Prolonged water-only fasting in the management of low-grade follicular lymphoma: a case series.

BACKGROUND: Follicular lymphoma typically follows an indolent and relapsing course often requiring several treatment cycles to achieve remission. Some patients opt to use complementary and alternative therapies particularly when observation is a treatment option. CASE PRESENTATION: Here we present a case series of three patients, a 50-year-old, White, Hispanic female, 56-year-old, White, non-Hispanic male, and 49-year-old, White, non-Hispanic male, who elected to undergo one or more prolonged water-only fasting and refeeding interventions to manage low to intermediate grade follicular lymphoma. Fasting was well tolerated in each patient. Each patient also experienced a reduction in the size and avidity of hypermetabolic lymph nodes as independently determined by their respective oncologists. CONCLUSION: The reported cases demonstrate positive outcomes in low-grade follicular lymphoma coinciding with prolonged water-only fasting and exclusively whole-plant-food dietary interventions. These findings highlight the potential of such interventions and warrant further exploration through preliminary observational research.

A Six-Week Follow-Up Study on the Sustained Effects of Prolonged Water-Only Fasting and Refeeding on Markers of Cardiometabolic Risk.

(1) Background: Chronic inflammation and insulin resistance are associated with cardiometabolic diseases, such as cardiovascular disease, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Therapeutic water-only fasting and whole-plant-food refeeding was previously shown to improve markers of cardiometabolic risk and may be an effective preventative treatment but sustained outcomes are unknown. We conducted a single-arm, open-label, observational study with a six-week post-treatment follow-up visit to assess the effects of water-only fasting and refeeding on markers of cardiometabolic risk. (2) Methods: Patients who had voluntarily elected and were approved to complete a water-only fast were recruited from a single-center residential medical facility. The primary endpoint was to describe changes to Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores between the end-of-refeed visit and the six-week follow-up visit. Additionally, we report on changes in anthropometric measures, blood lipids, high-sensitivity C-reactive protein (hsCRP), and fatty liver index (FLI). Observations were made at baseline, end-of-fast (EOF), end-of-refeed (EOR), and six-week follow-up (FU). (3) Results: The study enrolled 40 overweight/obese non-diabetic participants, of which 33 completed the full study protocol. Median fasting, refeeding, and follow-up lengths were 14, 6, and 45 days, respectively. At the FU visit, body weight (BW), body mass index (BMI), abdominal circumference (AC), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein (LDL), hsCRP, and FLI were significantly decreased from baseline. Triglycerides (TG) and HOMA-IR scores, which had increased at EOR, returned to baseline values at the FU visit. (4) Conclusion: Water-only fasting and whole-plant-food refeeding demonstrate potential for long-term improvements in markers of cardiovascular risk including BW, BMI, AC, SBP, DBP, blood lipids, FLI, and hsCRP.

Potential Effects of Prolonged Water-Only Fasting Followed by a Whole-Plant-Food Diet on Salty and Sweet Taste Sensitivity and Perceived Intensity, Food Liking, and Dietary Intake.

The overconsumption of calorie-dense foods high in added salt, sugar, and fat is a major contributor to current rates of obesity, and methods to reduce consumption are needed. Prolonged water-only fasting followed by an exclusively whole-plant-food diet free of added salt, oil, and sugar may reduce the consumption of these hyper-palatable foods, but such effects have not been quantified. Therefore, we conducted a preliminary study to estimate the effects of this intervention on salty and sweet taste detection and recognition thresholds and perceived taste intensity after at least five days of fasting and at refeed day three. We also assessed the effects on sweet, salty, and fatty food preference and overall dietary consumption 30 days after the day three refeed visit. Based on this data, we estimated that 10 days after the start of the fasting, salty taste recognition, sweet taste detection, and sweet taste recognition thresholds decreased significantly, salty taste intensity ratings increased significantly, and sweet taste intensity ratings decreased significantly. We also have preliminary data that prolonged water-only fasting followed by refeeding on an exclusively whole-food-plant diet may reduce salty/fatty and sweet/fatty food liking, reduce sugar intake, and increase vegetable intake. These results support further research into the effects of fasting and diet on taste function and food likability and consumption.

The Effects of Prolonged Water-Only Fasting and Refeeding on Markers of Cardiometabolic Risk.

(1) Background: Cardiometabolic disease, including insulin resistance, hyperlipidemia, and hypertension, are major contributors to adverse health outcomes. Fasting has gained interest as a nonpharmacological therapeutic adjunct for these disorders. (2) Methods: We conducted a prospective, single-center study on the effects of prolonged water-only fasting followed by an exclusively whole-plant-food refeeding diet on accepted measures of cardiovascular risk and metabolic health. Participants were recruited from patients who had voluntarily elected to complete a water-only fast in order to improve their overall health according to an established protocol at an independent, residential medical center. Median fasting and refeed lengths were 17 and 8 days, respectively. The primary endpoint was to describe the mean glucose tolerance as indicated by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores at baseline, end-of-fast (EOF), and end-of-refeed (EOR) visits. Secondary endpoints were to describe the mean weight, body mass index (BMI), abdominal circumference (AC), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid panel, and high-sensitivity C-reactive protein (hsCRP) at the same time points. (3) Results: The study enrolled 48 overweight/obese non-diabetic participants, of which 26 completed the full study protocol. At the EOF visit, the median SBP, AC, low-density lipoprotein (LDL), and hsCRP were decreased and triglycerides (TG) and HOMA-IR scores were increased. Conclusion: Prolonged water-only fasting and whole-plant-food refeeding holds potential as a clinical therapy for cardiometabolic disease but increased TG and HOMA-IR values after refeeding necessitate further inquiry.

Exclusively plant, whole-food diet for polypharmacy due to persistent atrial fibrillation, ischaemic cardiomyopathy, hyperlipidaemia and hypertension in an octogenarian.

Polypharmacy is common and associated with negative health outcomes in the elderly. We report the case of an 82-year-old man with a history of polypharmacy due to coronary artery disease, myocardial infarction, ischaemic cardiomyopathy, hyperlipidaemia, hypertension and persistent atrial fibrillation who presented with memory loss, cognitive impairment, fatigue and weakness. His treatment plan included an exclusively plant, whole-food diet and moderate physical activity which resulted in a rapid reduction of hyperlipidaemia and high blood pressure and the discontinuation of statin, antihypertensive and beta blocker drug therapy. The patient also reported reversal of impaired cognition and symptoms associated with atrial fibrillation and ischaemic cardiomyopathy, including light-headedness, fatigue and weakness. This case demonstrates that dietary and lifestyle modifications have the potential to improve symptoms of cardiovascular disease and reduce polypharmacy along with associated negative consequences in the elderly.

JMJD-1.2 controls multiple histone post-translational modifications in germ cells and protects the genome from replication stress.

Post-translational modifications of histones, constitutive components of chromatin, regulate chromatin compaction and control all DNA-based cellular processes. C. elegans JMJD-1.2, a member of the KDM7 family, is a demethylase active towards several lysine residues on Histone 3 (H3), but its contribution in regulating histone methylation in germ cells has not been fully investigated. Here, we show that jmjd-1.2 is expressed abundantly in the germline where it controls the level of histone 3 lysine 9, lysine 23 and lysine 27 di-methylation (H3K9/K23/K27me2) both in mitotic and meiotic cells. Loss of jmjd-1.2 is not associated with major defects in the germ cells in animals grown under normal conditions or after DNA damage induced by UV or ionizing irradiation. However, jmjd-1.2 mutants are more sensitive to replication stress and the progeny of mutant animals exposed to hydroxyurea show increased embryonic lethality and mutational rate, compared to wild-type. Thus, our results suggest a role for jmjd-1.2 in the maintenance of genome integrity after replication stress and emphasize the relevance of the regulation of histone methylation in genomic stability.

Is fasting safe? A chart review of adverse events during medically supervised, water-only fasting.

BACKGROUND: Evidence suggests that fasting, during which only water is consumed, results in potentially health promoting physiological effects. However, peer-reviewed research assessing the safety of water-only fasting is lacking. To address this, we conducted a chart review to describe adverse events (AEs) that occurred during medically supervised, water-only fasting. METHODS: Electronic charts from patient visits to a residential medical facility from 2006 to 2011 were reviewed. Patients who were at least 21 years of age and water-only fasted for ≥2 consecutive days with a refeeding period equal to half of the fast length were included. Out of 2539 charts, 768 visits met our inclusion and exclusion criteria. AEs were abstracted from chart notes and classified according to CTCAE (v4.03) and MedDRA (v12.1) terminology. Descriptive analysis of AEs is reported. RESULTS: During the protocol period, the highest grade AE (HGAE) in 555 visits was a grade 2 event or lower, in 212 visits it was a grade 3 event, in 1 visit it was a grade 4 event, and there were no grade 5 events. There were 2 (0.002%) visits with a serious adverse event (SAE). The majority of AEs identified were mild (n = 4490, 75%) in nature and known reactions to fasting. CONCLUSIONS: To our knowledge, this is the most comprehensive analysis of AEs experienced during medically supervised, water-only fasting conducted to date. Overall, our data indicate that the majority of AEs experienced were mild to moderate and known reactions to fasting. This suggests that the protocol used in this study can be safely implemented in a medical setting with minimal risk of a SAE.

Impaired removal of H3K4 methylation affects cell fate determination and gene transcription.

Methylation of histone 3 lysine 4 (H3K4) is largely associated with promoters and enhancers of actively transcribed genes and is finely regulated during development by the action of histone methyltransferases and demethylases. H3K4me3 demethylases of the KDM5 family have been previously implicated in development, but how the regulation of H3K4me3 level controls developmental processes is not fully established. Here, we show that the H3K4 demethylase RBR-2, the unique member of the KDM5 family in C. elegans, acts cell-autonomously and in a catalytic-dependent manner to control vulva precursor cells fate acquisition, by promoting the LIN-12/Notch pathway. Using genome-wide approaches, we show that RBR-2 reduces the H3K4me3 level at transcription start sites (TSSs) and in regions upstream of the TSSs, and acts both as a transcription repressor and activator. Analysis of the lin-11 genetic locus, a direct RBR-2 target gene required for vulva precursor cell fate acquisition, shows that RBR-2 controls the epigenetic signature of the lin-11 vulva-specific enhancer and lin-11 expression, providing in vivo evidence that RBR-2 can positively regulate transcription and cell fate acquisition by controlling enhancer activity.

Water-only fasting and an exclusively plant foods diet in the management of stage IIIa, low-grade follicular lymphoma.

Follicular lymphoma (FL), the second most common non-Hodgkin's lymphoma (NHL), is well characterised by a classic histological appearance and an indolent course. Current treatment protocols for FL range from close observation to immunotherapy, chemotherapy and/or radiotherapies. We report the case of a 42-year-old woman diagnosed by excisional biopsy with stage IIIa, grade 1 FL. In addition to close observation, the patient underwent a medically supervised, 21-day water-only fast after which enlarged lymph nodes were substantially reduced in size. The patient then consumed a diet of minimally processed plant foods free of added sugar, oil and salt (SOS), and has remained on the diet since leaving the residential facility. At 6 and 9-month follow-up visits, the patient's lymph nodes were non-palpable and she remained asymptomatic. This case establishes a basis for further studies evaluating water-only fasting and a plant foods, SOS-free diet as a treatment protocol for FL.

EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner.

Glioblastoma (GBM)-derived tumorigenic stem-like cells (GSCs) may play a key role in therapy resistance. Previously, we reported that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. Here, we demonstrate that the catalytic subunit of Polycomb repressive complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are coexpressed in GBM and significantly induced in postirradiation recurrent tumors whose expression is inversely correlated with patient prognosis. Through a gain-and loss-of-function study, we show that MELK or FOXM1 contributes to GSC radioresistance by regulation of EZH2. We further demonstrate that the MELK-EZH2 axis is evolutionarily conserved in Caenorhabditis elegans. Collectively, these data suggest that the MELK-FOXM1-EZH2 signaling axis is essential for GSC radioresistance and therefore raise the possibility that MELK-FOXM1-driven EZH2 signaling can serve as a therapeutic target in irradiation-resistant GBM tumors.

Wnt signal from multiple tissues and lin-3/EGF signal from the gonad maintain vulval precursor cell competence in Caenorhabditis elegans.

The Caenorhabditis elegans vulva has been a valuable paradigm for defining components of signaling pathways and elucidating how signaling events are coordinated to generate a developmental pattern. Vulval precursor cells (VPCs) are induced to adopt vulval fates in the third larval stage by LIN-3, an EGF-like signal produced by the gonad. Competence to respond to the inductive signal requires that the VPCs do not fuse to the major hypodermal syncytium, hyp7. We found that two Wnt-encoding genes, cwn-1 and egl-20, play a major role in preventing fusion of VPCs with hyp7 in the second larval stage. By using tissue-specific rescue of mig-14/Wntless, which is required for the production of Wnt ligands, we found that Wnt signal produced by multiple tissues, including neurons and muscles, promotes or maintains VPC competence before vulval induction. In addition, through laser ablation and genetic analysis, we provide evidence that LIN-3 signal from the gonad also plays a significant role in preventing VPCs from fusing with hyp7. We propose that Wnt signaling plays a permissive role in preventing VPCs from fusing with hyp7 and reevaluate the roles of Wnt and LIN-3/EGF signaling in competence and induction.

SynMuv genes redundantly inhibit lin-3/EGF expression to prevent inappropriate vulval induction in C. elegans.

Activation of EGFR-Ras-MAPK signaling in vulval precursor cells (VPCs) by LIN-3/EGF from the gonad induces vulval development in C. elegans. The prevailing view is that LIN-3 overcomes an "inhibitory signal" from the adjacent hyp7 hypodermal syncytium. This view originated from observations indicating that inactivation of functionally redundant Synthetic Multivulva (SynMuv) genes in hyp7 can activate EGFR-Ras-MAPK signaling in the VPCs. Many SynMuv genes encode transcription and chromatin-associated factors, including the Rb ortholog. Here, we show that the SynMuv A and SynMuv B gene classes are functionally redundant for transcriptional repression of the key target gene, lin-3/EGF, in the hypodermis. These observations necessitate a revision of the concept of "inhibitory signaling." They also underscore the importance of preventing inappropriate cell signaling during development and suggest that derepression of growth factors may be the mechanism by which tumor suppressor genes such as Rb can have cell nonautonomous effects.

lin-35 Rb acts in the major hypodermis to oppose ras-mediated vulval induction in C. elegans.

Specification of vulval precursor cell (VPC) fates in C. elegans has served as an important signal transduction paradigm. Genetic studies have indicated that a large group of synthetic multivulva (SynMuv) genes, including the Rb ortholog lin-35, antagonizes the activity of the EGF receptor-Ras-MAP kinase pathway during VPC specification. A prevalent view has been that Rb-mediated transcriptional regulation and chromatin remodeling activities act in the VPCs to antagonize Ras activation through effects on promoters of target genes of the EGF receptor-Ras-MAP kinase pathway that promote vulval fates. Here, we have investigated the cellular focus of lin-35 using conventional genetic mosaic analysis and tissue-specific expression. Our results indicate that lin-35 activity is required in the major hypodermal syncytium and not in the VPCs to inhibit vulval fates. LIN-35 Rb may inhibit vulval fates by regulating a signal from hyp7 to the VPCs or the physiological state of hyp7.