Comparative immune profiling of pancreatic ductal adenocarcinoma progression among South African patients.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer characterized by an immunosuppressive microenvironment. Patients from specific ethnicities and population groups have poorer prognoses than others. Therefore, a better understanding of the immune landscape in such groups is necessary for disease elucidation, predicting patient outcomes and therapeutic targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients of African ancestry. METHODS: Blood samples were obtained from a total of 6 healthy volunteers (HC), 6 Chronic Pancreatitis (CP) and 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC). Real-time Quantitative Polymerase Chain reactions (RT-qPCR), Metabolomics, Enzyme-Linked Immunosorbent Assay (ELISA), Reactive Oxygen Species (ROS), and Immunophenotyping assays were conducted. Statistical analysis was conducted in R (v 4.3.2). Additional analysis of single-cell RNA data from 20 patients (16 PDAC and 4 controls) was conducted to interrogate the distribution of T-cell and Natural Killer cell populations. RESULTS: Granulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD3 T-cell subpopulations (helper and double negative T-cells) decreased when compared to HC. Although both NK (p = 0.014) and NKT (p < 0.001) cell levels increased as the disease progressed, their subsets: NK CD56dimCD16- (p = 0.024) and NKTs CD56+ (p = 0.008) cell levels reduced significantly. Of note is the negative association of NK CD56dimCD16- (p < 0.001) cell levels with survival time. The gene expression analyses showed no statistically significant correlation when comparing the PDAC groups with the controls. The inflammatory status of PDAC was assessed by ROS levels of serum which were elevated in CP (p = 0.025), (RPC (p = 0.003) and LAPC (p = 0.008)) while no significant change was observed in MPC, compared to the HC group. ROS was shown to be positively correlated with GlycA (R = 0.45, p = 0.0096). Single-cell analyses showed a significant difference in the ratio of NKT cells per total cell counts in LAPC (p < 0.001) and MPC (p < 0.001) groups compared with HC, confirming observations in our sample group. CONCLUSION: The expression of these immune cell markers observed in this pilot study provides insight into their potential roles in tumour progression in the patient group and suggests their potential utility in the development of immunotherapeutic strategies.

Prevalence, treatment, and neural correlates of apathy in different forms of dementia: a narrative review.

OBJECTIVES: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD). METHODS: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included. RESULTS: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy. CONCLUSION: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

Intrinsic capacity and recent falls in adults 80 years and older living in the community: results from the ilSIRENTE Study.

BACKGROUND: Falls in older adults significantly impact overall health and healthcare costs. Intrinsic capacity (IC) reflects functional reserve and is an indicator of healthy aging. AIMS: To explore the association between IC and recent falls (≤ 90 days) in community-dwelling octogenarians from the Aging and Longevity in the Sirente geographic area (IlSIRENTE) study. METHODS: The Minimum Data Set for Home Care (MDS-HC) and supplementary questionnaires and tests were used to assess the five IC domains: locomotion, cognition, vitality, psychology, and sensory. Scores in each domain were rescaled using the percent of maximum possible score method and averaged to obtain an overall IC score (range 0-100). RESULTS: The study included 319 participants (mean age 85.5 ± 4.8 years, 67.1% women). Mean IC score was 80.5 ± 14.2. The optimal IC score cut-off for predicting the two-year risk of incident loss of at least one activity of daily living (ADL) was determined and validated in a subset of 240 individuals without ADL disability at baseline (mean age 84.7 ± 4.4 years, 67.1% women). Participants were then stratified into low (< 77.6) and high (≥ 77.6) IC categories. Those with high IC (63.9%) were younger, more often males, and had lower prevalence of recent falls, disability, multimorbidity, and polypharmacy. Logistic regression models including IC as a continuous variable revealed a significant association between higher IC and lower odds of falls. This association was significant in the unadjusted (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94-0.98, p < 0.001), age- and sex-adjusted (OR 0.96, 95% CI 0.94-0.98, p < 0.001), and fully adjusted models (OR 0.96, 95% CI 0.93-0.99, p = 0.003). When considering IC as a categorical variable, unadjusted logistic regression showed a strong association between high IC and lower odds of falls (OR 0.31, 95% CI 0.16-0.60, p < 0.001). This association remained significant in both the age- and sex-adjusted (OR 0.30, 95% CI 0.15-0.59, p < 0.001) and fully adjusted models (OR 0.33, 95% CI 0.16-0.82, p = 0.007). The locomotion domain was independently associated with falls in the unadjusted (OR 0.98, 95% CI 0.97-0.99, p < 0.001), age- and sex-adjusted (OR 0.97, 95% CI 0.96-0.99, p < 0.001), and fully adjusted model (OR 0.98, 95% CI 0.96-0.99, p < 0.001). DISCUSSION: This is the first study using an MDS-HC-derived instrument to assess IC. Individuals with higher IC were less likely to report recent falls, with locomotion being an independently associated domain. CONCLUSIONS: Lower IC is linked to increased odds of falls. Interventions to maintain and improve IC, especially the locomotion domain, may reduce fall risk in community-dwelling octogenarians.

Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer.

A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119-mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7-driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.

Somatic genome alterations in relation to age in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common cause of global cancer-related mortality and the major risk factor is smoking consumption. By analyzing 486 LUAD samples from The Cancer Genome Atlas, we detected a higher mutational burden among younger patients in the global cohort as well as in the TP53-mutated subcohort. The interaction effect of patient age and TP53 mutations significantly affected the mutational rate of younger TP53-mutated patients. Furthermore, we detected a significant enrichment of the smoking-related signature SI4 (SI4) among younger TP53-mutated patients, meanwhile the age-related Signature 1 (SI1) significantly increased in proportion to patient age. Although present and past smoking is reported in the TP53 wild-type patients, we observed a lower average number of somatic mutations, with no correlation with patient age. Overall, TP53 mutations were significantly higher in younger patients and mainly characterized by SI4 and Signature 24 (SI24). Therefore, TP53 seemed to acquire a particular sensitivity to smoking related C>A mutations in younger patients. We hypothesize that TP53 mutations at a younger age might be a crucial factor enhancing the sensitivity to smoking-related mutations leading to a burst of somatic alterations. The mutational profile of cancer cell might reflect the mutational processes operative in aging in a given tissue. Therefore, TP53-mutated and TP53 wild-type patient groups might represent phenotypes which endure aging-related mutational processes with different strength. Our study provides indications of age-dependent differences in mutational backgrounds that might be relevant for cancer prevention and age-adjusted treatment approaches.

KODAMA: an R package for knowledge discovery and data mining.

Summary: KODAMA, a novel learning algorithm for unsupervised feature extraction, is specifically designed for analysing noisy and high-dimensional datasets. Here we present an R package of the algorithm with additional functions that allow improved interpretation of high-dimensional data. The package requires no additional software and runs on all major platforms. Availability and Implementation: KODAMA is freely available from the R archive CRAN ( http://cran.r-project.org ). The software is distributed under the GNU General Public License (version 3 or later). Contact: s.cacciatore@imperial.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

Urinary Metabolic Phenotyping of Women with Lower Urinary Tract Symptoms.

Lower urinary tract symptoms (LUTS), including urinary incontinence, urgency and nocturia, affect approximately half of women worldwide. Current diagnostic methods for LUTS are invasive and costly, while available treatments are limited by side effects leading to poor patient compliance. In this study, we aimed to identify urine metabolic signatures associated with LUTS using proton nuclear magnetic resonance (1H NMR) spectroscopy. A total of 214 urine samples were collected from women attending tertiary urogynecology clinics (cases; n = 176) and healthy control women attending general gynecology clinics (n = 36). Despite high variation in the urine metabolome across the cohort, associations between urine metabolic profiles and BMI, parity, overactive bladder syndrome, frequency, straining, and bladder storage were identified using KODAMA (knowledge discovery by accuracy maximization). Four distinct urinary metabotypes were identified, one of which was associated with increased urinary frequency and low BMI. Urine from these patients was characterized by increased levels of isoleucine and decreased levels of hippurate. Our study suggests that metabolic profiling of urine samples from LUTS patients offers the potential to identify differences in underlying etiology, which may permit stratification of patient populations and the design of more personalized treatment strategies.

Knowledge discovery by accuracy maximization.

Here we describe KODAMA (knowledge discovery by accuracy maximization), an unsupervised and semisupervised learning algorithm that performs feature extraction from noisy and high-dimensional data. Unlike other data mining methods, the peculiarity of KODAMA is that it is driven by an integrated procedure of cross-validation of the results. The discovery of a local manifold's topology is led by a classifier through a Monte Carlo procedure of maximization of cross-validated predictive accuracy. Briefly, our approach differs from previous methods in that it has an integrated procedure of validation of the results. In this way, the method ensures the highest robustness of the obtained solution. This robustness is demonstrated on experimental datasets of gene expression and metabolomics, where KODAMA compares favorably with other existing feature extraction methods. KODAMA is then applied to an astronomical dataset, revealing unexpected features. Interesting and not easily predictable features are also found in the analysis of the State of the Union speeches by American presidents: KODAMA reveals an abrupt linguistic transition sharply separating all post-Reagan from all pre-Reagan speeches. The transition occurs during Reagan's presidency and not from its beginning.

Unbiased Metabolomic Investigation of Alzheimer's Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism.

Alzheimer's disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation.

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies.

Transcription Factors in Prostate Cancer: Insights for Disease Development and Diagnostic and Therapeutic Approaches.

Transcription factors (TFs) are proteins essential for the regulation of gene expression, and they regulate the genes involved in different cellular processes, such as proliferation, differentiation, survival, and apoptosis. Although their expression is essential in normal physiological conditions, abnormal regulation of TFs plays critical role in several diseases, including cancer. In prostate cancer, the most common malignancy in men, TFs are known to play crucial roles in the initiation, progression, and resistance to therapy of the disease. Understanding the interplay between these TFs and their downstream targets provides insights into the molecular basis of prostate cancer pathogenesis. In this review, we discuss the involvement of key TFs, including the E26 Transformation-Specific (ETS) Family (ERG and SPDEF), NF-κB, Activating Protein-1 (AP-1), MYC, and androgen receptor (AR), in prostate cancer while focusing on the molecular mechanisms involved in prostate cancer development. We also discuss emerging diagnostic strategies, early detection, and risk stratification using TFs. Furthermore, we explore the development of therapeutic interventions targeting TF pathways, including the use of small molecule inhibitors, gene therapies, and immunotherapies, aimed at disrupting oncogenic TF signaling and improving patient outcomes. Understanding the complex regulation of TFs in prostate cancer provides valuable insights into disease biology, which ultimately may lead to advancing precision approaches for patients.

Predictive values of relative fat mass and body mass index on cardiovascular health in community-dwelling older adults: Results from the Longevity Check-up (Lookup) 7.

OBJECTIVES: To assess the predictive value of relative fat mass compared to body mass index for hypertension, diabetes, hyperlipidemia, and heightened cardiovascular risk in a cohort of community-dwelling older adults from the Longevity Check-up 7+ cohort. STUDY DESIGN: Retrospective cross-sectional study. MAIN OUTCOME MEASURES: Hyperlipidemia was defined as total cholesterol ≥200 mg/dL or ongoing lipid-lowering treatment. Diabetes was defined either as self-reported diagnosis or fasting blood glucose >126 mg/dL or a random blood glucose >200 mg/dL. Hypertension was defined as blood pressure ≥ 140/90 mmHg or requiring daily antihypertensive medications. Heightened cardiovascular risk was operationalized as having at least two of these conditions. RESULTS: Analyses were conducted in 1990 participants (mean age 73.2 ± 6.0 years; 54.1 % women). Higher proportions of men than women had hypertension and diabetes, while hyperlipidemia was more prevalent in women. Receiver operating curve analysis indicated relative fat mass was a better predictor of hypertension in women and diabetes in both sexes. Body mass index performed better in predicting hyperlipidemia in women. Relative fat mass thresholds of ≥27 % for men and ≥40 % for women were identified as optimal indicators of heightened cardiovascular risk and so were used to defined high adiposity. Moderate correlations were found between high adiposity or body mass index ≥25 kg/m2 and the presence of hypertension, hyperlipidemia and heightened cardiovascular risk, while a strong correlation was found with diabetes. Logistic regression analysis highlighted significant associations between high adiposity and increased odds of hypertension, diabetes, and heightened cardiovascular risk. CONCLUSIONS: Proposed cut-offs for relative fat mass were more reliable indices than the usual cut-offs for body mass index for identifying individuals at heightened cardiovascular risk. Our findings support the role of anthropometric measures in evaluating body composition and the associated metabolic and cardiovascular conditions in older adults.

How to Manage Beta-Blockade in Older Heart Failure Patients: A Scoping Review.

Beta blockers (BBs) play a crucial role in enhancing the quality of life and extending the survival of patients with heart failure and reduced ejection fraction (HFrEF). Initiating the therapy at low doses and gradually titrating the dose upwards is recommended to ensure therapeutic efficacy while mitigating potential adverse effects. Vigilant monitoring for signs of drug intolerance is necessary, with dose adjustments as required. The management of older HF patients requires a case-centered approach, taking into account individual comorbidities, functional status, and frailty. Older adults, however, are often underrepresented in randomized clinical trials, leading to some uncertainty in management strategies as patients with HF in clinical practice are older than those enrolled in trials. The present article performs a scoping review of the past 25 years of published literature on BBs in older HF patients, focusing on age, outcomes, and tolerability. Twelve studies (eight randomized-controlled and four observational) encompassing 26,426 patients were reviewed. The results indicate that BBs represent a viable treatment for older HFrEF patients, offering benefits in symptom management, cardiac function, and overall outcomes. Their role in HF with preserved EF, however, remains uncertain. Further research is warranted to refine treatment strategies and address specific aspects in older adults, including proper dosing, therapeutic adherence, and tolerability.

Blockchain technology in Cardiovascular Medicine: a glance to the future? Results from a social media survey and future perspectives.

The leverage of digital facilities in medicine for disease diagnosis, monitoring, and medical history recording has become increasingly pivotal. However, the advancement of these technologies poses a significant challenge regarding data privacy, given the highly sensitive nature of medical information. In this context, the application of Blockchain technology, a digital system where information is stored in blocks and each block is linked to the one before, has the potential to enhance existing technologies through its exceptional security and transparency. This paradigm is of particular importance in cardiovascular medicine, where the prevalence of chronic conditions leads to the need for secure remote monitoring, secure data storage and secure medical history updating. Indeed, digital support for chronic cardiovascular pathologies is getting more and more crucial. This paper lays its rationale in three primary aims: 1) to scrutinize the existing literature for tangible applications of blockchain technology in the field of cardiology; 2) to report results from a survey aimed at gauging the reception of blockchain technology within the cardiovascular community, conducted on social media; 3) to conceptualize a web application tailored specifically to cardiovascular care based on blockchain technology. We believe that Blockchain technology may contribute to a breakthrough in healthcare digitalization, especially in the field of cardiology; in this context, we hope that the present work may be inspiring for physicians and healthcare stakeholders.

Management of Cardiovascular Complications in Antiphospholipid Syndrome: A Narrative Review with a Focus on Older Adults.

Antiphospholipid syndrome (APS), also known as Hughes syndrome, is an acquired autoimmune and procoagulant condition that predisposes individuals to recurrent thrombotic events and obstetric complications. Central is the role of three types of antiphospholipid antibodies that target phospholipid-binding proteins: lupus anticoagulant (LAC), anti-ß2-glycoprotein I (ß2-GPI-Ab), and anti-cardiolipin (aCL). Together with clinical data, these antibodies are the diagnostic standard. However, the diagnosis of APS in older adults may be challenging and, in the diagnostic workup of thromboembolic complications, it is an underestimated etiology. The therapeutic management of APS requires distinguishing two groups with differential risks of thromboembolic complications. The standard therapy is based on low-dose aspirin in the low-risk group and vitamin K antagonists in the high-risk group. The value of direct oral anticoagulants is currently controversial. The potential role of monoclonal antibodies is investigated. For example, rituximab is currently recommended in catastrophic antiphospholipid antibody syndrome. Research is ongoing on other monoclonal antibodies, such as daratumumab and obinutuzumab. This narrative review illustrates the pathophysiological mechanisms of APS, with a particular emphasis on cardiovascular complications and their impact in older adults. This article also highlights advancements in the diagnosis, risk stratification, and management of APS.

Correction: Candida albicans PPG1, a serine/threonine phosphatase, plays a vital role in central carbon metabolisms under filament-inducing conditions: a multi-omics approach.

[This corrects the article DOI: 10.1371/journal.pone.0259588.].

Recent Advances and Future Directions in Syncope Management: A Comprehensive Narrative Review.

Syncope is a highly prevalent clinical condition characterized by a rapid, complete, and brief loss of consciousness, followed by full recovery caused by cerebral hypoperfusion. This symptom carries significance, as its potential underlying causes may involve the heart, blood pressure, or brain, leading to a spectrum of consequences, from sudden death to compromised quality of life. Various factors contribute to syncope, and adhering to a precise diagnostic pathway can enhance diagnostic accuracy and treatment effectiveness. A standardized initial assessment, risk stratification, and appropriate test identification facilitate determining the underlying cause in the majority of cases. New technologies, including artificial intelligence and smart devices, may have the potential to reshape syncope management into a proactive, personalized, and data-centric model, ultimately enhancing patient outcomes and quality of life. This review addresses key aspects of syncope management, including pathogenesis, current diagnostic testing options, treatments, and considerations in the geriatric population.

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.

Effects of intra- and post-operative ischemia on the metabolic profile of clinical liver tissue specimens monitored by NMR.

Metabolomic profiles of tissues could greatly contribute to advancements in personalized medicine but are influenced by differences in adopted preanalytical procedures; nonhomogeneous pre- and post-excision ischemia times are potential sources of variability. In this study, we monitored the impact of ischemia on the metabolic profiles, acquired with high-resolution magic-angle-spinning (1)H NMR, of 162 human liver samples collected during and up to 6 h after routine surgery. The profiles changed significantly as a function of intraoperative warm ischemia (WI) and postresection cold ischemia (CI) time, with significant variations in the concentration of the same 16 metabolites. Therefore, a tight control of the preanalytical phase is essential for reliable metabolomic analyses of liver diseases. The NMR profiles provide a reliable "fingerprint" of ischemia and have predictive value: the best-performing predictive models are found to discriminate extreme time points of CI (0' vs 360 ') in the training set with cross-validation accuracy of ~90%; samples in the validation cohort can discriminate short (≤60') from long (≥180') CI with an accuracy of ~80%. For WI, the corresponding figures are 95.6 and 92%, respectively. Therefore, ischemia NMR profiles might become a tool for tissue quality control in biobanks.

Preventing Osteoporosis, Sarcopenia and Obesity to Care about Quality of Life.

A recent review by Kumari and Khanna examined the prevalence of sarcopenic obesity using various comorbidities, diagnostic markers, and possible therapeutic approaches. The authors discussed the strong impact of sarcopenic obesity on quality of life (QoL) and physical health. In addition, there are significant interactions among bone, muscle, and adipose tissue, and the concomitant presence of osteoporosis, sarcopenia, and obesity, termed osteosarcopenic obesity, represents a terrible trio for postmenopausal women and older adults as each of these conditions is associated with adverse outcomes in terms of morbidity, mortality, and QoL in several domains. Timely diagnosis, prevention, and pro-health education are crucial for improving QoL in patients with osteoporosis, sarcopenia, and obesity. Education and prevention play a pivotal role in the long term for individuals to have longer and healthier lives. Osteoporosis, sarcopenia, and obesity share modifiable risk factors that may benefit from physical activity, a healthy and balanced diet, and lifestyle changes. "Prevention is better than cure" and planning are proven strategies for individuals and sustainable healthcare.