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Recently renamed, metabolic dysfunction-associated steatotic liver disease remains a leading cause of chronic liver disease worldwide. Regular physical activity is recommended as a treatment for all with this condition because it is highly efficacious, especially when exercise training is undertaken with a specific goal in mind. Despite decades of research demonstrating exercises efficacy, key questions remain about the mechanism of benefit and most efficacious dose, as well as the independent impact on liver histology. To answer these questions, we present the design of a 16-week randomized controlled clinical trial of 45 adults aged 18-69 years with metabolic dysfunction-associated steatohepatitis. The primary aim of this study is to better understand the dose required and mechanisms to explain how exercise impacts multiple clinical end points in metabolic dysfunction-associated steatohepatitis. The primary outcome is MRI-measured liver fat. Secondary outcomes include other biomarkers of liver fibroinflammation, liver histology, and mechanistic pathways, as well as cardiometabolic risk and quality of life. This is the first study to compare different doses of exercise training to determine if there is a differential impact on imaging and serum biomarkers as well as liver histology.

Natural photosystems couple light harvesting to charge separation using a 'special pair' of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C2-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry. Spectroscopy revealed that the chlorophylls are excitonically coupled, and fluorescence lifetime imaging demonstrated energy transfer. The cryo-electron microscopy structure of a designed 24-chlorophyll octahedral nanocage with a special pair on each edge closely matched the design model. The results suggest that the de novo design of artificial photosynthetic systems is within reach of current computational methods.

Abstract Introduction Patients with ulcerative colitis (UC) receiving liver transplantation (LT) due to primary sclerosing cholangitis (PSC) have higher risk of developing colorectal cancers (CRC). Aim of this systematic review was to define the patients’ features, immunosuppressive management, and oncological outcomes of LT recipients with UC-PSC developing CRC. Methods Searches were conducted in PubMed (MEDLINE), Cochrane Library, Web of Science for all English articles published until September 2023. Inclusion criteria were original articles including patients specifying outcomes of interest. Primary endpoints comprised incidence of CRC, disease free survival (DFS), overall survival (OS) and cancer recurrence. Secondary endpoints were patient’s and tumor characteristics, graft function, immunosuppressive management and PSC recurrence. PROSPERO CRD42022369190. Results Fifteen studies included, 88 patients were identified. Patients (mean age: 50 years) had a long history of UC (20 years), mainly with active colitis (79%), and developed tumor within the first 3 years from LT, while receiving a double or triple immunosuppressive therapy. Cumulative incidence of tumor was 5.5%. At one, two and three years, DFS was 92%, 82% and 75%, while OS was 87%, 81% and 79% respectively. Disease progression rate was 15%. After CRC surgery, 94% of patients maintained a good graft functionality, with no reported cases of PSC recurrence. Conclusions After LT, patients with PSC and UC have an increased risk of CRC, especially in presence of long history of UC and active colitis. Surgical resection guarantees satisfactory mid-term oncological outcomes, but samples are limited, and long-term data are lacking. National and international registry are auspicial to evaluate long-term oncological outcomes and to optimize clinical management.

Abstract Background Lung cancer, a leading global cause of cancer-related mortality, necessitates enhanced prognostic markers for improved treatment outcomes. We have previously shown a tumor suppressive role of cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1), which is targeted for degradation upon phosphorylation at S14 (pCASTOR1) in multiple types of cancer. This study focuses on the predictive value of pCASTOR1 in lung adenocarcinoma (LUAD) patients with KRAS mutations. Results Employing a newly developed pCASTOR1 specific antibody, we found that tumor cells exhibited significantly elevated pCASTOR1 scores compared to non-tumor cells (P

ABSTRACT: In this study, the main objective was to assess if long luteal phases could have causes other than pregnancy loss. We enrolled Holstein dairy cows ≥50 DIM from a commercial herd in Brazil from October 2016 to August 2017. All cows received an estradiol-based synchronization protocol, and, on the day of insemination (d 0), were randomly assigned either an AI or a placebo insemination (PBO) in a 3:1 ratio. An ultrasound was used to assess the presence of a corpus luteum (CL) on d 17, 24, and 31, which, combined to the information from patches for the detection of estrus, was used to determine the length of the luteal phase following AI or PBO. Pregnancy was assessed by ultrasound on d 31 and cows that were pregnant were excluded from the analyses. The length of the estrous cycles was categorized as short (

Abstract Background Distinguishing reactive atypia from dysplasia in cholecystectomy specimens can be histologically challenging. The aim of this study was to evaluate the utility of IMP3, p53, and S100P immunostains in differentiating reactive atypia from dysplasia in cholecystectomies. Methods Fifty-four cholecystectomies were reviewed and characterized into 5 groups: 2 normal, 29 reactive atypia, 16 low-grade dysplasia, 2 high-grade dysplasia, and 5 adenocarcinoma. IMP3, p53, and S100P immunostains were performed and evaluated. IMP3 (nuclear) and S100P (nuclear or nuclear/cytoplasmic) were categorized into negative or positive expression, and p53 was categorized into wild-type and aberrant/mutant expression. Chi-square test was used for statistical analysis. Results The patients were mostly middle-aged women (mean 44, range 19–87 years, 81% female), with predominantly Hispanic White ethnicity (80%). The majority of the normal and reactive atypia cases showed negative IMP3 (100% and 75.9%, respectively) and wild-type p53 (100% and 89.7%, respectively) staining. Over half (56.3%) of the low-grade dysplasia and all the high-grade dysplasia cases showed IMP3 positivity. Aberrant p53 staining pattern was seen in half of both low and high-grade dysplasia cases. Adenocarcinoma showed IMP3 positivity in 80% and p53 aberrancy in all cases. S100P showed no statistical significance among the diagnostic categories. Significant differences in staining patterns were found between reactive atypia vs. low-grade dysplasia, and reactive atypia vs. low-grade + high-grade dysplasia using a combination of IMP3 and p53 stains (all p

Abstract Interactions between colorectal cancer (CRC) cells and the noncancerous cells in the tumor microenvironment (TME) induce mechanisms for the escape of tumor cells from immune attack. Hepcidin, a peptide that controls immune cell functions, is overproduced by CRC cells. This study aimed to evaluate whether hepcidin acts as a regulator of anti-tumor immunity in CRC. Hepcidin silencing in CRC cells was followed by enhanced TNF-driven caspase-dependent cleavage of GSDM E and death. Mice engrafted with hepcidin-deficient CT26 cells developed fewer and smaller tumors than control mice as a result of the action of tumor-infiltrating CD8+ T lymphocytes and were protected from the development of tumors in a vaccination model and exhibited long-lasting tumor protection. Additionally, hepcidin deficiency enhanced the response of mice bearing CT26-derived tumors to anti-PD-1 therapy. These results suggest that targeting hepcidin in CRC cells enhances the production of TNF thereby triggering a caspase/GSDM E-driven lytic cell death with the downstream effect of boosting a robust immune response against tumor antigens.

Abstract Objectives Thrombocytosis is a clinical condition generally associated with poor prognosis in patients with cancer. Thrombocytosis may be present after lung cancer resection, but the clinical significance of thrombocytosis remains unclear. Herein, we evaluated whether postoperative thrombocytosis was a negative prognostic factor in patients undergoing thoracoscopic lobectomy for lung cancer. Methods It was a retrospective monocentric study including consecutive patients undergoing thoracoscopic lobectomy for lung cancer from January 2020 to January 2023. The outcome of patients with postoperative thrombocytosis (defined as platelet count ≥ 450 × 10^9/L at 24 h after the surgery and confirmed at postoperative day 7) was compared with a control group. Postoperative morbidity, mortality, and survival were compared between the two groups to define whether thrombocytosis negatively affected outcomes. Results Our study population included 183 patients; of these, 22 (12%) presented postoperative thrombocytosis: 9 (5%) mild thrombocytosis (451–700 × 10^9/L), 10 (5%) moderate thrombocytosis (701–900 × 10^9/L), and 3 (2%) severe thrombocytosis (901–1000 × 10^9/L). No significant differences were found regarding postoperative morbidity (p = 0.92), mortality (p = 0.53), overall survival (p = 0.45), and disease-free survival (p = 0.60) between the two study groups. Thrombocytosis was associated with higher rate of atelectasis (36% vs. 6%, p

Abstract Background A number of Italian grape berry varieties, such as Fiano (F) and Pallagrello Nero (P), represent National strategic products. Therefore, it is important to identify soil conditions emphasizing their peculiar characteristics as well as find innovative and sustainable treatments improving their compositional and nutraceutical quality. The field spray preparation 500 is a biodynamic product that is presumed to serve as biostimulant on the vine. However, so far, the scientific results probing its effectiveness are still lacking. Moreover, it is necessary to establish a reliable relationship between the grape quality and the spatial microvariability of the vineyard’s soil. On this basis, the main objective of this work consisted in correlating structural and morphological characteristics (via MRI), the primary metabolome (via semi-solid state HRMAS NMR) and important nutraceutical parameters (total phenols and antioxidants via DPPH assay) of F and P grapes with both the action of preparation 500 biostimulant and the vineyard soil microvariability, based on soil apparent electrical conductivity. Results HRMAS enabled the identification of the primary metabolome of F and P. The elaboration of 1H NMR spectra through chemometrics revealed significant changes in F and P grapes, accounting for both soil microvariability and the application of field spray (the latter also confirmed by PLS-DA and Heat-map clustering). Interestingly, for both F and P it was observed a significantly lower content of carbohydrates after biostimulant treatment while MRI revealed diagnostic structural and internal details of intact grapes. The combined use of proton parametric indices, such as relaxation times and diffusion coefficients, indicated alterations induced in grapes by both the spatial microvariability of the soil and the effects of investigated biostimulant. Interestingly, a tight correlation was found between MRI transverse relaxation time and the contents in total phenols and antioxidants. Conclusions Our results have proven that both soil spatial microvariability and the application of field spray preparation 500 significantly affect the structural, metabolomic and nutraceutical characteristics of grapes. Moreover, the preparation 500 treatment has increased the nutraceutical value of grapes. Importantly, these data may be potentially used to promote and protect biodynamic grape and predict the quality of the resulting wines. Graphical Abstract