Joana Guedes

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BHD Research Blog
248 posts

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  • December 2, 2016
  • 07:48 AM
  • 85 views

Case studies: BHD syndrome associated with pulmonary malformation and with lung neoplasm

by Joana Guedes in BHD Research Blog

Matsutani et al. (2016) reported for the first time BHD syndrome accompanied by pulmonary arteriovenous malformation. The patient, a young male with no significant medical history, presented with chest pain. Chest X-ray and CT revealed emphysematous changes in both lungs and a tumour with pleural fluid. A thoracoscopy revealed dark red pleural fluid and multiple cysts in the lung. The tumour lesion was resected and identified as a non-malignant intrapulmonary hematoma caused by a significant haemorrhage in the pulmonary parenchyma, which was diagnosed as intrapulmonary hematoma. ... Read more »

Matsutani, N., Dejima, H., Takahashi, Y., Uehara, H., Iinuma, H., Tanaka, F., & Kawamura, M. (2016) Birt-Hogg-Dube syndrome accompanied by pulmonary arteriovenous malformation. Journal of Thoracic Disease, 8(10). DOI: 10.21037/jtd.2016.09.68  

Gunji-Niitsu, Y., Kumasaka, T., Kitamura, S., Hoshika, Y., Hayashi, T., Tokuda, H., Morita, R., Kobayashi, E., Mitani, K., Kikkawa, M.... (2016) Benign clear cell “sugar” tumor of the lung in a patient with Birt-Hogg-Dubé syndrome: a case report. BMC Medical Genetics, 17(1). DOI: 10.1186/s12881-016-0350-y  

  • November 25, 2016
  • 06:40 AM
  • 126 views

FLCN haploinsufficiency leads to lung fibroblast dysfunction in patients with BHD syndrome

by Joana Guedes in BHD Research Blog

Birt–Hogg–Dubé syndrome (BHD) is caused by germline mutations in the FLCN gene and characterized by fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal tumours. The stretch hypothesis for pulmonary cyst formation proposes that cysts in BHD arise from defects in cell–cell adhesion, leading to repeated respiration-induced physical stretch-induced stress and, over time, expansion of alveolar spaces particularly in vulnerable regions of lung (Kennedy et al., 2016). A new study by Hoshika et al. (2016) has shed some light on this mechanism. The authors isolated lung fibroblasts from BHD patients and evaluated them by testing chemotaxis to fibronectin and three-dimensional (3-D) gel contraction. They showed that FLCN is associated with chemotaxis in lung fibroblasts and that, together with reduced TGF-β1 expression by BHD lung fibroblasts, FLCN haploinsufficiency seems to cause lung fibroblast dysfunction, impairing tissue repair.... Read more »

Hoshika, Y., Takahashi, F., Togo, S., Hashimoto, M., Nara, T., Kobayashi, T., Nurwidya, F., Kataoka, H., Kurihara, M., Kobayashi, E.... (2016) Haploinsufficiency of the gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome . Physiological Reports, 4(21). DOI: 10.14814/phy2.13025  

  • November 18, 2016
  • 07:25 AM
  • 180 views

Mutated mTOR regulator RRAGC proteins decrease interactions with FLCN

by Joana Guedes in BHD Research Blog

Follicular lymphoma is a B-cell lymphoma that remains incurable with conventional therapies. Ying et al. (2016) present a new study exploring the biological and genetic features of follicular lymphoma and identifying potential new therapeutic targets. The authors identified recurrent mutations in the mTOR regulator RRAGC, a small G-protein, in approximately 10% of follicular lymphoma cases. Mutations in RRAGC localized to one protein surface area surrounding the GTP/GDP–binding sites. In stable retrovirally transfected HEK293T cells, multiple RRAGC mutations showed higher mTOR activation. A similar phenotype was observed in lymphoma cell lines and in yeast. Mutated RRAGC proteins showed increased binding to RPTOR, a binding protein for RRAG heterodimers, and decreased interactions with FLCN , a known tumour suppressor that plays a role in mTOR signalling and the causative gene of BHD syndrome.... Read more »

Ying ZX, Jin M, Peterson LF, Bernard D, Saiya-Cork K, Yildiz M, Wang S, Kaminski MS, Chang AE, Klionsky DJ.... (2016) Recurrent Mutations in the MTOR Regulator RRAGC in Follicular Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 22(21), 5383-5393. PMID: 27267853  

  • November 11, 2016
  • 05:10 AM
  • 166 views

RCC clinical trials: positive results and new phase III clinical study

by Joana Guedes in BHD Research Blog

Renal cell carcinoma (RCC) is by far the most common type of kidney cancer and it can be caused by genetic conditions such as BHD (Randall et al., 2014). BHD patients can develop multiple kidney tumours. In most cases these tumours can be surgically removed. However, surgery and traditional chemotherapies can leave patients with reduced renal function and at risk of relapse. In addition, advanced or metastatic RCC is difficult to treat with surgery. Therefore, the development and improvement of molecular targeted drug treatments is becoming a very active field. The standard first-line treatment for RCC is an anti-angiogenic and anti-proliferative tyrosine kinase inhibitor (TKI) such as sunitinib or sorafenib. This blog summarises recent results from a clinical trial assessing a new RCC drug treatment and the initiation of a new study.... Read more »

  • November 4, 2016
  • 06:12 AM
  • 170 views

Two recent case reports on BHD – Epidemiologic study of patients in Asia and new FLCN mutation

by Joana Guedes in BHD Research Blog

Furuya et al. (2016) present a new study describing genetic, epidemiologic and clinicopathologic features of 312 Asian individuals with BHD manifestations based on data from 120 probands from different families (119 Japanese and 1 Taiwanese), 36 siblingss with genetic testing and 156 siblings without genetic testing.... Read more »

Furuya M, Yao M, Tanaka R, Nagashima Y, Kuroda N, Hasumi H, Baba M, Matsushima J, Nomura F, & Nakatani Y. (2016) Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome. Clinical genetics, 90(5), 403-412. PMID: 27220747  

  • October 28, 2016
  • 06:14 AM
  • 173 views

Lack of Tsc2 in Mesenchymal Cells Causes Kidney Cysts and Defective Lung Alveolarization

by Joana Guedes in BHD Research Blog

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that shares clinical similarities with BHD. TSC results from germline mutations in the Tsc1 or Tsc2 gene, affecting multiple organs, including the kidney and lung. In the kidney, lesions such as multiple renal cysts and renal cell carcinoma can occur. In the lung, patients can develop multifocal micronodular pneumocyte hyperplasia and LAM. TSC proteins are negative regulators of the mTORC1 pathway. The mechanisms of organ-specific manifestations in TSC remain unknown, and the impact of TSC on mesenchymal lineage cells has not yet been addressed. In a recent study, Ren et al. (2016) deleted Tsc2 specifically in mesoderm-derived mesenchymal cells in a variety of organs in mice. Inactivation of Tsc2 in mesoderm-derived cells caused impaired body growth, premature death, increased cell proliferation in the kidneys but reduced cell proliferation in the lungs, renal cysts, and deficient lung alveolarization.... Read more »

  • October 21, 2016
  • 05:39 AM
  • 208 views

Chest CT in patients with spontaneous pneumothorax is cost-effective

by Joana Guedes in BHD Research Blog

Patients that present with a spontaneous pneumothorax (SP) without a known medical history of lung disease are usually diagnosed as primary spontaneous pneumothorax - a pneumothorax that occurs without underlying diseases. However, underlying diffuse cystic lung diseases such as Birt-Hogg-Dube syndrome (BHD), lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH) may have a spontaneous pneumothorax as their first symptom. In their new study, Gupta et al. (2016) evaluate the cost-effectiveness of high resolution computed tomographic (HRCT) chest imaging for early diagnosis of LAM, BHD, and PLCH in patients presenting with an apparent primary SP. In their analysis the authors show that HRCT image screening for BHD, LAM and PLCH in patients with apparent primary SP is cost-effective and suggest that clinicians should consider performing a screening HRCT in these patients.... Read more »

  • September 30, 2016
  • 06:12 AM
  • 271 views

BHD at the International Rare Lung Diseases Research Conference 2016

by Joana Guedes in BHD Research Blog

The International Rare Lung Diseases Research Conference (RLDC) and LAM symposium were held last week over four days. They brought together clinicians, scientists, patients and families to Cincinnati to review research developments in rare lung disease and to promote dialogue between the research community and patients. Next week’s blog will focus on the highlights of the entire conference. This week the blog is focused on the BHD syndrome specific talk and poster.... Read more »

Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B.... (2007) Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. American journal of respiratory and critical care medicine, 175(10), 1044-53. PMID: 17322109  

  • September 23, 2016
  • 04:14 PM
  • 271 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
  • 279 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
  • 334 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
  • 329 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
  • 334 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
  • 350 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
  • 414 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
  • 457 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
  • 397 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
  • 491 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
  • 516 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
  • 469 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 »

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