Time-restricted feeding delays the emergence of the age-associated, neoplastic-prone tissue landscape

Aging increases the risk of cancer partly through alterations in the tissue microenvironment. Time-restricted feeding (TRF) is being proposed as an effective strategy to delay biological aging. In the present studies, we assessed the effect of long-term exposure to TRF on the emergence of the age-associated, neoplastic-prone tissue landscape. Animals were exposed to either ad libitum feeding (ALF) or TRF for 18 months and then transplanted with hepatocytes isolated from pre-neoplastic nodules. Both groups were continued ALF and the growth of transplanted cells was evaluated 3 months later. A significant decrease in frequency of larger size clusters of pre-neoplastic hepatocytes was seen in TRF-exposed group compared to controls. Furthermore, TRF modified several parameters related to both liver and systemic aging towards the persistence of a younger phenotype, including a decrease in liver cell senescence, diminished fat accumulation and up-regulation of SIRT1 in the liver, down-regulation of plasma IGF-1, decreased levels of plasma lipoproteins and up-regulation of hippocampal brain-derived growth factor (BDNF).These results indicate that TRF was able to delay the onset of the neoplastic-prone tissue landscape typical of aging. To our knowledge, this is the first investigation to describe a direct beneficial effect of TRF on early phases of carcinogenesis

Optimal force evaluation for isotonic fatigue characterization in mouse Tibialis Anterior muscle

Skeletal muscle fatigue is most often studied as a response to repeated stimulations in isometric conditions and it is usually quantified as the progressive loss of force generating capability over time. However, physical dynamic activity is based on the shortening of skeletal muscles. Therefore, the condition that best mimics body movements is the isotonic one, in which muscle is allowed to shorten against a constant load. In the literature, the isotonic fatigue test is performed allowing the muscle to lift a load corresponding to one-third of the maximal isometric force (reference optimal force), as best representative of the force at which the tissue develops its maximum power. The goal of this study was to devise a new testing protocol in which each muscle was tested for isotonic fatigue by shortening against its own optimal force, i.e. the force at which it really developed the maximum power. Our hypothesis was that testing all the muscle at a standard reference value would introduce significant errors in the parameters associated to muscle fatigue and in their variance. The proposed protocol was based on the real-time measurement of the maximum power a muscle was able to generate through the application of the after-load technique and a mathematical interpolation to the Hill's equation, that therefore allowed to determine the experimental optimal force to be applied during the fatigue test. Experimental results showed that the muscles tested with the experimental optimal force had a fatigue time significantly lower than the control muscles tested with the reference optimal force. A decrease, even if not statistically significant, was also measured for the power and work generated during the fatigue test. Of note, for all these parameters a huge decrease in the measurement variance was reported, confirming that a precise assessment of the muscle experimental optimal force was needed to increase the accuracy of the measurements. On the other hand, the application of the protocol proposed in this work required an increase in the test duration, due to the application of the after-load technique, and a real time measurement of the power generated by the tissue

Ethical issues of unrelated hematopoietic stem cell transplantation in adult thalassemia patients

Background: Beta thalassemia major is a severe inherited form of hemolytic anemia that results from ineffective erythropoiesis. Allogenic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative therapy. Unfortunately, the subgroup of adult thalassemia patients with hepatomegaly, portal fibrosis and a history of irregular iron chelation have an elevated risk for transplantation-related mortality that is currently estimated to be about 29 percent. Discussion: Thalassemia patients may be faced with a difficult choice: they can either continue conventional transfusion and iron chelation therapy or accept the high mortality risk of HSCT in the hope of obtaining complete recovery. Throughout the decision making process, every effort should be made to sustain and enhance autonomous choice. The concept of conscious consent becomes particularly important. The patient must be made fully aware of the favourable and adverse outcomes of HSCT. Although it is the physician's duty to illustrate the possibility of completely restoring health, considerable emphasis should be put on the adverse effects of the procedure. The physician also needs to decide whether the patient is eligible for HSCT according to the "rule of descending order". The patient must be given full details on self-care and fundamental lifestyle changes and be fully aware that he/she will be partly responsible for the outcome. Summary: Only if all the aforesaid conditions are satisfied can it be considered reasonable to propose unrelated HSCT as a potential cure for high risk thalassemia patients

Pre-Diagnostic Biomarkers of Metabolic Dysregulation and Cancer Mortality

INTRODUCTION: The obesogenic milieu is a pro-tumorigenic environment that promotes tumor initiation, angiogenesis and metastasis. In this prospective cohort, we examined the association between pre-diagnostic metabolic biomarkers, plasma adiponectin, resistin, leptin and lipoprotein (a), and the risk of cancer mortality. METHODS: Prospective data was obtained from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort of Blacks and Whites followed from 2003 through 2012 for cancer mortality. We determined the association between metabolism biomarkers (log-transformed and tertiles) and risk of cancer mortality using Cox Proportional Hazards models with robust sandwich estimators to calculate the 95% confidence intervals (CIs), and adjusted for baseline covariates, including age, gender, income, education, physical activity, BMI, smoking status, alcohol use, and comorbidity score. RESULTS: Among 1764 participants with available biomarker data, each SD higher log-leptin was associated with a 54% reduced risk of total cancer mortality (HR: 0.46, 95% CI: 0.23 - 0.92) and obesity-related cancer mortality (HR: 0.55, 95% CI: 0.39-0.79). Among Blacks only, each SD higher log-resistin was associated with a nearly 7-fold increased risk of cancer mortality (adjusted HR: 6.68, 95% CI: 2.10 - 21.21). There were no significant associations of adiponectin or Lp(a) and cancer mortality. CONCLUSIONS: Leptin is involved in long-term regulation of energy balance, while resistin is involved in chronic inflammation and LDL production. These findings highlight the biological mechanisms linking metabolic dysregulation with cancer mortality, and the influence of resistin on cancer mortality only among Blacks suggests that this hormone may be a useful biomarker of racial differences in cancer mortality that deserves further study. IMPACT: Our observed increased risk of cancer mortality associated with higher serum resistin levels among Blacks suggests that if validated in larger cohorts, clinical strategies focused on resistin control may be a promising cancer prevention strategy

Nitric oxide synthase-dependent NADPH-diaphorase activity in the optic lobes of male and female Ceratitis capitata mutants

Nitric oxide (NO) is acknowledged as a messenger molecule in the nervous system with a pivotal role in the modulation of the chemosensory information. It has been shown to be present in the optic lobes of several insect species. In the present study, we used males and females from four different strains of the medfly Ceratitis capitata (Diptera, Tephritidae): or; or,wp (both orange eyed); w,M360 and w,Heraklion (both white eyed), as models to further clarify the involvement of NO in the mutants' visual system and differences in its activity and localization in the sexes. Comparison of the localization pattern of NO synthase (NOS), through NADPH-diaphorase (NADPHd) staining, in the optic lobes of the four strains, revealed a stronger reaction intensity in the retina and in the neuropile region lamina than in medulla and lobula. Interestingly, the intensity of NADPHd staining differs, at least in some strains, in the optic lobes of the two sexes; all the areas are generally strongly labelled in the males of the or and w,M360 strains, whereas the w,Heraklion and or,wp mutants do not show evident sexdependent NADPHd staining. Taken as a whole, our data point to NO as a likely transmitter candidate in the visual information processes in insects, with a possible correlation among NOS distribution, eye pigmentation and visual function in C. capitata males. Moreover, NO could influence behavioural differences linked to vision in the two sexes

Association of baseline inflammatory biomarkers with cancer mortality in the REGARDS cohort

This study examines the association between inflammatory biomarkers and risk of cancer mortality by race. Data were obtained from 1,856 participants in the prospective REGARDS cohort who were cancer-free at baseline, and analyzed in relation to cancer mortality prospectively. Biomarkers were log-transformed and categorized into tertiles due to non-normal distributions, and Cox proportional hazard regression models were utilized to compute hazard ratios with 95% confidence intervals using robust sandwich methods. Individuals in the highest tertile of IL-6 had over a 12-fold increased risk of cancer mortality (HR: 12.97, 95% CI: 3.46-48.63); those in the highest tertile of IL-8 had over a 2-fold increased risk of cancer mortality (HR: 2.21, 95% CI: 0.86-5.71), while those in the highest tertile of IL-10 had over a 3-fold increased risk of cancer mortality (HR: 3.06, 95% CI: 1.35-6.89). In race-stratified analysis, each unit increase in IL-6 was associated with increased risk of cancer mortality among African-Americans (HR: 3.88, 95% CI: 1.17-12.88) and Whites (5.25, 95% CI: 1.24-22.31). If replicated in larger, racially diverse prospective cohorts, these results suggest that cancer patients may benefit from clinical or lifestyle approaches to regulate systemic inflammation as a cancer prevention strategy

Failure to establish HIV care: characterizing the no show phenomenon

It is estimated that up to one-third of persons with known human immunodeficiency virus (HIV) infection in the United States are not engaged in care. We evaluated factors associated with patients\u27 failure to establish outpatient HIV care at our clinic and found that females, racial minorities, and patients lacking private health insurance were more likely to be no shows. At the clinic level, longer waiting time from the call to schedule a new patient visit to the appointment date was associated with failure to establish care. Because increased numbers of patients will be in need of outpatient HIV care as a result of recent Centers for Disease Control and Prevention guidelines advocating routine HIV testing, it is imperative that strategies to improve access are developed to overcome the no show phenomenon

Reassessing the approach to informed consent: The case of unrelated hematopoietic stem cell transplantation in adult thalassemia patients

Introduction: The informed consent process is the legal embodiment of the fundamental right of the individual to make decisions affecting his or her health., and the patient's permission is a crucial form of respect of freedom and dignity, it becomes extremely important to enhance the patient's understanding and recall of the information given by the physician. This statement acquires additional weight when the medical treatment proposed can potentially be detrimental or even fatal. This is the case of thalassemia patients pertaining to class 3 of the Pesaro classification where Allogenic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment. Unfortunately, this kind of intervention is burdened by an elevated transplantation-related mortality risk (TRM: all deaths considered related to transplantation), equal to 30% according to published reports. In thalassemia, the role of the patient in the informed consent process leading up to HSCT has not been fully investigated. This study investigated the hypothesis that information provided by physicians in the medical scenario of HSCT is not fully understood by patients and that misunderstanding and communication biases may affect the clinical decision-making process.Methods: A questionnaire was either mailed or given personally to 25 patients. A second questionnaire was administered to the 12 physicians attending the patients enrolled in this study. Descriptive statistics were used to evaluate the communication factors.Results: The results pointed out the difference between the risks communicated by physicians and the risks perceived by patients. Besides the study highlighted the mortality risk considered to be acceptable by patients and that considered to be acceptable by physicians.Conclusions: Several solutions have been suggested to reduce the gap between communicated and perceived data. A multi-disciplinary approach may possibly help to attenuate some aspects of communication bias. Several tools have also been proposed to fill or to attenuate the gap between communicated and perceived data. But the most important tool is the ability of the physician to comprehend the right place of conscious consent in the relationship with the patient