Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast ...cancer, without diabetes and a BMI over 18 kg m
, to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90-100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449.
Autophagy is essential for the maintenance of cellular homeostasis during
periods of stress. Eisenberg and colleagues (
Eisenberg et al., 2014
) now describe the central and conserved role
for ...acetyl-CoA synthetase in regulating lifespan in yeast and flies by a
mechanism involving autophagy.
Ras: the other pro-aging pathway Longo, Valter D
Science of aging knowledge environment,
2004-Sep-29, Volume:
2004, Issue:
39
Journal Article
Studies in worms, flies, and mice point to the insulin/insulin-like growth factor-1 (IGF-1)/phosphatidylinositol 3-kinase/Akt-like pathway as a central regulator of longevity. A similar pathway, ...which includes Sch9, a functional mammalian Akt/protein kinase B homolog, regulates longevity in yeast. Chronological aging in yeast is also regulated by a second pathway that includes Ras, adenylate cyclase, protein kinase A, the transcription factors Msn2 and Msn4, and Sod2. Although Ras proteins have not been implicated in longevity regulation in worms or flies, the major role of Ras in mammalian IGF-1 signaling raises the possibility that homologs of yeast Ras2 might accelerate aging in mammals. Here I review the data from experiments at both the organismal and cellular levels that support a role for Ras in the regulation of stress resistance and life span in eukaryotes.
Lymphokine-activated killing has enormous potential in the treatment of cancer. Lymphoid effectors have the potential to recognize and lyse a wide array of tumor cells, a phenomenon which has been ...seen in vitro and to some extent in vivo. However, studies have indicated that complexity exists not only in the nature of the lymphocyte that can be activated ex vivo for therapeutic use, but also in the delivery of such therapy in a clinical setting. This review attempts to deal with both issues. The nature of the cells mediating lymphokine-activated killer activity, their heterogeneous phenotype, their activation requirements, and a hypothetical mechanism of action are discussed. In addition, previous clinical studies are reviewed and key issues are raised that need to be addressed in upcoming clinical trials.
Profiling the dynamic interaction of p300 with proximal promoters of human T cells identified a class of genes that rapidly coassemble p300 and RNA polymerase II (pol II) following mitogen ...stimulation. Several of these p300 targets are immediate early genes, including FOS, implicating a prominent role for p300 in the control of primary genetic responses. The recruitment of p300 and pol II rapidly transitions to the assembly of several elongation factors, including the positive transcriptional elongation factor (P-TEFb), the bromodomain-containing protein (BRD4), and the elongin-like eleven nineteen lysine-rich leukemia protein (ELL). However, transcription at many of these rapidly induced genes is transient, wherein swift departure of P-TEFb, BRD4, and ELL coincides with termination of transcriptional elongation. Unexpectedly, both p300 and pol II remain accumulated or "bookmarked" at the proximal promoter long after transcription has terminated, demarking a clear mechanistic separation between the recruitment and elongation phases of transcription in vivo. The bookmarked pol II is depleted of both serine-2 and serine-5 phosphorylation of its C-terminal domain and remains proximally positioned at the promoter for hours. Surprisingly, these p300/pol II bookmarked genes can be readily reactivated, and elongation factors can be reassembled by subsequent addition of nonmitogenic agents that, alone, have minimal effects on transcription in the absence of prior preconditioning by mitogen stimulation. These findings suggest that p300 is likely to play an important role in biological processes in which transcriptional bookmarking or preconditioning influences cellular growth and development through the dynamic priming of genes for response to rechallenge by secondary stimuli.
Abstract This paper reviews the scientific evidence for the safety of carbon monoxide (CO) and nitric oxide (NO) inhalation to measure pulmonary diffusing capacity (DLCO and DLNO ) in pregnant women ...and their fetuses. In eight earlier studies, 650 pregnant women had DLCO measurements performed at various times during pregnancy, with a minimum of two to four tests per session. Both pregnant subjects that were healthy and those with medical complications were tested. No study reported adverse maternal, fetal, or neonatal outcomes from the CO inhalation in association with measuring DLCO . Eleven pregnant women, chiefly with pulmonary hypertension, and 1105 pre-term neonates, mostly with respiratory failure, were administered various dosages of NO (5–80 ppm for 4 weeks continuously in pregnant women, and 1–20 ppm for 15 min to 3 weeks for the neonates). NO treatment was found to be an effective therapy for pregnant women with pulmonary hypertension. In neonates with respiratory failure and pulmonary hypertension, NO therapy improved oxygenation and survival and has been associated with only minor, transient adverse effects. In conclusion, maternal carboxyhemoglobin (HbCO ) levels can safely increase to 5% per testing session when the dose-exposure limit is 0.3% CO inhalation for ≤3 min, and for NO, 80 ppm for ≤3 min. The risk of late fetal or neonatal death from increased HbCO from diffusion testing is considerably less than the risk of death from all causes reported by the Centers for Disease Control, and is therefore considered “minimal risk”.
The human cytokine, Recombinant Human Regulated on Activation, Normal T Expressed and Secreted (rhRANTES), is a small glycoprotein secreted by activated T cells and platelets and is structurally ...related to a family of chemotactic cytokines called chemokines. Evaluation of the effects of chemokines on human cells has largely been limited to in vitro binding assays. In an effort to study the in vivo effects of chemokines on human leukocyte migration, we examined the ability of rhRANTES to induce human T cell infiltration using a human/severe combined immune deficient (SCID) mouse model. SCID mice received human peripheral blood lymphocytes, followed by sequential subcutaneous injections of rhRANTES in the hind flank for 3 days. The skin and underlying tissue from the rhRANTES injection site were then biopsied and examined for the extent of human mononuclear cell infiltration. rhRANTES induced significant mononuclear cell accumulation 72 h after injection. Immunohistological evaluation determined that the majority of the cells recruited in response to rhRANTES injections were human CD3+ T cells with equal numbers of CD4+ and CD8+ cells. In contrast, subcutaneous injections of recombinant human macrophage colony-stimulating factors resulted in little human cellular infiltration. Murine mononuclear cell infiltration in response to rhRANTES was also present suggesting that the in vivo effects of rhRANTES may be both direct and indirect. These results demonstrate that rhRANTES induces significant human T cell migration in vivo and suggests that the human/SCID mouse model may provide an important tool in studying the in vivo effects of chemokines on human leukocytes and leukocyte subsets.
Tarsal tunnel syndrome Reade, B M; Longo, D C; Keller, M C
Clinics in podiatric medicine and surgery
18, Issue:
3
Journal Article
Peer reviewed
Most authors agree that surgical decompression is the treatment of choice for tarsal tunnel syndrome when conservative treatment fails. Overall, the results of surgical treatment for tarsal tunnel ...have been favorable. Studies have shown that surgical release improves or resolves symptoms of tarsal tunnel syndrome in 85% to 90% of cases.
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