Joana Guedes

239 posts · 127,152 views

BHD Research Blog
239 posts

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  • September 23, 2016
  • 04:14 PM
  • 69 views

PD-L1 expression associates with non-inactivated VHL ccRCC

by Joana Guedes in BHD Research Blog

The loss of the of the tumor suppressor gene VHL and the subsequent deregulation of VHL/HIF/VEGF signalling are known to play a role in development of clear cell renal cell carcinoma (ccRCC). Renal tumours associated with BHD syndrome are histologically diverse and include a percentage of ccRCC (Pavlovich et al., 2002). Anti-angiogenic therapies targeting the VHL/HIF/VEGF pathway have emerged in past years (Rini et al., 2006) but the development of resistance to these therapeutic agents is leading to the development of a new approach based on targeted immunotherapy against immune checkpoint PD1/PDL1 to restore antitumor immune response. In a new study Kammerer-Jacquet et al. (2016) assessed a large series of 98 cases of ccRCC and correlated PDL1 expression with clinical data follow-up of up to 10 years, expression of VEGF, PAR-3, CAIX and PD-1 and complete VHL status. The authors found PD-L1 expression to be associated with non-inactivated VHL tumors and in particular wild-type VHL ccRCC. These tumors could benefit from therapies inhibiting PD-L1/PD-1.... Read more »

  • September 16, 2016
  • 05:01 AM
  • 127 views

Air travel and diving possibly increase risk of pneumothorax in BHD patients

by Joana Guedes in BHD Research Blog

Birt–Hogg–Dubé syndrome is caused by germline mutations in the FLCN gene and characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax (SP) and renal cancer. Because sudden changes in air pressure can increase the chances of developing a collapsed lung, a concern many BHD patients have is whether it is safe to air travel and scuba dive, or whether this increases the chances of a pneumothorax. In a new study, Johannesma et al. (2016) evaluate the incidence of SP in patients with BHD during or shortly after air travel and diving. The study was conducted by sending a survey to a cohort of BHD patients. The authors assessed SP episodes occurring within 1 month after air travel or diving and concluded that exposure to changes in air pressure associated with flying and diving may increase the risk of developing pneumothorax.... Read more »

Johannesma, P., van de Beek, I., van der Wel, J., Paul, M., Houweling, A., Jonker, M., van Waesberghe, J., Reinhard, R., Starink, T., van Moorselaar, R.... (2016) Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt–Hogg–Dubé syndrome. SpringerPlus, 5(1). DOI: 10.1186/s40064-016-3009-4  

  • September 9, 2016
  • 10:24 AM
  • 175 views

C9orf72-SMCR8 complex, analogous to FLCN- FNIP, localizes to lysosomes and regulates mTORC1

by Joana Guedes in BHD Research Blog

The DENN protein module contains a longin domain, a DENN domain and a d-DENN domain. Nookala et al. (2012) identified a DENN module in folliculin (FLCN), the Birt-Hogg-Dube tumour suppressor. The DENN module is believed to be a GEF for Rab-GTPases, although FLCN is believed to act as a GAP for RagC (Tsun et al., 2013) as is its yeast homologue, LST7, in interaction with the yeast FNIP homologue Lst4 (Pacitto et al., 2015). A recent bioinformatic study identified DENN domains in several other proteins, including Folliculin Interacting Proteins (FNIP1/2), C9orf72 and SMCR8 (Zhang et al., 2012). SMCR8 was known to be involved in autophagy and C9orf72 in ALS and FTD (Behrends et al 2010; DeJesus-Hernandez et al., 2011; Renton et al., 2011; Smith et al., 2012). Now, Amick et al. (2016) show, interestingly, how they used genetic strategies to examine C9orf72 functions, interactions and subcellular localization.... Read more »

  • September 2, 2016
  • 07:28 AM
  • 195 views

Mitochondrial function during muscle fiber type transition by a miR‐499/Fnip1/AMPK circuit

by Joana Guedes in BHD Research Blog

Contractile fiber type and mitochondrial function are two key factors of skeletal muscle function. However, the exact mechanism for coupling the two remains unknown. The genes encoding type I myosins Myh7/Myh7b regulate muscle fiber type switching by encoding their intronic miRNAs, miR-208b and miR-499. In a new study, Liu et al., 2016 use transgenic mice to show that miR-499 directly targets the gene encoding folliculin‐interacting protein‐1 (Fnip1), which negatively regulates AMPK. AMPK is a known activator of Ppargc1a (PGC-1a), which is a transcriptional co‐regulator of mitochondrial function. Targeting of Fnip1 by miR-499 drives a PGC-1a-dependent mitocho... Read more »

  • August 26, 2016
  • 05:03 AM
  • 212 views

A new Birt-Hogg-Dubé Syndrome review

by Joana Guedes in BHD Research Blog

Gupta et al. (2016b) recently published a review about Birt-Hogg-Dubé Syndrome (BHD) exploring the key points and research advances in genetics and pathogenesis, clinical manifestations, diagnosis and disease management.... Read more »

Gupta N, Sunwoo BY, & Kotloff RM. (2016) Birt-Hogg-Dubé Syndrome. Clinics in chest medicine, 37(3), 475-86. PMID: 27514594  

  • August 12, 2016
  • 05:10 AM
  • 238 views

Simulation study suggests that mutations induce conformational changes in FLCN - possible cause of Birt-Hogg-Dubé syndrome

by Joana Guedes in BHD Research Blog

Germline mutations of the folliculin gene are normally responsible for Birt–Hogg–Dubé (BHD) syndrome. The 3D structure of the C-terminal domain of folliculin (FLCN), folliculin-CT, has been previously determined (Nookala et al., 2012). FLCN is a tumor suppressor and a guanine nucleotide exchange factor (GEF) for Rab35. GEF activity of FLCN towards its GTPase might be essential for cellular processes. Most of the reported FLCN mutations lead to the BHD phenotype (Lim et al., 2010) and to loss of GEF activity which triggers carcinogenesis (Nookala et al., 2012). A new study by Verma et al. (2016) examines the effect of FLCN mutations on the protein conformation and in loss of function. Authors performed molecular dynamics (MD) simulation on mutated protein variants to predict the protein conformation which is associated with BHD phenotype.... Read more »

  • August 5, 2016
  • 05:09 AM
  • 309 views

Multiple germline mutations in rare inherited cancer syndrome genes

by Joana Guedes in BHD Research Blog

A recent study by Whitworth et al. (2016) reports five new cases of multiple germline mutations in inherited cancer syndrome genes, three of them involve the combination of mutations in FLCN with NF1, TP53, and MSH2, respectively.... Read more »

Whitworth J, Skytte AB, Sunde L, Lim DH, Arends MJ, Happerfield L, Frayling IM, van Minkelen R, Woodward ER, Tischkowitz MD.... (2016) Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA oncology, 2(3), 373-9. PMID: 26659639  

  • July 22, 2016
  • 09:01 AM
  • 336 views

Update on clinical trials and treatments for RCC

by Joana Guedes in BHD Research Blog

Renal cell carcinoma (RCC) is the most common type of kidney cancer and although the majority of cases are sporadic approximately 3% of cases are caused by genetic conditions such as BHD, VHL, HLRCC and TSC (Randall et al., 2014). These inherited forms of RCC have provided great insights into sporadic cancer genetics. BHD patients can develop multiple kidney tumours. In most cases these tumours are small local RCCs that can be surgically removed. However, these treatments are not without risk, and sometimes complete nephrectomies are carried out which leave patients with severely reduced kidney function and at risk of recurrence. The development of selective drug treatments that target only cancer cells can therefore improve disease outcome and increase patient quality of life. Even though significant advances have been made in the treatment of kidney cancer, there is a need for effective and more tolerable treatments, both for single agent and combination use. This blog summarises recent results from clinical trials assessing new treatments.... Read more »

  • July 14, 2016
  • 10:14 AM
  • 299 views

Folliculin is required for embryonic brain development in zebrafish

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé syndrome (BHD) is caused by mutations in the gene encoding folliculin (FLCN). How this leads to the BHD clinical manifestations is not yet clear. Since homozygous mutations of FLCN are lethal in mice, rats and dogs at early embryonic stage (Hasumi et al., 2009), zebrafish is a valuable alternative model to study the developmental functions of FLCN. Newly published research from Kenyon et al. (2016) examines the role of FLCN in zebrafish development using morpholino oligonucleotides to generate a zebrafish BHD model and reconcile the expression of FLCN transcripts in the developing embryo with the phenotype associated with the morpholino knock-down of FLCN.... Read more »

Kenyon EJ, Luijten MN, Gill H, Li N, Rawlings M, Bull JC, Hadzhiev Y, van Steensel MA, Maher E, & Mueller F. (2016) Expression and knockdown of zebrafish folliculin suggests requirement for embryonic brain morphogenesis. BMC developmental biology, 16(1), 23. PMID: 27391801  

  • July 8, 2016
  • 12:38 PM
  • 375 views

FNIP1 and FNIP2 inhibit Hsp90 chaperone cycle and enhance drug binding

by Joana Guedes in BHD Research Blog

Heat shock protein-90 (Hsp90) is a molecular chaperone required for folding, stability and activity of many proteins, known as clients, including drivers of tumour initiation, progression and metastasis (Rohl et al. 2013). ATPase binding and hydrolysis is essential for the chaperone function of Hsp90. ATPase function is regulated by other proteins known as co-chaperones. In an interesting new study, Woodford et al. (2016) show that the stability of the tumour suppressor folliculin (FLCN), whose mutations cause Birt-Hogg-Dubé syndrome, is dependent on the chaperone function of Hsp90. Authors report that folliculin-interacting protein (FNIP)1 and FNIP2 act as co-chaperones of Hsp90 by regulating its ATPase activity and chaperoning. They also show that the Aha1 co-chaperone competes with FNIPs and can stimulate Hsp90 ATPase activity and that FNIPs enhance the binding of Hsp90 to its inhibitors.... Read more »

Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, Panaretou B, Hughes PF, Smith A, Ackerman W.... (2016) The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nature communications, 12037. PMID: 27353360  

  • June 17, 2016
  • 05:49 AM
  • 392 views

FLCN activates mTORC1 by maintaining lysosomal leucine level

by Joana Guedes in BHD Research Blog

The intracellular amino acid pool within the lysosome has been shown to activate the mTORC1 signaling pathway (Zoncu et al., 2011; Jewell et al., 2013). However, how the sequester of the signaling molecules within the lysosome occurs remains poorly understood. New research from Wu et al. (2016) shows that the suppression of FLCN, a tumour suppressor gene associated with the Birt-Hogg-Dubé (BHD) syndrome, controls mTORC1 activity by modulating the lysosomal leucine levels. FLCN exerts this new function by regulating the accumulation of the amino acid transporter PAT1 on the lysosome surface.... Read more »

  • June 10, 2016
  • 06:14 AM
  • 369 views

BHD syndrome and thyroid conditions

by Joana Guedes in BHD Research Blog

Dong et al., (2016) have recently reported two BHD syndrome patients also affected with papillary thyroid cancer. Lesions were bilateral and multifocal and small lymph node metastases occurred. Due to the small number of patients in the study the authors are unsure whether thyroid cancer in BHD patients is susceptible to exhibiting bilaterally and lymph node metastasis. However, they suggest considering thyroidectomy and prophylactic lymph node dissection for thyroid cancer patients with BHD. They also strongly recommend neck ultrasound for BHD patients and their families and suggest a large-scale investigation be conducted to evaluate the prevalence of thyroid cancer or nodules in patients with BHD.... Read more »

  • June 3, 2016
  • 11:43 AM
  • 356 views

Anonymising and sharing patient data

by Joana Guedes in BHD Research Blog

Patient data is extremely valuable for biomedical and healthcare research. Collecting and sharing patient data globally can lead to several benefits such as better understanding diseases, identifying patterns in public health and disease, developing and monotoring drugs and treatments, allowing researchers to build on the work of others efficiently and finding suitable candidates to take part in clinical trials. However, concerns about privacy have been a barrier for making patient data available. ... Read more »

El Emam K, Rodgers S, & Malin B. (2015) Anonymising and sharing individual patient data. BMJ (Clinical research ed.). PMID: 25794882  

  • May 27, 2016
  • 12:33 PM
  • 409 views

Starvation-induced FLCN association with lysosomes via a Rab34–RILP complex

by Joana Guedes in BHD Research Blog

Dynamic positioning of lysosomes in the cytoplasm plays an important role in their function and is, in part, regulated by cellular nutrient status. The FLCN/FNIP complex is known to be active on the lysosome surface, where it interacts with Rag GTPases, supports the nutrient‐dependent recruitment and activation of mTORC1, and regulates the localisation of lysosome associated transcription factors (Petit et al., 2013; Tsun et al., 2013). New research from Starling et al. (2016) now shows that folliculin (FLCN) also controls the dynamic cytoplasmic position of the lysosome itself.... Read more »

  • February 26, 2016
  • 04:50 AM
  • 429 views

BHD pulmonary cysts: The stretch hypothesis

by Joana Guedes in BHD Research Blog

The majority of BHD patients develop pulmonary cysts and approximately 1 in 3 will suffer a pneumothorax. Although BHD pulmonary cysts have defining characteristics compared to other cystic lung diseases (as discussed in recent reviews), the underlying pathogenesis is not yet clearly understood. A recent review from Kennedy, Khabibullin & Henske (2016) summarises the current understanding of BHD pulmonary pathology relative to the stretch hypothesis for cyst formation.... Read more »

  • February 12, 2016
  • 04:16 AM
  • 456 views

Maintained disomic chromosome 17 as a diagnostic marker for BHD-associated chromophobe RCC

by Joana Guedes in BHD Research Blog

Renal cell carcinomas (RCCs) can be life-threatening and although mostly sporadic, approximately 5% are associated with genetic conditions such as BHD. Early identification of families carrying cancer-predisposing mutations enables access to regular screening and earlier treatment. However, it can be difficult to distinguish between sporadic and inherited RCC based on standard immunohistological analysis. New research from Kato et al. (2016) assessed whether variability in the chromosomal status of chromosomes 17, 2, and 6 could be used to identify BHD-associated RCC.... Read more »

  • February 5, 2016
  • 09:00 AM
  • 519 views

TSC2 mutations confer everolimus sensitivity in hepatocellular carcinomas

by Joana Guedes in BHD Research Blog

Hepatocellular carcinomas (HCCs) are the third leading cause of cancer deaths globally; frequently diagnosed only in the advanced stages and aggressive in nature. Although enhanced mTOR activity has a key role in HCC tumourigenesis, the EVOLVE-1 clinical trial of mTOR inhibitor everolimus found no associated improvement in overall survival (Zhu et al., 2014). However, everolimus is an effective treatment for tuberous sclerosis complex (TSC) manifestations, a rare disease associated with mutations in TSC1 and TSC2 that result in high mTOR activity. New research from Huynh et al. (2016) assessed the frequency of TSC2 loss in HCC and suggests this could predict a selective response to everolimus.... Read more »

  • January 29, 2016
  • 04:23 AM
  • 528 views

A role for dermatologists in diagnosing BHD earlier

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé (BHD) syndrome was initially described as a heritable dermatological condition based on the presence of multiple fibrofolliculomas, trichodiscomas and acrochordons in a Canadian kindred (Birt et al., 1977). Now it is known that BHD patients can also develop pulmonary cysts, with an associated risk of pneumothorax, and bilateral, multifocal renal tumours. Due to the risk of tumour development it is important that patients are diagnosed early, enabling them to access regular screening and earlier treatment if required.... Read more »

Tellechea O, Cardoso JC, Reis JP, Ramos L, Gameiro AR, Coutinho I, & Baptista AP. (2015) Benign follicular tumors. Anais brasileiros de dermatologia, 90(6), 780-98. PMID: 26734858  

  • January 22, 2016
  • 04:57 AM
  • 461 views

Genome-wide genetic abnormalities in BHD-RCCs

by Joana Guedes in BHD Research Blog

Renal cell carcinoma (RCC) can be sporadic or associated with inherited mutations. These tumours frequently carry additional genetic abnormalities including copy number variations, deletions and amplifications. Although not all tumours have an altered genetic profile, sporadic RCC subtypes have common cytogenetic patterns. New research from Iribe et al. (2016) assessed several RCC subtypes from BHD patients to determine if they have similar or distinct patterns of genetic abnormalities.... Read more »

  • January 15, 2016
  • 05:59 AM
  • 548 views

Increased HIF-1α activity in RCC modulated by p62

by Joana Guedes in BHD Research Blog

Clear cell Renal Cell Carcinoma (ccRCC) is frequently associated with the loss of VHL, but gain of chromosome 5q35.3 – which contains the oncogene SQSTM1 – was also found in approximately 70% of tumours (Li et al., 2013). The SQSTM1 protein, p62, is a scaffold protein involved in cellular processes and signalling pathways related to malignant growth. New research from Chen et al., (2015) determined a role for p62 in regulating glucose metabolism, through HIF-1α signalling.... Read more »

Chen K, Zeng J, Xiao H, Huang C, Hu J, Yao W, Yu G, Xiao W, Xu H, & Ye Z. (2016) Regulation of glucose metabolism by p62/SQSTM1 through HIF1α. Journal of cell science. PMID: 26743088  

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