1989… The true difference / Der wahre Unterschied / Ten skutečný rozdíl

(en / de / cs)

Capitalism is better than socialism, but it’s worse than I have expected. / Kapitalismus ist besser als Sozialismus, aber schlimmer als ich erwartete. / Kapitalismus je lepší než socialismus, ale horší než jsem čekal.
by Jiří Suchý – Czech actor, songwriter, lyricist and director / tschechischer Schauspieler, Liedermacher, Texter und Regisseur

…inspired et al. to the following…

(en) Capitalism is better than socialism, but worse than I thought – these are the real differences:

  • In socialism, thieves stole toilet paper, soap, pencils. In capitalism, thieves steal factories including those producing toilet paper, soaps and pencils.
  • In socialism, workers got the surplus. In capitalism, they are the surplus.
  • In socialism, many people have stolen, but little, in capitalism few people steal, but a lot.
  • In socialism they wrote about criminals in a black chronicle and they were in jail. In capitalism one writes about them as celebrities and they’re in tax haven.

(de) Kapitalismus ist besser als Sozialismus, aber schlimmer als ich dachte – das sind die wirklichen Unterschiede:

  • Im Sozialismus stahlen die Diebe Toilettenpapier, Seife, Bleistifte. Im Kapitalismus stehlen Diebe Fabriken, auch die in denen Toilettenpapier, Seifen, Bleistifte hergestellt werden.
  • Im Sozialismus erhielten Arbeitskräfte den Überschuss. Im Kapitalismus sind sie der Überschuss.
  • Im Sozialismus haben viele Menschen gestohlen, aber wenig. Im Kapitalismus stehlen wenige, dafür sehr viel.
  • Im Sozialismus schrieb man über Verbrecher in einer schwarzen Chronik und sie sassen im Gefängnis. Im Kapitalismus wird über sie als Prominente geschrieben und sie sitzen in der Steueroase.

(cs) Kapitalismus je lepší než socialismus, ale horší než jsem si myslel – to jsou skutečné rozdíly mezi kapitalismem a socialismem:

  • V socialismu zloději kradli toaletní papír, mýdlo, tužky. V kapitalismu zloději kradou fabriky včetně těch vyrábějící toaletní papír, mýdla, tužky.
  • V socialismu dělníci dostávali přebytky. V kapitalismu, jsou dělníci přebytkem.
  • V socialismu kradlo hodně lidí, ale málo. V kapitalismu krade málo lidí, ale zato hodně.
  • V socialismu se o zlodějích psalo v černé kronice a seděli v base. V kapitalismu se o zlodějích píše jako o celebritách a sedí v daňovém ráji.

 

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Alcohol-abuse drug Antabuse (disulfiram) kills cancer cells

What the report “Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4” Nature, 6/14 Dec ’17 (1) is all about

“Alcohol-abuse drug Antabuse kills cancer cells”, writes one of the scientists of an international team(1) in a media release of his university (Alcohol-abuse drug Antabuse kills cancer cellsKarolinska Institutet, 7/12 Dec ’17) about their just published report Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4Nature, 6/14 Dec ’17(1) and continues that the scientist found out, “that the alcohol-abuse drug Antabuse is effective against cancer [and] identifies a potential mechanism of action for the anti-tumour effect.”

The report is about three issues:

  • The, highly interesting, progress in lab work on disufiram, which “fills an important knowledge gap regarding the anti-cancer mechanism of disulfiram and paves the way for future clinical trials,” as “[in] laboratory experiments, the team found that in mice and in the human body, disulfiram becomes metabolised into a molecule that causes a naturally occurring protein NPL4 to clump together with its partner, the body’s p97 enzyme. This process ‘freezes’ and thereby functionally disables the otherwise very mobile and tumour growth-supporting NPL4-p97 duo, resulting in cancer cell death…” (Jiří Bártek in the Karolinska media release)
    NOTE: the first clinical trial just began in Olomouc(2)
     
  • Yet another analyses/report of the records/cases, this time “of cancer patients across Denmark”. This, I think, may/should be “put into perspective” a bit more thoroughly and together with other cases(3), at least as long as the clinical tests are on the way.
     
  • The Nonprofit drugs issues, briefly mentioned by the authors. This theme, as a larger multidisciplinary project, is currently in preparation(4).
Notes, quotes, further reading

(1)

The countries and institutions of the international team…

  • Czech Rep – Palacky University, Olomouc; Charles University, Prague; Psychiatric Hospital, Sternberk
  • Denmark – Danish Cancer Society Research Center, Copenhagen
  • Sweden – Karolinska Institute, Stockholm
  • Switzerland – Kantonsspital St Gallen
  • USA – Caltech, Pasadena, California; Wayne State University, Detroit, Michigan; Amgen, Thousand Oaks, California
  • China – Guangzhou Medical University, Guangzhou

…and their report:

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4
Zdeněk Škrott+, Martin Mistřík+, Klaus Kaae Andersen, Søren Friis, Dušana Majera, Ján Gurský, Tomáš Oždian, Jiřina Bártková, Zsófia Turi, Pavel Moudrý, Marianne Kraus, Martina Michalová, Jana Václavková, Petr Džubák, Ivo Vrobel, Pavla Poučková, Jindřich Sedláček, Andrea Miklovičová, Anne Kutt, Jing Li, Jana Mattová, Christoph Driessen, Q. Ping Dou, Jørgen Olsen, Marián Hajdúch, Boris Cvek*, Raymond J. Deshaies*, Jiří Bártek* (+contributed equally, *corresponding authors)
Nature 552, 194–199 (14 Dec 2017), doi:10.1038/nature25016, published online: 06 Dec 2017

The authors sum up their findings in the report’s last section:

Model of DSF anti-cancer activity in patients
Fig. 4f

Skrott_et_al-2017-Nature_p5-fig4f_cropped

DSF = disulfiram (tetraethylthiuram disulfide)
DTC = diethyldithiocarbamate
CuET = DTC–copper complex (bis (diethyldithiocarbamate)–copper)

Discussion
Our results help to explain the anti-cancer activity of the alcohol-abuse drug disulfiram.
We propose a model for DSF cytotoxic activity, featuring rapid conversion of DSF into CuET, which accumulates in tumours. After entering cells, CuET binds NPL4 and induces its aggregation, consequently disabling the vital p97–NPL4–UFD1 pathway and inducing a complex cellular phenotype leading to cell death (Fig. 4f). Supporting CuET as the active metabolite is the correlation of CuET concentrations (active in the nanomolar range) with the biological effects and functional impact on the targeted pathway(s) in vivo.
In addition, CuET is the only known metabolite of DSF containing copper ions, a metal that enhances the anti-tumour effects of DSF; it is unlikely that another DSF metabolite could represent the major anti-cancer agent as levels of non-CuET metabolites should be lowered by copper addition.
We also present a method for CuET detection in tissues and plasma, as well as data suggesting that preferential accumulation of CuET in tumours may contribute to cancer cell toxicity, consistent with the high therapeutic tolerability of DSF3, as documented even after years of daily administration at doses comparable to those we used in our mouse experiments.
Considering the numerous studies on DSF and diverse opinions about the potential target of its anti-cancer effects44, identification of NPL4, a key component of the p97–NPL4–UFD1 segregase complex, as the molecular target of CuET is surprising. The CuET–NPL4 interaction leads to rapid formation of protein aggregates and immobilization of this otherwise very mobile multifunctional protein complex, resulting in a severe phenotype, induction of HSR and eventually cell death. While additional potential targets of CuET cannot be excluded, the malfunction of the p97 pathway due to the NPL4–p97 aggregate formation explains the major cell phenotypes and the consequent cell death.
Our work also reconciles the controversial studies6,12, suggesting that the proteasome is the DSF target, by demonstrating that neither 20S nor 26S proteasome, but the processing of ubiquitylated proteins by the NPL4-dependent segregase, is targeted by CuET.
Our results support the notion that the p97–NPL4 pathway is a promising therapeutic target in oncology45,46. Indeed, reports on p97 overabundance correlating with progression and metastasis of carcinomas of the breast, colon and prostate47–49 are consistent with our present nationwide epidemiological analysis, which revealed an association between continued use of DSF and favourable prognosis, an intriguing finding that should be investigated further, particularly given the currently limited therapeutic options for patients with metastatic cancer.
From a broader perspective, our study illustrates the potential of multifaceted approaches to drug repurposing, providing novel mechanistic insights, identification of new cancer-relevant targets and encouragement for further clinical trials, here with DSF, an old, safe and public domain drug4 that might help to save lives of patients with cancer worldwide.


3. Iljin, K. et al. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identfies disulfiram as an inhibitor of prostate cancer cell growth. Clin. Cancer Res. 15, 6070–6078 (2009).
4. Cvek, B. Nonprofit drugs as the salvation of the world’s healthcare systems: the case of Antabuse (disulfiram). Drug Discov. Today 17, 409–412 (2012).

6. Chen, D., Cui, Q. C., Yang, H. & Dou, Q. P. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 66, 10425–10433 (2006).

12. Lövborg, H. et al. Inhibition of proteasome activity, nuclear factor-κB translocation and cell survival by the antialcoholism drug disulfiram. Int. J. Cancer 118, 1577–1580 (2006).

44. Cvek, B. Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. Curr. Cancer Drug Targets 11, 332–337 (2011).
45. Deshaies, R. J. Proteotoxic crisis, the ubiquitin–proteasome system, and cancer therapy. BMC Biol. 12, 94 (2014).
46. Anderson, D. J. et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28, 653–665 (2015).
47. Cui, Y. et al. High expression of valosin-containing protein predicts poor prognosis in patients with breast carcinoma. Tumour Biol. 36, 9919–9927 (2015).
48. Yamamoto, S. et al. Expression of valosin-containing protein in colorectal carcinomas as a predictor for disease recurrence and prognosis. Clin. Cancer Res. 10, 651–657 (2004).
49. Tsujimoto, Y. et al. Elevated expression of valosin-containing protein (p97) is associated with poor prognosis of prostate cancer. Clin. Cancer Res. 10, 3007–3012 (2004).


(2)

clinical tests in Olomouc:


(3)

previous, further cases, reports in:


(4)

on Nonprofit drugs see also:

Disulfiram (Antabuse) against Cancer

Research, Case Reports, Clinical Trials

» DEUTSCHAntabuse (disulfiram) against Cancer
a presentation by
 Boris Cvek, Ph.D.
University of Olomouc, Social Health Institute OUSHI
(formerly at the Department of Cell Biology and Genetics)

Research in Cells and Animals

Many scientific publications have demonstrated that Antabuse (disulfiram), especially when combined with copper (cf. The Active Compound further below), kill cancer cells and is able to suppress tumors in mice.

The figure below, from our research now being prepared for publication (Nature, Dec 6/14 2017, doi:10.1038/nature25016, see Alcohol-abuse drug Antabuse (disulfiram) kills cancer cells), shows mice with a metastasis of human breast cancer, most effectively suppressed by the active compound.

antabuse-boris-cvek-01
gluCu = food supplement containing copper | Mock = control group

Case Report by Dr. Lewison (Prog. Clin. Biol. Res. 12, 47-53, 1977)

In 1977, Dr. Lewison from Johns Hopkins University in the USA published a case report of a patient with metastasizing breast cancer who become an alcoholic. Between 1961-1971 she used Antabuse and became cancer-free. She died in 1971 – not because of cancer, but by falling from a window while heavily drunk.

“However, in 1961 she became a severe alcoholic and it was necessary to discontinue all hormone therapy and Antabuse (Disulfiram) was started [for treatment of alcoholism]. Over the next 10 years – from 1961 to 1971 – complete resolution of all bone lesions in the spine, skull, pelvis and ribs gradually occurred and the patient remained clinically free of cancer with no further hormone therapy, chemotherapy, or radiation therapy. Frequent psychiatric care was required and she remained on and off Antabuse therapy for her continued drinking problem. She died in 1971 when she accidentally fell from a third floor window. The coroner’s report showed a high blood alcohol level and residual nests of metastatic carcinoma in the bone marrow.”

Ditiocarb Clinical Trial (Biotherapy 6, 9-13, 1993)

In 1993, French scientists published a phase II clinical trial of a drug called Ditiocarb. This compound is produced after ingestion of Antabuse. They used very low doses – 700 mg weekly, in comparison to a standard Antabuse dosage of 250-500 mg daily.

Sixty-four women with non-metastatic high risk breast cancer after surgery were divided into two equal groups. The first group were placed on standard chemo + placebo, while the second were on the same chemo + Ditiocarb. The drugs were taken for 9 months. After 5 years, 55% of patients were alive in the first group compared to 81% of patients in the second group.

It is to be expected that with higher doses, and after longer treatment, the effect might be much stronger. Our hypothesis is that the active compound (which occurs in the body after Ditiocarb reaction with copper, cf. The Active Compound below) was able to destroy micro metastases in some patients – even at such low doses and after only 9 months.

Case Report from Utah (Mol. Cancer Ther. 3, 1049-1060, 2004)

In 2004, scientists from Utah published a case report of a patient with melanoma metastasis in the liver, which – by using a combination of disulfiram and zinc – shrank after a few months and disappeared after three and a half years.

antabuse-boris-cvek-02

Today, the fact that the active compound is a copper combination is already known (in fact, the zinc compound does not exist in human body and disulfiram prefers copper that is naturally occurring in the body).

Disulfiram Clinical Trial (Oncologist 20, 366-367, 2015)

In 2015, the Oncologist journal published results of a clinical trial from Israel, where 40 patients with metastatic lung cancer were divided into two equal groups (of 20 each). The first group were placed on standard chemo, while the second group were on standard chemo + disulfiram (just 120 mg daily). Patients from the second group survived 3 months longer on average and, most importantly, two survived for a long time. The figure further shows that all the patients from the first group died after two years.

antabuse-boris-cvek-03

The Active Compound

We have various experimental evidence, now prepared for publication, showing that the active compound is a complex of Ditiocarb and copper; which occurs under normal conditions after Antabuse ingestion in the human body.

antabuse-boris-cvek-04

Phase II and phase III clinical trials

To get approval from state authorities for Antabuse to be used normally in oncology, we need to conduct further and larger clinical trials  – i.e. phase II clinical trials (hundreds of patients) and phase III in particular (thousands of patients). We need such trials to examine various cancers and to combine Antabuse with various standard chemo drugs.

Normally, clinical trials are funded by pharmaceutical companies. However, Antabuse is not patentable. The advantage is that it is affordable (hundreds of Dollars/Euros per patient per year), yet the weakness is that it is not interesting for business. Therefore, Antabuse clinical trials must be paid by charities and governments in the public interest. We want to finance such clinical trials.

If large phase III clinical trials show that Antabuse is able to cure some cancers, it would be, as an inexpensive drug, affordable even for patients in low-income countries.

First Steps and Further Progress – including fast-track approval

In Olomouc, where we have experience with Antabuse research, there are oncologists who are willing to conduct Antabuse clinical trials. In collaboration with them, we have designed a phase II clinical trial of 100 patients with metastatic breast cancer and 100 patients with metastatic lung cancer (500 mg Antabuse + 2 mg copper daily).

In all patients, overall survival will be determined, and if their tumors shrink, do not grow, or grow further. The results will be of value for the identification of patients who are most sensitive to Antabuse therapy, and for further research as to why some patients are more sensitive than others.

We would also like to conduct further trials in patients with different cancers. In the case of positive results, we would design phase III clinical trials and talk to the FDA and EMA to win a fast-track approval of Antabuse for metastatic cancer where it is curable. Negative results would instigate phase II clinical trials of Antabuse in combination with standard chemo.

Why Test Antabuse in Olomouc?

Those conservative ones among oncologists usually dismiss Antabuse, especially as a drug not developed by big pharmaceutical companies. However, in Olomouc we have a team of oncologists led by prof. Bohuslav Melichar, head of the Oncology Unit of the Teaching Hospital, who are willingto conduct clinical trials of Antabuse in patients with metastatic breast/lung cancer and other cancers – as soon as sufficient funding is found.

Cost Estimate of the 100 + 100 Trial

  • Wages of physicians (2 physicians), coordinator and supervisor of clinical trial
    some € 80,000 per year – for 2 years € 160,000
  • Material (Antabuse, copper supplementation, materials used for standard health care in hospitals), other services and non-material costs (examination of patients, insurance according to law),
    some € 120,000 per year – for 2 years € 240,000

  • Overall cost of 1 phase II clinical trial of 100 + 100 patients
    some € 200,000 per year – for 2 years € 400,000

This project is the result of our long-term scientific research of Antabuse anti-cancer activity here in Olomouc. Our experience and concept is (so far) unique to the world. There is only one team, besides us, focused on Antabuse application in oncology, (prof. Weiguang Wang in UK), but they are working on some patentable formulation of disulfiram.

Our strategy is unmatched and fits perfectly into the mission of Olomouc University Social Health Institute (OUSHI). It is not “only” about curing patients, but we have an ambition to change healthcare systems globally and to make them more affordable with “nonprofit drugs”. Details of this idea can be found in the article “Nonprofit drugs as the salvation for world‘s health care systems: the case of Antabuse” by B. Cvek, an OUSHI member, published in the prestigious international scientific journal Drug Discovery Today.


PROJECT HEADS / TEAMBoris Cvek, Ph.D. / prof. Peter Tavel, Ph.D. / et al. (Olomouc University (CZ)

COLLABORATIONprof. Ray Deshaies (California Institute of Technology, Pasadena CA (USA) / prof. Vikas Sukhatme (Dana-Farber/Harvard Cancer Research, Boston MA (USA) / prof. Jiri Bartek (Danish Cancer Society Research Center, Copenhagen (DK) / prof. Ping Dou (Barbara Ann Karmanos Cancer Institute, Detroit MI (USA) / prof. Christoph Driessen (Kantonsspital St. Gallen (CH) / prof. Pavla Pouckova (1st Medical Faculty Charles University, Prague (CZ)

No more wars, no more killings, by states – how to… Is Europe already so far?

In the middle of the 19th century, in the middle of Europe, the elites of what became multicultural Switzerland, decided not to participate in any wars. One of the questions this society asked: “How to be secure without wars?”

In the middle of the 20th century, the elites of what became EU decided not to fight each other – yet to go to any wars they wish to. One of the questions the EU did not ask yet: “How to be secure without wars?”

Another question asked by those people, in the middle of the 19th century, in the middle of Europe: “How to participate all in shaping all things common together?”

I think these two questions should be asked by today’s elites of Europe. Yet who are the elites of today? All the people? Is Europe already that far?

What that “anti minarets” initiative & referendum were really about

That state wide initiative and referendum were not about building minarets or mosques, they could not have been. Simply because building permits are communal matters.

They were, in their “ban on minarets” clothes, nothing more, nothing less than “caressing” Mr Blocher and his party. Which 30.7% of voters did.*)

As to those building permits, here specifically of mosques and minarets, which nobody can forbid, it is – really and precisely – about relations of a believers’ community with that of the citizens, the citizens themselves, who decide quite a lot of things.


*) 57.5% valid votes, with voters’ participation of 53.4% on this ballot, makes 57.5% x 53.4% = 30.7%, one of the fourth quarter’s voting topics, in the weeks ending Nov 29, 09

Klaus fears to lose sovereignty, Czechs say

nanofjórbyznys.cz – 22 Apr ’04

One week before the Czech Republic joins the European Union, Václav Klaus, also known as The Great euSkeptic, said that May 1 will spell the end of His Sovereignty. “In a few days, Our Majesty will cease to exist as an Independent and Sovereign Entity,” he wrote in an opinion piece published Thursday in the daily MF Dnes under the title “Let Us not lose Ourselves in the Union.”

While recognizing positive aspects, i.e. new money flowing in(to his and other cronies pockets), of the accession of ten mainly former communist countries to the current group of fifteen next week, he said that enlargement posed an “important risk” for the emerging twentyfive-strong European Union. Klaus warned in particular of “a too hasty de-communisation process … which does not sufficiently take into account economic status, geographic situation and national particularities of the Sovereign Majesties of Central and Eastern Europe.”

He said tensions could arise among EU members over a “majestic deficit in EU decision-making – in other words, insensitive decision-making by civil servants who are elected by no one.” A new competition to all those non-elected priviledged in Postsoviet satellites – the CEE Honorary Majesties, Cronies, Looters and Robbers.

The Czech Monarch urged: “Let Us do all We can to avoid losing Ourselves in the EU, so that the age-old work of our Honorary Majesties, Cronies, Looters and Robbers does not get diluted. The Monarchs of the East are the only Legitimate Force, and Vladimir Putin, Boris Yeltzin and Leonid Brezhnew our Great Prophets.”

However, some Czech sources report that Klaus is fearing competition of Brussel’s bureaucracy, he feels inferior to.

related articles: Czech Vaclav Klaus fears to lose sovereignty, cease to exist in the EU, April ’04 and beyond, EUbusiness et al.

Free Europeans, don’t leave yourselves alone!


European Citizens’ Convention and Constitution

Free Europeans, don’t leave yourselves alone!

EU Convention should be made permanent and together with the EU Constitution put under citizens’ sovereignty

Once upon a time, as I grew up in Switzerland (Europe), my second home, I too began to participate in approving of changes to our Federal Constitution. Nothing extraordinary, one of the most natural, almost everyday – perhaps slightly boring – things. One of our political rights as citizens. Initiating amendments to the Federal Constitution is another one of these our political rights, each of us, the Swiss, naturally has.

We, the citizens, are called the Sovereign – as written in our Constitution – and so must approve of every such amendment. If we wish, we initiate changes to our Constitution – to put things into it as we see them, as we please to see them. Our representatives’ task is to make these our wishes, when accepted by the majority of voters in one of the federal referendums, into working laws. Of course, they may propose their amendments, which we, the citizens, approve – or not, as we wish.

As all this keeps on going since some generations, our Constitution became a patchwork. A patchwork which I like, as all living things, that by their nature are like that – living, chaotic, and everyone’s thing. On the contrary tombstones, intended to be firm, don’t live, they just dissipate, their intended firmness becoming an illusion.

Yet other, more educated, people, our representatives, politicians, and lawyers, did not like this chaotic patchwork of bumpery text and made a revised version of it. For the second time since 1848. To be elegant, and to be read smoothly. Discussed widely by interested public, and in both chambers of the Federal Parliament. Naturally, we the simple citizens had the last say in the revision, approved it in one of the obligatory binding referendums, and now go on amending this streamlined version – turning it into a patchwork again.

And so we live on happily, wondering why the citizens of Europe don’t have these – most natural – rights and why on earth are they deprived of such a – most natural – participation in their very things. And wondering, why the EU Constitution has been brewed up by a handful of men, watched doing so in a Convention theatre by an audience of a selected couple of hundred. Passing on the presidential paper onto fifteen heads of states to approve it after their summer holidays. For – instead of – the millions of citizens.

Amazing middle ages, to our simple Swiss ears, eyes and minds. Since a couple of generations, we do have our initiatives and referendums – our citizens’ Convention – and are Sovereign also to our Constitution. In this our permanent citizens’ Convention we keep on initiating changes to it and approving of all changes to it. So our kids will do, and their kids, and their kids, and so on.

Free Europeans, do you want to leave the Swiss alone in enjoying the most natural political rights? No? So, dear co-Europeans: Why don’t you demand that the EU Convention be made permanent and together with the EU Constitution put under your, citizens’, sovereignty.

You too are free and responsible citizens, aren’t you? Free Europeans, get your – natural – rights!

Free Europeans, don’t leave yourselves alone!

Vladimir Rott
Zurich / Prague, Europe
26 August 2003


released in August 2003 through NDDIE Network for Direct Democracy in Europe – you may find some of it’s people at • citizens-initiative.eu • democracy-international.org • democratie.nu • mehr-demokratie.de (you may contact and/or join in the working circle mehr-demokratie.de/ak_europa.html) • meerdemocratie.nl • referendumplatform.nl • sdnl.nl/wit-view.htm (WIT)…

available as pdf download (300kb) at: vjrott.com/eccc-call-2003-en-nl-cs.pdf – in Englisch, Dutch/Flemish and Czech