS, there was no looking back.
2. Is SOLIDWORKS the only CAD software taught at ACC?
At Alamance Community College, we teach two semesters of AutoCad and then three semesters of SOLIDWORKS. Once introduced to it, students will take six classes, which include SOLIDWORKS as a required design tool. This includes Fluid Mechanics (Flow), Machine Design (Simulation), Mechanics (FEA) and Design projects (Assemblies and 3D printing).
3. What are your roles/responsibilities in your local SWUG?
My role is the Burlington-Alamance County NC SWUG (BACoN SWUG) group leader. As this is a new group, I do not yet have a co-leader which means that I do it all. I presently plan all meetings, schedule locations, meals, presentations, recruit new members and work with the sponsors to build the support of our group. It all makes for a very busy evening at home, but it is worth the effort.
4. How did you become involved in the SWUG?
I created the group after learning how many SOLIDWORKS users in the area didn't participate in any groups. After successfully connecting with local businesses that use the software, I now have 55 users on my mailing list. I plan to hold eight to ten meetings annually, so all members have ample opportunities to attend at least six meetings in a year.
One of the best parts with the new group thus far has been in deciding upon a name and developing the logo. I have joined an elite crew of users known as the #BACON Brotherhood (if you have never heard of these guys, make plans to attend SOLIDWORKS WORLD 2018). It seemed like a perfect fit to incorporate bacon into the new group name.
While I didn't plan to build a new user group in this area,it sort of jumped in my lap. I had met many local users who wouldn't make the drive to other regional groups. I saw this as an opportunity to reach out to the local business community and foster a professional network for local users, including students as well as industry users. Both education and industry coming together to promote and combine new technology with professional skills which allow all members to grow and get to know each other.
5. How has being a leader in this group helped you in your career, your life and your overall growth as an engineer?
BACoN SWUG is the second user group I have lead. My previous group, SoVA SWUG, in Danville Virginia, was where it all began. As a group leader, I have developed professional contacts which have brought career opportunities to my students as well as helped them begin building their own professional networks.
Additionally, I have met a lot of great people at the meetings and promote my CAD program to local businesses where I am developing partnerships and personal relationships. On a personal side, I have completed a couple of certification exams with plans to sit for several others as time permits, developing training.
As a leader, I have also had the opportunity to attended a couple of SOLIDWORKS World conferences and worked with professionals from all over the world. Through these conferences I have gotten to know a few SOLIDWORKS corporate directors as well as certified SOLIDWORKS experts. Not only does this provide a tremendous resource, but some of them have visited my groups as guest speakers and presenters. Many thanks to Richard Doyle, Casey Gorman and Sal Lama for their time, support and work they do for all SWUG's.
6. How do you become a leader in a SWUG group? What steps or tips would you provide someone who is seeking to become a leader in the group?
First and foremost, search for SOLIDWORK User Groups near you, and determine if there is another group within a short drive of your location. If so, find out if the group is active and possibly get involved with it. If there isn't one nearby, you can request a group to be set up in your area. You will need to do some research to ensure there are enough local users to support the group.
You can contact local VARs like TriMech, and let them know you are interested in setting up a group. While they cannot give out contact information, they can help promote the group. I searched the job want ads for jobs which required SOLIDWORKS experience and wrote to the companies announcing my group. This resulted in more than a dozen responses with new members.
The SWUG site also includes general information about regional contacts who are responsible for user groups in their assigned areas. If you have questions or are looking for general information, they are great people to contact.
It is also important to develop a good relationship with sponsors as they provide additional resources for the groups. TriMech has been a great sponsor for both of my user groups and has provided a lot of wonderful door prizes to each. More importantly though has been the presentation support, and TriMech's willingness to send Application Engineers to the meetings. These guys are CSWE-level users who have a willingness to share their knowledge and demonstrate their expertise in intriguing presentations, like TriMech Application Engineer Justin Lingerfelt. .
7. How does the SWUG help aid students at ACC directly?
My students have gotten involved with the user group and have all seen ways that SOLIDWORKS is used in industry. They have also started developing professional contacts, which may one day result in a job opportunity for them. Many of them have also won some great door prizes at the meetings while they also are learning ways they can complete their class projects faster and more effectively. It is a win-win for the students.
8. In your opinion, are most students gaining experience in SOLIDWORKS vs. other CAD programs?
You might expect me to have a biased opinion when it comes to education, but I believe that there are a lot of missed opportunities here due to other software packages being free to education. Many school systems use other programs due to the cost while some are mandated by the states to use competing products. If companies use SOLIDWORKS and they prefer employees with experience in it, they should contact their local school system and provide input to that effect.
9. What are the advantages of gaining experience in SOLIDWORKS vs. other software products?
I do believe there are advantages in having SOLIDWORKS experience, if for no other reason than that the job market is looking for it. I have been tracking job ads seeking SOLIDWORKS experience as well as other competing products. There have been consistently four times more jobs available for SOLIDWORKS than other similar programs. This is within a 50-mile radius of ACC's campus.
10. Please explain the most regarded benefits of user groups to the SOLIDWORKS community at ACC.
Alamance Community College has been great to provide support for the BACoN SWUG members. They provide a meeting location which includes audio visual equipment for the presentations, saving the group a lot of money planning. Plus, the college also provides training opportunities for local companies, either as custom classes or as continuing education. ACC is the place to be for SOLIDWORKS users.
We (ACC) are also able to provide certification testing for student users free of charge as well as free student licenses. Members of the user group have direct access to these classes as well as a direct access to ACC personnel who can assist them in setting up specialized training as needed.
The local SOLIDWORKS community has the opportunity to participate in professional development, training and observe the latest in advanced design and 3D printing technology available.
12. In what ways do you reach out to prospective students/users in the SWUG?
My recruiting efforts of students include visiting local area high schools, local maker fair events, career fairs and hosting special presentations and public demonstrations during activities which I believe will draw prospective students.
As another outreach, I attend the user group meetings of the Piedmont Triad SWUG in Greensboro where Stephen Frick is the user group leader. They also meet monthly on the second Wednesday of the month where as I try to meet my group on the first Thursday of the month.
For more insight on SOLIDWORKS User Groups, check out our training page for groups in your area.


MONSTER RARE 1974 CHRISTIAN PSYCH LP FROM SCOTLAND ON THE ORIGINAL SCOTIA LABEL. COVER IS A NICE EX, NO SPLITS OR WRITING! THE DISC IS A NICE VG+ WITH ONLY SOME LIGHT SCUFFS AND PLAYS COOL! SUPER SCARCE HIGH-POWERED BLUESY GARAGE/PSYCH HARD-ROCK BEAST, PACKED TO THE GILLS WITH CHEESY ORGAN, JUBILANT FUZZ GUITAR, AND FRENZIED DRUMMING ('THE ARCHIVIST')! THIS JUST NEVER TURNS UP!!