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Short-term starvation lombo molto male per ritardare fasting protects normal cells, mice, and potentially humans from the harmful side effects of a variety of chemotherapy drugs. Here, we show that treatment with starvation conditions sensitized yeast cells Saccharomyces cerevisiae expressing the oncogene-like RAS2 val19 to oxidative stress and 15 of 17 mammalian cancer cell lines to chemotherapeutic agents.

Cycles of starvation were as effective as chemotherapeutic agents in delaying progression of different tumors and increased the effectiveness of these drugs against melanoma, glioma, and breast cancer cells. In mouse models of neuroblastoma, fasting cycles plus chemotherapy drugs—but not either treatment alone—resulted in long-term cancer-free survival. In 4T1 breast cancer cells, short-term starvation resulted in increased phosphorylation of the stress-sensitizing Akt and S6 kinases, increased oxidative stress, caspase-3 cleavage, DNA damage, and apoptosis.

These studies suggest that multiple cycles of fasting promote differential stress sensitization in a wide range of tumors and could potentially replace or augment the efficacy of certain chemotherapy drugs in the treatment of various cancers. Because of this broad ability to promote stress resistance, DR could in theory be applied in the clinic to protect patients from toxic side effects of chemotherapy.

However, DR is not feasible for patients already prone to weight loss from the cancer itself or from the chemotherapy, because, based on animal studies, several lombo molto male per ritardare may be necessary for patients undergoing DR to reach a protected state. Thus, in addition to requiring major life-style changes, DR would inevitably also cause chronic weight loss. Also, DR only retards the progression of specific cancers, possibly because of its relatively small effect on glucose and growth factors 78.

In humans, DR does not reduce growth-promoting insulin-like growth factor 1 IGF-1 unless it is combined with protein restriction 9. Finally, it is not known whether DR would also protect cancer cells from chemotherapy. By contrast, a limited exposure to a severely restricted diet short-term starvation or fasting can protect yeast, mammalian cells, mice, and possibly patients from the toxic effects of oxidative and chemotherapeutic agents without causing chronic weight loss 10 - For lombo molto male per ritardare, fasting for 48 to 60 hours protected mice of three different genetic backgrounds from the chemotherapy drug etoposide Fasting apparently protects normal cells by reallocating energy toward maintenance pathways from reproduction and growth processes when nutrients are scarce or absent 21013lombo molto male per ritardare This switch to a protected mode occurs only in normal cells, not cancer cells, because oncogenes prevent the activation of stress resistance.

This feature of cancer cells thus provides a way to enhance cancer treatment by selectively increasing protection only in normal cells [differential stress resistance DSR ] rather than by the more typical strategy of increasing the toxicity of drugs to cancer cells 10 - DSR in mice and mammalian cells is mediated in part by the reduction of extracellular glucose and IGF-1 concentration and signaling 10 - 12 Potentially harnessing DSR for clinical cancer therapy is attractive because fasting for 2 to 3 days before and 24 hours after chemotherapy is well tolerated by cancer patients receiving a variety of toxic treatments and may even reduce the common side effects caused by chemotherapy Further, in mouse models, fasting protects against ischemia-reperfusion injury 17and deprivation of a single amino acid results in both lower Lombo molto male per ritardare levels and protection against renal and hepatic ischemic injury The therapeutic potential of fasting would be even greater if it also increased the death of cancer cells.

Here, we tested this possibility by studying the lombo molto male per ritardare of fasting on cancer cell survival in the presence or absence of chemotherapeutic agents. We have previously shown that, unlike wild-type cells, yeast cells expressing an oncogene-like constitutive active form of Ras RAS2 val19 are not protected from oxidative and chemotherapeutic agents by prior starvation 10 We repeated these experiments by switching normal yeast cells from glucose medium containing amino acids and other essential nutrients to water 1920 for 24 hours before exposure to various toxic agents.

The starvation water treatment increased the survival of wild-type cells under oxidative stress induced by hydrogen peroxide or menadione, both of which mimic the oxidation-dependent cytotoxicity of many chemotherapy drugs Fig.

In contrast, starvation sensitized yeast lombo molto male per ritardare carrying the RAS2 lombo molto male per ritardare mutation so that they were less able to withstand heat shock or oxidative stress Fig. These data suggest that, in contrast to the protection afforded to normal cells, starvation increases the susceptibility of yeast cells expressing an oncogene-like protein to stress 7 Effect of lombo molto male per ritardare starvation on stress resistance and DXR sensitivity of cancer cell lines.

Starvation was modeled by culturing nondividing yeast cells in water for 24 hours as described 19 For oxidative stress resistance assays, cells were diluted to an absorbance at nm of 1 in K-phosphate buffer pH 6.

C Effect of starvation 0. Starvation was applied to cells 24 hours before and 24 hours during DXR treatment. Control groups were cultured in glucose 1. Lombo molto male per ritardare groups were cultured in glucose 0. Survival was determined by MTT reduction. See the Supplementary Materials for additional data, including the effects of CP. See also figs. S1 to S4. To test whether sensitization by short-term starvation may also occur in mammalian tumor cells, we incubated various cancer cell lines in medium containing serum collected from mice either fed ad lib or fasted for 48 hours.

Murine breast cancer cells 4T1 cultured in medium supplemented with serum from fasted mice were lombo molto male per ritardare susceptible to the chemotherapeutic drugs doxorubicin DXR and cyclophosphamide CP compared to cells incubated in serum from mice fed ad lib Fig.

Restricting glucose and growth factors in this way greatly retarded proliferation Fig. S2 and S4. S2 and S3. These results indicate that short-term starvation can sensitize a broad range of cancer types to chemotherapeutic agents. Our previous studies suggested that reduced serum levels of IGF-1 are important for the protective effects of fasting and showed that IGF-1 infusion can reverse the fasting-induced protection of mice from the side effects caused by high-dose chemotherapy We found that adding IGF-1 to starvation-treated 4T1 cells incubated in medium containing reduced concentrations of growth factors, including IGF-1 reversed this sensitization Fig.

Thus, the decrease in IGF-1 levels caused by fasting may contribute to the sensitization of 4T1 cells to stress. Fasting was achieved by complete food withdrawal for 48 to 60 hours while allowing mice access to water.

In mice bearing subcutaneous breast cancer 4T1two lombo molto male per ritardare of fasting alone 48 hours each were as effective as two cycles of CP treatment Fig.

S5Ayet the mice were able to regain normal weight within 5 days of refeeding Fig. Similar effects were observed in mice bearing subcutaneous melanoma masses Lombo molto male per ritardare treated with DXR Fig. Lombo molto male per ritardarealthough the growth of melanoma cells was not affected by the second cycle of fasting, indicating that cancer cells may in some cases acquire resistance to fasting alone.

Effect of fasting on the sensitivity of allograft and xenograft tumors to chemotherapeutic agents in mice. Fasting in the glioma model was applied only once due to the rapid tumor growth in the control ad lib, no chemotherapy group. In both xenograft models, fasted mice treated with DXR did not experience death from chemotherapy toxicity.

S5 and S6. For 4T1 breast cancer, two fasting cycles combined with CP maintained tumor size at less than half of that in the CP treatment alone lombo molto male per ritardare, even 20 days after the last treatment Fig. Similar effects were observed in subcutaneous melanoma and glioma models Fig.

Prefasted mice receiving chemotherapy returned to their normal weight soon after the last fasting cycle Fig. The growth of subcutaneous human breast cancer MDA-MB and ovarian cancer OVCAR3 xenografts was also retarded by fasting but returned to a size similar lombo molto male per ritardare that in animals on the control diet after refeeding Fig.

This post-fasting cancer growth may be the result of overfeeding and weight gain by prefasted mice given an ad lib diet. However, when fasting was combined with DXR, the progression of the human breast cancer tumors was markedly retarded and the tumor did not progress Fig. In lombo molto male per ritardare with our previous results, fasting also allowed multiple treatments with a dose of DXR that lombo molto male per ritardare lethal to all normally fed mice by day 14 fig.

To test the effect of fasting alone in a model of human metastatic cancer, we applied cycles of hour fasting in immunocompromised nude mice subcutaneously injected with human ACN neuroblastoma cells Fig.

After 34 days and five fasting cycles, tumor size was less than half of that in normally fed mice Fig. In agreement with the other tumor mouse models, animals were able to return to the normal weight after each cycle Fig. These results suggest that cycles of fasting can delay the growth of some cancer cell types, in some cases as effectively as chemotherapy drugs, but that the combination of fasting and chemotherapy cycles provides a more effective, consistent, and potent effect on a wide range of tumors.

Because advanced metastatic tumors are extremely difficult to cure once tumor masses have spread to different organs, we studied whether the combination of multiple fasting cycles and high-dose chemotherapy can increase survival in aggressive metastatic models before large tumor masses can be formed. To perform this experiment, we intravenously injected immunocompetent mice with murine breast cancer lombo molto male per ritardare 4T1melanoma cells B16and two neuroblastoma lombo molto male per ritardare lines NXS2 and Neuro-2a.

Fasting potentiated the effects of chemotherapy and extended the survival of mice injected with each type of cancer cell Fig. In the model of metastatic melanoma, one cycle of DXR treatment alone was not sufficient to extend survival, and only mice that were both fasted and treated with DXR showed extended maximum survival time Fig. The tumor load in these mice was estimated by bioluminescence imaging.

By day 28, fasting alone caused a significant reduction in bioluminescence, which was further reduced in mice treated with both fasting and DXR fig. S7, A and B. Body weight was rapidly recovered upon refeeding fig.

Fasting alone, but to a greater extent fasting combined with DXR, reduced the metastases of B16 melanoma cells to some organs compared to mice fed the standard diet Fig. Lung metastases were detected in all mice, as expected, and served as a control for tumor seeding. In addition, unlike normally fed mice, metastases were not detected in the ovaries or lymph of fasted mice whether they received chemotherapy or not Fig.

In agreement with the results for melanoma cells, a single fasting cycle potentiated the effects of chemotherapy and extended survival lombo molto male per ritardare mice bearing metastatic breast tumor cells 4T1 Fig. Effect of fasting on survival and tumor load in metastatic mouse models of cancer treated with chemotherapeutic agents.

Statistical significance for all survival curves was determined by log-rank test. See also fig. To more closely mimic cancer treatment in humans and to lombo molto male per ritardare whether lombo molto male per ritardare combination of fasting cycles and chemotherapy has the potential to cure subjects with aggressive metastatic malignancies, we tested the effect of multiple cycles of fasting cycles in combination with chemotherapy drugs on a schedule that more closely reflects the therapy regimen administered to children with neuroblastoma.

We monitored the survival of two mouse models of metastatic neuroblastoma. We injected murine neuroblastoma cells Neuro-2a intravenously into mice and allowed the tumor cells to spread for 9 days before initiating chemotherapy Fig. At days, the mice remained cancer-free. These results suggest that fasting cycles potently sensitize a wide variety of lombo molto male per ritardare cell types to several of the most widely used chemotherapy drugs.

This fasting-dependent potentiation of chemotherapeutic action significantly extended overall survival time and allowed long-term cancer-free survival, even in mice with a large number of dispersed cancer cells.

To identify the gene expression changes that may be regulating the differential resistance to chemotherapeutics in normal and cancer cells in response to fasting, we performed genome-wide microarray analyses on the liver, heart, skeletal muscle, and subcutaneous 4T1 breast tumor masses removed from mice that were either fasted for 48 hours or fed an ad lib diet. Fasting differentially regulated, in normal and cancer cells, many genes involved in cellular proliferation such as the insulin signaling adaptor Irs2 and the mitogenic hormone prolactin receptor Prlr Fig.

In lombo molto male per ritardare cases, proliferation-associated genes were down-regulated in normal tissues but upregulated or unaffected in cancer cells. In agreement with these results, 4T1 cells cultured under starvation conditions for 48 hours displayed a major increase in cellular protein concentration Fig. Similar results were observed in 4T1 cells undergoing starvation in vitro, although Akt phosphorylation was not induced by starvation conditions alone but only by starvation plus CP treatment Fig.

Despite this starvation-dependent activation of translation control pathways, cancer cell number was greatly reduced in vitro by starvation conditions Fig. Effect of lombo molto male per ritardare on genes involved in growth and proliferation. GAPDH, glyceraldehydephosphate dehydrogenase. In agreement with our previous studies 10 - 12these results indicate that fasting promotes differential regulation of pro-growth and pro-translation genes in normal and cancer cells.

To determine the mechanisms by which short-term starvation cycles reduce tumor progression, we tested the hypothesis that lower concentrations of extracellular glucose and growth factors lombo molto male per ritardare increase DNA damage in cancer cells.

In both cultured 4T1 breast cancer cells Fig.