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post Posted: Today, 04:41 AM
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In Reply To: royco's post @ Today, 04:08 AM

I totally agree with you! T -19 days (only 14 trading days left). Will we see an early approval on Sept 20th???

Now, we are entering the phase with the highest slope:

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post Posted: Today, 04:08 AM
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Any day now...
Expedited priority orphan fast track delayed for 3 months after 2 years of review

They could give a few days now dont you think?!


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post Posted: Yesterday, 06:35 AM
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In Reply To: hibchibbler's post @ Yesterday, 02:07 AM

Don’t forget your ice baths and cold showers, boys

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post Posted: Yesterday, 02:07 AM
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In Reply To: IntiRaymi's post @ Sep 14 2019, 07:54 PM

I wish I understood more too. But, I know enough to stay long and strong smile.gif

Digging into your previous thought..

This abstract:

"Alpha-melanocyte-stimulating hormone, acting through melanocortin-4 receptor signaling pathways, influences the regulation of every aspect of energy balance, including BAT thermogenesis (Fan et al., 2005)."

So, then another abstract about BAT,

goes onto say that:
" Brown adipose tissue (BAT), in contrast to bona fide white fat, can dissipate significant amounts of chemical energy through uncoupled respiration and heat production (thermogenesis)"

Which the paper seems to indicate that the result of that is:
" Promotion of BAT activity or the browning of WAT is associated with in vivo cold tolerance, increased energy expenditure, and protection against obesity and type 2 diabetes."

Therefore, a-msh makes me strong like cave-man!

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post Posted: Yesterday, 01:26 AM
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In Reply To: LevelHeaded2000's post @ Sep 14 2019, 08:32 PM

Not sure if France denies reimbursement or if our Australian friends not even yet submitted the request for local approval and reimbursement... from Cuv we have never heard anything about the status in France

post Posted: Sep 14 2019, 10:05 PM
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More readable article, Scientific America. Maybe the Dermatology powerhouse couple should read this. Less wordy for them.
P53 activation from MSH activation

And yes, the tan (pigment) protects against UVR oxidative damage, plus MSH/P53 DNA repair mechanisms.

A Protein Twofer That Triggers Tanning and Protects against Skin Cancer
Researchers find that a protein activated to repair DNA damage also activates tanning, which can protect against melanoma

A powerful protein known as p53 has long been considered the master regulator of the genome because of its amazing ability to repair damaged DNA. Now scientists at Harvard's Dana-Farber Cancer Institute have discovered that p53 not only mends genetic material but also kicks off the chemical cascade that results in tanning.

The researchers report in Cell that when p53 is activated (in response to DNA damage caused by the sun's ultraviolet (UV) rays and other factors), it triggers production of alpha-MSH, a hormone that then prompts production of melanin, or pigment. Recognizing that p53 is the linchpin of this chain of events could result in a way to "give people tans without needing the sun" (or creams or sprays to artificially color their skin), says senior study author David Fisher, director of Dana-Farber's Cutaneous Oncology and Melanoma Program.

In many types of cancer, p53 is disabled and cannot fulfill its role as a tumor suppressor. Deprived of their ability to fix new DNA damage, defective cells often become tumor cells and proliferate unchecked. In the case of skin cancer—which Fisher notes is "the most common and most preventable" form of the disease—the ability to tan is an extremely strong predictor of cancer susceptibility: Fair-skinned people who are more likely to burn than tan in the sun are at higher risk of developing skin cancer than individuals who tan easily.

In work published last year, the Dana-Farber group found that alpha-MSH, needed to induce melanin production, does not come from melanocytes (melanin-producing cells in the skin). They believe the hormone, instead, is produced in keratinocytes, the most common type of skin cells. The reason: they found broken alpha-MSH receptors on the surface of melanocytes in subjects with an inability to tan.

Other lab work had shown that p53 activates during tanning. And, sure enough, when the Dana-Farber team probed the protein pro-opiomelanocortin (POMC)—which splits to make several hormones including alpha-MSH—it discovered "a perfect p53 binding element there," Fisher says. When testing both mouse and human keratinocytes in vitro, the team observed that after six hours of exposure to UV radiation, p53, POMC and alpha-MSH levels had all jumped dramatically, with the latter's rising 30 times higher than normal. The finding was confirmed in knockout mice missing the gene that codes for p53: Without the protein, POMC was never activated, the mice did not tan (on their hairless ears and tails), and eventually they all developed melanomas.

"What we were stumbling into here was actually a role for p53 in absolutely normal cells," Fisher says, "and it's a normal physiologic response that happens anytime any of us walks out of the house in the morning." He adds that people have a "love-hate relationship" with UV rays, which stimulate vitamin D production needed to keep bones strong and healthy, but also cause potentially deadly skin cancer and premature wrinkling.

Barbara Gilchrest, chair of the Department of Dermatology at Boston University School of Medicine, says that the new findings demonstrate that the p53 system is a broad-response mechanism that has both reparative and preventative properties for DNA damage. "When you damage DNA in cells, they not only work very hard to fix that DNA, but they also work hard to prepare the cell and tissue to be resistant to future DNA damage," she says. "Once you have that tan, your DNA is better protected for the next time that you're out in the sun, because of that melanin cover over the nucleus shielding it from UV rays that would damage [the] DNA inside."
Fisher says that, in theory, the p53 pathway could be a "druggable" one. "In fact, one of the directions that we're taking to use this information is to try to identify small molecules that could potentially be delivered topically," he reveals, "to either increase or decrease pigmentation through interfering [with] or mimicking this pathway."

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post Posted: Sep 14 2019, 09:55 PM
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In Reply To: IntiRaymi's post @ Sep 14 2019, 07:54 PM

Agreed, these concepts are beyond myself as well. But there are pathways to repair. Some are more likely specific to certain tissues and tumors.

Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches
Felix Dietlein1,2, Lisa Thelen1, and H. Christian Reinhardt1,2

Defects in DNA repair pathways enable cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. However, tumors rely on residual DNA repair capacities to survive the damage induced by genotoxic stress. This dichotomy might explain why only isolated DNA repair pathways are inactivated in cancer cells. Accordingly, synergism has been observed between DNA-damaging drugs and targeted inhibitors of DNA repair. DNA repair pathways are generally thought of as mutually exclusive mechanistic units han- dling different types of lesions in distinct cell cycle phases. Recent preclinical studies, however, provide strong evidence that multifunctional DNA repair hubs, which are involved in multiple conventional DNA repair pathways, are frequently altered in cancer. We therefore propose that targeted anticancer therapies should not only exploit synthetic lethal interactions between two single genes but also consider alterations in DNA repair hubs. Such a network-based approach considerably increases the opportunities for targeting DNA repair- defective tumors.

During the cell cycle, cells progress through a series of cell cycle checkpoints before mitotic cell division and distribu- tion of the genomic material to the daughter cells [1]. In response to genotoxic stress, cells activate these check- points to prevent further progression through the cell cycle and initiate DNA repair [2]. If the extent of DNA damage is beyond repair capacity, additional signaling pathways leading to the induction of apoptosis are activated, elimi- nating potentially dangerous mutated cells [3]. This sig- naling network, which is commonly referred to as the DNA damage response (DDR), is tightly controlled and involves regulation at the transcriptional, post-transcriptional, and post-translational levels [1,4,5].

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post Posted: Sep 14 2019, 08:32 PM
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In Reply To: FarmaZutical's post @ Sep 14 2019, 03:40 AM

It is a reminder that Clinuvel is doing good work and creating a positive change on people's lives. No matter what the company does I am proud to be part of this company. Here is a quote from the French page for EPP that touched me:
I am affected by the EPP, I am followed in the hospital of porphyria. The Scenesse is our great hope to have a pretty normal life and finally be able to enjoy finally with our 3 family life daughters outside the walls.

Sad that even with this great treatment some people are living in the dark due to the selfishness of government. Hopefully France stops it's cruelty and let's these people bathe in the light for the first time in their life.

post Posted: Sep 14 2019, 07:54 PM
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In Reply To: hibchibbler's post @ Sep 14 2019, 01:09 AM

I’ve read somewhere, and would like to try to dig it up again that MSH is upregulated during cold exposure/as part of ‘cold-thermogenesis’

I wish I understood more of the biochemistry so I can appreciate some of these findings regarding p53 and what Punkassderm provided below

I do feel intuitively that this molecule and melanocortins in general could have some amazing potential health/longevity effects that we keep hearing about and mentioning on this board

post Posted: Sep 14 2019, 05:16 AM
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In Reply To: IntiRaymi's post @ Sep 14 2019, 12:06 AM

Multiple mechanisms and pathways.
Discussion of lung adenocarcioma.
Answer is some cases yes.
Cells with MC1R receptors? Specific transcription mistakes?



α-MSH is a propigmentation hormone, which is produced and secreted by both keratinocytes and melanocytes in the skin following UV irradiation (10, 32, 33). Normal synthesis of α-MSH and ACTH is crucial for constitutive human pigmentation and the cutaneous response to UV irradiation (10, 34, 35). In addition to being the key factor in UV-induced melanogenesis, α-MSH also has crucial antiinflammatory effects in response to UV irradiation (36, 37). These data indicate that POMC/α-MSH functions as a “protective factor” against the harmful effects of UV irradiation to maintain epidermal homeostasis and genomic stability. We have further shown that the downstream target of p53 in keratinocytes (POMC/α-MSH) is also an activator of DNA repair in these cells after UV irradiation, independent of its previously known role in inducing pigmentation.

It has been previously shown by Abdel-Malek's and Schwarz's groups that α-MSH protects HPMs from UV-induced apoptosis and DNA damage (photoproducts production and oxidative stress; refs. 1, 6–8). Specifically, the antiapoptotic effects of α-MSH were mediated by the activation of the inositol triphosphate kinase–Akt pathway and microphthalmia-associated transcription factor (8). The Abdel-Malek group has also developed melanocortin analogues, which, in addition to stimulating pigmentation, effectively reduced and repaired DNA damage resulting from exposure to solar UV radiation (1, 3). Together, these studies suggest the existence of alternative mechanisms for pigmentation induction through which α-MSH protects skin from UV irradiation.

Interestingly, Abdel-Malek, Schwarz, and their colleagues have found that α-MSH does not induce the cell cycle arrest nor the activation of apoptosis-related proteins (6–8). One recent report showed that α-MSH prevented the UVB-induced suppression of a pathway functioning in protection against oxidative stress (38). In particular, it showed that UVB failed to inhibit Nrf2, a transcription factor critical to antioxidant induction, and Nrf-dependent genes upon α-MSH treatment in both keratinocytes and melanocytes (38). Complementary to these results, we showed that α-MSH is involved in the protection against UV-induced DNA damage through the activation of DNA repair machinery, including XAB1 and XPA DNA repair factors.

Several independent groups have characterized the expression of MC1R in keratinocytes (39, 40). However, the role of MC1R in keratinocytes is still unclear. Here, we showed that MC1R is required in the α-MSH–mediated UV-induced DNA repair in keratinocytes. Usually, following the binding of hormones to the membrane receptors, the receptors undergo conformational changes, which will permit the receptor to augment the exchange of GTP for GDP on a subunit of the trimeric G protein. The GTP-bound and activated G-protein subunits finally interact with their respective effectors to generate the appropriate signals (41). Here, we determined that the protective effect of α-MSH against DNA damage works in a MC1R-, XAB1-, and XPA-dependent manner. Thus, we postulated the signaling pathway of α-MSH–mediated DNA repair as shown in Supplementary Fig. S7. Following the binding of α-MSH, MC1R, which couples with a specific G protein, is activated and acts as a guanine nucleotide exchange factor for its respective G proteins. The α-MSH binding elicits a conformational change on MC1R, permitting it to augment the exchange of GTP for GDP on a subunit of the trimeric G protein. The XAB1 GTPase activity is then activated after the binding of GTP and eventually induces the nuclear translocation of the XPA protein to accelerate the clearance of photoproducts.

cAMP, a pivotal second messenger, regulates a diverse range of key cellular behaviors, including cell metabolism, cell growth and differentiation, apoptosis, and inflammatory responses. It is produced by an enzymatic reaction catalyzed by adenylyl cyclase. In eukaryotic cells, the effects of cAMP are mediated by two intracellular cAMP receptors, cAMP-dependent kinase (PKA), and Epac (42). Previous reports have shown that Epac proteins bind to cAMP with high affinity and activate the Ras superfamily small GTPase Rap1 and Rap2 (43). We showed that adenylyl cyclase is required in the activation of XAB1 GTPase activity needed for α-MSH–mediated DNA repair after UV irradiation. Our results also show that Epac, not PKA, is required for α-MSH–mediated DNA repair.

Cells use the NER system to eliminate DNA photoproducts. XPA is part of the core incision complex of the NER system (44). Here, we showed that α-MSH induces/augments XPA nuclear import and then activates the core incision complex in the NER system. We also found that the α-MSH–mediated translocation of XPA is modulated by XAB1. One group has shown that endogenous XPA protein is phosphorylated after UV irradiation in a lung adenocarcinoma cell line (45). However, we did not detect the phosphorylated XPA protein after UVB irradiation in keratinocytes nor any effect of α-MSH in the regulation of XPA phosphorylation. It is possible that the phosphorylated XPA is not as abundant in keratinocytes and therefore was below the detection threshold in our assay. It is also possible that XPA activity is modulated via different mechanisms in different cell types.

After UV-induced and p53-transactivated POMC/α-MSH is secreted from keratinocytes, it then binds to MC1R in both melanocytes and keratinocytes. Interestingly, distinct pathways downstream of MSH/MC1R become activated in these two cell types to reduce UV-induced DNA damages. In melanocytes, the α-MSH/MC1R complex activates the cAMP pathway and then induces melanin production. Melanin (eumelanin) functions as a physical barrier that scatters incident UV light, serving as a filter to reduce the penetration of UV light through the epidermis (46). In keratinocytes, the α-MSH/MC1R complex upregulates adenylyl cyclase activity and XAB1 GTPase activity inducing the nuclear translocation of XPA to repair the damaged DNA. In both the pigmentation induction and DNA repair activation processes, POMC/α-MSH functions as the crucial downstream target of the “guardian of genome” protein p53 (47).

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