30 Matching Annotations
  1. Jan 2023
    1. increased blood concentration of ketone bodies, which downmodulate PD-L1 expression in monocytes, thus inhibiting their immunosuppressive properties (34);

      Connect ketones to immune system right here.

      I consider cancer to be both a genetic (a mutation that causes uncontrolled cell proliferation), metabolic ( cancer cells are anabolic) and immune disease (normally before you "get cancer" our immune cells spot and destroy small tumors. There is a reason why Car-T immune therapy exists.

    2. it remains unclear whether fasting/FMD regimens of shorter duration (e.g., 19 hours) can recapitulate the broad reshaping of systemic and, more importantly, intratumor immunity that we reported in this study.

      So probably stick to the time they used.

    3. In addition, some FMD-induced systemic immunologic modifications, such as the modulation of monocyte, MDSC, and NK cells, are long-lasting, that is, they are maintained at least 40 days after the end of FMD.

      Not bad for a 5 day investment, I think.

    4. We also showed that FMD-induced reduction of serum IGF1 levels is associated with the downregulation of total and activated IGF1R at the tumor level, thus providing first evidence of “pharmacodynamic” activity of FMD in human cancers. This result paves the way for combining the FMD with inhibitors of different nodes of the IGF1R/PI3K/AKT/mTORC1 axis in future clinical trials.

      Might want to look into inhibitory drugs to these protein pathways!

    5. Nevertheless, our experimental FMD regimen reduced median blood glucose, insulin, and IGF1 concentration by 18.6%, 50.7%, and 30.3%, respectively, that is, more than 1 to 3 days of water-only fasting (31, 33).

      I would rather get to eat a little bit each day for 5 days than do a 3 day water fast.

    6. One major issue related to the use of fasting/FMD in patients with cancer is the risk of causing progressive weight loss by inducing or accelerating the release of amino acids, glycerol, and fatty acids from skeletal muscles and adipose tissue (28). For this reason, patients who were underweight, or at higher risk to become malnourished, were excluded from enrollment. With these selection criteria, only 4% of patients discontinued the FMD due to progressive BMI reduction, and we observed restoration of baseline BMI in patients who completed at least three FMD cycles. These results indicate that the FMD is unlikely to cause progressive weight loss if patients are properly selected and strict discontinuation rules are used in the case of insufficient weight recovery.

      Good sign for BMI. Don't want to lose too much weight!

    7. The incidence of G3/G4 FMD-related AEs was 12.9%, which allowed us to reject the null hypothesis that the real incidence is 20%, a threshold that we considered clinically significant to proceed with further investigation of the FMD. Of note, this threshold is significantly lower than that reported in recent clinical trials evaluating different types of innovative targeted therapies and immunotherapy strategies that received approval by regulatory agencies in the United States and in Europe (24–26).

      Looks good.

    8. This intense cytotoxic response can in part be explained by the recruitment of activated/cytotoxic T cells through the CCR5/CX3CR1 chemokine pathways, as suggested by the upregulation of genes encoding CCR5/CX3CR1 ligands (CCL4L2, CCL3L1, CCL5, and CX3CL1, respectively) and of the adhesion marker ICAM1 (Fig. 4B and ​andC),C), which are critical for immune-mediated tumor rejection


    9. Overall, the FMD induced profound changes of intratumor transcriptional programs (Supplementary Tables S11–S13). Single-gene level analysis revealed a dramatic increase in the expression of several immune-related genes (see Methods for details; Fig. 4A). Notably, the IFNγ-activating signature (IFNG.GS), which is selectively activated in tumor-infiltrating immune cells and is associated with favorable clinical outcomes (16), was enriched in post-FMD tumor specimens, while the IFNγ-resistant signature (ISG.RS), which is prevalently expressed in cancer cells and is associated with resistance to immunotherapy through the induction of T-cell exhaustion, was not significantly modulated (Fig. 4A and ​andB).B).

      Sounds good.

    10. Each FMD cycle also reduced patient BMI (first cycle: median reduction: 4.52%; second cycle: median reduction: 4.51%; third cycle: median reduction: 4.55%) regardless of concomitant treatments (Fig. 1G–I). During the first three FMD cycles, the BMI was only partially recovered, thus resulting in progressive BMI reduction (Fig. 1G).

      Should be noted.

    11. FMD-related AEs

      Check out this table.

    12. The trial met its primary endpoint, with an incidence of severe grade 3 or 4 (G3/G4) FMD-related AEs of 12.9% (90% CIs: 7.8–19.7%), that is, significantly lower than the prespecified 20% threshold

      Another good sign.

    13. 72 (71.3%) patients were fully compliant with the FMD, while 95 (94.1%) patients were fully compliant or reported only minor deviations

      Dieting is hard. Not bad!

    14. Reasons for FMD discontinuation were: inability to maintain the body mass index (BMI) above 20 kg/m2 (4%)

      At ~138 pounds and 5'7", my BMI is 21.6. BMI 20 is very thin. More about BMI maintenance later in the paper.

    15. G,

      See G, H, I

    16. F, Serum IGF1 concentration

      See F

    17. urinary ketone bodies (mg/dL)

      Urine ketone sticks for diabetics might help. Can also get a ketone blood meter for better accuracy. I use the alphatrak one for Mookitty.

    18. fasting and FMD were shown to boost tumor infiltration by CD8+ T cells—the effectors of antitumor immune responses—and to reduce immunosuppressive regulatory T cells (Treg) in syngeneic mouse models


    19. insulin-like growth factor 1 (IGF1) concentration

      I saw mention of drug inhibitors of IGF1 specifically in the context of mesothelioma in another paper.


      I think its absolutely a good idea to look into benefits of IGF1 reduction whether that be through this diet, intermittent fasting, ketogenic diet (if it has that effect) or any other method.

    20. II/III

      Purpose of Phase 1 is: safety, finding side effects, and seeing downstream effects of the treatment.

      101 people is a pretty big sample size for a phase 1 (20 -100 people).

    21. Abstract

      Good parts to read: Abstract, Intro, the Headers of the Results Section, Discussion, and Methods section that describes the actual diet.

      Most of the paper is heavy because it spends a lot of time discussing the relative qualities of different immune cells with different cell surface markers (like Cd8+ t cells). I did not delve into that.

    22. Because IL6 plays an important role in the pathogenesis of cachexia (28), FMD-induced upregulation of the IL6/SOCS3/LIF signature at the tumor level may raise concerns about a potential cachexia-inducing effect of the FMD. However, the following arguments tend to exclude this hypothesis:

      Glad they are looking into this because muscle loss would also be bad.

    23. Together, these results show that five-day FMD is sufficiently potent to broadly reshape intratumor immunity within 7 to 10 days in patients with limited-stage breast cancer, thus reducing biomarkers associated with immune suppression and promoting tumor infiltration by activated and cytotoxic immune cell populations.

      They did a substudy in just breast cancer patients in the study. Still interesting.

    24. Of note, FMD-induced metabolic changes were independent of the type of primary tumor (breast cancer, colorectal cancer, lung cancer, others), concomitant anticancer treatments (ChT, other therapies) and tumor stage (limited, advanced; Supplementary Fig. S2A–S2C)


    25. the most common AE was fatigue, which occurred in 90.2% of patients and was G3/G4 in 4% of patients. Other G3/G4 FMD-related AEs were hypoglycemia (5%), syncope (1%), nausea (1%), dizziness (1%), and increased aspartate aminotransferase levels (1%)

      I would expect some fatigue in a fasting diet.

    26. Mesothelioma11

      I think it is a good sign that they enrolled a mesothelioma patient into this study. If they didn't think the effects of fasting could benefit a patient with that type of cancer, I don't see why they would have them do it.

    27. An FMD cycle was defined as five-day FMD followed by 16 to 23 days of refeeding.

      Nice because it doesn't look like something she would have to do all the time. Less stressful and easier to accomplish I think than keto.

    28. I'd start with abstract, intro, and discussion.

  2. Oct 2021
    1. Significance

      Antisense oligonucleotides (ASOs) have also been used to cause passive reactivation of X Linked genes. Jeannie Lee's lab at Harvard designed a therapeutic approach to reactivate methyl-CpG binding protein 2 (MECP2) by combining Azo targetting of XIST with 5-aza-2'-deoxycytidine. With this combined approach they were able to upregulate MECP2 30,000 fold.

  3. Jan 2021
    1. We observed that for genes subject to XCI, a general increase in methylation on the Xi occurs at gene promoters. In comparison, genes escaping XCI show higher levels of methylation within gene bodies on both the Xa and Xi, but reduced promoter methylation only on the Xi.

      They found that there were higher levels of DNA methylation in the promoters of genes that underwent XCI on the Xi. Escapee genes, by contrast, have less promoter methylation on Xiin their promoters o the Xi, but an increase in methylation within gene bodies.