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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]

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.)

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]

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]

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]

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]

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]

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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]

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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]

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]

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]

Von Hippel‐Lindau disease is a rare inherited cancer‐predisposition syndrome. The authors report the updated recommendations for the multiorgan surveillance protocols. [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 FROM AUTHOR]

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 FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Opinion Statement: Current treatment options for patients with metastatic renal cell carcinoma (mRCC) are limited to immunotherapy with checkpoint inhibitors and targeted therapies that inhibit the vascular endothelial growth factor receptors (VEFG-R) and the mammalian target of rapamycin (mTOR). Despite significantly improved outcomes over the last few decades, most patients with mRCC will ultimately develop resistance to these therapies, thus highlighting the critical need for novel treatment options. As part of the VHL–HIF–VEGF axis that rests at the foundation of RCC pathogenesis, hypoxia-inducible factor 2α (HIF-2α) has been identified as a rationale target for mRCC treatment. Indeed, one such agent (belzutifan) is already approved for VHL-associated RCC and other VHL-associated neoplasms. Early trials of belzutifan indicate encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan and other HIF-2α inhibitors into the mRCC treatment armamentarium either as a single agent or as combination therapy would be a welcome addition for patients with mRCC. [ABSTRACT FROM AUTHOR]

In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development. We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients' heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs. Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients' selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors. [ABSTRACT FROM AUTHOR]

Von Hippel–Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapy has revolutionized renal cell carcinoma treatment. Patients previously thought to be palliative now occasionally achieve complete cures from ICI. However, since immunotherapies stimulate the immune system to induce anti-tumor immunity, they often lead to adverse autoimmunity. Furthermore, some patients receive no benefit from ICI, thereby unnecessarily risking adverse events. In many tumor types, PD-L1 expression levels, immune infiltration, and tumor mutation burden predict the response to ICI and help inform clinical decision making to better target ICI to patients most likely to experience benefits. Unfortunately, renal cell carcinoma is an outlier, as these biomarkers fail to discriminate between positive and negative responses to ICI therapy. Emerging biomarkers such as gene expression profiles and the loss of pro-angiogenic proteins VHL and PBRM-1 show promise for identifying renal cell carcinoma cases likely to respond to ICI. This review provides an overview of the mechanistic underpinnings of different biomarkers and describes the theoretical rationale for their use. We discuss the effectiveness of each biomarker in renal cell carcinoma and other cancer types, and we introduce novel biomarkers that have demonstrated some promise in clinical trials. [ABSTRACT FROM AUTHOR]

Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular‐genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia‐inducible factor 2 alpha (HIF2A) or Von Hippel–Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non‐genetic factors in erythrocytosis manifestation may involve variants of Piezo‐type mechanosensitive ion channel component 1 (PIEZO1) or Ten‐eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL‐ and HIF2A‐mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to describe the molecular characteristics of Renal Cell Carcinoma (RCC) and develop a small panel of RCC-associated genes from a large panel of cancer-related genes. Materials and methods: Clinical data of 55 patients with RCC diagnosed in four hospitals from September 2021 to August 2022 were collected. Among the 55 patients, 38 were diagnosed with clear cell RCC (ccRCC), and the other 17 were diagnosed with non-clear cell RCC (nccRCC), including 10 cases of papillary renal cell carcinoma, 2 cases of hereditary leiomyomatosis and RCC syndrome (HLRCC), 1 eosinophilic papillary RCC, 1 tubular cystic carcinoma, 1 TFE3 gene fusion RCC, and 2 RCC with sarcomatoid differentiation. For each patient, 1123 cancer-related genes and 79 RCC-associated genes were analyzed. Results: the most frequent mutations in a large panel of 1123 cancer-related genes in the overall population of RCC patients were VHL (51%), PBRM1 (35%), BAP1 (16%), KMT2D (15%), PTPRD (15%), and SETD2 (15%). For ccRCC patients, mutations in VHL, PBRM1, BAP1, and SERD2 can reach 74%, 50%, 24%, and 18%, respectively, while for nccRCC patients, the most frequent mutation was FH (29%), MLH3 (24%), ARID1A (18%), KMT2D (18%), and CREBBP (18%). The germline mutation rate in all 55 patients reached 12.7% (five with FH, one with ATM, and one with RAD50). The small panel containing only 79 RCC-associated genes demonstrated that mutations of VHL, PBRM1, BAP1, and SETD2 in ccRCC patients were 74%, 50%, 24%, and 18% respectively, while for the nccRCC cohort, the most frequent mutations were FH (29%), ARID1A (18%), ATM (12%), MSH6 (12%), BRAF (12%), and KRAS (12%). For ccRCC patients, the spectrum of mutations by large and small panels was almost the same, while for nccRCC patients, the mutation spectrum showed some differences. Even though the most frequent mutations (FH and ARID1A) in nccRCC were both demonstrated by large panels and small panels, other less frequent mutations such as MLH3, KMT2D, and CREBBP were not shown by the small panel. Conclusion: Our study revealed that nccRCC is more heterogeneous than ccRCC. For nccRCC patients, the small panel shows a more clear profile of genetic characteristics by replacing MLH3, KMT2D, and CREBBP with ATM, MSH6, BRAF, and KRAS, which may help predict prognosis and make clinical decisions. [ABSTRACT FROM AUTHOR]

Selective autophagy of mitochondria, mitophagy, is linked to mitochondrial quality control and as such is critical to a healthy organism. We have used a CRISPR/Cas9 approach to screen human E3 ubiquitin ligases for influence on mitophagy under both basal cell culture conditions and upon acute mitochondrial depolarization. We identify two cullin‐RING ligase substrate receptors, VHL and FBXL4, as the most profound negative regulators of basal mitophagy. We show that these converge, albeit via different mechanisms, on control of the mitophagy adaptors BNIP3 and BNIP3L/NIX. FBXL4 restricts NIX and BNIP3 levels via direct interaction and protein destabilization, while VHL acts through suppression of HIF1α‐mediated transcription of BNIP3 and NIX. Depletion of NIX but not BNIP3 is sufficient to restore mitophagy levels. Our study contributes to an understanding of the aetiology of early‐onset mitochondrial encephalomyopathy that is supported by analysis of a disease‐associated mutation. We further show that the compound MLN4924, which globally interferes with cullin‐RING ligase activity, is a strong inducer of mitophagy, thus providing a research tool in this context and a candidate therapeutic agent for conditions linked to mitochondrial dysfunction. Synopsis: Mitophagy is tightly regulated upon acute mitochondrial depolarization, but its control under basal conditions is less understood. Here, a screen identifies two cullin‐RING ubiquitin ligase adaptors, FBXL4 and VHL, as negative regulators of Parkin‐independent mitophagy, downregulating the common target NIX via distinct mechanisms. A CRISPR‐based screen of E3 ubiquitin ligases identifies cullin‐RING ligase substrate adaptors, FBXL4 and VHL, as strong suppressors of Parkin‐independent mitophagy.Both FBXL4 and VHL limit expression levels of mitophagy receptors NIX and BNIP3.VHL exerts a well‐established transcriptional control of BNIP3 (and NIX) via destabilization of HIF1α, whereas FBXL4 directly ubiquitylates and decreases protein stability of NIX.NIX is the main mediator of enhanced mitophagy observed in FBXL4‐deficient cells.The cullin‐RING ligase inhibitor MLN4924 can be used to enhance mitophagy. [ABSTRACT FROM AUTHOR]

Although age younger than 46 years has been an independent criterion for genetic testing in hereditary renal cell carcinoma (hRCC), there is a lack of evidence in the literature. This study aims to analyze whether a 46-year-old cut-off should be considered an independent genetic testing criterion and to elucidate risk factors predicting a positive genetic test. Observational study from January 2010 to December 2021. All patients under 46 years with a non-metastatic kidney mass and surgical indication were included. We assume patients who relapse in the first 5 years of follow- up could have a positive genetic test. As risk factors for relapse, ergo positive genetic test, we consider those patients who presented multifocal, bilateral, or previous renal tumor. Of 2,232 nephrectomies for kidney cancer, 301 patients met the inclusion criteria. The median follow-up was 60 months (IQR 29-101). The estimated five-year RFS was 94.4% (95% CI 91.3-97.5). Tumor size, previous renal tumor, multifocality, bilaterality, and pT3 or pT4 stage were independent recurrence risk factors. Genetic testing was performed on 24 patients. 10 patients had pathogenic variants in the test, 8 of which recurred during their life. 46-year-old cut-off has shown low performance in genetic testing. Therefore, we recommend that it be considered only if other hRCC risk criteria exist. Multifocality, bilaterality, and previous renal tumor could predict a positive genetic test. [ABSTRACT FROM AUTHOR]

The genetic profiling of renal tumors has revealed genomic regions commonly affected by structural changes and a general genetic heterogeneity. The VHL, PTEN, and BAP1 genes are often mutated in renal tumors. The frequency and clinical relevance of these mutations in renal tumors are still being researched. In our study, we investigated VHL, PTEN, and BAP1 genes and the sequencing of 24 samples of patients with renal tumors, revealing that VHL was mutated at a noticeable frequency (25%). Six of the investigated samples showed mutations, and one genetic polymorphism (rs779805) was detected in both heterozygote and homozygote forms. PTEN gene mutation was observed in only one sample, and one specimen showed genetic polymorphism. In the case of the BAP1 gene, all of the samples were wild types. Interestingly, VHL mutation was detected in two female patients diagnosed with AML and in one with oncocytoma. We assume that VHL or PTEN mutations may contribute to the development of human renal cancer. However, the overall mutation rate was low in all specimens investigated, and the development and prognosis of the disease were not exclusively associated with these types of genetic alterations. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether high-intensity training with voluntary hypoventilation at low lung volume (VHL) in cycling could improve running performance in team-sport athletes. Methods: Twenty well-fit subjects competing in different team sports completed, over a 3-week period, 6 high-intensity training sessions in cycling (repeated 8-s exercise bouts at 150% of maximal aerobic power) either with VHL or with normal breathing conditions. Before (Pre) and after (Post) training, the subjects performed a repeated-sprint-ability test (RSA) in running (12 × 20-m all-out sprints), a 200-m maximal run, and the Yo-Yo Intermittent Recovery Level 1 test (YYIR1). Results: There was no difference between Pre and Post in the mean and best velocities reached in the RSA test, as well as in performance and maximal blood lactate concentration in the 200-m-run trial in both groups. On the other hand, performance was greater in the second part of the RSA test, and the fatigue index of this test was lower (5.18% [1.3%] vs 7.72% [1.6%]; P <.01) after the VHL intervention only. Performance was also greater in the YYIR1 in the VHL group (1468 [313] vs 1111 [248] m; P <.01), whereas no change occurred in the normal-breathing-condition group. Conclusion: This study showed that performing high-intensity cycle training with VHL could improve RSA and possibly endurance performance in running. On the other hand, this kind of approach does not seem to induce transferable benefits for anaerobic performance. [ABSTRACT FROM AUTHOR]

RSUME-RWDD3 gene has been shown to be involved in tumorigenesis and angiogenesis by its negative regulation of the von Hippel-Lindau (VHL) protein. Using different clear cell renal cell carcinoma (ccRCC) patient datasets, including TCGA-KIRC, the present study explores RSUME expression as an independent and adverse factor in ccRCC acting on metabolic and ROS pathways. Introduction: RSUME (RWD domain-containing protein SUMO Enhancer), RWD domain containing 3 (RWDD3) gene product, is upregulated by hypoxia and expressed in organs prone to develop von Hippel-Lindau (VHL) syndrome tumors. Materials and Methods: We evaluated RSUME prognostic value in clear cell renal cell carcinoma (ccRCC) based mainly on the dataset (KIRC) from patients in The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and oneway analysis of variance (ANOVA) followed by Tukey's test were used to evaluate relationships between clinicopathological features and RSUME expression and univariate and multivariate Cox regression analysis methods were used to evaluate prognostic factors. The biological function of RSUME was assessed by gene set enrichment analysis (GSEA). For validation, total amount of ROS was detected in ccRCC cell lines using dichlorofluorescin diacetate. Results: RSUME is highly expressed in tumor tissues compared with normal tissues (P = .006, P = .039, P = .002, P = .036, P < .001) and associates with tumor T (P = .018) and tumor M (P = .036) advanced stages and higher extent cysts (P = .005). RSUME expression appears to be an independent risk factor for overall survival (OS) (P = .002) and diseasespecific survival (DSS) (P = .026) in ccRCC patients. GSEA showed enrichment of relevant glycerophospholipid- and ROS-related pathways in RSUME high-expression phenotype. ROS diminished levels in RSUME-silenced ccRCC cell lines validated RSUME relevance in ROS-related pathways. Conclusion: RSUME high expression may predict poor prognosis in ccRCC and impact through its action on metabolism and ROS related pathways. [ABSTRACT FROM AUTHOR]

Hemangioblastoma, one of the characteristic tumors associated with Von Hippel-Lindau (VHL) disease, most often presents in the central nervous system (CNS) but can uncommonly arise in extraneuraxial, or previously referred to as peripheral, locations. Without the clinical context of known VHL disease, hemangioblastoma may not enter the differential for a soft tissue mass outside the CNS. Here, we present two patients with diagnostically challenging extraneuraxial hemangioblastoma to highlight the importance of considering this entity within the differential diagnosis of soft tissue neoplasms containing clear cells and delicate vasculature. We review the relevant diagnostic features, including a suggested immunohistochemical panel, along with the potential associated clinical implications of making this diagnosis. It is recommended that affected patients be offered genetic counseling to assess for underlying VHL disease. [ABSTRACT FROM AUTHOR]

STING acts as a cytosolic nucleotide sensor to trigger host defense upon viral or bacterial infection. While STING hyperactivation can exert anti-tumor effects by increasing T cell filtrates, in other contexts hyperactivation of STING can contribute to autoimmune and neuroinflammatory diseases. Several STING targeting agonists and a smaller subset of antagonists have been developed, yet STING targeted degraders, or PROTACs, remain largely underexplored. Here, we report a series of STING-agonist derived PROTACs that promote STING degradation in renal cell carcinoma (RCC) cells. We show that our STING PROTACs activate STING and target activated/phospho-STING for degradation. Locking STING on the endoplasmic reticulum via site-directed mutagenesis disables STING translocation to the proteasome and resultingly blocks STING degradation. We also demonstrate that PROTAC treatment blocks downstream innate immune signaling events and attenuates the anti-viral response. Interestingly, we find that VHL acts as a bona fide E3 ligase for STING in RCC; thus, VHL-recruiting STING PROTACs further promote VHL-dependent STING degradation. Our study reveals the design and biological assessment of VHL-recruiting agonist-derived STING PROTACs, as well as demonstrates an example of hijacking a physiological E3 ligase to enhance target protein degradation via distinct mechanisms. [ABSTRACT FROM AUTHOR]

Retinal capillary hemangioblastoma (RCH), while sporadic in some cases, is the most common and earliest manifestation of von Hippel-Lindau disease (VHL). This is the first report on different types of VHL variants and genotype-phenotype correlations in Iranian families with RCH. In this prospective observational case series study, 17 families with RCH were included. PCR was performed to amplify 3 exons of VHL gene. Afterward, Sanger sequencing was performed on all PCR products. For the detection of VHL copy number variations, MLPA was used. Our study identified 10 different types of VHL variants. Missense mutations were the most common variants found and affected the structure of α domain of the VHL protein (pVHL). The majority of mutations (72.7%) in the patients with RCH and central nervous system hemangioblastoma (CNS-HB) were located on α domain. α domain of VHL may play a potential role in the pathogenesis of RCH. Our findings suggest that genotype-phenotype characteristics in those variants in α- domain may predispose patients to RCH with CNS-HB. [ABSTRACT FROM AUTHOR]

Background: The United States is becoming increasingly diverse, but few molecular studies have assessed the progression of clear cell renal cell carcinoma (ccRCC) in diverse patient populations. This study examined ccRCC molecular variations in non‐Hispanic White (NHW) and Hispanic patients and their effect on the association of gene expression with high‐grade (Grade 3 or 4) ccRCC and overall mortality. Methods: A total of 156 patients were included in VHL sequencing and/or TempO‐Seq analysis. DESeq2 was used to identify the genes associated with high‐grade ccRCC. Logistic regression analysis was performed to assess whether race and ethnicity was associated with high/moderate impact VHL somatic mutations and the ccA/ccB subtype. Cox regression analysis was performed to assess association of molecular subtype and gene expression with overall mortality. Results: NHWs had moderate or high impact mutations in the VHL gene at a higher frequency than Hispanics (40.2% vs. 27.4%), while Hispanics had a higher frequency of the ccA subtype than NHWs (61.9% vs. 45.8%). ccA was more common in patients with BMI≥35 (65.2%) than in those with BMI < 25 (45.0%). There were 11 differentially expressed genes between high‐ and low‐grade tumors. The Haptoglobin (HP) gene was most significantly overexpressed in high‐ compared to low‐grade ccRCC in all samples (p‐adj = 1.7 × 10−12). When stratified by subtype, the 11 genes were significantly differentially expressed in the ccB subtype, but none of them were significant after adjusting for multiple testing in ccA. Finally, patients with the ccB subtype had a significantly increased risk of overall mortality (HR 4.87; p = 0.01) compared to patients with ccA, and patients with high HP expression and ccB, had a significantly increased risk of mortality compared to those with low HP expression and ccA (HR 6.45, p = 0.04). Conclusion: This study reports ccRCC molecular variations in Hispanic patients who were previously underrepresented. [ABSTRACT FROM AUTHOR]

Tumors exhibiting histopathological findings similar to those of hemangioblastoma of the central nervous system (CNS-HB) rarely develop in the kidneys. Currently, renal hemangioblastoma (RHB) is considered analogous to CNS-HB; however, they differ in gross appearance, as well as immunohistochemical and molecular findings. In contrast, some renal cell carcinomas reportedly comprise distinct, clear cell renal cell carcinoma (CCRCC)- and hemangioblastoma (HB)-like areas. Initially, renal cell carcinomas with HB-like features (RCC-HBs) were considered a morphological variant of CCRCC owing to their diverse histological findings. However, the immunohistochemical and molecular findings of RCC-HBs suggest that RCC-HB is distinct from CCRCC. Additionally, one of the RCC-HBs had a focal leiomyomatous stroma and TSC2 variant, suggesting that RCC-HB and RCC with fibromyomatous stroma (RCC-FMS) might belong to the same disease entity. Therefore, we comprehensively reviewed the clinical, pathological, and molecular features of RHB, RCC-HB, and the related tumors and discussed the similarities, differences, and relationships between them. We believe that our review would serve as a foundation for further investigation on elucidating the relationship between CNS-HB, RHB, RCC-HB, and RCC-FMS. [ABSTRACT FROM AUTHOR]

Individuals with genetic disease face unique challenges related to navigating dating relationships. While previous studies have explored the impact of hereditary breast and ovarian cancer syndrome on dating, research investigating psychosocial implications for young adults with early-onset multi-organ tumor predisposition syndromes such as von Hippel-Lindau disease (VHL) is scarce. This study assessed young adults' attitudes towards dating and decisions related to disclosing a diagnosis of VHL to a dating partner. Twenty-six young adults with VHL participated in semi-structured interviews exploring this issue, using a guide informed by the literature in consultation with providers and an individual with VHL. Interviews were coded with a primarily deductive approach using codes derived from the literature, with inductive coding employed for perspectives unique to VHL. Our results support previous findings that genetic disease contributes to fear of rejection due to decreased desirability. However, participants report that partners' reactions to VHL uniquely exacerbate this concern due to unfamiliarity with VHL and a perception that it is exceptionally serious, leading to different strategies in disclosure. While many cited negative reactions from partners, participants also described how disclosure can strengthen relationships by deepening trust. Participants discussed a desire for healthcare providers to offer support in this context and described the benefit of speaking with peers about their dating experiences and approaches to disclosure. Our findings provide insight into the diverse needs of young adults with VHL as they approach romantic relationships and decision-making regarding disclosure and highlight the importance of patient-centered support from providers and patient organizations. [ABSTRACT FROM AUTHOR]

Background: Von Hippel‐Lindau (VHL) disease is an autosomal dominant disorder caused by pathogenic variants in VHL gene. The common manifestations include hemangioblastomas (HB) of the central nervous system (CNS) and retina (RH); pheochromocytoma (PHEO); clear cell renal cell carcinoma (ccRCC); pancreatic and renal cysts (PRC) and pancreatic neuroendocrine neoplasm (PNEN). Methods: The first characterization of VHL in Brazil was published in 2003 and included 20 families with a history of VHL. The aim of this study was to expand the previous Brazilian cohort to include more families, as well as to collect prospectively both clinical and molecular characteristics of patients with VHL to build the VHL Brazilian Registry (VHLBR). Patients with VHL were selected through review of data from medical records of experts and from social networks of support for families with VHL in Brazil. Results: A total of 142 subjects representing 62 unrelated Brazilian families with VHL were registered. The mean age of VHL onset was 28.78 years old and 128 individuals (90.1%) had at least one VHL‐related lesion. CNS HB was the most common manifestation occurring in 91 (71%) patients, followed by multiple PRC (48.4%), RH (39.8%), ccRCC (28.9%), PHEO (12.5%) and PNEN (7.8%). Of the 97 subjects whose presence of VHL variants was confirmed, 51 (52.6%) had missense variants, 22 (22.7%) large deletions, 10 (10.3%) frameshift, 7 (7.2%) splice site, 4 (4.1%) nonsense and 3 (3.1%) in‐frame deletions. Regarding surveillance, 115 (81%) participants had at least one physician responsible for their outpatient follow‐up; however, 69 (60%) of them did not report a regular frequency of tests. Conclusion: We built the largest prospective VHLBR with organized collections of clinical and genetic data from families with VHL, which will be helpful to guide policies for VHL care and oncogenetics in Brazil. Although there have been improvements in diagnosis and clinical screening methods, VHL care in Brazil is still deficient, especially regarding surveillance and regular medical appointments with experts. [ABSTRACT FROM AUTHOR]

Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel–Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D , FH , MDH2 , IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1 , are warranted. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer, and inactivation of the VHL tumor suppressor gene is found in almost all cases of hereditary and sporadic ccRCCs. CcRCC is associated with the reprogramming of fatty acid metabolism, and stearoyl-CoA desaturases (SCDs) are the main enzymes controlling fatty acid composition in cells. In this study, we report that mRNA and protein expression of the stearoyl-CoA desaturase SCD5 is downregulated in VHL-deficient cell lines. Similarly, in C. elegans vhl-1 mutants, FAT-7/SCD5 activity is repressed, supporting an evolutionary conservation. SCD5 regulation by VHL depends on HIF, and loss of SCD5 promotes cell proliferation and a metabolic shift towards ceramide production. In summary, we identify a novel regulatory function of VHL in relation to SCD5 and fatty acid metabolism, and propose a new mechanism of how loss of VHL may contribute to ccRCC tumor formation and progression. [ABSTRACT FROM AUTHOR]

Background: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from chromaffin cells in the adrenal medulla and extra-adrenal ganglia, respectively. The study was aimed to investigate the clinical and genetic characteristics of 22 individuals from six families. Methods: The medical records of six PPGL probands who presented to our hospital between 2016 and 2021 were retrospectively studied. DNA isolated from the probands was analyzed using whole exome sequencing. The identified genetic variants were confirmed by Sanger sequencing and undergone bioinformatic analysis. Results: Six different genetic variants in the six probands were identified, respectively, of which three were novel. A novel von Hippel-Lindau (VHL) variant, c.602T>C (p.L201P), in exon 3 was found. Two novel genetic variants in SDHB (succinate dehydrogenases subunit B), c.423 + 1 G>T and c.662A>G (p.D221G), were identified. Two recurrent genetic variants of VHL, c.C284G (p.P95R) and c.558_ 560AGAdel (p.186Edel), and one in RET (ret proto-oncogene), c.1901G>A (p.C634Y), were also found. The ClinVar accession number for the present variants are SCV002028348, and SCV002028352 to SCV002028361. Conclusion: Genetic variants in VHL, SDHB and RET were identified in Chinese PPGL patients, which contributed to the knowledge of the genetic etiology and clinical outcome of these tumors. [ABSTRACT FROM AUTHOR]

The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD's activity. [ABSTRACT FROM AUTHOR]

Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades. [ABSTRACT FROM AUTHOR]

The most common subtype of renal cell carcinoma (RCC) is clear cell type (ccRCC), which accounts for approximately 75% of cases. von Hippel-Lindau (VHL) gene has been shown to be affected in more than half of ccRCC cases. Two single nucleotide polymorphisms (SNPs) located in VHL gene, rs779805 and rs1642742, are reported to be involved in the occurrence of ccRCC. The aim of this study was to assess their associations with clinicopathologic and immunohistochemical parameters, as well as risk and survival of ccRCC. The study population consisted of 129 patients. No significant differences in genotype or allele frequencies of VHL gene polymorphisms were observed between ccRCC cases and control population, and we have found that our results do not indicate a significant relationship of these SNPs with respect to ccRCC susceptibility. Additionally, we did not observe a significant association of these two SNPs with ccRCC survival. However, our results conclude that rs1642742 and rs779805 in the VHL gene are associated with increased tumor size, which is the most important prognostic indicator of renal cancer. Moreover, our analysis showed that patients with genotype AA of rs1642742 have a trend towards higher likelihood of developing ccRCC within their lifetime, while allele G of rs779805 can have a preventive effect against the development of renal cancer in stage 1. Therefore, these SNPs in VHL may be useful as genetic tumor markers for the molecular diagnostics for ccRCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinoma (ccRCC) progression, which is the most common form of kidney cancer, is associated with the loss of the Von Hippel-Lindau (VHL) gene in renal epithelium. VHL promotes proteasomal degradation of Hypoxia Inducible Factor alpha (HIF-α) thereby inhibiting the transcription of genes that are required for cell growth and proliferation during hypoxia (lack of oxygen). Accumulation of HIF-α consequent to VHL loss results in the activation of HIF target genes irrespective of oxygen availability which initiates tumorigenesis in the kidney. In this review, we discuss which signaling networks and genes are upregulated in response to HIF-α activation and how they drive ccRCC progression. We also highlight the potential therapies available to treat ccRCC patients as well as several medical and scientific challenges that impede the scientific investigation in this field. The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review the biology, drug development, and clinical data regarding the efficacy and safety of belzutifan (MK-6482), a small molecule inhibitor of HIF-2α. Recent Findings: Belzutifan, a second-generation HIF-2α inhibitor, was shown to provide clinically meaningful benefit in the treatment of VHL-associated tumors (including ccRCC, pancreatic lesions as well as neuroendocrine tumor, and CNS hemangioblastomas). The recommended dose of belzutifan is 120 mg orally daily and half-life is 14 h. In pretreated ccRCC, belzutifan achieved disease control rate of 80% in phase I trial. The most common side effects include anemia and hypoxia related symptoms. Summary: Investigation into the important role HIF-2α plays in the expression of genes associated with angiogenesis, erythropoiesis, carcinogenesis, and progression of tumors and the discovery of structural vulnerability within HIF-2α have resulted in the development of a new therapy that has demonstrated efficacy and safety in recent clinical trials. Further research is ongoing to optimize therapeutic benefits from this new exciting therapeutic modality and to improve the outcome of HIF-2α-driven tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The compounds named PROTACs are formed by two fragments, which bring together a particular protein with a ubiquitinating enzyme. This allows ubiquitination and degradation of the targeted protein. Ubiquitination-mediated protein degradation is an important regulatory process to control the expression levels of proteins and maintain the homeostatic conditions in cells. Thus, by re-directing a mechanism that is normally used for cell regulation, PROTACs allow to remove specific proteins associated to particular diseases or pathological conditions. In this paper, we report a type of PROTAC that targets for degradation the protein named p38α, whose functions have been linked to cancer and other diseases. We show that these PROTACs effectively reduce p38α protein expression not only in several cancer cell lines but also in tumors generated in mice. These compounds may provide an attractive strategy to evaluate potential therapeutic applications for targeting p38α in the clinical context. We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38α-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38α degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38α degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38α signaling in cultured cells and in vivo. [ABSTRACT FROM AUTHOR]