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Triple Negative Breast Cancer (TNBC)

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(@j)
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Posted by: @j

Posted by: @j

@rosed Yes estrogen will do that, I really hope she agrees to give you a prescription for tamoxifen. 

Synergistic inhibition of drug resistant breast cancer cells growth by the combination of luteolin and tamoxifen involves Nrf2 downregulation

https://www.jocpr.com/abstract/synergistic-inhibition-of-drug-resistant-breast-cancer-cells-growth-by-the-combination-of-luteolin-and-tamoxifen-involve-6169.html

Synergistic apoptotic effect of celecoxib and luteolin on breast cancer cells

https://www.researchgate.net/publication/233891877_Synergistic_apoptotic_effect_of_celecoxib_and_luteolin_on_breast_cancer_cells

Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer https://www.researchgate.net/publication/247153548_Celecoxib_inhibits_insulin-like_growth_factor_1_induced_growth_and_invasion_in_non-small_cell_lung_cancer

more possible synergistic anticancer effects in combination with celecoxib (see image)

 

 

@rosed

Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769166/

5-Day Fasting Mimicking Diet Meal Plan

https://creativeinmykitchen.com/five-day-fast-mimicking-vegan-and-lectin-light-cleanse/

 


   
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(@j)
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@rosed

Quercetin blocks the aggressive phenotype of triple-negative breast cancer by inhibiting IGF1/ IGF1R-mediated EMT program

https://lawdata.com.tw/File/PDF/J991/A04972901_098.pdf

 


   
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jens
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(@jens)
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@j Hi Johan. It was nice to get away for a bit from her sickness and listen. Thank you.


   
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(@j)
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Luteolin inhibits triple-negative breast cancer by inducing apoptosis and autophagy through SGK1-FOXO3a-BNIP3 signaling

https://www.frontiersin.org/articles/10.3389/fphar.2023.1200843/full#F7

Synergies with celecoxib, tamoxifen, I3C,...


   
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(@j)
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Thymoquinone Inhibition of Chemokines in TNF-α-Induced Inflammatory and Metastatic Effects in Triple-Negative Breast Cancer Cells

https://pubmed.ncbi.nlm.nih.gov/37373025/

Abstract
The lack of identifiable molecular targets or biomarkers hinders the development of treatment options in triple-negative breast cancer (TNBC). However, natural products offer a promising alternative by targeting inflammatory chemokines in the tumor microenvironment (TME). Chemokines are crucial in promoting breast cancer growth and metastasis and correlate to the altered inflammatory process. In the present study, we evaluated the anti-inflammatory and antimetastatic effects of the natural product thymoquinone (TQ) on TNF-α-stimulated TNBC cells (MDA-MB-231 and MDA-MB-468) to study the cytotoxic, antiproliferative, anticolony, antimigratory, and antichemokine effects using enzyme-linked immunosorbent assays, quantitative real-time reverse transcription-polymerase chain reactions, and Western blots were used in sequence to validate the microarray results further. Four downregulated inflammatory cytokines were identified, CCL2 and CCL20 in MDA-MB-468 cells and CCL3 and CCL4 in MDA-MB-231 cells. Furthermore, when TNF-α-stimulated MDA-MB-231 cells were compared with MDA-MB-468 cells, the two cells were sensitive to TQ's antichemokine and antimetastatic effect in preventing cell migration. It was concluded from this investigation that genetically different cell lines may respond to TQ differently, as TQ targets CCL3 and CCL4 in MDA-MB-231 cells and CCL2 and CCL20 in MDA-MB-468 cells. Therefore, the results indicate that TQ may be recommended as a component of the therapeutic strategy for TNBC treatment. These outcomes stem from the compound's capacity to suppress the chemokine. Even though these findings support the usage of TQ as part of a therapy strategy for TNBC associated with the identified chemokine dysregulations, additional in vivo studies are needed to confirm these in vitro results.


   
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(@j)
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CXCR4 expression is elevated in TNBC patient derived samples and Z-guggulsterone abrogates tumor progression by targeting CXCL12/CXCR4 signaling axis in preclinical breast cancer model

https://www.sciencedirect.com/science/article/abs/pii/S0013935123011398


   
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(@j)
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Thymoquinone anticancer activity is enhanced when combined with royal jelly in human breast cancer

(note that royal jelly is one of the few natural products that contain small amounts of phenylbutyrate)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173327/

"enhanced anticancer activity of TQ when combined with RJ against MDA-MB-231 cell line. Cancer cell viability decreased significantly in response to different combinations as compared to the treatment with each drug alone. Cell death was amplified by 3- and 5-fold in response to the combination of 5 µg/mL of RJ with 10 µmol/L and 15 µmol/L of TQ, respectively, with the lowest combination index obtained upon the combination of 5 µg/mL RJ with 10 µmol/L TQ, suggesting synergistic interaction. These results are consistent with the previous studies that reported the synergism of TQ in combination with different agents including melatonin[53] and piperine[24] against breast cancer, diosgenin on squamous cell carcinoma[54], docetaxel against prostate cancer[55], in addition to arsenic and interferon-alpha against human T-cell leukemia/lymphoma[56].


   
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(@j)
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Involvement of AKT/PI3K Pathway in Sanguinarine's Induced Apoptosis and Cell Cycle Arrest in Triple-negative Breast Cancer Cells

https://pubmed.ncbi.nlm.nih.gov/37400144/

"SANG shows anticancer properties and apoptosis-related gene expression changes in the two TNBC cell lines and suggests AKT/PI3K pathway implication in apoptosis induction and cell cycle arrest. Thus, we propose SANG's potential as a solitary or supplementary treatment agent against TNBC."


   
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(@j)
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interesting: https://scholarworks.uni.edu/cgi/viewcontent.cgi?article=2366&context=jias


   
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(@j)
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The Synergistic Effect of Proanthocyanidin and HDAC Inhibitor Inhibit Breast Cancer Cell Growth and Promote Apoptosis

https://www.mdpi.com/1422-0067/24/13/10476

"PA + Chi can synergistically inhibit breast cancer cell growth and proliferation, and promote apoptosis."

Chi = Chidamide (Tucidinostat)


   
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(@j)
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Posted by: @rosed

@jI have had 5 tests of IGF...... 4 out of the 5 were high. I am starting 3-day water fast.  I did this awhile ago...... I was fine...... just need to get myself mentally psyched.  I am going to starve those rogue cells.  They are too fat and happy now.  They are in for it. hahahahah.    I am going to ask for tamoxifen.  Funny this morning I read about selenium and came up with completely contradictory papers, so I agree with you.... that's out.   But I did read something about estrogen stimulating IGF....... SO I AM GOING TO GET TAMOXIFEN......gonna contact integrative onco now.  THank you so much for giving me this paper to send to her. I will also up my Luteolin!!!!  Thanks so much!

@rosed

An interesting finding regarding IGF-1 and calorie restriction:

"Calorie restriction had no effect on serum concentrations of PDGF‐AB and TGFβ‐1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF‐1 concentration"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786582/

 


   
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(@j)
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Plant-based (vegan) to lower IGF-1 

https://nutritionfacts.org/video/how-plant-based-to-lower-igf-1/

 


   
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(@j)
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Posted by: @j

Posted by: @rosed

@jI have had 5 tests of IGF...... 4 out of the 5 were high. I am starting 3-day water fast.  I did this awhile ago...... I was fine...... just need to get myself mentally psyched.  I am going to starve those rogue cells.  They are too fat and happy now.  They are in for it. hahahahah.    I am going to ask for tamoxifen.  Funny this morning I read about selenium and came up with completely contradictory papers, so I agree with you.... that's out.   But I did read something about estrogen stimulating IGF....... SO I AM GOING TO GET TAMOXIFEN......gonna contact integrative onco now.  THank you so much for giving me this paper to send to her. I will also up my Luteolin!!!!  Thanks so much!

@rosed

An interesting finding regarding IGF-1 and calorie restriction:

"Calorie restriction had no effect on serum concentrations of PDGF‐AB and TGFβ‐1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF‐1 concentration"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786582/

 

I linked to the wrong paper, sorry. Here is the link I wanted to share:

https://pubmed.ncbi.nlm.nih.gov/26443692/

Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: a randomized clinical trial

 


   
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(@j)
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Carglumic acid promotes apoptosis and suppresses cancer cell proliferation in vitro and in vivo

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731631/

Abstract
Drug repurposing is a therapeutic strategy that applies drugs to treat different diseases based on new therapeutic function. Carglumic acid (Carbaglu; Orphan Europe) is an orphan drug approved by the FDA for hyperammonemia. Administration of carglumic acid for treatment of hyperammonemia has few side effects and has been used for 10 years to effectively treat hyperammonemia symptoms of both adult and pediatric patients. Here, we tested the potential of carglumic acid to be repurposed as an anticancer agent and showed that carglumic acid promotes apoptosis and inhibits cancer cell growth ina wide variety of human cancers, including pancreatic ductal adenocarcinoma, triple-negative breast cancer (TNBC), hepatoma, and lung cancer. Our data from in vivo models indicates that orally taking 10% of the carglumic acid dose currently used for the treatment of hyperammonemia is effective to suppress the growth of pancreatic ductal adenocarcinoma and TNBC. If given intravenously, only 5% of the carglumic acid doseis needed to be effective against TNBC. These findings suggest that carglumic acid may serve as a safe and effective therapeutic to treat both TNBC and pancreatic cancer.


   
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(@j)
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Trifolium pratense L. (red clover) extract and doxorubicin synergistically inhibits proliferation of 4T1 breast cancer in tumor-bearing BALB/c mice through modulation of apoptosis and increase antioxidant and anti-inflammatory related pathways

https://onlinelibrary.wiley.com/doi/full/10.1002/fsn3.1724

Abstract
Therapeutic strategies against triple-negative breast cancer (TNBC) are associated with drug-induced toxicities. The tropical edible red clover (Trifolium pratense L.) is rich in polyphenolic compounds which confer the plant potential anticancer properties. The aim of this study was to investigate the effects of T. pratense and doxorubicin (DOX) on the apoptosis and proliferation of 4T1 tumor cells in an allograft model of tumor-bearing BALB/c mice. Fifty-six female 4T1-tumor bearing- BALB/c mice were randomly divided into 7 groups (n = 8/group) to receive different doses and combinations of DOX and T. pratense extract for 35 days. On the 36th day, serum estradiol (E2), IL-12 and IFN-γ cytokines, and glutathione peroxidase (GPx) activity were measured. Tumor's ferric reducing antioxidant power (FRAP) and the expressions of apoptosis-related genes (p53, Bax, Bcl-2, and caspase-3) were also evaluated. Immunohistochemical staining for Ki-67 and p53 were performed. Our results showed that the co-treatment of DOX and T. pratense (100–400 mg/kg) inhibited the proliferation of 4T1 tumor cells in dose- and time-dependent manners. The co-treatment of DOX and T. pratense (especially at the dose of 400 mg/kg) decreased the serum level of E2 (as a stimulant for breast tumor growth) and increased the serum levels of IL-12 and IFN-γ along with significant increments in serum GPx and tumor FRAP activities. The co-administration of DOX and T. pratense also decreased the expression of Ki-67 proliferation marker and increased the number p53 positive (i.e., apoptotic) cells within tumors. This was accompanied with the upregulation of pro-apoptotic and down-regulation of antiapoptotic genes. The key findings indicated the synergistic effects of DOX and T. pratense against TNBC xenografts.


   
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(@j)
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Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss

https://www.nature.com/articles/s41467-023-38594-3

"supplementation of alanine restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells."

 

 


   
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(@j)
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" My preliminary data support the idea that ammonia is an immunosuppressive factor since it strongly inhibits the  cytotoxic activity of NK cells toward target cancer cells and may ultimately impact all forms of cancer immunotherapies."

https://pnitt.wum.edu.pl/en/node/13845

Hence, reducing ammonia will increase the efficacy of immunotherapies and increase # NK cells thus reducing metastasis.


   
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(@j)
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Posted by: @j

Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss

https://www.nature.com/articles/s41467-023-38594-3

"supplementation of alanine restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells."

 

Alanine is suggested as an important ammonia-scavenging molecule.

 

 


   
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(@j)
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"A widely accepted current hypothesis is that tumor cells use glutamine as a preferred carbon source for energy and reducing power, which has been used to explain both glutaminolysis and the Warburg effect. Here we provide evidence to show that supplying nitrogen, not the carbon skeleton, underlies the major biological importance of glutaminolysis for proliferating cells. We show that alternative nitrogen supplying mechanisms rescue cell proliferation in glutamine-free media. Particularly, we show that ammonia is sufficient to maintain a long-term survival and proliferation of Hep3B in glutamine-free media."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047752/


   
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(@rosed)
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@j I don't think I can get a hold of this carglumic acid. But in another post you say alanine..... is there a particular form of alanine.  Also, what kind of dosing do you think for alanine?  Thanks Johan!!!!!!  Hope you are doping well. 😊 


   
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(@j)
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Posted by: @rosed

@j I don't think I can get a hold of this carglumic acid. But in another post you say alanine..... is there a particular form of alanine.  Also, what kind of dosing do you think for alanine?  Thanks Johan!!!!!!  Hope you are doping well. 😊 

@rosed Thanks, Rosaleen. I think L-alanine is the preferred form but I have read beta-alanine can also reduce ammonia. I'd go for L-alanine. I'll look into the dosing.

 


   
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(@j)
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Posted by: @j

Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss

https://www.nature.com/articles/s41467-023-38594-3

"supplementation of alanine restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells."

 

@rosed

the researchers used 4g/kg (mice), the HED would be just under 18 grams for a 55kg human. The results from supplementing ALA were almost as good as cisplatin and the combination of cisplatin+alanin was very effective (see attached figure). 

bulksupplements.com has L-alanine

 

 

 


   
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(@j)
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amino acids such as ornithine and taurine can also help reduce ammonia.

https://pubmed.ncbi.nlm.nih.gov/12729839/

https://www.pieronline.jp/content/article/0386-3603/41080/797


   
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(@j)
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Posted by: @j

amino acids such as ornithine and taurine can also help reduce ammonia.

https://pubmed.ncbi.nlm.nih.gov/12729839/

https://www.pieronline.jp/content/article/0386-3603/41080/797

L-carnitine also reduces ammonia and seems like it's OK to use in TNBC

Investigation of L-carnitine effects on CD44+ cancer stem cells from MDA-MB-231 breast cancer cell line as anti-cancer therapy

https://www.sciencedirect.com/science/article/pii/S2352320423000627

 


   
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(@j)
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Carnitine is found mostly in meat milk and cheese, foods many people don't associate with a good anticancer diet. But it's not because some compounds can have an anticancer effect that you want to get them from the food that has most of it. Sometimes that's a good idea, sometimes it's not. Ammonia is produced from the breakdown of proteins, so you don't want to eat meat to reduce ammonia in spite of the fact that meat has high levels of l-carnitine. It's probably in there in high amounts to help deal with ammonia in the first place. Like bromelain, a digestive enzyme in pineapple, most of it is found in the stem, the hardest part of the fruit.


   
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(@rosed)
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@j Thank you so much, Johan!


   
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(@j)
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Posted by: @j

Posted by: @j

amino acids such as ornithine and taurine can also help reduce ammonia.

https://pubmed.ncbi.nlm.nih.gov/12729839/

https://www.pieronline.jp/content/article/0386-3603/41080/797

L-carnitine also reduces ammonia and seems like it's OK to use in TNBC

Investigation of L-carnitine effects on CD44+ cancer stem cells from MDA-MB-231 breast cancer cell line as anti-cancer therapy

https://www.sciencedirect.com/science/article/pii/S2352320423000627

 

Chemerin [also known as retinoic acid receptor responder 2 (RARRES2) or tazarotene induced gene 2 (TIG2)]

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

https://mmrjournal.biomedcentral.com/articles/10.1186/s40779-023-00470-y

"We found that down-regulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment."

and

https://www.sciencedirect.com/science/article/abs/pii/S0188440916301916?via%3Dihub

" LC supplementation is effective in treatment of NAFLD and reducing chemerin."

 

So, L-carnitine supplementation could be a double-edged sword. I think it's best avoided unless there's no evidence of Brain metastasis but how do you really know?

This also raises some doubts about using curcumin in such a setting

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202847/

 

 

 

 


   
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(@j)
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A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer

In previous work (4, 26, 27), we identified RPL39 and MLF2 genes to be associated with treatment resistance. Through bioinformatic analyses, we determined that iNOS signaling is a primary pathway common to both genes. iNOS has been described as a mediator of metastasis in different cancer types (2830), and elevated iNOS expression has been linked to poor survival in patients with breast cancer (31, 32). We recently reported that increased iNOS expression correlated with metastasis and poor survival in patients with TNBC (8). The pan-NOS inhibitor L-NMMA in combination with the chemotherapeutic drug docetaxel was evaluated in four preclinical mouse models with TNBC patient-derived tumors (8, 33). In all four models, the addition of L-NMMA reduced tumor volume compared to treatment with docetaxel alone. The clinical study was designed on the basis of these preclinical findings.
 
Here, we report that the recommended phase 2 dose of L-NMMA resulted in an on-target reduction of serum nitrites and nitrates in treated patients, although the reduction was not to zero presumably because of the impact of diet and the gut microbiota (3436). The overall response rate was 45.8% for the whole patient cohort, with 16.7% achieving a complete response. For metastatic TNBC, a response rate of 15.4% and a clinical benefit rate of 53.8% are noteworthy for patients who had already received a median of five prior chemotherapy regimens (3738). In the patient cohort with chemorefractory LABC, the response rate was 81.8%, with 36.4% achieving a complete response. A total of 27.3% of the patients with anthracycline refractory LABC achieved a pathological complete response at surgery where the expected response based on historic published data would be less than 5% (39). The anticipated blood pressure elevation due to iNOS inhibition was manageable with the addition of oral amlodipine. The L-NMMA and taxane drug regimen was well tolerated, and only 21% of patients had grade 3 or higher toxicity, with none of the grade 3 or higher toxicity attributable to L-NMMA.

   
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(@j)
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Using two different mouse models of lung tumors and glioma, Cheng et al. (2022) validate that inhibiting ammonia binding to SCAP suppresses the tumor growth.
https://www.cell.com/cell-metabolism/pdf/S1550-4131(22)00229-7.pdf

Therapies targeting ammonia-SCAP binding could have clinical potential. 25-hydroxycholesterol (25-HC, an oxysterol)) has been reported to enhance SCAP-Insig binding (Yang et al., 2002), which can mimic inhibition of ammonia binding to SCAP.

Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia
https://www.sciencedirect.com/science/article/pii/S2213231718300995


   
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(@j)
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Metabolomic Impact of Lidocaine on a Triple Negative Breast Cancer Cell Line

https://www.frontiersin.org/articles/10.3389/fphar.2022.821779/full

 

 


   
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