PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. ...Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.
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•PBRM1 is a bona fide tumor suppressor in the pathogenesis of ccRCC•PBRM1 prevents self-perpetuating amplification of HIF1/STAT3 signaling in Vhl−/− cell•Loss of Vhl and Pbrm1 in mouse kidney results in multifocal, transplantable ccRCC•In ccRCC, mTORC1 activation is the third driver event after loss of VHL and PBRM1
Nargund et al. present a three-step process in the pathogenesis of mouse and human clear cell kidney cancer. After the loss of VHL, the loss of SWI/SNF tumor suppressor protein PBRM1/BAF180 further activates HIF1/STAT3 signaling in mouse kidney and positions mTORC1 activation as the preferred third driver event.
Two recent studies describe the largest molecular profiling analyses to date of clear-cell renal cell carcinoma (ccRCC) and report remarkably similar findings. The recurrent pathway alterations ...identified in these studies open new avenues for therapeutic advances in this chemotherapy- and radiation-resistant disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer ...types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.
Maternal antibodies in cases of chronic autoimmune thyroiditis may be transferred to the baby via the transplacental route, leading to transient hyperthyroidism or hypothyroidism. The development of ...hyperthyroidism in one sibling and hypothyroidism in the other, however, is an extremely rare condition. We present two siblings, one with transient neonatal hyperthyroidism and the other with transient neonatal hypothyroidism, born to a euthyroid mother who was being treated for Hashimoto's thyroiditis.
A term male baby was evaluated due to tachycardia, high fT4 and low TSH. Following a diagnosis of Neonatal thyrotoxicosis, the patient was started on methimazole and propranolol treatments. The doses were gradually reduced and methimazole was stopped in the 5
month of treatment.
A male baby was referred with elevated TSH identified in the neonatal screening program, with TSH >100 mIU/L and fT4 7.5 pmol/l (N: 12-22) found in a venous blood sample. The patient was started on 50 µg/day LT4, which was gradually decreased and stopped when the baby was 5.5 months old.
It should be kept in mind that antibodies may change character in mothers with autoimmune thyroiditis, and may cause different clinical pictures in babies in different pregnancies.
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, ranking as the third most malignant. The incidence of CRC has been increasing with time, and it is reported that Westernized ...diet and lifestyle play a significant role in its higher incidence and rapid progression. The intake of high amounts of omega-6 (
- 6) PUFAs and low levels of omega-3 (
- 3) PUFAs has an important role in chronic inflammation and cancer progression, which could be associated with the increase in CRC prevalence. Oxylipins generated from PUFAs are bioactive lipid mediators and have various functions, especially in inflammation and proliferation. Carcinogenesis is often a consequence of chronic inflammation, and evidence has shown the particular involvement of
- 6 PUFA arachidonic acid-derived oxylipins in CRC, which is further described in this review. A deeper understanding of the role and metabolism of PUFAs by their modifying enzymes, their pathways, and the corresponding oxylipins may allow us to identify new approaches to employ oxylipin-associated immunomodulation to enhance immunotherapy in cancer. This paper summarizes oxylipins identified in the context of the initiation, development, and metastasis of CRC. We further explore CRC chemo-prevention strategies that involve oxylipins as potential therapeutics.
Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as ...it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.
Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive ...MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.
•MLL fusion renders cancer type-specific hypersensitivity to proteasome inhibitors•Proteasome inhibitors engage extrinsic cell death pathway in pro-B MLL leukemia cells•Bortezomib activates p27 through a pro-B leukemia-specific PAX5/MLL-fusion complex•In vivo efficacy against pro-B MLL leukemia was observed with proteasome inhibitors
Liu et al. show that high levels of MLL fusion proteins selectively suppress pro-B, but not myeloid MLL leukemia cells. In addition, clinical proteasome inhibitors kill pro-B MLL leukemia cells by inducing MLL fusion protein accumulation and show a promising clinical benefit in patients with pro-B MLL leukemia.
Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small ...subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the context of intratumor heterogeneity.
We analyzed archived tumor tissue of 5 patients with renal cell carcinoma, who previously achieved durable disease control with rapalogs (median duration, 28 months). DNA was extracted from spatially separate areas of primary tumors and metastases. Custom target capture and ultradeep sequencing was used to identify alterations across 230 target genes. Whole-exome sequence analysis was added to investigate genes beyond this original target list.
Five long-term responders contributed 14 specimens to explore clonal heterogeneity. Genomic alterations with activating effect on mTOR signaling were detected in 11 of 14 specimens, offering plausible explanation for exceptional treatment response through alterations in two genes (TSC1 and MTOR). In two subjects, distinct yet functionally convergent alterations activated the mTOR pathway in spatially separate sites. In 1 patient, concurrent genomic events occurred in two separate pathway components across different tumor regions.
Analysis of outlier cases can facilitate identification of potential biomarkers for targeted agents, and we implicate two genes as candidates for further study in this class of drugs. The previously reported phenomenon of clonal convergence can occur within a targetable pathway which might have implications for biomarker development beyond this disease and this class of agents.
PurposeTo compare the surgical results, complications, and recurrence rates of primary pterygium excision with conjunctival autografts (CA) vs platelet-rich fibrin (PRF) grafts.Patients and methodsA ...total of 35 eyes of 35 patients with primary pterygium were included in the study. The patients underwent excision of pterygium followed by closure of the bare sclera by CA (group 1, n=20) vs PRF grafts (group 2, n=15). The PRF was generated from the patients' own whole-blood sample by centrifugation and pressing. The surgery times, intra/postoperative complications, recurrence rates of pterygium, and changes in visual acuity (VA) were evaluated and compared within groups.ResultsThe mean follow-up period was 14.3±6.5 months (6-24 months). The mean preoperative and postoperative VAs were same (20/25) (P=0.204). The mean surgery time was shorter in group 2 (22.1±1.9 min) compared to group 1 (33.8±7.8 min) (P=0.001). The recurrence was observed only in one (6.6%) case of group 2, while none of the cases showed recurrence in group 1. Graft loss was observed in 2 (10%) cases in group 1, and 1 (6.6%) case in group 2. No other intra/postoperative complications such as tear in the graft, excessive bleeding, scleral necrosis, graft necrosis, pannus formation, or symblepharon occurred in both groups.ConclusionsThis preliminary study showed encouraging results of the application of PRF for conjuntivoplasty after pterygium excision. The use of PRF in pterygium surgery is a simple, easily applicable, and a promising method with low rates of recurrence and complications.
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