[Gothic Metal] The Gathering – Mandylion

This week marked the 21st anniversary of the release of The Gathering “Mandylion”album. I missed the 20th anniversary last year but later than never no?

The Gathering is a dutch gothic metal band formed in the early 1990s. You may not know them but you may know Anneke Van Giersbergen (The Gentle Storm). Yep, that the first band in Anneke career and what I can tell with Anneke on board that this band has experienced a lot. A lot that they went from full doom metal in their freshman album “Always” (with Bart Smits as the growl front singer) into full progressive and acoustic rock before their breakup.
Why I love this album? Maybe because it was the first album that dove me into female-fronted metal, maybe because it was the way I got introduced to the band (special thanks for Jean-Roch R. about this), maybe it was the nice guitar solo ballads mixed with the keyboards, maybe it was listening to Anneke.
For many reasons, I feel “Mandylion” and the next album “Nighttime Birds” the best albums. I got into it via their only videoclip of this album “Leaves”. Love at first sight! Back then iTunes was just released and finding a physical copy of the album was almost impossible. So I got into it via Napster and MP3 sharing.
Considering the release of the album in 1995, it is still impressive that after 20 years it still sound fresh and accessible. There are several nice tracks, starting with “Strange Machines” (the first song of the album) using footage of the movie “H.G.Wells Time Machine”, nicely blending Anneke’s voice with bass shredding. My second love is “Eleanor” that starts with keyboards and nicely begin with a guitar and bass, followed by Anneke. It starts mellow and then ramp up in speed. I like it so much I refer as the classical “The Gathering” style. The interesting part of the album is “In Motion #1” coming in the middle of the album and its ending part “In Motion #2”, but also pure instrumental track such as “Mandylion” and “Sand & Mercury”.
This album is in my opinion one of these album that were like preparing the metal scene with the arrival of FFM bands and the first generation of female metal singers including Tarja Turunen (Nightwish, Finland), Sharon Den Adel (Within Temptation, Netherlands), Liv Kristin (Theatre of Tragedy, Norway) and Cristina Scabbier (Lacuna Coil, Italy) and Europe launch the invasion of FFM bands worldwide with a new wave of gothic metal that will quickly evolve into Symphonic metal, propelled by Therion “Theli”.
If you have to pick one album from their discography, it should be this one. A timeless masterpiece of the band.
As a treat, I posted the video of “Leaves”, note it is an edited version of the album. It is interesting to see Anneke back in her beginning.

[Stroke/BBB] Hyperfibrinolysis increases blood brain barrier permeability by a plasmin and bradykinin-dependent mechanism

This is an article sharing from Oscar, a follower of this page in which he has co-authored (see link to the study below). It is a peer-reviewed article recently published in Blood (a fairly good and robust journal, the official journal of the American Society of Hematology) that focused on the effect of the overexpression of tissue plasminogen activator (tPA) on the BBB integrity.
tPA is the drug of choice for ischemic stroke (80% of total stroke), as it acts as a clot buster (it basically breaks down any clots blocking small brain vessels into pieces). tPA is also until now the only FDA-approved drug. However, tPA has severe downsides. First it has a very limited time-window efficacy that places it uses only for stroke events that have initiated less than 5 hours. Usually this time period is often passed, between the onset of the stroke outcome (the FAST signs), the arrival of 911 and drive to the appropriate stroke center and the differential diagnosis between ischemic and hemorrhagic stroke. After that time-window, tPA becomes pretty useless.
The second issue with tPA is that although it may help reperfuse the ischemic brain tissue and save the neurons inside it during the first hours, it is accompanied by a risk of hemorrhagic transformation within the first 72 hours after stroke by increasing the risk of brain bleeding. Hemorrhagic stroke is even more noxious than ischemic stroke as we have several issues to deal with: a massive entrance of water and ions resulting in brain swelling but foremost the release of hemoglobin (due to the rupture of red blood cells) inside the brain. The heme inside such hemoglobin is a very reactive and aggressive chemical. It is normally inactivated as it transformed into bilirubin and excreted via the bile. But when you have an important release of heme, you have an accumulation of bilirubin (responsible of the jaundice) that has still a toxicity. Therefore, it is important to find a protection mechanism against tPA-induced hemorrhagic stroke injury.
This paper elegantly describe the effect of overexpression of tPA in mice and what does it means in terms of increased plasmin production and its mechanism on action at the BBB. It suggest that plasmin production induced by tPA induces the production of bradykinin (BK), which in turn induces the BBB disruption. Such hypothesis is further supported by the presence of some data obtained from human patients following tPA administration after ischemic stroke injury, in which the authors have measured an elevation of BK levels.
I would say the only drawback of this paper is the absence of in vitro data that directly demonstrate the direct impact of BK on the BBB function and the mechanism by which BK impact the BBB integrity (tight junctions remodeling? destruction of tight junctions by matrix metalloproteinases?).

If you are interested to learn more about this study, you can find the full-text below (behind paywall): http://www.bloodjournal.org/content/early/2016/08/16/blood-2016-03-705384

[TV/Horror] The Walking Dead Season 1-6 feedback and thoughts.

I admit, I have been late, very late on catching on the Walking Dead frenzy. So late that it took me this summer to hang and binge watch 6 years worth of the Walking Dead seasons in less than 6 weeks. But thanks to AMC “The Walking Dead” marathons ran every Sundays this summer, I caught it. I still have to catch “TWD” Comic book series but dang, it was worth it. So much for me to catch and hang on a TV serie, the last one that I hanged on from beginnning to end was……Lost. I guess there are several elements of Lost narrative that are also present in the TWD.
I am not gonna spoil that much on TWD but there will be elements of the six seasons discussed. You are warned.
First, the walkers, the rotten, the crawlers….in other words the living dead. They are the closest of the orginal living dead from Georges A. Romero’s “Night of The Living Dead”. Flacid, slow, flesh-eating creatures that are only ghosts of their former past life. Those bitten by them are also becoming part of the living dead as well. They are devoid of any feelings, any memories and solely relying on their reptilian brain. Indeed, this has became the main method to kill them (by stabbing a knife straight throught the temporal lobe). Again, as in the “Night of the Dead”, we dont know the origin of the outbreak, although at the end of the season 1, as Dr. Edwin Jenner (I guess it is not a coincidence he shares similar name than Edward Jenner, the inventor of the vaccination process), one former scientist of the CDC implies it is a viral infection that is present in every person. Such virus is spreading fast and transform the outbreak into an unsustainable mass extinction, enough to overrun the National Guards.
The starting of Season 1 really felt a lot like “28 days later…” as Rick Grimes (portrayed by Andrew Lincoln) wakes up from a coma to only find a deserted place in chaos. As Rick wanders around, we discover the gravity of the situation and met Morgan, the first survivor we witness as Rick. Morgan also will become a redudant character through the six seasons as we see him loosing his mind to better come back to sanity after his encounter with Eastman. The wandering of Rick in Atlanta streets on a horseback ride was surrealistic, as he will meet Glenn and seal one of the pillar of TWD. Glenn, an Asian-American, strongly remembers me from Romero’s main hero that was an antipode of the classical white man savior. Glenn is certainly the voice of reason and patience of the group that certainly made him one of my favorite character.
It seems that each season will bring one essential pillar to the team.
Rick becomes by default the leader of the group by default, without asking for it. Same that Jack Shepard from “Lost” did by the middle of the first season. He helps the small group of survivors located into a building in Downtown Atlanta to escape, not without leaving Merle (Darryl’s brother) handcuffed on the rooftop without the key to unlock his cuffs. As we progress through, Rick found his wife Lorie now in bed with Shane, his workmate and best friend that once saved his life during the intervention that sent Rick into a comatose. Tensions flare progressively between Rick and Shane for his wife and Carl, his son. This season also learn us a very dramatic and redudant thematic of TWD: the double grievance of seeing one of your dearests dying before your eyes and also the killing of their reincarnation as a living dead. This is certainly what makes the serie so captivating as you get sentimentally attached to many of these characters, making their separation much harder (this is why I speculate it is Eugene that will eat Negan’s baseball bat at the beginning of Season 7, unless the writers are complete jerks ready to infuriate the hardcore fans).
As the seasons go, we end up in a central location that will make the central theme of the season. In Season 1, it is Atlanta and the camp outside it, in season 2 it is Hershel’s farm, in Season 3 and 4 it is the Prison and Woodbury, in Season 5 it is the Terminus and Gabriel’s Church and in Season 6 it is Alexandria.
We see solid characters building tough to the situation such as Carol and Carl, we see hard-boiled men keeping on their principles such as Abraham and Darryl, we see fearless characters becoming human such as Michonne. We see characters that went into Hell and back as Morgan, but we also see characters forging a toughness without sacrifying their humanity such as Glenn and Maggie couple.
All brings this idea that the group finally found a safe haven in which they will be resting and possibly thrive, to only see their hope fading away in flames and torn apart by the walkers. It is probably an allegory of life in which we only learn to savior the comfort of our lives only to be taken by a natural disaster. This is one thing that this serie made me appreciate is to cherish any time of the day because it may vanish within a glimpse of a moment.
One of the remarkable aspect I have to admit is the impressive job done by the decoration and photography, that has made the post-apocalyptic environment so realistic you would expect. It we had some outbreak tomorrow that would shut down the society as we know it, we would be something similar to this.
A thematic that is also present is this idea of tribalism and clanism. We consider it in our modern society as an obsolete and archaic concept of primitive society. Yet, it becomes the essential aspect of survival. Look at Hershel’s family, the Governor’s town, the Terminaliens, the communities of Alexandria and Hilltop and finally Negan’s Saviors and the forecoming Ezekiel’s kingdom. Some are into insane cultism (as the Terminus reverted to cannibalism as their method of survival), herd survivalism (the cops holding in Atlanta’s Gray Memorial Hospital) to the closest form of democracy (Alexandria is appeared the closest of a semblant of democracy).
There are sometimes we feel the writers lost in their writings leading to a lot of empty periods broke only by intense final seasons and new seasons. In particularly I really felt a major chunk of Season 4 and a good half of Season 5. It reminds a lot what we experienced with the hatch and the early Dharma experiment.
Well, now I am back on track I cannot wait on TWD premiere in October and also giving a try to “Fear The Walking Dead” that leaves the Peach state for the arid region of Tijuana and the American-Mexican border.

[SciFi/Star Wars] Rogue One Trailer and RIP Kenny Baker

A very bipolar series of breaking news hit the hyper space this week: the release of the last official trailer of Star Wars: Rogue One and the passing of Kenny Baker within a 72 hours.

First, the trailer. The latest trailer was in my opinion very exciting and dark. It is very promising and makes me excited to see it at the holiday season. So much, I would almost not mind to have the insult from Episode I and the half of episode II remade. This is how I feel Star Wars is about.

The second was the death of Kenny Baker. You may not know his name but you may certainly know R2-D2. Kenny was the soul behind R2, he was so much in his role that it insufflated life into R2 quickly becoming “our little friend” as Obi-Wan would introduce us in Episode IV. Although rumors and notes claim that Kenny Baker and Anthony Daniels were having bad blood out of stage, the duo was kind of antagonistic but so unique in the Sci-fi Universe. Where C3PO was reserved and diplomat, R2 was the little fighter that could go mercurial with his bleeps and stand against much stronger creatures than him (remember standing against the robot manager in Jabba’s workshop or the first encounter with Yoda). My sincere condolences for his family and relatives and a thank you for Kenny for illuminating my childhood and bringing me fascinations for robots and droids.

 

[Symphonic Metal] Marion Lamita – Triangle of Light (Lyric Video)

Marion Lamita, front singer of the disbanded Darkonelly band, just released her first song of her solo project. “Triangle of Light” being her first official track, accompanied by a lyric video just hit the waves.
Again, Marion’s voice is just fantastic and the musical arrangement is in my opinion sounds like the good old days of Nightwish, you know an “Oceanborn” when the metal riffs were still priming over the keyboards.
In other words, I really like it and now very curious to see how this will take shape into an album.
You can listen “Triangle of Light” lyric video below:

[Metal/Symphonic Metal] Therion – Theli 20th anniversary or how the seeds of Symphonic Metal were seeded

A few days ago, on August 9th, Therion album “Theli” celebrated its 20th anniversary.
This album has been considered by many as the seminal album to the genre of Symphonic Metal by adding the voices of choirs and an heavier influence of keyboards than any bands previously done.
The idea of blending classical with metal is not new and surely can be traced back to the progressive rock from the 70s in which complex melodies and the blending of electrical guitars with other instruments (in particular with keyboards) was seeded. This was further translated into the British New Wave of Heavy Metal in which bands such as Bruce Dickinson’s Iron Maiden, Rob Halford’s Judas Priest and Ronnie Dio’s Rainbow were already mixing some elaborated guitar riffs with tale-telling lyrics.
In an another location, Yngwie Malmsteen, as a rebel teenager decided to become an outcast from a family deeply entrenched in classical music and decided to infuse his experience of classical music into an electrical guitar, using his magic touch and incredible guitar play to instillate a classical music sense into metal via the neoclassical metal genre.
But yet, not much bands were blending much metal with orchestral arrangement and opera choirs.
Indeed, it will come from the most unprobable band that will come the spark that will create the symphonic metal genre and inspire off-spins in other genres that have a more aggressive pattern, as the blending of death metal with symphonic elements gave rise to melodic death metal. It will come from a Swedish death metal band, inspired itself by Celtic Frost, a Swiss-German black metal band created in the early 1980s. It will come from a band that never settled in a niche and always experimented new ideas and concepts, often raising the ire of its fanbase. This band is Therion, their name inspired by Celtic Frost “To Mega-Therion” released in 1985 and already experimenting with orchestral elements.
The origin of symphonic metal is not easy to attribute to one single band. I personally consider Nightwish and Within Temptation as being the first generation of symphonic metal bands by the presence of a trained soprano female-fronting singer and a fine arrangement of keyboards as the bands that set the standard for many bands.
Therion set the the first milestone of symphonic metal with their 1996 album “Theli”, deviating from their original death metal influence.
The album starts with “Preludium” an orchestral instrumental sequence using a synthesizer keyboard, giving this particular obscure and occult sound, setting a certain prototypic sound and showing the potential of keyboards to achieve the classical sound.
Then comes “To Mega Therion” in which we are straight welcomed by a female choir, followed by a more conventional metal sound. But this track sets the tone, we will have a blend of the beauty of a classical choir with the harshness of metal. It continues with “Cult of the Shadow”, this times blending the classical with the gothic metal and “In The Desert of Set” that has a tune predicting the masterpiece song “Rise of Sodom and Gomorrah” that will come few years later. This is the song that set Therion into the Symphonic Metal and that make the mark of using professional male and female choirs all along their next discography decade. Then comes an interlude named “Interludium” rightly showing the potential and blasting effect of mixing professional vocals with metal. “Opus Eclipse” comes and heavily rely on the violin, an instrument that will become a staple of any symphonic metal bands with an variable usage of it. “Siren of The Woods” is certainly the lighter and ballad track of the album, simple but efficient. You can feel in it the potential of Therion to mix and arrange the two genres into one. Finally the album concludes with “Grand Finale/Postludium” a fast-paced and captivating track  heavily relying on the keyboards.
This album is certainly not the typical symphonic metal album you will hear in 2016, but you can feel in that it brought the prototype of something we never have heard before. It came right at the time when metal got faded by the exuberance of “hair metal” and the fad of “grunge”. It also got inspiration from the darker side of metal, especially from the gothic and doom metal genre that were remaining underground and accessible only by being initiated. To listen to Paradise Lost or Anathema, you had to hang around with goth friends as the Internet just started to get public and yet the MP3 format had to come in.
Therion indeed came at the right time and inspired many other bands to take inspirations from them. If Therion did not step into that direction, the current symphonic metal scene would be completely different and maybe it would be among other crypto-sub genres that have a very limited number of bands and distribution.

 

[BBB/Neurosciences] Why chemo is less effective on brain cancers than other types of cancer?

This is a post that termed from a  message left by one follower on my Facebook asking me: why does chemo do no penetrate the blood-brain barrier?
This was indeed a very good question that surely many non-scientists may ask themselves but have little or no reply on that topic.
To understand why chemo do not penetrate the BBB, you have to understand the obstacle a chemotherapeutic agent has to cross to get inside the brain.
In order for any drugs to get into the brain, you have to cross the BBB. If you are a drug, you are sorted into two class: hydrophilic drugs and lipophilic drugs. Hydrophilic drugs are “water-soluble” and dissolve easily in biological fluids (blood, gastric juice…) by their own. The problem however is that such drugs cannot enter the cells unless they have a protein carrier, also named “transporter”, that can bring this drug inside.
The second class of drugs are lipophilic drugs. These are drugs that dissolve poorly in water and other biological fluids but dissolve very well in fat and oils. Because cell membrane are made of fatty acids and cholesterol (yep, that’s why we need cholesterol as we also use it to make bile salts to dissolve fats from our food and also as a prime brick for the production of steroid hormones), lipophilic drugs can passively diffuse through the cells and reach the target.
Thats a boon and a bane in the same time when you are in the drug discovery side. A boon because it means your drug will not have issues to get into its target and can be given orally, a bane because it is also mean these drugs will be substrate of drug efflux pumps.
bbb_human_new

Drug efflux pumps are belonging to a super-family of molecules called “ABC transporters”. ABC stands for ATP-binding cassettes, as these pumps use ATP (Adenosine triphosphate, the major source of energy storage in cells) to function. These transporters function in a very similar fashion that exit door you can experience in a subway station: you can get from the subway system from it but you cannot get into the system from it.
Such efflux pumps were firstly described in cancer cells that developed drug resistance to their chemotherapy and later identified to be expressed by various tissues including intestine, liver and the BBB.
At the BBB, we have an array of different ABC transporters: ABCA (cholesterol efflux), ABCB1 (P-glycoprotein or P-gp), ABCCs (multi drug resistant polypeptides or MRPs) and ABCG2 (also called breast cancer resistant protein or BCRP). They have one job and only one job: to pump things out. Some have a very narrow spectrum (ABCA transporters mostly efflux cholesterol), some have such a broad spectrum (ABCB1 and ABCG2 share a common pool of substrates) that it is impossible to predict if your drug candidate will be substrate of these pumps or not. These pumps are so efficient to keep xenobiotics (any molecule not produced by your body) that we estimate over 95% of chemicals known by humans are not capable to cross the BBB. Thats a boon because many of these compounds can have severe neurotoxic effects, it is also a bane because it means that delivering drugs to the brain will be challenged by the BBB.
Unfortunately, a lot of chemotherapeutic agents have been shown to be substrate for one of these pumps. This has been recently brought into a white paper from the first  CNS Anticancer Drug Discovery and Development Conference (source:http://neuro-oncology.oxfordjournals.org/content/17/suppl_6/vi1.long)  co-authored by Dr. Quentin Smith (Texas Tech University Health Sciences Center, Amarillo, TX) and by William “Bill” Elmquist (University of Minnesota, St Paul-Minneapolis, MN), two eminent experts in the field of CNS tumors and BBB.
In 35 years of research, we have been able to extend the life expectancy of patients with glioblastoma multiform (GBM), one of the most aggressive type of cancer, from 7 months to 14 months. This is a fairly grim results in comparison to other types of cancer in which we are not talking about extending life expectancy but talking about how many patients stay cancer-free and overcome their cancer.
We certainly failed from bringing miracles to patients with brain cancer, but we are learning from our mistakes and by correcting them we are closer from finding better cures.
One mistake we have done was assuming that brain tumors were like any other tumors and were only good at making leaky and botched blood vessels. Turned out brain tumors surely make some botched blood vessels but they also find a way to keep chemotherapeutics away via the presence of a blood-tumor barrier (BTB).
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The second mistake was to consider that efflux pumps were equal in distribution and function, with a distinct preference for certain molecules.

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As you can see we have different pumps with an overlapping catalog of substrates but also an heterogenous activity, with P-gp and BCRP considered the main players. There are speculation that a rodent BBB and a human BBB are not similar in terms of activity of P-gp and BCRP (some studies suggest that the BBB in mice and rats rely heavily on Pgp, whereas in humans BCRP lift most of the weight). It also turned out that trying to block these transporters may have little or no advantages (http://onlinelibrary.wiley.com/doi/10.1038/clpt.2013.34/abstract;jsessionid=03AF5C34128C830A05FEDDF895E4A5B2.f02t04).
Finally, we are also learning that there is not such a “one size fits all” in brain tumors. Brain tumors are very heterogenous between their types and even between tumor sites within the same patient, as depicted in one figure presented in the white paper cited above.
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You can see that the uptake of 17 different compounds between a healthy brain region and a tumor brain were poorly correlating to each other.
Therefore, a lot of scientists are working on to find way to circumvent this issue. One approach is to enhance our odds to remove the tumor during surgery by using a glowing tag to label brain tumors (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343207/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343207/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343207/) and depicted below:
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Some try to develop some Trojan horses to bypass the BBB and deliver the chemo directly inside the brain and some try to basically transiently open the BBB by using micro bubbles in combination of focused ultrasounds (FUS) that induce a local dilation of these bubbles and a small opening of the BBB.
Science is a long learning process made of high expectations and a high number of failures, bringing scientists back to square one in the design of new treatments. Brain tumors are certainly the worst and as a BBB scientist that collaborated on some aspect and attended a couple of international conferences discussing brain tumors, it is heartbreaking to have little or no options that we can offer to patients.
However, as we learn from our mistake, we are understanding that success will not come for a magic bullet but indeed by small incremental steps bringing us closer to a treatment for these particular types of cancer.