Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.
- MeSH
- HCT116 Cells MeSH
- Colorectal Neoplasms * pathology genetics metabolism MeSH
- Cullin Proteins * metabolism genetics MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Proteins * metabolism genetics MeSH
- Smad3 Protein * metabolism genetics MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Wnt Signaling Pathway MeSH
- Ubiquitination MeSH
- Ubiquitin-Protein Ligases * metabolism genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
In this review, we emphasize the significance of the Liebeskind-Srogl cross-coupling reaction, a palladium-catalyzed process involving the reaction between a thioester and a boronic acid. This reaction has emerged as a fundamental technique in synthetic methodologies aimed at the development of biologically active compounds. The Liebeskind-Srogl cross-coupling method has become an essential approach in chemistry, facilitating the diversification of complex structures that would be significantly more challenging to synthesize through alternative approaches. In this review, we aim to outline the numerous possibilities for preparing a wide range of derivatives, each with notable biological potential.
DC-SIGN, a C-type lectin receptor expressed on immune cells, is considered a promising target for immunomodulatory and antiviral therapies. While mannose-based glycomimetics have been extensively studied as DC-SIGN ligands, fucose-based strategies remain underexplored. This study explores the fucosylation of linear alcohols and sugars using eight different fucosyl donors, aiming at designing strategies for the development of fucose-based glycomimetics targeting DC-SIGN. Four types of leaving groups and two different acyl-based protecting groups on the donors were tested. The glycosylation of 3-azidopropan-1-ol exclusively yielded the β-anomer, demonstrating high stereoselectivity. The azido group in the product is versatile, allowing for direct click chemistry reactions or reduction to an amine for further functionalization. Both types of reactions were demonstrated in a model reaction. In the glycosylation of a sugar, a disaccharide moiety of Lewis X antigen was selected as a target molecule. Only one of the eight tested fucosyl donors worked well in this reaction and provided the product in a reasonable yield. The disaccharide was also equipped with the 3-azidopropyl linker, facilitating future modifications. Finally, NMR studies confirmed compatibility of the linker with canonical Ca2+-dependent carbohydrate binding to DC-SIGN, suggesting potential for further development of fucose-based glycomimetics targeting this C-type lectin receptor.
- MeSH
- Fucose * chemistry MeSH
- Glycosides * chemistry chemical synthesis pharmacology metabolism MeSH
- Glycosylation MeSH
- Lectins, C-Type * metabolism antagonists & inhibitors MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Adhesion Molecules * metabolism antagonists & inhibitors MeSH
- Receptors, Cell Surface * metabolism antagonists & inhibitors MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND AND OBJECTIVE: We present a summary of the 2025 update for the European Association of Urology (EAU) guidelines for upper urinary tract urothelial carcinoma (UTUC). The aim is to provide practical recommendations on the clinical management of UTUC with a focus on diagnosis, treatment, and follow-up. METHODS: For the 2025 guidelines on UTUC, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. KEY FINDINGS AND LIMITATIONS: Key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with UTUC. The guidelines stress the importance of appropriate treatment taking into account patient values and preferences. Key updates in the 2025 UTUC guidelines include: significant changes to the recommendations for UTUC diagnosis; complete revision of the sections addressing risk stratification, ureteroscopy, and the surgical approach for radical nephroureterectomy; addition of four new recommendations, two related to kidney-sparing management of localised low-risk UTUC and a further two related to management of high-risk nonmetastatic UTUC; a review and adaptation of recommendation for UTUC follow-up; and addition of a new section addressing quality indicators for UTUC management. CONCLUSIONS AND CLINICAL IMPLICATIONS: This overview of the 2025 EAU guidelines on UTUC offers valuable insights into risk factors, diagnosis, classification, treatment, and follow-up for UTUC. The guidelines contain information on the management of individual patients according to the current best evidence and are designed for effective integration in clinical practice.
- MeSH
- Carcinoma, Transitional Cell * therapy diagnosis MeSH
- Humans MeSH
- Kidney Neoplasms * therapy diagnosis MeSH
- Ureteral Neoplasms * therapy diagnosis MeSH
- Societies, Medical MeSH
- Urology standards MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Practice Guideline MeSH
- Geographicals
- Europe MeSH
BACKGROUND AND OBJECTIVE: The European Association of Urology (EAU) renal cell carcinoma (RCC) guideline panel has updated their evidence-based guidelines and recommendations for the management of RCC. Here we present a summary of the 2025 RCC guidelines updated with standardised methodology to provide reproducible evidence for the management of RCC. METHODS: For the 2025 update, a literature search was performed covering the period from May 1, 2023 to May 1, 2024 using the Medline, EMBASE, and Cochrane Libraries. The data search focused on meta-analyses, systematic reviews, randomised controlled trials (RCTs), and retrospective or controlled comparator-arm studies. Evidence was synthesised as outlined for all EAU guidelines. KEY FINDINGS AND LIMITATIONS: Clinical practise recommendations were updated in all chapters of the RCC guidelines on the basis of a structured literature search. The studies included were predominantly retrospective with matched or unmatched cohorts based on single- or multi-institutional data. Several prospective studies and RCTs provided data that resulted in recommendations based on higher levels of evidence. Specifically, updates include new recommendations on stereotactic body radiotherapy for localised RCC, adjuvant therapy, systemic therapy for clear-cell RCC in later lines, other subtypes, and a new chapter on hereditary RCC. CONCLUSIONS AND CLINICAL IMPLICATIONS: The 2025 RCC guidelines have been updated by a multidisciplinary panel of experts using methodological standards to provide a contemporary evidence base for the management of RCC.
- MeSH
- Carcinoma, Renal Cell * therapy diagnosis MeSH
- Humans MeSH
- Kidney Neoplasms * therapy diagnosis MeSH
- Societies, Medical MeSH
- Urology standards MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Practice Guideline MeSH
- Geographicals
- Europe MeSH
Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.
- MeSH
- Clinical Relevance MeSH
- Humans MeSH
- DNA, Mitochondrial genetics MeSH
- Mitochondria * genetics metabolism MeSH
- Neoplasms * genetics pathology metabolism MeSH
- Gene Transfer, Horizontal * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: The hypothalamus (HT) plays a crucial role in regulating eating behaviors. Disruptions in its function have been linked to the development of weight-related disorders. Nevertheless, its characterization remains a challenge. OBJECTIVES: We assessed the structural alterations of individual HT nuclei related to eating behaviors in patients with weight-related disorders, and their association with body mass index (BMI) and severity of eating disorders. METHODS: Forty-four young females with normal weight (HC, n = 21), restrictive anorexia nervosa (AN, n = 13), and living with obesity (OB, n = 10) were explored in vivo using 7-T high-resolution (0.6 mm isotropic voxel) T1 quantitative magnetic resonance imaging (MRI). Volumes and quantitative T1 values of individual HT nuclei were compared after whole-brain normalization using nonparametric tests (corrected for multiple comparisons for groups and regions). We investigated the parameters associated with BMI and eating disorders, such as MRI parameters of HT nuclei, ghrelin and leptin levels, depression, and anxiety using multivariate nonlinear partial least square (NIPALS). RESULTS: Both AN and OB showed higher volumes of HT relative to HC (Zscores: 0.78 ± 1.06; 1.43 ± 1.51). AN showed significantly higher volumes and T1 values of the right paraventricular nucleus (PaVN) (volume Zscore: 1.82 ± 1.45; T1 Zscore: 3.76 ± 4.67), and higher T1 values of the left PaVN (Zscore: 2.25 ± 2.37) and right periventricular nuclei (Zscore: 3.73 ± 4.81). NIPALS models showed that lower BMI in AN was associated with structural alterations of the bilateral PaVN, right anterior commissure, and left fornix (FX). Higher BMI in OB was associated with structural alterations within the right PaVN, bilateral FX, left posterior hypothalamic nucleus, right lateral HT, and right anterior hypothalamic area. Finally, the severity of eating disorders was associated with larger structural alterations within the bilateral PaVN, bilateral arcuate hypothalamic nuclei, right bed nucleus of stria terminalis, left medial preoptic nucleus, and right tubero-mammillary hypothalamic nucleus. CONCLUSIONS: Weight-related disorders are associated with significant micro and macrostructural alterations in HT nuclei involved in eating behaviors.
- MeSH
- Adult MeSH
- Hypothalamus * diagnostic imaging pathology MeSH
- Body Mass Index MeSH
- Leptin blood MeSH
- Humans MeSH
- Magnetic Resonance Imaging * MeSH
- Anorexia Nervosa * diagnostic imaging pathology MeSH
- Adolescent MeSH
- Young Adult MeSH
- Obesity * diagnostic imaging pathology MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
At a population level, the European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter and Microbiota Study Group (EHMSG), and the European Society of Pathology (ESP) suggest endoscopic screening for gastric cancer (and precancerous conditions) in high-risk regions (age-standardized rate [ASR] > 20 per 100 000 person-years) every 2 to 3 years or, if cost-effectiveness has been proven, in intermediate risk regions (ASR 10-20 per 100 000 person-years) every 5 years, but not in low-risk regions (ASR < 10).ESGE/EHMSG/ESP recommend that irrespective of country of origin, individual gastric risk assessment and stratification of precancerous conditions is recommended for first-time gastroscopy. ESGE/EHMSG/ESP suggest that gastric cancer screening or surveillance in asymptomatic individuals over 80 should be discontinued or not started, and that patients' comorbidities should be considered when treatment of superficial lesions is planned.ESGE/EHMSG/ESP recommend that a high quality endoscopy including the use of virtual chromoendoscopy (VCE), after proper training, is performed for screening, diagnosis, and staging of precancerous conditions (atrophy and intestinal metaplasia) and lesions (dysplasia or cancer), as well as after endoscopic therapy. VCE should be used to guide the sampling site for biopsies in the case of suspected neoplastic lesions as well as to guide biopsies for diagnosis and staging of gastric precancerous conditions, with random biopsies to be taken in the absence of endoscopically suspected changes. When there is a suspected early gastric neoplastic lesion, it should be properly described (location, size, Paris classification, vascular and mucosal pattern), photodocumented, and two targeted biopsies taken.ESGE/EHMSG/ESP do not recommend routine performance of endoscopic ultrasonography (EUS), computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)-CT prior to endoscopic resection unless there are signs of deep submucosal invasion or if the lesion is not considered suitable for endoscopic resection.ESGE/EHMSG/ESP recommend endoscopic submucosal dissection (ESD) for differentiated gastric lesions clinically staged as dysplastic (low grade and high grade) or as intramucosal carcinoma (of any size if not ulcerated or ≤ 30 mm if ulcerated), with EMR being an alternative for Paris 0-IIa lesions of size ≤ 10 mm with low likelihood of malignancy.ESGE/EHMSG/ESP suggest that a decision about ESD can be considered for malignant lesions clinically staged as having minimal submucosal invasion if differentiated and ≤ 30 mm; or for malignant lesions clinically staged as intramucosal, undifferentiated and ≤ 20 mm; and in both cases with no ulcerative findings.ESGE/EHMSG/ESP recommends patient management based on the following histological risk after endoscopic resection: Curative/very low-risk resection (lymph node metastasis [LNM] risk < 0.5 %-1 %): en bloc R0 resection; dysplastic/pT1a, differentiated lesion, no lymphovascular invasion, independent of size if no ulceration and ≤ 30 mm if ulcerated. No further staging procedure or treatment is recommended.Curative/low-risk resection (LNM risk < 3 %): en bloc R0 resection; lesion with no lymphovascular invasion and: a) pT1b, invasion ≤ 500 μm, differentiated, size ≤ 30 mm; or b) pT1a, undifferentiated, size ≤ 20 mm and no ulceration. Staging should be completed, and further treatment is generally not necessary, but a multidisciplinary discussion is required. Local-risk resection (very low risk of LNM but increased risk of local persistence/recurrence): Piecemeal resection or tumor-positive horizontal margin of a lesion otherwise meeting curative/very low-risk criteria (or meeting low-risk criteria provided that there is no submucosal invasive tumor at the resection margin in the case of piecemeal resection or tumor-positive horizontal margin for pT1b lesions [invasion ≤ 500 μm; well-differentiated; size ≤ 30 mm, and VM0]). Endoscopic surveillance/re-treatment is recommended rather than other additional treatment. High-risk resection (noncurative): Any lesion with any of the following: (a) a positive vertical margin (if carcinoma) or lymphovascular invasion or deep submucosal invasion (> 500 μm from the muscularis mucosae); (b) poorly differentiated lesions if ulceration or size > 20 mm; (c) pT1b differentiated lesions with submucosal invasion ≤ 500 μm with size > 30 mm; or (d) intramucosal ulcerative lesion with size > 30 mm. Complete staging and strong consideration for additional treatments (surgery) in multidisciplinary discussion.ESGE/EHMSG/ESP suggest the use of validated endoscopic classifications of atrophy (e. g. Kimura-Takemoto) or intestinal metaplasia (e. g. endoscopic grading of gastric intestinal metaplasia [EGGIM]) to endoscopically stage precancerous conditions and stratify the risk for gastric cancer.ESGE/EHMSG/ESP recommend that biopsies should be taken from at least two topographic sites (2 biopsies from the antrum/incisura and 2 from the corpus, guided by VCE) in two separate, clearly labeled vials. Additional biopsy from the incisura is optional.ESGE/EHMSG/ESP recommend that patients with extensive endoscopic changes (Kimura C3 + or EGGIM 5 +) or advanced histological stages of atrophic gastritis (severe atrophic changes or intestinal metaplasia, or changes in both antrum and corpus, operative link on gastritis assessment/operative link on gastric intestinal metaplasia [OLGA/OLGIM] III/IV) should be followed up with high quality endoscopy every 3 years, irrespective of the individual's country of origin.ESGE/EHMSG/ESP recommend that no surveillance is proposed for patients with mild to moderate atrophy or intestinal metaplasia restricted to the antrum, in the absence of endoscopic signs of extensive lesions or other risk factors (family history, incomplete intestinal metaplasia, persistent H. pylori infection). This group constitutes most individuals found in clinical practice.ESGE/EHMSG/ESP recommend H. pylori eradication for patients with precancerous conditions and after endoscopic or surgical therapy.ESGE/EHMSG/ESP recommend that patients should be advised to stop smoking and low-dose daily aspirin use may be considered for the prevention of gastric cancer in selected individuals with high risk for cardiovascular events.
- MeSH
- Biopsy MeSH
- Early Detection of Cancer * methods standards MeSH
- Gastroscopy * standards MeSH
- Risk Assessment MeSH
- Helicobacter Infections complications MeSH
- Humans MeSH
- Stomach Neoplasms * pathology diagnosis therapy MeSH
- Precancerous Conditions * pathology diagnosis therapy MeSH
- Societies, Medical MeSH
- Gastric Mucosa pathology diagnostic imaging MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Practice Guideline MeSH
- Geographicals
- Europe MeSH
