Search

Purpose: To investigate the effects of repeated-sprint training with voluntary hypoventilation at low (RSH-VHL) and high (RS-VHH) lung volume on repeated-sprint ability (RSA) in female athletes. Methods: Over a 6-week period, 24 female soccer players completed 12 sessions of repeated 30-m running sprints with end-expiratory breath holding (RSH-VHL, n = 8), end-inspiratory breath holding (RS-VHH, n = 8), or unrestricted breathing (RS-URB, n = 8). Before and after training, a running RSA test consisting of performing 30-m all-out sprints until exhaustion was implemented. Results: From before to after training, the number of sprints completed during the RSA test was increased in both RSH-VHL (19.3 [0.9] vs 22.6 [0.9]; P <.01) and RS-VHH (19.3 [1.5] vs 20.5 [1.7]; P <.01) but not in RS-URB (19.4 [1.3] vs 19.5 [1.7]; P =.67). The mean velocity and the percentage decrement score calculated over sprints 1 to 17 were, respectively, higher (82.2% [1.8%] vs 84.6% [2.1%] of maximal velocity) and lower (23.7% [3.1%] vs 19.4% [3.2%]) in RSH-VHL (P <.01), whereas they remained unchanged in RS-VHH and RS-URB. The mean arterial oxygen saturation recorded during training at the end of the sprints was lower in RSH-VHL (92.1% [0.4%]) than in RS-VHH (97.3% [0.1%]) and RS-URB (97.8% [0.1%]). Conclusions: This study shows that female athletes can benefit from the RSH-VHL intervention to improve RSA. The performance gains may have been limited by the short sprinting distance with end-expiratory breath holding, which provoked only moderate hypoxemia. The increase in the number of sprints in RS-VHH seems to show that factors other than hypoxia may have played a role in RSA improvement. [ABSTRACT FROM AUTHOR]

CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1, and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard-of-care agent, axitinib. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2 independent. [ABSTRACT FROM AUTHOR]

While renal cell carcinoma (RCC) is often linked to smoking, obesity, and hypertension, hereditary forms also account for about 3% of RCC cases. Notably, NCCN guidelines identify 7 major hereditary syndromes associated with an increased RCC risk. Inherited mutations in DNA repair genes, such as ATM, BRCA, and TP53, significantly increase the risk of various cancers. Biallelic pathogenic mutations in ATM cause Ataxia-Telangiectasia (A-T) syndrome, while heterozygous germline pathogenic ATM mutations, present in about 1% of the population, also elevate cancer risk. RCC has not traditionally been associated with germline pathogenic ATM mutations, only limited retrospective analyses have identified such mutations. This case report presents a 68-year-old woman with a germline pathogenic ATM mutation (c.8786+1 G>A) who developed high-risk clear cell RCC followed by an acquired somatic VHL mutation in RCC and a 3-cm serous cystadenoma, illustrating the double-hit phenomenon. Her brother, who shares the same germline pathogenic mutation, was diagnosed with pancreatic cancer and prostate cancer. This case highlights the potential use for enhanced screening protocols for RCC in patients who have germline pathogenic ATM mutations and the importance of research in targeted treatments for tumors driven by dual genetic mechanisms. Increased awareness and vigilant screening for RCC are crucial in managing hereditary cancer syndromes effectively. [ABSTRACT FROM AUTHOR]

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10–12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include "old genes" associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up. [ABSTRACT FROM AUTHOR]

AURKA is predominantly famous as an essential mitotic kinase. Recent findings have also established its critical role in a plethora of other biological processes including ciliogenesis, mitochondrial dynamics, neuronal outgrowth, DNA replication and cell cycle progression. AURKA overexpression in numerous cancers is strongly associated with poor prognosis and survival. Still no AURKA-targeted drug has been approved yet, partially because of the associated collateral toxicity and partly due to its limited efficacy as a single agent in a wide range of tumors. Mechanistically, AURKA overexpression allows it to phosphorylate numerous pathological substrates promoting highly aggressive oncogenic phenotypes. Our review examines the most recent advances in AURKA regulation and focuses on 33 such direct cancer-specific targets of AURKA and their associated oncogenic signaling cascades. One of the common themes that emerge is that AURKA is often involved in a feedback loop with its substrates, which could be the decisive factor causing its sustained upregulation and hyperactivation in cancer cells, an Achilles heel not exploited before. This dynamic interplay between AURKA and its substrates offers potential opportunities for targeted therapeutic interventions. By targeting these substrates, it may be possible to disrupt this feedback loop to effectively reverse AURKA levels, thereby providing a promising avenue for developing safer AURKA-targeted therapeutics. Additionally, exploring the synergistic effects of AURKA inhibition with its other oncogenic and/or tumor-suppressor targets could provide further opportunities for developing effective combination therapies against AURKA-driven cancers, thereby maximizing its potential as a critical drug target. [ABSTRACT FROM AUTHOR]

BACKGROUND: HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question. METHODS: We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation. RESULTS: We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo. CONCLUSIONS: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia. [ABSTRACT FROM AUTHOR]

The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel–Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1β, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein–protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

This review article focuses on von Hippel–Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body. It discusses the following aspects of the disease. Genetics: VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. Pathophysiology: The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. Clinical Manifestations: VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. Diagnosis: Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. Treatment: Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. Challenges: This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease. [ABSTRACT FROM AUTHOR]

Copyright of Osmangazi Journal of Medicine / Osmangazi Tip Dergisi is the property of Eskisehir Osmangazi University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The von Hippel-Lindau tumor suppressor protein (VHL), an E3 ubiquitin ligase, functions as a critical regulator of the oxygen-sensing pathway for targeting hypoxia-inducible factors. Recent evidence suggests that mammalian VHL may also be critical to the NF-κB signaling pathway, although the specific molecular mechanisms remain unclear. Herein, the roles of mandarin fish (Siniperca chuatsi) VHL (scVHL) in the NF-κB signaling pathway and mandarin fish ranavirus (MRV) replication were explored. The transcription of scVHL was induced by immune stimulation and MRV infection, indicating a potential role in innate immunity. Dual-luciferase reporter gene assays and reverse transcription quantitative PCR (RT-qPCR) results demonstrated that scVHL evoked and positively regulated the NF-κB signaling pathway. Treatment with NF-κB signaling pathway inhibitors indicated that the role of scVHL may be mediated through scIKKα, scIKKβ, scIκBα, or scp65. Co-immunoprecipitation (Co-IP) analysis identified scIκBα as a novel target protein of scVHL. Moreover, scVHL targeted scIκBα to catalyze the formation of K63-linked polyubiquitin chains to activate the NF-κB signaling pathway. Following MRV infection, NF-κB signaling remained activated, which, in turn, promoted MRV replication. These findings suggest that scVHL not only positively regulates NF-κB but also significantly enhances MRV replication. This study reveals a novel function of scVHL in NF-κB signaling and viral infection in fish. [ABSTRACT FROM AUTHOR]

Abstract AURKA is predominantly famous as an essential mitotic kinase. Recent findings have also established its critical role in a plethora of other biological processes including ciliogenesis, mitochondrial dynamics, neuronal outgrowth, DNA replication and cell cycle progression. AURKA overexpression in numerous cancers is strongly associated with poor prognosis and survival. Still no AURKA-targeted drug has been approved yet, partially because of the associated collateral toxicity and partly due to its limited efficacy as a single agent in a wide range of tumors. Mechanistically, AURKA overexpression allows it to phosphorylate numerous pathological substrates promoting highly aggressive oncogenic phenotypes. Our review examines the most recent advances in AURKA regulation and focuses on 33 such direct cancer-specific targets of AURKA and their associated oncogenic signaling cascades. One of the common themes that emerge is that AURKA is often involved in a feedback loop with its substrates, which could be the decisive factor causing its sustained upregulation and hyperactivation in cancer cells, an Achilles heel not exploited before. This dynamic interplay between AURKA and its substrates offers potential opportunities for targeted therapeutic interventions. By targeting these substrates, it may be possible to disrupt this feedback loop to effectively reverse AURKA levels, thereby providing a promising avenue for developing safer AURKA-targeted therapeutics. Additionally, exploring the synergistic effects of AURKA inhibition with its other oncogenic and/or tumor-suppressor targets could provide further opportunities for developing effective combination therapies against AURKA-driven cancers, thereby maximizing its potential as a critical drug target.

Abstract Background Patients with von Hippel-Lindau (VHL) disease are at risk of developing tumors in the eye, brain, kidney, adrenal gland, and other organs based on their gene mutations. The VHL tumor suppressor gene contains pathogenic variants responsible for these events. This meta-analysis aims to investigate the genetic differences among the various types of VHL syndrome and their correlation with the location of mutations (exons and domains) in the VHL gene. Method Papers eligible for publication until September 2023 were identified using the electronic databases of PubMed, Google Scholar, Scopus, and EMBASE. The Random Effect model was utilized to evaluate the genetic differences between type 1 and type 2 VHL syndromes. Results The prevalence of missense mutations (MSs) was found to be 58.9% in type 1, while it was 88.1% in type 2. Interestingly, the probability of observing MSs in type 1 was 0.42 times lower compared to type 2. The mutation hotspots of the VHL gene were R167Q/W, Y98H, R238W, and S65L, respectively. Although type 2 had a high presentation of Y98H and R238W, it did not have a higher S65L than type 1. The analysis demonstrated a statistically significant higher prevalence of truncated mutations (PTMs) in type 1. Among type 1, large/complete deletions (L/C DELs) were found in 16.9% of cases, whereas in type 2 only 3.7%. This difference was statistically significant with a p-value

Abstract Background Pheochromocytoma is a rare disease, and its familial occurrence is quite uncommon. The aim of this paper is to report a three-generation phenotypical expression of a case familial occurrence of pheochromocytoma. Case presentation A 25-year-old female, with a history of adrenalectomy for pheochromocytoma, arrived at the shock room during her third pregnancy with an adrenergic crisis and hypoglycemia. To prevent perinatal complications, the patient was stabilized and the newborn was delivered through a Kerr-type cesarean section. A detailed history revealed that the paternal grandfather of the patient had an unilateral pheochromocytoma, whereas her paternal uncle had a bilateral pheochromocytoma. Additionally, a brother of the patient presented a unilateral pheochromocytoma. Amplicons for PCR assays were designed to span the protein-coding segments of the three Von Hippel–Lindau (VHL) exons, and the PCR products were sequenced using the Sanger method. In the trace of exon 3, we detected in the sample of the proband a heterozygous guanine to adenine transition (NM_000551.4 c. 552G > A) within the protein-coding segment of exon 3 of the VHL gene, which leads to a substitution of the arginine residue at position 161 by a glutamine residue in the encoded peptide (NP_000542.1p.R161Q). This mutation was absent in two unaffected daughters. Conclusion A VHL mutation was suspected and confirmed in this family that was not transmitted to a fourth generation. This case illustrates the importance of molecular genetics methodologies to assist genetic counseling in cases of pheochromocytoma where familial aggregation is presumed.

Introduction: Optic nerve and chiasm hemangioblastomas are rare tumors, occurring sporadically or in the context of von Hippel-Lindau (VHL) disease. They have only been portrayed in isolated case reports and small cohorts. Their natural history and therapeutic strategies are only scarcely described. To better characterize these rare tumors, we retrospectively analyzed an optic nerve and chiasm hemangioblastoma series of 12 VHL patients. By combining our own experience to a review of all known cases in literature, we intended to create treatment recommendations for optic nerve and chiasm hemangioblastomas in VHL patients. Methods: We reviewed two electronic databases in the hospitals of our senior authors, searching for VHL patients with optic nerve or chiasm hemangioblastomas. Clinical data were summarized. Tumor size and growth rate were measured on contrast enhanced MRI. Comparable data were collected by literature review of all available cases in VHL patients (Pubmed, Trip, Google and Google Scholar). Results: Of 269 VHL patients, 12 had optic nerve or chiasm hemangioblastomas. In 10 of 12 patients, tumors were diagnosed upon annual ophthalmoscopic/MRI screening. Of 8 patients who were asymptomatic at diagnosis, 7 showed absent or very slow annual progression, without developing significant vision impairment. One patient developed moderate vision impairment. Two symptomatic patients suffered from rapid tumor growth and progressive vision impairment. Both underwent late-stage surgery, resulting in incomplete resection and progressive vision impairment. One patient presented with acute vision field loss. A watchful-waiting approach was adopted because the hemangioblastoma was ineligible for vision-sparing surgery. One patient developed progressive vision impairment after watchful waiting. In the literature we found 45 patient cases with 48 hemangioblastomas. Discussion: When optic nerve and chiasm hemangioblastomas are diagnosed, we suggest annual MRI follow-up as long as patients do not develop vision impairment. If tumors grow fast, threaten the contralateral eye, or if patients develop progressive vision deficiency; surgical resection must be considered because neurological impairment is irreversible, and resection of large tumors carries a higher risk of further visual decline. [ABSTRACT FROM AUTHOR]

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer. [ABSTRACT FROM AUTHOR]

Background: Pheochromocytoma is a rare disease, and its familial occurrence is quite uncommon. The aim of this paper is to report a three-generation phenotypical expression of a case familial occurrence of pheochromocytoma. Case presentation: A 25-year-old female, with a history of adrenalectomy for pheochromocytoma, arrived at the shock room during her third pregnancy with an adrenergic crisis and hypoglycemia. To prevent perinatal complications, the patient was stabilized and the newborn was delivered through a Kerr-type cesarean section. A detailed history revealed that the paternal grandfather of the patient had an unilateral pheochromocytoma, whereas her paternal uncle had a bilateral pheochromocytoma. Additionally, a brother of the patient presented a unilateral pheochromocytoma. Amplicons for PCR assays were designed to span the protein-coding segments of the three Von Hippel–Lindau (VHL) exons, and the PCR products were sequenced using the Sanger method. In the trace of exon 3, we detected in the sample of the proband a heterozygous guanine to adenine transition (NM_000551.4 c. 552G > A) within the protein-coding segment of exon 3 of the VHL gene, which leads to a substitution of the arginine residue at position 161 by a glutamine residue in the encoded peptide (NP_000542.1p.R161Q). This mutation was absent in two unaffected daughters. Conclusion: A VHL mutation was suspected and confirmed in this family that was not transmitted to a fourth generation. This case illustrates the importance of molecular genetics methodologies to assist genetic counseling in cases of pheochromocytoma where familial aggregation is presumed. [ABSTRACT FROM AUTHOR]

Dynamic combinatorial chemistry (DCC) leverages a reversible reaction to generate compound libraries from constituting building blocks under thermodynamic control. The position of this equilibrium can be biased by addition of a target macromolecule towards enrichment of bound ligands. While DCC has been applied to select ligands for a single target protein, its application to identifying chimeric molecules inducing proximity between two proteins is unprecedented. In this proof‐of‐concept study, we develop a DCC approach to select bifunctional proteolysis targeting chimeras (PROTACs) based on their ability to stabilize the ternary complex. We focus on VHL‐targeting Homo‐PROTACs as model system, and show that the formation of a VHL2 : Homo‐PROTAC ternary complex reversibly assembled using thiol‐disulfide exchange chemistry leads to amplification of potent VHL Homo‐PROTACs with degradation activities which correlated well with their biophysical ability to dimerize VHL. Ternary complex templated dynamic combinatorial libraries allowed identification of novel Homo‐PROTAC degraders. We anticipate future applications of ternary‐complex directed DCC to early PROTAC screenings and expansion to other proximity‐inducing modalities beyond PROTACs. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a significant oncological challenge due to its heterogeneous nature and limited treatment options. The PAX developmental gene family encodes nine highly conserved transcription factors that play crucial roles in embryonic development and organogenesis, which have been implicated in the occurrence and development of RCC. This review explores the molecular landscape of RCC, with a specific focus on the role of the PAX gene family in RCC tumorigenesis and disease progression. Of the various RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most prevalent, characterized by the loss of the von Hippel–Lindau (VHL) tumor suppressor gene. Here, we review the published literature on the expression patterns and functional implications of PAX genes, particularly PAX2 and PAX8, in the three most common RCC subtypes, including ccRCC, papillary RCC (PRCC), and chromophobe RCC (ChRCC). Further, we review the interactions and potential biological mechanisms involving PAX genes and VHL loss in driving the pathogenesis of RCC, including the key signaling pathways mediated by VHL in ccRCC and associated mechanisms implicating PAX. Lastly, concurrent with our update regarding PAX gene research in RCC, we review and comment on the targeting of PAX towards the development of novel RCC therapies. [ABSTRACT FROM AUTHOR]

Aims: The 2022 WHO classification for kidney tumours recently downgraded clear cell tubulopapillary (also known as clear cell papillary) renal cell carcinoma (RCC) to a benign neoplasm (i.e. clear cell tubulopapillary renal cell tumour) based on the overwhelmingly banal nature of this neoplasm. However, it has been recognized that some clear cell tubulopapillary renal cell tumours demonstrate vascular, adipose or pelvicalyceal invasion, raising the possibility of more aggressive behaviour. The goal of this study was to determine if these 'high stage' features have an effect on tumour prognosis, warranting a carcinoma designation. Methods and Results: After excluding cases with tissue artefact (i.e. prior core biopsy track changes) and other RCC subtypes with next‐generation sequencing, nine clear cell tubulopapillary renal cell tumours with these so‐called 'high stage' features, and otherwise classic morphologic and immunophenotypic findings, including low‐grade cytology and 'cup‐like' CA9 expression, were evaluated. Median tumour size was 2.2 cm with a range of 0.8 to 6.7 cm. Eight cases (89%) demonstrated perinephric or hilar adipose tissue invasion, although most of these cases showed a bulging (in contrast to an infiltrative) growth pattern. One case demonstrated renal vascular invasion in addition to hilar adipose tissue invasion, and one case demonstrated extension into the pelvicalyceal system. There were no recurrences or evidence of metastatic disease. Conclusion: These overall findings continue to support the benign designation for clear cell tubulopapillary renal cell tumours, despite morphologic features that might raise the possibility of a 'higher stage' neoplasm. [ABSTRACT FROM AUTHOR]

Cellular therapies against solid tumors face three major barriers: low persistence, insufficient specificity, and high costs. In a recent study, Pal et al. tackle these challenges in kidney cancer by using novel, 'persistence-tuned' allogeneic chimeric antigen receptor (CAR) T cells directed against a stable antigen. [ABSTRACT FROM AUTHOR]

Radiogenomics, a burgeoning field in biomedical research, explores the correlation between imaging features and genomic data, aiming to link macroscopic manifestations with molecular characteristics. In this review, we examine existing radiogenomics literature in clear cell renal cell carcinoma (ccRCC), the predominant renal cancer, and von Hippel–Lindau (VHL) gene mutation, the most frequent genetic mutation in ccRCC. A thorough examination of the literature was conducted through searches on the PubMed, Medline, Cochrane Library, Google Scholar, and Web of Science databases. Inclusion criteria encompassed articles published in English between 2014 and 2022, resulting in 10 articles meeting the criteria out of 39 initially retrieved articles. Most of these studies applied computed tomography (CT) images obtained from open source and institutional databases. This literature review investigates the role of radiogenomics, with and without texture analysis, in predicting VHL gene mutation in ccRCC patients. Radiogenomics leverages imaging modalities such as CT and magnetic resonance imaging (MRI), to analyze macroscopic features and establish connections with molecular elements, providing insights into tumor heterogeneity and biological behavior. The investigations explored diverse mutations, with a specific focus on VHL mutation, and applied CT imaging features for radiogenomic analysis. Moreover, radiomics and machine learning techniques were employed to predict VHL gene mutations based on CT features, demonstrating promising results. Additional studies delved into the relationship between VHL mutation and body composition, revealing significant associations with adipose tissue distribution. The review concludes by highlighting the potential role of radiogenomics in guiding targeted and selective therapies.

ABSTRACTInfectious spleen and kidney necrosis virus (ISKNV), a member of the genus Megalocytivirus in the family Iridoviridae, can infect over 50 fish species and cause significant economic losses in Asia. Our previous study showed that hypoxia triggers the hypoxia-inducible factor pathway (HIF-pathway), leading to increased replication of ISKNV through promoting the upregulation of viral hypoxic response genes like orf077r. This study delved into the molecular mechanism of how ISKNV manipulates the HIF-pathway to enhance its replication. In vitro and in vivo experiments confirmed that ISKNV infection activated the HIF-pathway, which in turn promoted ISKNV replication. These findings suggest that ISKNV actively manipulates the HIF-pathway. Co-immunoprecipitation experiments revealed that the ISKNV-encoded protein VP077R interacts with the Von Hippel−Lindau (VHL) protein at the HIF-binding region, competitively inhibiting the interaction of HIF-1α with VHL. This prevents HIF degradation and activates the HIF-pathway. Furthermore, VP077R interacts with factor-inhibiting HIF (FIH), recruiting FIH and S-phase kinase-associated protein 1 (Skp1) to form an FIH – VP077R – Skp1 complex. This complex promotes FIH protein degradation via ubiquitination, further activating the HIF-pathway. These findings indicated that ISKNV takes over the HIF-pathway by releasing two “brakes” on this pathway (VHL and FIH) via VP077R, facilitating virus replication. We speculate that hypoxia initiates a positive feedback loop between ISKNV VP077R and the HIF pathway, leading to the outbreak of ISKNV disease. This work offers valuable insights into the complex interactions between the environment, host, and virus.

In the current era of tumor genome sequencing, single amino acid missense variants in the von Hippel-Lindau (VHL) tumor suppressor gene are frequently identified in clear cell renal carcinoma (ccRCC). Due to the incomplete knowledge of the structural architecture of VHL protein, the functional significance of many missense mutations cannot be assigned. L169P is one such missense mutation identified in the case of aggressive, metastatic ccRCC. Here, we characterized the biochemical activity, transcriptomic hypoxia signature and biological functions of the L169P variant. Lentiviral vector expressing either wildtype (WT) or L169P VHL were used to transduce two VHL-deficient human ccRCC cell lines, 786-O and RCC4. The stability of the VHL protein and the expression level of VHL, HIF1α and HIF2α were analyzed. The impact of restoring L169P or WT VHL on the hypoxia gene expression program in 786-O cells was assessed by mRNA sequencing (RNAseq) and computed hypoxic scores. The impact of restoring VHL expression on the growth of ccRCC models was assessed in cell cultures and in chorioallantoic membrane (CAM) xenografts. In the 786-O cells, the protein stability of L169P VHL was comparable to WT VHL. No obvious difference in the capability of degrading HIF1α and HIF2α was observed between WT and L169P VHL in the 786-O or RCC4 cells. The hypoxic scores were not significantly different in the 786-O cells expressing either wildtype or L169P VHL. From the cellular function perspective, both WT and L169P VHL slowed cell proliferation in vitro and in vivo. The L169P VHL variant is comparable to WT VHL in terms of protein stability, ability to degrade HIF1α factors and ability to regulate hypoxia gene expression, as well as in the suppression of ccRCC tumor cell growth. Taken together, our data indicate that the L169P VHL variant alone is unlikely to drive the oncogenesis of sporadic ccRCC.

To develop guidelines for ocular surveillance and early intervention for individuals with von Hippel-Lindau (VHL) disease. Systematic review of the literature. Expert panel of retina specialists and ocular oncologists. A consortium of experts on clinical management of all-organ aspects of VHL disease was convened. Working groups with expertise in organ-specific features of VHL disease were tasked with development of evidence-based guidelines for each organ system. The ophthalmology subcommittee formulated questions for consideration and performed a systematic literature review. Evidence was graded for topic quality and relevance and the strength of each recommendation, and guideline recommendations were developed. The quality of evidence was limited, and no controlled clinical trial data were available. Consensus guidelines included: (1) individuals with known or suspected VHL disease should undergo periodic ocular screening (evidence type, III; evidence strength, C; degree of consensus, 2A); (2) patients at risk of VHL disease, including first-degree relatives of patients with known VHL disease, or any patient with single or multifocal retinal hemangioblastomas (RHs), should undergo genetic testing for pathologic VHL disease gene variants as part of an appropriate medical evaluation (III/C/2A); (3) ocular screening should begin within 12 months after birth and continue throughout life (III/C/2A); (4) ocular screening should occur approximately every 6 to 12 months until 30 years of age and then at least yearly thereafter (III/C-D/2A); (5) ocular screening should be performed before a planned pregnancy and every 6 to 12 months during pregnancy (IV/D/2A); (6) ultra-widefield color fundus photography may be helpful in certain circumstances to monitor RHs, and ultra-widefield fluorescein angiography may be helpful in certain circumstances to detect small RHs (IV/D/2A); (7) patients should be managed, whenever possible, by those with subspecialty training, with experience with VHL disease or RHs, or with both and ideally within the context of a multidisciplinary center capable of providing multiorgan surveillance and access to genetic testing (IV/D/2A); (8) extramacular or extrapapillary RHs should be treated promptly (III/C/2A). Based on available evidence from observational studies, broad agreement was reached for a strategy of lifelong surveillance and early treatment for ocular VHL disease. These guidelines were endorsed by the VHL Alliance and the International Society of Ocular Oncology and were approved by the American Academy of Ophthalmology Board of Trustees. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Purpose: To describe two cases of retinal hemangioblastoma regression following treatment with belzutifan in patients with von Hippel-Lindau syndrome. Methods: Clinical information was extracted from the charts and tumor imaging of two patients with von Hippel-Lindau-associated retinal hemangioblastoma. Results: In Case 1, a 40-year-old man was treated with belzutifan for spine hemangioblastomas after diagnosis of a 2.0 · 2.0 · 1.3 mm left-eye retinal hemangioblastoma temporal to the macula associated with intraretinal edema, subretinal fluid, and mild retinal traction. In Case 2, a 66-year-old woman presented with a right eye 2.0 · 1.5 · 1.3 mm juxtapapillary lesion with subretinal fluid, intraretinal fluid, and nasal traction, and a 4.0 · 3.5 · 1.1 mm inferior midperiphery lesion with subretinal fluid, intraretinal fluid, and active exudation. She was treated for 2.5 years with belzutifan for renal cell carcinoma on the National Institutes of Health trial. The patient in case 1 demonstrated a 10% reduction in largest tumor diameter and 8% reduction in thickness, along with improving subretinal fluid, intraretinal edema, and retinal traction, after 4 weeks of treatment. After 2.5 years of treatment, the patient in Case 2 demonstrated similar margins of her now fibrotic-appearing juxtapapillary lesion with a 45% reduction in thickness, along with resolved subretinal fluid and greatly improved intraretinal fluid and traction. The inferior lesion demonstrated 12.5% reduction in largest diameter, 36% reduction in thickness, and was without active subretinal fluid or exudation. Neither patient demonstrated new lesions while on treatment. Conclusion: Belzutifan is a promising treatment for retinal hemangioblastoma with the potential for both rapid and sustained tumor regression. [ABSTRACT FROM AUTHOR]

An important component contributing to the onset of epilepsy is the death of hippocampal neurons. Several studies have shown that Dravet syndrome model mice: Scn1a KO mice have a high number of apoptotic neurons following seizures, but the precise mechanism underlying this remains unclear. The aim of this research was to elucidate the potential molecular mechanism of neuronal apoptosis in Scn1a KO mice by integrating proteomics and transcriptomics, with the ultimate goal of offering better neuroprotection. We found that apoptotic processes were enriched in both proteomic and transcriptomic GO analyses, and KEGG results also indicated that differential proteins and genes play a role in neurotransmission, the cell cycle, apoptosis, and neuroinflammation. Then, we examined the upstream and downstream KGML interactions of the pathways to determine the relationship between the two omics, and we found that the HIF-1 signaling pathway plays a significant role in the onset and apoptosis of epilepsy. Meanwhile, the expression of the apoptosis-related protein VHL decreased in this pathway, and the expression of p21 was upregulated. Therefore, this study suggests that VHL/HIF-1α/p21 might be involved in the apoptosis of hippocampal neurons in Scn1a KO mice. [ABSTRACT FROM AUTHOR]

Von Hippel--Lindau (VHL) disease is an autosomal dominant syndrome and affects many organs. We aim to report an adult patient with VHL disease having bilateral adrenal pheochromocytoma and multiple neuroendocrine tumors of the pancreas who was successfully treated with simultaneous function-preserving adrenalectomy and pancreatectomy. A 27-year-old woman was admitted to hospital with hypertension. The computed tomography of the abdomen revealed a solid tumor in both adrenal glands with the sizes of 12x7 cm on the right and 4x4 cm on the left. She also had two pancreatic solid masses in the head and three in the tail with varying sizes. The laboratory tests are all within normal limits except elevated 24-hour urinary metanephrine and normetanephrine. I-123 MIBG scanning showed increased uptake in both adrenal glands. Fine needle aspiration biopsy of the tumor on head of pancreas via endoscopic ultrasonography showed neuroendocrine tumor. Those findings were compatible with bilateral pheochromocytoma and multiple pancreatic neuroendocrine tumors and genetic tests revealed the mutation which confirmed the diagnosis of VHL disease. After suppression with alpha-1 inhibitor, right total, left cortical-sparing adrenalectomy, Whipple procedure for the pancreatic head lesions and spleen-preserving distal pancreatectomy were performed and pancreatic corpus was preserved. This case showed that multiple function-preserving procedures can be safely performed with oncological principles in patients with VHL disease. [ABSTRACT FROM AUTHOR]

The Von Hippel–Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α. Synopsis: PHD1-mediated prolyl hydroxylation targets HIF-1α for VHL-dependent ubiquitination and is a key step in the cell's oxygen sensing machinery. This work shows that PHD1 and VHL also inhibit Beclin1 and autophagy initiation, with dysregulation leading to clear-cell renal cell carcinoma progression. PHD1 mediates Beclin1 Pro54 hydroxylation on pre-autophagosomal structures in clear-cell renal cell carcinoma cells. VHL binds to Pro54-hydroxylated Beclin1 and prevents the association between ATG14L and Beclin1/VPS34. VHL inhibits VPS34-dependent PI(3)P production, autophagy initiation, and kidney tumor growth. The Von Hippel-Lindau (VHL) E3 ligase binds to proline-hydroxylated Beclin1, inhibiting the initiation of autophagy and blocking kidney tumor growth. [ABSTRACT FROM AUTHOR]

Copyright of Wiener Klinisches Magazin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To summarize and analyze the clinical phenotypes, hereditary features and treatment and follow-up strategies of different hereditary pheochromocytoma/paragangliomas (PCC/PGL) and related syndromes. Methods Forty-four clinically diagnosed PCC/PGL patients admitted in our hospital from January 2000 to August 2022 were enrolled, and the clinical data of them and their family members were collected.Second-generation sequencing was performed on 43 patients for genetic detection, and Sanger sequencing was applied to verify the mutation of the probands and family members. Results There were 15 patients diagnosed with hereditary PCC/PGL, including 7 cases of von Hippel-Lindau (VHL) syndrome, 3 cases of multiple endocrine neoplasia type 2(MEN2), and 5 cases of familial paraganglioma syndrome.Seven VHL syndrome families were diagnosed as VHL2A (c.500G>A), VHL2B (c.239G>T and c.444_457del), and VHL2C (c.293A>G) according to their clinical manifestations.All probands received surgical treatment, and 2 cases of recurrent PCC and the patients with multiple renal cancer also received targeted therapy with sunitinib.Three MEN2 families carried c.1901G>C, c.1832G>A, and c.1901G>A missense mutations, respectively, and were diagnosed with MEN2A clinically.All of them underwent adrenalectomy and thyroidectomy, including one for preventive thyroidectomy.Among the 5 familial paraganglioma syndrome families, 4 patients carried SDHB mutations (SDHB: c.343C>T, c.541-2A>G, c.575G>A, c.268C>T) and 1 patient carried an SDHD mutation (SDHD: c.337_340del).Sporadic retroperitoneal PGL were most common. Conclusion More than 1/3 of PCC/PGL patients carry germline gene mutations, showing obvious genotype-phenotype correlation.Genetic diagnosis technology plays an important guidance role for clinical precision treatment and follow-up, and genetic counseling.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10–12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include “old genes” associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up.

Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is an extremely rare kidney tumor seen mainly in patients with end-stage renal disease. Currently, there are few reports on this type of tumor. We describe the case of a 58-year-old man who had been receiving peritoneal dialysis for more than nine years due to chronic renal insufficiency and uremia. One year after undergoing left renal clear cell renal cell carcinoma resection, a spaceoccupying lesion was found in the right kidney for which he underwent right nephrectomy. The histopathology of this tumor showed solid or tubular cell arrangements, with some areas of cyst formation. Vacuoles of varying sizes were present in the cytoplasm, and varying amounts of calcium oxalate crystals were found in the tumor cells or interstitium. The pathological diagnosis was ACDRCC. Next-generation sequencing detected mutations in the PTCH1, MTOR, FAT1, SOS1, RECQL4, and CDC73 genes in the right renal tumor. This is a rare case of a patient with ACD-RCC in the right kidney and clear cell renal cell carcinoma in the left kidney. The findings suggest that mutations in PTCH1 associated with ACD-RCC may have acted as oncogenic drivers for the development of ACKD-RCC, together with providing insight into mechanisms underlying ACD-RCC development, as well as diagnostic and treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: Belzutifan, a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, has emerged as an exciting new treatment option not only for patients with Von Hippel-Lindau (VHL)-related renal cell carcinoma (RCC) but also for sporadic RCC. While initial clinical data are promising, potential resistance with HIF-2α inhibitors may occur with increased understanding of this class of therapy. Potential ways to further increase the antitumor activity of HIF-2α targeting include combination strategies with immune checkpoint inhibitors and other targeted agents as well as newer generation HIF-2α inhibitors that are currently under development. Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC. [ABSTRACT FROM AUTHOR]

The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in up to 90% of clear cell renal cell carcinoma (ccRCC) cases, thus playing a key role in ccRCC pathogenesis. ccRCC can be classified as a metabolic disease in which alterations in fatty acid metabolism facilitate cancer cell proliferation. Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH) is an enzyme involved in peroxisomal fatty acid degradation. It is primarily expressed in renal proximal tubule cells, presumably the origin of ccRCC. Although EHHADH is still a relatively unexplored gene, it is known to be differentially expressed in several tumors. In this study, analysis of several databases revealed that EHHADH expression is downregulated in ccRCC samples compared to healthy kidney samples. Moreover, cell culture experiments were performed to investigate the relationship between EHHADH and VHL at the gene and protein level. qPCR and Western blot analyses using the human ccRCC cell line RCC4 revealed that EHHADH is expressed in a VHL-dependent manner. RCC4 cells reconstituted with VHL show significantly higher EHHADH mRNA and protein levels than VHL-deficient RCC4 control cells. These results indicate that the downregulation of EHHADH in ccRCC reported may be due to the loss of VHL function. This study is the first to molecularly characterize EHHADH, a key enzyme in peroxisomal ß-oxidation, in relation to VHL, suggesting a potential pathogenic interaction that is worthy of further investigation. [ABSTRACT FROM AUTHOR]

This study aimed to assess the physiological responses to repeated running exercise performed at supramaximal intensity and with end-expiratory breath holding (EEBH) up to the breaking point. Eight male runners participated in two running testing sessions on a motorized treadmill. In the first session, participants performed two sets of 8 repetitions at 125% of maximal aerobic velocity and with maximum EEBH. Each repetition started at the onset of EEBH and ended at its release. In the second session, participants replicated the same procedure, but with unrestricted breathing (URB). The change in cerebral and muscle oxygenation (Δ[Hbdiff]), total haemoglobin concentration (Δ[THb]) and muscle reoxygenation were continuously assessed. End-tidal oxygen (PETO2) and carbon dioxide pressure (PETCO2), arterial oxygen saturation (SpO2) and heart rate (HR) were also measured throughout exercise. On average, EEBH was maintained for 10.1 ± 1 s. At the breaking point of EEBH, PETO2 decreased to 54.1 ± 8 mmHg, whereas PETCO2 increased to 74.8 ± 3.1 mmHg. At the end of repetitions, SpO2 (nadir values 74.9 ± 5.0 vs. 95.7 ± 0.8%) and HR were lower with EEBH than with URB. Cerebral and muscle Δ[Hbdiff] were also lower with EEBH, whereas this condition induced higher cerebral and muscle Δ[THb] and greater muscle reoxygenation. This study showed that performing repeated bouts of supramaximal running exercises with EEBH up to the breaking point induced a fall in arterial, cerebral and muscle oxygenation compared with the URB condition. These phenomena were accompanied by increases in regional blood volume likely resulting from compensatory vasodilation to preserve oxygen delivery to the brain and muscles. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) treatment has undergone three major paradigm shifts in recent years, first with the introduction of molecular targeted therapies, then with immune checkpoint inhibitors, and, more recently, with immune-based combinations. However, to date, molecular predictors of response to targeted agents have not been identified for ccRCC. The WHO 2022 classification of renal neoplasms introduced the molecularly defined RCC class, which is a first step in the direction of a better molecular profiling of RCC. We reviewed the literature data on known genomic alterations of clinical interest in ccRCC, discussing their prognostic and predictive role. In particular, we explored the role of VHL, mTOR, chromatin modulators, DNA repair genes, cyclin-dependent kinases, and tumor mutation burden. RCC is a tumor whose pivotal genomic alterations have pleiotropic effects, and the interplay of these effects determines the tumor phenotype and its clinical behavior. Therefore, it is difficult to find a single genomic predictive factor, but it is more likely to identify a signature of gene alterations that could impact prognosis and response to specific treatment. To accomplish this task, the interpolation of large amounts of clinical and genomic data is needed. Nevertheless, genomic profiling has the potential to change real-world clinical practice settings.

Abstract Background Under conditions of hypoxia, cancer cells with hypoxia inducible factor-1α (HIF-1α) from heterogeneous tumor cells show greater aggression and progression in an effort to compensate for harsh environmental conditions. Extensive study on the stability of HIF-1α under conditions of acute hypoxia in cancer progression has been conducted, however, understanding of its involvement during the chronic phase is limited. Methods In this study, we investigated the effect of SIRT1 on HIF1 stability in a typical chronic hypoxic conditon that maintains cells for 24 h under hypoxia using Western blotting, co-IP, measurement of intracellular NAD + and NADH levels, semi-quantitative RT-PCR analysis, invasion assay, gene knockdown. Results Here we demonstrated that the high concentration of pyruvate in the medium, which can be easily overlooked, has an effect on the stability of HIF-1α. We also demonstrated that NADH functions as a signal for conveyance of HIF-1α degradation via the SIRT1 and VHL signaling pathway under conditions of chronic hypoxia, which in turn leads to attenuation of hypoxically strengthened invasion and angiogenic activities. A steep increase in the level of NADH occurs during chronic hypoxia, leading to upregulation of acetylation and degradation of HIF-1α via inactivation of SIRT1. Of particular interest, p300-mediated acetylation at lysine 709 of HIF-1α is recogonized by VHL, which leads to degradation of HIF-1α via ubiquitin/proteasome machinary under conditions of chronic hypoxia. In addition, we demonstrated that NADH-elevation-induced acetylation and subsequent degradation of HIF-1α was independent of proline hydroxylation. Conclusions Our findings suggest a critical role of SIRT1 as a metabolic sensor in coordination of hypoxic status via regulation of HIF-1α stability. These results also demonstrate the involvement of VHL in degradation of HIF-1α through recognition of PHD-mediated hydroxylation in normoxia and p300-mediated HIF-1α acetylation in hypoxia.

Abstract Background Ubiquitin‐conjugating enzyme E2S (UBE2S), an E2 enzyme, is associated with the development of various tumors and exerts oncogenic activities. UBE2S is overexpressed in tumors, including hepatocellular carcinoma (HCC). However, the key molecular mechanisms of UBE2S in HCC still need additional research. The aim of this study was to explore the role of UBE2S in HCC. Methods The expression levels of UBE2S in HCC tissues and cells were detected by western blot analysis, quantitative real‐time polymerase chain reaction analysis (qRT–PCR), and immunohistochemistry (IHC). A 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay, wound healing assay, colony formation assay transwell assay, and animal models were used to detect the proliferation and migration ability of HCC cells. Western blot analysis, qRT–PCR, immunofluorescence, small‐interfering RNA (siRNA), and plasmid transfection and coimmunoprecipitation (Co‐IP) assays were performed to detect the interaction among UBE2S, von Hippel–Lindau (VHL), hypoxia‐inducible factor 1‐alpha (HIF‐1α), Janus kinase‐2 (JAK2), and signal transducer and activator of transcription 3 (STAT3). Results In this study, we found that high UBE2S expression was associated with poor prognosis in HCC patients. In addition, UBE2S expression was upregulated in HCC tissues and cell lines. Knockdown of UBE2S inhibited the proliferation and migration of HCC cells in vitro and in vivo by directly interacting with VHL to downregulate the HIF‐1α and JAK2/STAT3 signaling pathways. Accordingly, overexpression of UBE2S significantly enhanced the proliferation and migration of HCC cells in vitro via VHL to upregulate HIF‐1α and JAK2/STAT3 signaling pathways. Furthermore, we found that downregulation of UBE2S expression enhanced the sensitivity of HCC cells to sorafenib in vivo and in vitro. Conclusion UBE2S enhances malignant properties via the VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and reduces sensitivity to sorafenib in HCC. The findings of this study may open a new approach for HCC diagnosis and provide a potential option for the treatment of HCC.

This review article focuses on von Hippel–Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body. It discusses the following aspects of the disease. Genetics: VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. Pathophysiology: The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. Clinical Manifestations: VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. Diagnosis: Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. Treatment: Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. Challenges: This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease.

Renal cell carcinoma (RCC) is a significant oncological challenge due to its heterogeneous nature and limited treatment options. The PAX developmental gene family encodes nine highly conserved transcription factors that play crucial roles in embryonic development and organogenesis, which have been implicated in the occurrence and development of RCC. This review explores the molecular landscape of RCC, with a specific focus on the role of the PAX gene family in RCC tumorigenesis and disease progression. Of the various RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most prevalent, characterized by the loss of the von Hippel–Lindau (VHL) tumor suppressor gene. Here, we review the published literature on the expression patterns and functional implications of PAX genes, particularly PAX2 and PAX8, in the three most common RCC subtypes, including ccRCC, papillary RCC (PRCC), and chromophobe RCC (ChRCC). Further, we review the interactions and potential biological mechanisms involving PAX genes and VHL loss in driving the pathogenesis of RCC, including the key signaling pathways mediated by VHL in ccRCC and associated mechanisms implicating PAX. Lastly, concurrent with our update regarding PAX gene research in RCC, we review and comment on the targeting of PAX towards the development of novel RCC therapies.

Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25–40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclu sively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%), SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.