Site Audit Isavuconazole ( 241479-67-4 )and Intermediates

       Follow EOS to learn more about Acalabrutinib 241479-67-4       

API: Isavuconazonium sulfate   

CAS:946075-13-4

Chemical Formula: C35H36F2N8O9S2 
Molecular Weight: 814.84 
Elemental Analysis: C, 51.59; H, 4.45; F, 4.66; N, 13.75; O, 17.67; S, 7.87

Structural formula:

  Part one : Isavuconazole( 241479-67-4 )and Intermediates  

Product name:Isavuconazole

CAS:241479-67-4

Chemical Formula: C22H17F2N5OS 
Exact Mass: 437.1122 
Molecular Weight: 437.4688 
Elemental Analysis: C, 60.40; H, 3.92; F, 8.69; N, 16.01; O, 3.66; S, 7.33

Structural formula:

We have more than1kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

➤ Acalabrutinib Intermeidtaes:

1.Name:(2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2,3-diol

cas:241479-72-1

Structural formula:

We have more than2.5kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

2.Name:QYOWWJNQQPRWCO-QPUJVOFHSA-N

CAS:241479-73-2

Structural formula:

We have more than1.5kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

3.Name:SYSUFNUKZJVPBI-TVQRCGJNSA-N

CAS:241479-74-3

Structural formula:

We have more than1.2kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

4.Name: (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)

butanethioamide  cas:368421-58-3

Structural formula:

We have more than2.3kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

5.Name: [2-(methylamino)pyridin-3-yl]methanol

CAS:32399-12-5

Structural formula:

We have more than2.6kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

6.Name:(2-(Methylamino)pyridin-3-yl)methyl 2-((tert-butoxycarbonyl)(methyl)amino)acetate

CAS:1180002-01-0

Structural formula:

We have more than1.7kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

7.Name:(2-(((1-Chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-((tert-butoxycarbonyl)(methyl)amino)acetate

CAS:338990-31-1

Structural formula:

We have more than1.9kg in stock, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Contact information：

EOS Med Chem, Medchem is Big

執大象，天下往，往而無害，安平泰

WEB: www.eosmedchem.com

EMAIL: info@eosmedchem.com; eosmedchem@gmail.com; eosmedchem@qq.com  

TEL: 0086-531-69905422

GMP PLANT: No. 37, Yulong Road, Qufu City, Shandong Province.

            Part two:  Isavuconazole impurities           

➤➤Isavuconazole impurities :

Isavuconazole Impurity1

Isavuconazole Impurity2

Isavuconazole Impurity3

Isavuconazole Impurity4

Isavuconazole Impurity5

Isavuconazole Impurity6

Isavuconazole Impurity7

Isavuconazole Impurity8

Isavuconazole Impurity9

Isavuconazole Impurity10

Isavuconazole Impurity11

Isavuconazole Impurity12

Isavuconazole Impurity13

Isavuconazole Impurity14

Isavuconazole Impurity15

Isavuconazole Impurity16

Isavuconazole Impurity17

Isavuconazole Impurity18

Isavuconazole Impurity19

Isavuconazole Impurity20

Isavuconazole Impurity21

Isavuconazole Impurity22

Isavuconazole Impurity23

Isavuconazole Impurity24

Isavuconazole Impurity25

Isavuconazole Impurity26

Isavuconazole Impurity27

Isavuconazole Impurity28

Isavuconazole Impurity29

Isavuconazole Impurity30

Contact information：

EOS Med Chem, Medchem is Big

執大象，天下往，往而無害，安平泰

WEB: www.eosmedchem.com

EMAIL: info@eosmedchem.com; eosmedchem@gmail.com; eosmedchem@qq.com  

TEL: 0086-531-69905422

GMP PLANT: No. 37, Yulong Road, Qufu City, Shandong Province.

➤➤➤Reference

1: Donnelley MA, Zhu ES, Thompson GR 3rd. Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections. Infect Drug Resist. 2016 Jun 2;9:79-86. doi: 10.2147/IDR.S81416. eCollection 2016. Review. PubMed PMID: 27330318; PubMed Central PMCID: PMC4898026.

2: Wiederhold NP, Kovanda L, Najvar LK, Bocanegra R, Olivo M, Kirkpatrick WR, Patterson TF. Isavuconazole is Effective for the Treatment of Experimental Cryptococcal Meningitis. Antimicrob Agents Chemother. 2016 Jun 20. pii: AAC.00229-16. [Epub ahead of print] PubMed PMID: 27324761.

3: Desai A, Yamazaki T, Dietz AJ, Kowalski D, Lademacher C, Pearlman H, Akhtar S, Townsend R. Pharmacokinetic and Pharmacodynamic Evaluation of the Drug-Drug Interaction between Isavuconazole and Warfarin in Healthy Subjects. Clin Pharmacol Drug Dev. 2016 Jun 9. doi: 10.1002/cpdd.283. [Epub ahead of print] PubMed PMID: 27278712.

4: Townsend R, Dietz A, Hale C, Akhtar S, Kowalski D, Lademacher C, Lasseter K, Pearlman H, Rammelsberg D, Schmitt-Hoffmann A, Yamazaki T, Desai A. Pharmacokinetic Evaluation of CYP3A4-mediated Drug-Drug Interactions of Isavuconazole with Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults. Clin Pharmacol Drug Dev. 2016 Jun 8. doi: 10.1002/cpdd.285. [Epub ahead of print] PubMed PMID: 27273461.

5: Groll AH, Desai A, Han D, Howieson C, Kato K, Akhtar S, Kowalski D, Lademacher C, Lewis W, Pearlman H, Mandarino D, Yamazaki T, Townsend R. Pharmacokinetic Assessment of Drug-Drug Interactions of Isavuconazole with the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults. Clin Pharmacol Drug Dev. 2016 Jun 8. doi: 10.1002/cpdd.284. [Epub ahead of print] PubMed PMID: 27273343.

6: Yamazaki T, Desai A, Han D, Kato K, Kowalski D, Akhtar S, Lademacher C, Kovanda L, Townsend R. Pharmacokinetic Interaction between Isavuconazole and a Fixed-Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects. Clin Pharmacol Drug Dev. 2016 Jun 8. doi: 10.1002/cpdd.282. [Epub ahead of print] PubMed PMID: 27273248.

7: Yamazaki T, Desai A, Goldwater R, Han D, Howieson C, Akhtar S, Kowalski D, Lademacher C, Pearlman H, Rammelsberg D, Townsend R. Pharmacokinetic Effects of Isavuconazole Co-Administration with the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects. Clin Pharmacol Drug Dev. 2016 Jun 8. doi: 10.1002/cpdd.281. [Epub ahead of print] PubMed PMID: 27273149.

8: Yamazaki T, Desai A, Goldwater R, Han D, Lasseter KC, Howieson C, Akhtar S, Kowalski D, Lademacher C, Rammelsberg D, Townsend R. Pharmacokinetic Interactions between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects. Clin Pharmacol Drug Dev. 2016 Jun 8. doi: 10.1002/cpdd.280. [Epub ahead of print] PubMed PMID: 27273004.

9: Kovanda LL, Desai AV, Lu Q, Townsend RW, Akhtar S, Bonate P, Hope WW. Isavuconazole Population Pharmacokinetic Analysis Using Non-Parametric Estimation in Patients with Invasive Fungal Disease: Results from the VITAL Study. Antimicrob Agents Chemother. 2016 May 16. pii: AAC.00514-16. [Epub ahead of print] PubMed PMID: 27185799.

10: Thompson GR 3rd, Rendon A, Ribeiro Dos Santos R, Queiroz-Telles F, Ostrosky-Zeichner L, Azie N, Maher R, Lee M, Kovanda L, Engelhardt M, Vazquez JA, Cornely OA, Perfect JR. Isavuconazole Treatment of Cryptococcosis and Dimorphic Mycoses. Clin Infect Dis. 2016 May 11. pii: ciw305. [Epub ahead of print] PubMed PMID: 27169478.

11: Graves B, Morrissey CO, Wei A, Coutsouvelis J, Ellis S, Pham A, Gooi J, Ananda-Rajah M. Isavuconazole as salvage therapy for mucormycosis. Med Mycol Case Rep. 2016 Mar 8;11:36-9. doi: 10.1016/j.mmcr.2016.03.002. eCollection 2016 Mar. PubMed PMID: 27158585; PubMed Central PMCID: PMC4845387.

12: Kovanda LL, Petraitiene R, Petraitis V, Walsh TJ, Desai A, Bonate P, Hope WW. Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints. J Antimicrob Chemother. 2016 Jul;71(7):1885-91. doi: 10.1093/jac/dkw098. Epub 2016 Apr 15. PubMed PMID: 27084921; PubMed Central PMCID: PMC4896411.

13: Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR 3rd, Alangaden GJ, Brown JM, Fredricks DN, Heinz WJ, Herbrecht R, Klimko N, Klyasova G, Maertens JA, Melinkeri SR, Oren I, Pappas PG, Ráčil Z, Rahav G, Santos R, Schwartz S, Vehreschild JJ, Young JH, Chetchotisakd P, Jaruratanasirikul S, Kanj SS, Engelhardt M, Kaufhold A, Ito M, Lee M, Sasse C, Maher RM, Zeiher B, Vehreschild MJ; VITAL and FungiScope Mucormycosis Investigators. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016 Mar 8. pii: S1473-3099(16)00071-2. doi: 10.1016/S1473-3099(16)00071-2. [Epub ahead of print] PubMed PMID: 26969258.

14: Roilides E, Antachopoulos C. Isavuconazole: an azole active against mucormycosis. Lancet Infect Dis. 2016 Mar 8. pii: S1473-3099(16)00127-4. doi: 10.1016/S1473-3099(16)00127-4. [Epub ahead of print] PubMed PMID: 26969257.

15: Horn D, Goff D, Khandelwal N, Spalding J, Azie N, Shi F, Franks B, Shorr AF. Hospital resource use of patients receiving isavuconazole vs voriconazole for invasive mold infections in the phase III SECURE trial. J Med Econ. 2016 Jul;19(7):728-34. doi: 10.3111/13696998.2016.1164175. Epub 2016 Mar 30. PubMed PMID: 26960060.

16: Ahmed Y, Delaney S, Markarian A. Successful Isavuconazole therapy in a patient with acute invasive fungal rhinosinusitis and acquired immune deficiency syndrome. Am J Otolaryngol. 2016 Mar-Apr;37(2):152-5. doi: 10.1016/j.amjoto.2015.12.003. Epub 2015 Dec 9. PubMed PMID: 26954873.

17: Desai A, Schmitt-Hoffmann AH, Mujais S, Townsend R. Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment. Antimicrob Agents Chemother. 2016 Apr 22;60(5):3025-31. doi: 10.1128/AAC.02942-15. Print 2016 May. PubMed PMID: 26953193; PubMed Central PMCID: PMC4862513.

18: Petraitis V, Petraitiene R, Moradi PW, Strauss GE, Katragkou A, Kovanda LL, Hope WW, Walsh TJ. Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2718-26. doi: 10.1128/AAC.02665-15. Print 2016 May. PubMed PMID: 26883703; PubMed Central PMCID: PMC4862472.

19: Arendrup MC, Meletiadis J, Mouton JW, Guinea J, Cuenca-Estrella M, Lagrou K, Howard SJ; Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). EUCAST technical note on isavuconazole breakpoints for Aspergillus, itraconazole breakpoints for Candida and updates for the antifungal susceptibility testing method documents. Clin Microbiol Infect. 2016 Feb 3. pii: S1198-743X(16)00077-X. doi: 10.1016/j.cmi.2016.01.017. [Epub ahead of print] PubMed PMID: 26851656.

20: Slavin MA, Thursky KA. Isavuconazole: a role for the newest broad-spectrum triazole. Lancet. 2016 Feb 20;387(10020):726-8. doi: 10.1016/S0140-6736(15)01218-0. Epub 2015 Dec 10. PubMed PMID: 26684608.

Umeclidinium /Incruse Ellipta®

Basic Information

Developed by GlaxoSmithKline (GSK), sulphide bromide was first approved by Health Canada on April 17, 2014, and then obtained by the European Medicines Agency (EMA) on April 28, 2014. Approved for listing, then approved by the US Food and Drug Administration (FDA) on April 30, 2014, and later approved by the Japan Pharmaceutical and Medical Device Administration (PMDA) on March 26, 2015. Marketed by GSK under the trade names Incruse Ellipta®, Incruse® and Encruse®.

Indole bromide is a long-acting, competitive and reversible muscarinic choline receptor antagonist (mAChRs) that maintains bronchiectasis. This drug is indicated for the treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

Incruse Ellipta® is an inhaled powder containing 62.5 μg of indole bromide. The recommended dose is 62.5 μg per inhalation (inhalation once) once daily.

Structural formula

Mechanism

Indole bromide is a long-acting choline receptor antagonist (LAMA) that relaxes bronchial smooth muscle. The kinetic selectivity for the M3 receptor is higher than that of the M2 receptor, and the dissociation with the M3 receptor is slower than M2. It has anti-parasympathetic effects and can inhibit the action of the M3 receptor.

synthetic route

Research key data

 This article is reproduced from:https://translate.google.cn/#zh-CN/en/%E6%9C%AC%E6%96%87%E8%BD%AC%E8%BD%BD%E8%87%AA

 

 

Reveal the cell culprits that cause chronic sinusitis

Chronic sinusitis (chronic rhinosinusitis) is different from seasonal allergy. It causes inflammation and swelling of the sinuses for months to years, which causes breathing difficulties and other symptoms that can cause pain to the patient. In some people, chronic sinusitis also produces tissue growth called nasal polyp, and when the condition is severe, the nasal polyps must be surgically removed.

In a new study, researchers from the Massachusetts Institute of Technology and Brigham and Women's Hospital built the first of human barrier tissue during chronic sinusitis by performing genome-wide analysis of thousands of single cells from human patients. A global cell map. Analysis of these data led them to propose a new mechanism that might explain what maintains chronic sinusitis. The results of the study were published online August 22, 2018 in the journal Nature, entitled "Allergic inflammatory memory in human respiratory epithelial progenitor cells".

Image courtesy of Nature, doi: 10.1038/s41586-018-0449-8.

Their findings also explain why some patients with sinusitis produce nasal polyps caused by airway epithelial cells. In addition, their research may have a broader impact on how scientists think about and treat other barrier tissue chronic inflammatory diseases such as asthma, eczema, and inflammatory bowel disease.

The author of the paper is Alex K. Shalek, a core member of the Institute of Medical Engineering at MIT, and Nora Barrett, assistant professor of medicine at Brigham and Women's Hospital. The first author of the paper is Jose Ordovas-Montanes, a postdoctoral fellow at the Massachusetts Institute of Technology's Institute of Medical Engineering, and Daniel Dwyer, a researcher at Brigham and Women's Hospital.

 ➽ Clinical single cell RNA sequencing

Last year, Shalek and his colleagues developed a new portable technology that can quickly sequence the RNA content of thousands of single cells from a small number of clinical samples in parallel. The technology, called Seq-Well, allows scientists to see which transcription programs are turned on in a single cell, giving them insight into the identity and function of these cells.

In this latest study, the researchers applied this technique to upper respiratory tract cells from patients with chronic sinusitis and speculated that different gene expression patterns in these epithelial cells may reveal why some patients develop nasal polyps. Other patients do not develop nasal polyps.

This analysis revealed significant differences in gene expression in basal epithelial cells (a tissue stem cell) from patients with chronic sinusitis with and without nasal polyps. In patients with chronic sinusitis and healthy people who do not develop nasal polyps, these cells usually form a flat layer of basal tissue covering the interior of the nasal cavity. In patients with chronic sinusitis who develop nasal polyps, these cells begin to accumulate and form thicker tissue layers rather than differentiate into subpopulations of epithelial cells required for host defense.

Scientists have observed this type of tissue abnormality for decades through histological experiments, but this new study reveals that basal cells from patients with chronic sinusitis that produce nasal polyps have initiated a specific gene expression program, which explains Their slow differentiation trajectories. This procedure appears to be directly maintained by IL-4 and IL-13, which are known to be over-produced at the pathological level of immune response cytokines that promote allergic inflammation.

The researchers found that these basal cells also retained their "memory" of exposure to IL-4 and IL-13: when they removed basal cells from non-nasal polyps and nasal polyps, they were cultured under the same conditions. One month, and then exposed to IL-4 and IL-13, it was found that unstimulated basal cells from patients with chronic sinusitis producing polyps have expressed many of them after induction in patients with chronic sinusitis without polyps. gene. Among the IL-4 and IL-13 responsive memory signals, a gene derived from a cell signal transduction pathway called Wnt that controls cell differentiation is included.

Immunologists have long known that B cells and T cells can store the memory of the allergens they have contacted, which explains why the immune system may overreact the next time it encounters the same allergen. However, these new findings have greatly increased the contribution of children and basal cells to this memory.

Given that as a stem cell, basal cells produce other cells found in the airway epithelium, this memory may affect their subsequent gene expression patterns and their ability to produce mature specialized epithelial cells. These researchers noted that the cell type balance in the airway epithelium of patients with severe disease was severely affected, which led to a reduction in the diversity of cell populations.

 ➽ Blocking cytokines in the body

These findings suggest that efforts to block the effects of IL-4 and IL-13 may be a good way to try to treat chronic sinusitis. Against this hypothesis, these researchers used antibodies that block the same receptor for both cytokines. This antibody has been approved for the treatment of eczema and is being tested for other uses. The researchers analyzed genes expressed in basal cells obtained from a patient with chronic sinusitis who developed nasal polyps before and after receiving this antibody treatment. They found that most of the genes activated by IL-4 and IL-13 (but from time to time all genes) have returned to normal expression levels. This suggests that blocking IL-4 and IL-13 helps restore basal and secretory cells to a healthier state, but there is still some residual genetic trait.

These researchers are now planning further detailed analysis of how the basal cells store the molecular mechanisms of inflammatory memory, which may help them discover other drug targets. They are also studying inflammatory diseases affecting other parts of the body, such as inflammatory bowel disease, in which inflammation usually causes polyps that may turn into cancer. Studying whether stem cells in the gut may also remember immune events, maintain disease, and play a role in tumor formation will be key to developing early interventions for inflammation-induced cancer.

This article is reproduced from:https://news.pharmacodia.com/news/html/info/info-detail.html?id=29298

Empagliflozin/Jardiance®

Basic Information

Engeljein was jointly developed by Boehringer Ingelheim and Eli-Lilly and was first approved by the European Medicines Agency (EMA) on May 22, 2014, on August 1, 2014. Approved by the US Food and Drug Administration (FDA), approved by the Japan Pharmaceutical and Medical Device Administration (PMDA) on December 26, 2014, and obtained by the China Food and Drug Administration (CFDA) on September 20, 2017. Approved for listing. It is jointly marketed by Boehringer Ingelheim and Lilly, under the trade name Jardiance®, and is marketed in China under the trade name Ou Tangjing®.

Englitavir is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Combined with exercise and diet as an adjunct to improve glycemic control in adult patients with type 2 diabetes.

Jardiance® is an oral tablet containing 10 mg or 25 mg of enclave per tablet. The recommended starting dose is 10 mg each time, once a day, the maximum dose is 25 mg each time, once a day.

Structural formula

 Mechanism 

Engliflozin is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor that blocks the reabsorption of glucose in the kidneys and excretes excess glucose into the body, thereby reducing blood sugar levels. And the hypoglycemic effect is independent of beta cell function and insulin resistance.

Synthetic route

Research key data

This article is reproduced from：https://news.pharmacodia.com/news/html/info/info-detail.html?id=29203

New discovery of cancer treatment ! Reversal of missing immune T cells can fight deadly brain tumors

Author:Tan Suojun

T cell dysfunction contributes to tumor immune escape in cancer patients and is particularly severe in glioblastoma (GBM). Recently, researchers at the Duke Cancer Institute have discovered traces of missing T cells in GBM patients, which are largely isolated in the bone marrow. Isolation of T cells in the bone marrow is a tumor-adapted pattern of T cell dysfunction, and its reversal may be a promising aid for immunotherapy.

GBM can have an unusual effect on the body's immune system, often leading to a sharp decline in the number of circulating T cells that help strengthen the body's defenses. Although more and more people use immunotherapy to stimulate the body's natural ability to resist invasive tumors, the fate of T cells remains unclear.

Now, researchers at the Duke Cancer Institute track down missing T cells in patients with glioblastoma – they find a lot of glial cells in the bone marrow. The study, published in the August 13 issue of Nature Medicine, opened up a new area of ​​exploration for adjuvant treatment of cancer.

"The problem with all these immunotherapies is that the immune system has been hit, especially for glioblastoma and other tumors that spread to the brain," said lead author of the article, Peter E, director of neurosurgical brain tumor immunotherapy programs at Duke University. Dr. Fecci said, "If the goal is to activate T cells, but T cells do not exist, then the treatment effect can not be said."

Fecci led the team to look for missing T cells after observing that many of the newly diagnosed glioblastoma patients had the same immune system as the immune system of AIDS patients.

Most normal people have CD-4 "helper" T cells, counted between 700 and 1000, and many untreated glioblastoma patients have a count of 200 or less, indicating that their immune function is very high. Poor, susceptible to various infections, and even lead to cancer deterioration.

 

Image source: Alisa Weigandt /Duke Health

Researchers at the Duke Cancer Institute tracked missing T cells in patients with glioblastoma in the bone marrow.

Initially, the researchers looked for missing T cells in the spleen, because under certain conditions, the spleen hides T cells. But the spleen is abnormally small, and the thymus is also a potential T-cell sanctuary. They then decided to examine the bone marrow and found clusters of T cells there.

Fecci said: "This is very strange, this phenomenon can not be seen under any disease state. The brain can regulate the mechanism of T cell entry, but it is being replaced by tumors, thus limiting the ability of the immune system to attack tumors."

When examining hidden T cells, Fecci and colleagues found that there is a lack of a receptor called S1P1 on the surface of T cells, which is the key "key" for T cells to leave the bone marrow and lymphatic system. Without the "key", T cells are locked in, unable to spread and fight infection, let alone cancer.

To clarify how the brain triggers this S1P1 receptor dysfunction, the research team did further research. The current theory is that the S1P1 receptor receives a signal in some way that retracts from the cell surface back into the cell.

"Interestingly, when we recovered T cell receptors in mice, T cells left the bone marrow and entered the tumor, so we know the process is reversible," Fecci said excitedly.

Fecci's team is working with Duke University scientist Robert Lefkowitz (received the Nobel Prize in Chemistry for the S1P1 receptor category) to develop molecules that restore cell surface receptors.

Fecci said: "We hope this discovery can provide a new way to calm down autoimmune disorders by activating T cell sequestration, allowing more people to benefit from immunotherapy."

This article is reproduced from：https://news.pharmacodia.com/news/html/info/info-detail.html?id=29072

Why do elephants have a low cancer rate? "Zombie gene" is the key

Why do elephants have a low cancer rate? 

"Zombie gene" is the key

    Guide    

Elephants have the same life expectancy as humans, about 70 years. In general, the larger the volume, the greater the number of cancer cells in the body. It is estimated that up to 17% of people worldwide die from cancer, and the probability that an elephant with 100 times more cancer cells will die from cancer is only 5%! What is the reason? Recently, the University of Chicago team found that a "zombie" gene in elephants is the key to their freedom from cancer.

Humans, like all other animals, have a major tumor suppressor gene, P53. This gene enables humans and elephants to recognize unrepaired DNA damage (which is a precursor to cancer) and then remove these damaged cells.

Three years ago, a research team from the University of Chicago began researching this. The most surprising finding during the period was that there were only 20 copies of P53 in the elephant compared to the only copy of P53 in most animals. ! This makes their cells more sensitive to damaged DNA and can clean damaged cells more quickly.

In the August 14 issue of Cell Reports, the team described the second element of elephant resistance to cancer: they discovered an anti-cancer gene, LIF6, that has recovered from the death gene.

Dr. Vincent Lynch, assistant professor of human genetics at the University of Chicago and senior author of the study, said: "Genes are constantly replicating themselves, but sometimes replication errors occur, producing non-functional pseudogenes. We often call these dead genes (dead Genes)."

However, it is not. When studying the elephant P53 gene, Lynch and colleagues found that this dead gene, called leukemia inhibitor 6 (LIF6), somehow evolved a new switch. And the LIF6 that escaped into the body turned into a valuable work gene!

When P53 is activated, the LIF6 gene produces a protein that quickly enters the cell's main energy plant, the mitochondria, and digs holes in the mitochondria, which in turn kills the corresponding cancer cells. Further research found that elephants have eight LIF genes, but it is known that only LIF 6 is functional and seems to have been functioning for a long time.

Image source: Cell Reports

"This dead gene is revived like a zombie. When it is reactivated by damaged DNA, it quickly kills the corresponding cancer cells. Lynch said, "This is beneficial because it responds to genetic errors and prevents it." Related cancers. ”

Not only that, but this remedy for cancer suppression may also be a key factor in making elephants so versatile. The researchers explained that the fossil record shows that the elephant's predecessor was the size of a small marmot between 25 and 30 million years ago. With more cells, the body will gradually become larger and eventually lead to the emergence of modern elephants.

However, larger animals have more cells, and they tend to live longer, which means higher chances of accumulating carcinogenic mutations. Large long-lived animals must evolve powerful mechanisms to suppress or eliminate cancer cells in order to live longer and reach adult size. Researchers believe that LIF6 may be an important reason for maintaining the balance between large animal size and cancer.

Finally, the mechanism by which LIF6 induces apoptosis is still unclear. The author points out that this will be the focus of future research.

Article reprinted from：https://news.pharmacodia.com/news/html/info/info-detail.html?id=28971