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Exercise has emerged as fundamental therapeutic medicine in the management of cancer. Exercise improves health-related outcomes, including quality of life, neuromuscular strength, physical function, and body composition, and it is associated with a lower risk of disease recurrence and increased survival. Moreover, exercise during or post cancer treatments is safe, can ameliorate treatment-related side effects, and may enhance the effectiveness of chemotherapy and radiation therapy. To date, traditional resistance training (RT) is the most used RT modality in exercise oncology. However, alternative training modes, such as eccentric, cluster set, and blood flow restriction are gaining increased attention. These training modalities have been extensively investigated in both athletic and clinical populations (e.g., age-related frailty, cardiovascular disease, type 2 diabetes), showing considerable benefits in terms of neuromuscular strength, hypertrophy, body composition, and physical function. However, these training modes have only been partially or not at all investigated in cancer populations. Thus, this study outlines the benefits of these alternative RT methods in patients with cancer. Where evidence in cancer populations is sparse, we provide a robust rationale for the possible implementation of certain RT methods that have shown positive results in other clinical populations. Finally, we provide clinical insights for research that may guide future RT investigations in patients with cancer and suggest clear practical applications for targeted cancer populations and related benefits.

Rye (Secale cereale L.) cultivation has a long history in the Alpine region, where local ecotypes have been honed through generations of human selection. Despite the introduction of commercial varieties during the 20th century, traditional ecotypes are believed to persist in Valtellina, especially in the medium/upper valley (Teglio and Bormio). Our study aims to identify and preserve these local rye ecotypes by comparing them to commercial varieties. We examined 14 rye accessions through population genetic analyses (by using eight SSR makers), agronomic trials (germplasm characters, plant traits, and yields), and phytochemical analyses (total phenolic compound, flavonoids, and the radical scavenging activity). Two commercial varieties were used—one from Poland, previously genetically characterized (C_POL_P1; i.e., P1 ancestry), and one with an unknown origin. Additionally, we analyzed eleven accessions from Valtellina (medium and upper valley) and one from another alpine valley in South Tirol (Laimburg; LAI). Molecular markers analysis revealed the presence of two distinct genetic lineages: the first (P1) comprised all Teglio accessions and the commercial one from Poland, while the second (P2) grouped the two alpine accessions from Bormio (upper Valtellina) and South Tirol, along with a commercial one of uncertain origin. The clusters P2 exhibited significantly lower average values of the number of alleles (z = 2.03; p < 0.05), Shannon index (z = 2.35; p < 0.05), and expected heterozygosity (z = 1.97; p < 0.05) than in P1. Significant differences were observed in plant traits and agronomic performance between P1 and P2 accessions, with the latter displaying superior traits. For instance, the seed weight of germplasm was the highest in P2 (H(chi2) = 22.44; p < 0.001). Phytochemical analyses did not reveal a clear pattern between genetic lineages but identified some very well-performing Valtellina landraces in terms of scavenging activity. Characterizing these local rye varieties helps establish a short food supply chain to support Valtellina’s mountain economy. The medium valley (P1) and upper valley (P2) varieties have the potential for agroecological valorization, benefiting local farmers. Phytochemical analyses identified better accessions within P1 and P2 for nutraceutical use and commercialization. Additionally, selecting and conserving resilient ecotypes can address future challenges from extreme climate conditions.

Aim: In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC). Methods: The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context. Results: High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity (P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors. Conclusions: In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations.

Earth’s rotation generates the basic circadian rhythm of day and night to which all living organisms must adapt to survive. In mammals, this happens thanks to a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and to peripheral clock genes at the cellular level. The main environmental cue capable of synchronizing such clocks is light sensed by retinal ganglion cells signaling through a complex nervous pathway to the pineal gland which ultimately regulates melatonin synthesis that occurs during the night, darkness hours in all mammals. The central clock synchronized by melatonin drives the circadian oscillation of the sympathetic nervous system (SNS) adrenergic activity which in turn controls glucocorticoid production in the adrenal glands. These oscillations are integrated with peripheral cellular clocks by still not completely understood mechanisms and drive the homeostatic control of activity-rest (sleep) cycles, cardiovascular activity, body temperature, and immune-hematopoietic functions. The neuronal and hormonal mechanisms governing the circadian oscillation of hematopoiesis and immunity will be addressed in this review focusing on those offering therapeutic perspectives.

Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the “holy grail” for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expressed in fetal pancreas, in beta cell precursors and in in vitro embryonic-derived endocrine progenitors. TMEM219 signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 further rescued beta cell precursor and proliferation markers, and decreased cell death, both in islets and in in vitro-derived endocrine progenitors, allowing for beta cell preservation. While addressing the upstream controlling TMEM219 expression, we determined the TMEM219 miRNet; indeed, one of those miRNAs, miR-129-2, is highly expressed in human islets, particularly in patients at risk or with established type 1 diabetes. miR-129-2 mimic downregulated TMEM219 expression in islets, in in vitro embryonic-derived endocrine progenitors and in highly proliferating insulinoma-derived cells. Moreover, miR-129-2 inhibitor induced a TMEM219 overexpression in insulinoma-derived cells, which restored cell proliferation and functional markers, thus acting as endogenous regulator of TMEM219 expression. The TMEM219 upstream regulator miR129-2 controls the fate of beta cell precursors and may unleash their regenerative potentials to replenish beta cells in type 1 diabetes.

In all mammals, the circulating pool of MLTs is synthesized in the pineal gland during the night’s darkness hours. Its main function is synchronizing the organism in the photoperiod. In contrast, extra-pineal MLT is synthesized in peripheral organs, does not follow any circadian rhythm or circulate, and plays a detoxifying and cytoprotective role. Circulating MLT may stimulate both innate and acquired immune responses through its circadian action and by activating high-affinity receptors on immunocompetent cells. Extra-pineal MLT may have antioxidant and anti-inflammatory effects that dampen the innate immune response. These two seemingly divergent roles may be considered to be two sides of the same coin. In fact, the integration of both circulating and extra-pineal MLT functions might generate a balanced and effective immune response against microbial pathogens. The studies described in this review investigated the effects of exogenous MLT in various models of infectious diseases using extremely different doses and treatment schedules. None of them evaluated the possibility of integrating the non-circadian anti-inflammatory effect with the circadian immunoenhancing action of MLT. As a consequence, in spite of the fact that most studies agree that MLT has a beneficial effect against infections, it seems difficult to draw any definite conclusion about its possible therapeutic use.

The localization of condensin along chromosomes is crucial for their accurate segregation in anaphase. Condensin is enriched at telomeres but how and for what purpose had remained elusive. Here, we show that fission yeast condensin accumulates at telomere repeats through the balancing acts of Taz1, a core component of the shelterin complex that ensures telomeric functions, and Mit1, a nucleosome remodeler associated with shelterin. We further show that condensin takes part in sister-telomere separation in anaphase, and that this event can be uncoupled from the prior separation of chromosome arms, implying a telomere-specific separation mechanism. Consistent with a cis-acting process, increasing or decreasing condensin occupancy specifically at telomeres modifies accordingly the efficiency of their separation in anaphase. Genetic evidence suggests that condensin promotes sister-telomere separation by counteracting cohesin. Thus, our results reveal a shelterin-based mechanism that enriches condensin at telomeres to drive in cis their separation during mitosis.

IntroductionAlthough prostate cancer (PCa) is one of the most common cancers among men, the impact of modifiable risk and protective factors is still being debated. This review aims to qualitatively summarize the most recent studies related to potential healthy lifestyle factors affecting the development of PCa.Methods for data acquisitionThe literature focusing on modifiable risk factors for prostate cancer was reviewed. Medline and Embase via the Ovid database were searched, and all relevant and inherent articles were analyzed. Non-eligible publications, such as review articles, editorials, comments, guidelines, or case reports, were excluded.Synthesis of the evidence obtained from data analysisThis review confirms that there is strong evidence that being overweight or obese increases the risk of advanced prostate cancer (assessed by body mass index (BMI), waist circumference, and waist–hip ratio), particularly considering central adiposity and ethnicity as contributing factors. The possible contribution of smoking still seems not entirely clear, while alcohol seems to affect PCa prevention in patients taking 5α-reductase inhibitors (5-ARIs). Dietary fibers may have anti-inflammatory properties and improve insulin sensitivity by reducing IGF bioactivity. In particular, dietary fiber intake like insoluble and legume fibers may be inversely associated with prostate cancer risk. Also, hyperglycemia and hyperinsulinemia, with untreated diabetic fasting blood glucose levels, could be modifiable prostate cancer risk factors. In two studies, aspirin was associated with a lower risk of lethal PCa and overall mortality. Concerning the role of vitamins, despite conflicting and divergent results, serum retinol concentration seems to be associated with an increased risk of prostate cancer and high-grade prostate cancer. Some studies resulted in disagreement about the role of selenium and vitamin E. We found inconsistent and controversial findings about the association between vitamin D and prostate cancer risk.ConclusionFar from being conclusive evidence, our findings confirm some strong evidence already found in the previous literature and highlight the need to clarify the role of some risk factors whose role is not yet completely known. This effort would facilitate the cultural and social change that may allow the shift from the treatment of prostate cancer when diagnosed to the real efforts needed for systematic prevention.

Summary: In most eukaryotes, meiotic crossovers (COs) are limited to 1–3 per chromosome, and are prevented from occurring close to one another by CO interference. The fission yeast Schizosaccharomyces pombe, an exception to these general rules, was reported to have the highest CO number per chromosome and no or weak interference. However, global CO frequency was indirectly estimated, calling for confirmation. Here, we used an innovative strategy to determine COs genome-wide in S. pombe. We confirmed weak CO interference, acting at physical distances compatible with the patterning of recombination precursors. We revealed a slight co-variation in CO number between chromosomes, suggesting that a limiting pro-CO factor varies between meiocytes. CO number per chromosome varies proportionally with chromosome size, with the three chromosomes having, on average, 15.9, 12.5, and 7.0 COs, respectively. This reinforces S. pombe’s status as the eukaryote with the highest CO number per chromosome described to date.

Diabetic kidney disease (DKD) is the first cause of end-stage kidney disease in patients with diabetes and its prevalence is increasing worldwide. It encompasses histological alterations that mainly affect the glomerular filtration unit, which include thickening of the basement membrane, mesangial cell proliferation, endothelial alteration, and podocyte injury. These morphological abnormalities further result in a persistent increase of urinary albumin-to-creatinine ratio and in a reduction of the estimated glomerular filtration rate. Several molecular and cellular mechanisms have been recognized, up to date, as major players in mediating such clinical and histological features and many more are being under investigation. This review summarizes the most recent advances in understanding cell death mechanisms, intracellular signaling pathways and molecular effectors that play a role in the onset and progression of diabetic kidney damage. Some of those molecular and cellular mechanisms have been already successfully targeted in preclinical models of DKD and, in some cases, strategies have been tested in clinical trials. Finally, this report sheds light on the relevance of novel pathways that may become therapeutic targets for future applications in DKD.

Urothelial carcinoma (UC) is the most frequent malignancy of the urinary tract, which consists of bladder cancer (BC) for 90%, while 5% to 10%, of urinary tract UC (UTUC). BC and UTUC are characterized by distinct phenotypical and genotypical features as well as specific gene- and protein- expression profiles, which result in a diverse natural history of the tumor. With respect to BC, UTUC tends to be diagnosed in a later stage and displays poorer clinical outcome. In the present review, we seek to highlight the individuality of UTUC from a biological, immunological, genetic-molecular, and clinical standpoint, also reporting the most recent evidence on UTUC treatment. In this regard, while the role of surgery in nonmetastatic UTUC is undebated, solid data on adjuvant or neoadjuvant chemotherapy are still an unmet need, not permitting a definite paradigm shift in the standard treatment. In advanced setting, evidence is mainly based on BC literature and retrospective studies and confirms platinum-based combination regimens as bedrock of first-line treatment. Recently, immunotherapy and target therapy are gaining a foothold in the treatment of metastatic disease, with pembrolizumab and atezolizumab showing encouraging results in combination with chemotherapy as a first-line strategy. Moreover, atezolizumab performed well as a maintenance treatment, while pembrolizumab as a single agent achieved promising outcomes in second-line setting. Regarding the target therapy, erdafitinib, a fibroblast growth factor receptor inhibitor, and enfortumab vedotin, an antibody-drug conjugate, proved to have a strong antitumor property, likely due to the distinctive immune-genetic background of UTUC. In this context, great efforts have been addressed to uncover the biological, immunological, and clinical grounds in UTUC patients in order to achieve a personalized treatment.

Background: Current guidelines for the diagnosis and treatment of pericarditis refer to the general adult population. Few and fragmentary data regarding recurrent pericarditis in older adults exist. Objective of the Study: Given the absence of specific data in scientific literature, we hypothesized that there might be clinical, laboratory and outcome differences between young adults and older adults affected by idiopathic recurrent pericarditis. Materials and Methods: We performed an international multicentric retrospective cohort study analyzing data from patients affected by recurrent pericarditis (idiopathic or post‐cardiac injury) and referring to tertiary referral centers. Clinical, laboratory, and outcome data were compared between patients younger than 65 years (controls) and patients aged 65 or older. Results: One hundred and thirty‐three older adults and 142 young adult controls were enrolled. Comorbidities, including chronic kidney diseases, atrial fibrillation, and diabetes, were more present in older adults. The presenting symptom was dyspnea in 54.1% of the older adults versus 10.6% in controls (p < 0.001); pain in 32.3% of the older adults versus 80.3% of the controls (p < 0.001). Fever higher than 38°C was present in 33.8% versus 53.5% (p = 0.001). Pleural effusion was more prevalent in the older adults (55.6% vs 34.5%, p < 0.001), as well as severe pericardial effusion (>20 mm) (24.1% vs 12.7%, p = 0.016) and pericardiocentesis (16.5% vs 8.5%, p = 0.042). Blood leukocyte counts were significantly lower in the older adults (mean + SE: 10,227 + 289/mm3 vs 11,208 + 285/mm3, p = 0.016). Concerning therapies, NSAIDS were used in 63.9% of the older adults versus 80.3% in the younger (p = 0.003), colchicine in 76.7% versus 87.3% (p = 0.023), corticosteroids in 49.6% versus 26.8% (p < 0.001), and anakinra in 14.3% versus 23.9% (p = 0.044). Conclusions: Older adults affected by recurrent pericarditis show a different clinical pattern, with more frequent dyspnea, pleural effusion, severe pericardial effusion, and lower fever and lower leukocyte count, making the diagnosis sometimes challenging. They received significantly less NSAIDs and colchicine, likely due to comorbidities; they were also treated less commonly with anti‐IL1 agents, and more frequently with corticosteroids. [ABSTRACT FROM AUTHOR]

Background/Objectives: Anemia during acute inflammation is not well described in the literature. We aimed to study whether patients develop a transient hemoglobin decrease during an acute attack of recurrent pericarditis. Methods: We retrospectively analyzed patients with recurrent pericarditis. The primary endpoint was the difference in hemoglobin levels during an acute attack and in the following remission. As secondary endpoints, we correlated this variation with laboratory and clinical features; we also evaluated the available baseline hemoglobin values. Results: Sixty-two patients, including thirty females (48.4%), with a median age of 39 years, were observed during an acute attack and remission. The attack indexed was the first in 21 patients and the second or the third in 41, with pre-attack hemoglobin levels available for the latter group. Median hemoglobin levels (IQR) were 13.8 (12.8–15.1) g/dL at baseline, 12.0 (11.2–13.4) during attacks and 13.6 (13.1–14.0) during remission (p < 0.001). The median hemoglobin reduction between an acute attack and remission was 1.4 g/dL. Their mean corpuscular volume remained in the normal range. Hb reduction significantly correlated with C-reactive protein (CRP) elevation, neutrophilia and the neutrophil-to-lymphocyte ratio, but not serosal involvement. Only CRP elevation remained associated with the variation of Hb in a multivariate analysis (p = 0.007). Conclusions: This study is a proof of concept: hemoglobin levels may decline rapidly during acute inflammation in correlation with CRP elevation, with transient normocytic anemia, followed by a rapid rebound. In this regard, idiopathic pericarditis may represent a pathogenetic model of this type of anemia. [ABSTRACT FROM AUTHOR]

The efficacy and complication rates of percutaneous radiofrequency ablation (RFA) and cryoablation (CA) in the treatment of T1 renal masses in two Northern Italy hospitals were retrospectively investigated. Eighty-two patients with 80 T1a tumors and 10 T1b tumors treated with thermal ablation from 2015 through 2020 were included. A total of 43 tumors in 38 patients were treated with RFA (2.3 ± 0.9 cm), and 47 tumors in 44 patients were treated with CA (2.1 ± 0.8 cm). The mean follow-up observation period was 26 ± 19 months. The major complications and efficacy, as measured using the technical success and local tumor recurrence rates, were recorded. There were three (6.9%) technical failures with RFA and one (2.1%) with cryoablation (p = 0.30). Among the 40 tumors that were successfully treated with RFA, 1 tumor (2.5%) developed local tumor recurrence; 5/46 tumors that were treated with cryoablation (10.8%) developed local tumor recurrence (p = 0.17). T1b lesions (4.0 ± 0.7 cm) resulted in 1/6 technically unsuccessful cases with RFA and 0/4 with CA. No recurrent disease was detected in the T1b lesions. Major complications occurred after 2.3% (1/43) of RFAs and 0/47 of cryoablation procedures. RFA and cryoablation are both effective in the treatment of renal masses. Major complications with either procedure are uncommon.

In oligo-metastatic renal cell carcinoma (RCC), neither computed tomography (CT) nor bone scan is sensitive enough to detect small tumor deposits hampering early treatment and potential cure. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the neo-vasculature of numerous malignant neoplasms, including RCC, that can be targeted by positron emission tomography (PET) using PSMA-targeting radioligands. Our aim was to investigate whether PSMA-expression patterns of renal cancer in the primary tumor or metastatic lesions on immunohistochemistry (IHC) are associated with PET/CT findings using [68Ga]-PSMA-HBED-CC (PSMA-PET/CT). We then analyzed the predictive and prognostic role of the PSMA-PET/CT signal. In this retrospective single-center study we included patients with renal cancer submitted to PSMA-PET/CT for staging or restaging, with tumor specimens available for PSMA-IHC. Clinical information (age, tumor type, and grade) and IHC results from the primary tumor or metastases were collected. The intensity of PSMA expression at IHC was scored into four categories: 0: none; 1: weak; 2: moderate; 3: strong. PSMA expression was also graded according to the proportion of vessels involved (PSMA%) into four categories: 0: none; 1: 1–25%; 2: 25–50%; 3: >50%. The intensity of PSMA expression and PSMA% were combined in a three-grade score: 0–2 absent or mildly positive, 3–4 moderately positive, and 5–6 strongly positive. PSMA scores were used for correlation with PSMA-PET/CT results. Results: IHC and PET scans were available for the analysis in 26 patients (22 ccRCC, 2 papillary RCC, 1 chromophobe, 1 “not otherwise specified” RCC). PSMA-PET/CT was positive in 17 (65%) and negative in 9 patients (35%). The mean and median SUVmax in the target lesion were 34.1 and 24.9, respectively. Reporter agreement was very high for both distant metastasis location and local recurrence (kappa 1, 100%). PSMA-PET detected more lesions than conventional imaging and revealed unknown metastases in 4 patients. Bone involvement, extension, and lesion number were greater than in the CT scan (median lesion number on PET/CT 3.5). The IHC PSMA score was concordant in primary tumors and metastases. All positive PSMA-PET/CT results (15/22 ccRCC, 1 papillary cancer type II, and 1 chromofobe type) were revealed in tumors with strong or moderate PSMA combined scores (3–4 and 5–6). In ccRCC tissue samples, PSMA expression was strong to moderate in 20/22 cases. The SUVmax values correlated to the intensity of PSMA expression which were assessed using IHC (p = 0.01), especially in the ccRCC subgroup (p = 0.009). Median survival was significantly higher in patients with negative PSMA-PET/CT (48 months) compared to patients with a positive scan (24 months, p= 0.001). SUVmax ≥ 7.4 provides discrimination of patients with a poor prognosis. Results of PSMA-PET/CT changed treatment planning. Conclusions: in renal cancer, positive PSMA-PET/CT is strongly correlated to the intensity of PSMA expression on immunohistochemistry in both ccRCC and chromophobe cancer. PSMA-PET/CT signal predicts a poor prognosis confirming its potential as an aggressiveness biomarker and providing paramount additional information influencing patient management.

In this new study the Authors demonstrated that the IGFBP3/TMEM219 pathway is a physiological regulator of pancreatic beta cell homeostasis and it is dysregulated in diabetes. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.

Objective: The major strengths of surgical treatment of benign prostatic hyperplasia with laser are reduced morbidity compared to endoscopic resec-tion. No studies analysed the different risk of intra/peri-opera-tive events between patients undergoing Thulium and GreenLight procedures. Materials and methods: We retrospectively reviewed 100 con-secutive cases undergoing GreenLight vaporization and Thulium procedures performed during the learning curve of two expert endoscopic surgeons. Pre-operative data, intra and post-opera-tive events at 90 days were analysed. Results: Patients on antiplatelet/anticoagulant therapy were pre-dominant in the Green group (p < 0.0001). Rates of blood trans-fusion (p < 0.0038), use of resectoscope (p < 0.0086), and tran-sient stress urinary incontinence were statistically higher in the Thulium group. On the contrary conversions to TURP (p < 0.023) were more frequent in GreenLight patients. Readmissions were more frequently necessary in GreenLight group (24%) vs. Thulium group (26.6%). The overall complica-tion rate in GreenLight and Thulium groups were 31% and 53%respectively; Clavien 3b complications were 13% in Thulium patients versus 1% in GreenLight patients. Conclusions: GreenLight and Thulium treatments show similar safety profiles. Randomized controlled trial are needed to better clarify the rate of major complications in Thulium group, and the incidence of post-operative storage symptoms in these patients’ populations.