Danielle Stevenson

234 posts · 119,782 views

BHD Research Blog
234 posts

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  • August 26, 2016
  • 05:03 AM
  • 75 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
  • 162 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., 20........ Read more »

  • August 5, 2016
  • 05:09 AM
  • 207 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
  • 237 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,........ Read more »

  • July 14, 2016
  • 10:14 AM
  • 253 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 oligonuc........ 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
  • 301 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 ........ 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
  • 299 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 f........ Read more »

  • June 10, 2016
  • 06:14 AM
  • 317 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. Th........ Read more »

  • June 3, 2016
  • 11:43 AM
  • 310 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 availabl........ 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
  • 334 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 f........ Read more »

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

BHD pulmonary cysts: The stretch hypothesis

by Danielle Stevenson 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
  • 417 views

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

by Danielle Stevenson 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........ Read more »

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

TSC2 mutations confer everolimus sensitivity in hepatocellular carcinomas

by Danielle Stevenson 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 mutation........ Read more »

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

A role for dermatologists in diagnosing BHD earlier

by Danielle Stevenson 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 ........ 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
  • 415 views

Genome-wide genetic abnormalities in BHD-RCCs

by Danielle Stevenson 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
  • 465 views

Increased HIF-1α activity in RCC modulated by p62

by Danielle Stevenson 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  

  • January 8, 2016
  • 05:03 AM
  • 580 views

HIF-2α regulates PD-L1 expression in RCC

by Danielle Stevenson in BHD Research Blog

Tumour cells can create immunosuppressive microenvironments by hijacking natural mechanisms such as PD-L1 expression to impair T-cell function. Several new immunotherapy treatments target the PD-1/PD-L1 pathway and have produced some long-lasting responses in patients (Motzer et al., 2015) but not all patients respond. High expression of PD-L1 in clear cell RCC (ccRCC) has been shown to correlate with metastasis and poor outcome (Thompson et al., 2007). New research from Messai et al. (2015) has........ Read more »

  • December 18, 2015
  • 04:54 AM
  • 516 views

New HLRCC patient-derived cell line to model papillary RCC

by Danielle Stevenson in BHD Research Blog

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genetic condition caused by mutations in fumarate hydratase (FH). HLRCC patients are at risk of developing type 2 papillary renal cell carcinoma (pRCC2) which typically has an early onset with high metastatic potential. Existing targeted treatments have very limited response rates in both primary and metastatic pRCC2 tumours. Developing more effective treatments relies on preclinical models such as the new FH-deficient cell lin........ Read more »

Perrier-Trudova V, Huimin BW, Kongpetch S, Huang D, Ong P, LE Formal A, Poon SL, Siew EY, Myint SS, Gad S.... (2015) Fumarate Hydratase-deficient Cell Line NCCFH1 as a New In Vitro Model of Hereditary Papillary Renal Cell Carcinoma Type 2. Anticancer research, 35(12), 6639-53. PMID: 26637880  

  • December 4, 2015
  • 04:46 AM
  • 402 views

CT Screening for pulmonary cysts to identify potential BHD patients

by Danielle Stevenson in BHD Research Blog

As discussed in our blog post from the beginning of this year a greater level of BHD awareness among pulmonologists and associated professionals could help increase early diagnoses. It has been reported that up to 10% of spontaneous pneumothorax patients are carrying FLCN mutations (Ren et al., 2008, Johannesma et al., 2015, Ding et al., 2015). The identification of BHD in these patients results in screening for the development of renal cell carcinoma in patients and their families leading to ea........ Read more »

Ferreira Francisco FA, Soares Souza A Jr, Zanetti G, & Marchiori E. (2015) Multiple cystic lung disease. European respiratory review : an official journal of the European Respiratory Society, 24(138), 552-64. PMID: 26621970  

Johannesma PC, Houweling AC, Menko FH, van de Beek I, Reinhard R, Gille JJ, van Waesberghe JT, Thunnissen E, Starink TM, Postmus PE.... (2015) Are lung cysts in renal cell cancer (RCC) patients an indication for FLCN mutation analysis?. Familial cancer. PMID: 26603437  

  • November 27, 2015
  • 05:52 AM
  • 584 views

Biomarkers in diagnosis, prognosis and treatment of RCC

by Danielle Stevenson in BHD Research Blog

Tumour biomarkers are measurable changes in cancer cells that could be used to improve available therapies. The identification of early biomarkers could increase early diagnosis rates and provide insight into tumour biology including aggressiveness. In addition tumour subtype-specific biomarkers could help identify the treatments most likely to be effective and also be used to measure response. The search for biomarkers in renal cell carcinoma (RCC) is an active field, with various types of pote........ Read more »

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