Danielle Stevenson

189 posts · 70,620 views

BHD Research Blog
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  • April 24, 2015
  • 09:00 AM
  • 19 views

FindZebra: a specialised search engine for rare diseases

by Danielle Stevenson in BHD Research Blog

Every doctor is taught to think of the common causes of a problem before contemplating the rare ones. This works for the majority of patients but occasionally the cause is something unusual – a “zebra” – and isn’t so easy to find. For rare disease patients a specific diagnosis can be elusive with 46% receiving at least one incorrect diagnosis and 20% waiting over five years for a final diagnosis (Rare Disease UK, 2010).... Read more »

Dragusin R, Petcu P, Lioma C, Larsen B, Jørgensen HL, Cox IJ, Hansen LK, Ingwersen P, & Winther O. (2013) FindZebra: a search engine for rare diseases. International journal of medical informatics, 82(6), 528-38. PMID: 23462700  

  • April 17, 2015
  • 04:38 AM
  • 119 views

Rhabdomyomas: an additional BHD hamartoma phenotype?

by Danielle Stevenson in BHD Research Blog

Hamartomas are benign, focal malformations formed by an excess of normal tissue growing in a disorganised fashion. Several hamartoma syndromes have been linked to aberrant mTOR signalling including BHD and Tuberous Sclerosis Complex (TSC). In addition to the predisposition of BHD patients to develop hair follicle hamartomas or fibrofolliculomas (Birt et al., 1977), Fuyura et al., (2012) propose that the pulmonary cysts in BHD patients are hamartoma-like cystic alveolar formations. The benign nat........ Read more »

Bondavalli D, White SM, Steer A, Pflaumer A, & Winship I. (2015) Is cardiac rhabdomyoma a feature of Birt Hogg Dubé syndrome?. American journal of medical genetics. Part A, 167(4), 802-4. PMID: 25655561  

  • April 10, 2015
  • 09:00 AM
  • 127 views

Intragenic deletions in folliculin identified and mapped

by Danielle Stevenson in BHD Research Blog

The phenotypes associated with BHD – fibrofolliculomas, pulmonary cysts with an increased risk of pneumothorax, and an increased risk of renal cell carcinoma (RCC) – show variable penetrance between and within families, making diagnosis difficult when only one symptom is present. Studies have found that up to 10% of patient cohorts diagnosed with Primary Spontaneous Pneumothorax (PSP) have folliculin (FLCN) mutations (Ren et al., 2008, Johannesma et al., 2015).

Patients suspected ........ Read more »

Ding Y, Zhu C, Zou W, Ma D, Min H, Chen B, Ye M, Pan Y, Cao L, Wan Y.... (2015) FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. American journal of medical genetics. Part A. PMID: 25807935  

  • April 10, 2015
  • 09:00 AM
  • 138 views

Intragenic deletions in folliculin identified and mapped

by Danielle Stevenson in BHD Research Blog

The phenotypes associated with BHD – fibrofolliculomas, pulmonary cysts with an increased risk of pneumothorax, and an increased risk of renal cell carcinoma (RCC) – show variable penetrance between and within families, making diagnosis difficult when only one symptom is present. Studies have found that up to 10% of patient cohorts diagnosed with Primary Spontaneous Pneumothorax (PSP) have folliculin (FLCN) mutations (Ren et al., 2008, Johannesma et al., 2015).

Patients suspected ........ Read more »

Ding Y, Zhu C, Zou W, Ma D, Min H, Chen B, Ye M, Pan Y, Cao L, Wan Y.... (2015) FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. American journal of medical genetics. Part A. PMID: 25807935  

  • March 27, 2015
  • 09:00 AM
  • 61 views

Fnip1 and Fnip2 play critical roles in kidney tumour suppression in cooperation with Flcn in mice

by Danielle Stevenson in BHD Research Blog

Folliculin (FLCN), through its association with renal tumours in BHD and knockout mouse models, is now recognised as a tumour suppressor. The loss of Flcn in kidney cells is linked to pro-tumourigenic changes in AMPK and mTOR activity, increased expression of PPARGC1A (PGC1α) and increased mitochondrial biogenesis (Baba et al., 2008, Hasumi et al., 2012). Two folliculin interacting proteins, FNIP1 and FNIP2, are known to facilitate FLCN function. A report from Hasumi et al., 2015 aimed to clari........ Read more »

Hasumi H, Baba M, Hasumi Y, Lang M, Huang Y, Oh HF, Matsuo M, Merino MJ, Yao M, Ito Y.... (2015) Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. Proceedings of the National Academy of Sciences of the United States of America. PMID: 25775561  

  • March 13, 2015
  • 09:00 AM
  • 57 views

Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines

by Danielle Stevenson in BHD Research Blog

Under hypoxic conditions the activation of HIF transcription factors enables cells to alter their metabolism and avoid stress-induced apoptosis. Aberrant HIF activity in the inherited renal cancers BHD, VHL, HLRCC and TSC, is linked to the expression of growth and pro-angiogenic factors that are important in tumour growth. A new report from Doonachar et al., (2015) focuses on the differential effects of the HIF-1α and HIF-2α isoforms on stress-induced apoptosis in two VHL-deficient r........ Read more »

Doonachar A, Gallo MD, Doukas D, Pasricha R, Lantsberg I, & Schoenfeld AR. (2015) Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines. Cancer cell international, 23. PMID: 25729330  

  • March 12, 2015
  • 11:31 AM
  • 135 views

Distinctive expression patterns of FLCN and GPNMB in BHD renal tumours

by Danielle Stevenson in BHD Research Blog

As discussed on this blog previously, developing histological screening techniques for renal cell carcinomas (RCCs) associated with BHD is important for early diagnosis. Individuals with folliculin (FLCN) mutations are more likely to develop multiple bilateral renal tumours (Zbar et al., 2002, Pavlovich et al., 2002). A misdiagnosis of sporadic RCC may compromise future treatment and wellbeing of the patient and other affected family members. Currently there are no known histological markers to ........ Read more »

  • February 13, 2015
  • 09:00 AM
  • 52 views

Characterisation of renal tumours in patients with Birt-Hogg-Dubé Syndrome

by Danielle Stevenson in BHD Research Blog

Due to mutations in their folliculin (FLCN) gene Birt-Hogg-Dubé (BHD) syndrome patients have a greater risk of developing renal cell carcinomas (RCC) than others (Zbar et al., 2002, Houweling et al., 2011). Unlike sporadic cases of RCC, where the majority are classified as clear cell RCC (ccRCC), studies of FLCN-related tumours have found that the majority are either chromophobe RCCs (34%) or hybrid oncocytoma/chromophobe tumours (HOCTs, 50%) with fewer cases of ccRCC (9%) and only rare o........ Read more »

Iribe Y, Kuroda N, Nagashima Y, Yao M, Tanaka R, Gotoda H, Kawakami F, Imamura Y, Nakamura Y, Ando M.... (2015) Immunohistochemical characterization of renal tumors in patients with Birt-Hogg-Dubé Syndrome. Pathology international. PMID: 25597876  

  • January 30, 2015
  • 09:00 AM
  • 38 views

The development of targeted therapy for renal cell carcinoma

by Danielle Stevenson in BHD Research Blog

Over 85% of kidney and renal pelvis cancers are renal cell carcinomas (RCC); a disease with multiple subtypes including clear cell, papillary, chromophobe and oncocytomic. The variable nature of RCC makes one blanket treatment impossible, and therefore targeted therapies may be more effective at enhancing survival. A recent review from Randall et al., (2014) summarises the current knowledge on RCC genetic aberrations and their effects, as well as discussing current and future treatment options.... Read more »

  • January 23, 2015
  • 09:00 AM
  • 138 views

Fnip1 regulates skeletal muscle fibre type specification, fatigue resistance, and susceptibility to muscular dystrophy

by Danielle Stevenson in BHD Research Blog

Summary of recent paper into the role of Fnip1 in skeletal muscle development.... Read more »

Reyes NL, Banks GB, Tsang M, Margineantu D, Gu H, Djukovic D, Chan J, Torres M, Liggitt HD, Hirenallur-S DK.... (2015) Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America, 112(2), 424-9. PMID: 25548157  

  • January 23, 2015
  • 03:00 AM
  • 148 views

Fnip1 regulates skeletal muscle fibre type specification, fatigue resistance, and susceptibility to muscular dystrophy

by Danielle Stevenson in BHD Research Blog

Folliculin (FLCN) and the associated folliculin-interacting proteins FNIP1 and FNIP2 have been shown to play a role in cell metabolism through regulation of the AMPK-mTOR pathways. Previously Hasumi et al. (2012) reported that selective deletion of Flcn in mouse skeletal … Continue reading →... Read more »

Reyes NL, Banks GB, Tsang M, Margineantu D, Gu H, Djukovic D, Chan J, Torres M, Liggitt HD, Hirenallur-S DK.... (2015) Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America, 112(2), 424-9. PMID: 25548157  

  • December 26, 2014
  • 04:00 AM
  • 61 views

BHD Research Blog: 2014 Annual Review

by Danielle Stevenson in BHD Research Blog

With the New Year upon us, we thought we would use this week’s blog to review the studies we’ve particularly enjoyed writing about, and to revisit emerging themes. During the summer-autumn period, there were a number of interesting studies that … Continue reading →... Read more »

Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ.... (2014) FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy, 10(10). PMID: 25126726  

Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, Li H, Gonzales L, Baba M, Linehan WM.... (2014) Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK. Cell reports, 7(2), 412-23. PMID: 24726356  

Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh HB, Sciarretta S, Nagashima K, Haines DC.... (2014) Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Human molecular genetics. PMID: 24908670  

Johannesma PC, van den Borne BE, Gille JJ, Nagelkerke AF, van Waesberghe JT, Paul MA, van Moorselaar RJ, Menko FH, & Postmus PE. (2014) Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients. BMC pediatrics, 171. PMID: 24994497  

Johannesma PC, Houweling AC, van Waesberghe JH, van Moorselaar RJ, Starink TM, Menko FH, & Postmus PE. (2014) The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: A hypothesis. Respirology (Carlton, Vic.), 19(8), 1248-50. PMID: 25302759  

Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, Laucho Contreras M, Zhang E, Parkhitko A, Yu JJ.... (2014) Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiological reports, 2(8). PMID: 25121506  

Park H, Tsang M, Iritani BM, & Bevan MJ. (2014) Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proceedings of the National Academy of Sciences of the United States of America, 111(19), 7066-71. PMID: 24785297  

Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L.... (2014) Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS genetics, 10(4). PMID: 24763318  

Postmus PE, Johannesma PC, Menko FH, & Paul MA. (2014) In-Flight Pneumothorax: Diagnosis May Be Missed because of Symptom Delay. American journal of respiratory and critical care medicine, 190(6), 704-5. PMID: 25221882  

Shuch B, Vourganti S, Ricketts CJ, Middleton L, Peterson J, Merino MJ, Metwalli AR, Srinivasan R, & Linehan WM. (2014) Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 32(5), 431-7. PMID: 24378414  

Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ.... (2014) Response and acquired resistance to everolimus in anaplastic thyroid cancer. The New England journal of medicine, 371(15), 1426-33. PMID: 25295501  

Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, Possik E, Coull BJ, Kharitidi D, Dydensborg AB.... (2014) The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. The Journal of clinical investigation. PMID: 24762438  

  • December 19, 2014
  • 04:00 AM
  • 53 views

A shower of second hit mutations causes bilateral, multifocal kidney cancer in TSC patients

by Danielle Stevenson in BHD Research Blog

Tuberous sclerosis complex (TSC) is caused by autosomal dominant inactivating mutations in either the TSC1 or TSC2 genes, and patients are predisposed to developing tumours in the brain, eyes, heart, skin, lungs and kidneys throughout their lifetime. While more than … Continue reading →... Read more »

Tyburczy ME, Jozwiak S, Malinowska IA, Chekaluk Y, Pugh TJ, Wu CL, Nussbaum RL, Seepo S, Dzik T, Kotulska K.... (2014) A shower of second hit events as the cause of multifocal renal cell carcinoma in Tuberous Sclerosis Complex. Human molecular genetics. PMID: 25432535  

  • December 12, 2014
  • 12:00 PM
  • 58 views

Providing written information significantly improves parents’ understanding of TSC

by Danielle Stevenson in BHD Research Blog

Last week, we launched the new patient information pages on the BHD Foundation website. The information has been rewritten with the principles of health literacy in mind, and we hope these will be of greater use to patients and their families. This week’s blog discusses a study which demonstrates the value of providing well-written patient information.

Tuberous Sclerosis Complex (TSC) is a paediatric genetic syndrome which causes tumours to form in the brain, eyes, heart, skin, lungs an........ Read more »

Samia P, Donald KA, Schlegel B, & Wilmshurst JM. (2014) Parental Understanding of Tuberous Sclerosis Complex. Journal of child neurology. PMID: 25414235  

  • December 5, 2014
  • 11:37 AM
  • 41 views

Introducing the new BHD patient information pages

by Danielle Stevenson in BHD Research Blog

Like many rare diseases, there is no cure for BHD. However, appropriate management of symptoms – particularly kidney cancer – can vastly reduce the likelihood of early death due to the disease (Menko et al., 2009, Stamatakis et al., 2013). … Continue reading →... Read more »

Gupta N, Seyama K, & McCormack FX. (2013) Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Familial cancer, 12(3), 387-96. PMID: 23715758  

Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER.... (2009) Birt-Hogg-Dubé syndrome: diagnosis and management. The Lancet. Oncology, 10(12), 1199-206. PMID: 19959076  

Stamatakis L, Metwalli AR, Middelton LA, & Marston Linehan W. (2013) Diagnosis and management of BHD-associated kidney cancer. Familial cancer, 12(3), 397-402. PMID: 23703644  

  • November 28, 2014
  • 04:56 AM
  • 180 views

The natural history of angiomyolipoma in cases of sporadic LAM

by Danielle Stevenson in BHD Research Blog

Lymphangioleiomyomatosis (LAM) is a cystic lung disease that predominantly affects women. Roughly 90% of cases are sporadic and are caused by somatic mutation of the TSC2 gene, but some patients develop LAM as part of the syndrome Tuberous Sclerosis Complex … Continue reading →... Read more »

  • November 21, 2014
  • 02:00 AM
  • 116 views

Computational approaches may expedite drug repurposing for rare diseases

by Danielle Stevenson in BHD Research Blog

Drug repurposing is predicated on the fact that many diseases are caused by the dysregulation of similar signaling pathways, or that drugs may affect several biological targets at once, meaning that a single drug may be able to treat multiple … Continue reading →... Read more »

  • November 14, 2014
  • 03:00 AM
  • 120 views

Nephron-sparing surgery reduces the risk of cardiovascular events

by Danielle Stevenson in BHD Research Blog

Radical nephrectomy is generally the preferred method to treat advanced kidney cancers, while partial nephrectomy is performed when the disease is localised, or if the patient has a genetic predisposition to developing kidney tumours. However, a recent study suggests that … Continue reading →... Read more »

  • November 7, 2014
  • 03:00 AM
  • 174 views

Cohort study describes the kidney tumour characteristics of 33 BHD patients

by Danielle Stevenson in BHD Research Blog

In order to determine the characteristics of renal cell carcinomas (RCC) in BHD patients, Benusiglio et al. (2014) recruited 124 French BHD patients from Hôpital Bicêtre near Paris, and the Edouard Herriot University Hospital in Lyon. Of the patients recruited, … Continue reading →... Read more »

  • October 31, 2014
  • 06:22 AM
  • 174 views

TSC1 is required for iNKT cell maturation and function

by Danielle Stevenson in BHD Research Blog

Invariant Natural Killer T (iNKT) cell development is highly regulated, starting at stage 0, where DP thermocytes become committed to the iNKT cell lineage, and ending as fully mature stage 3 iNKT cells, which are capable of illiciting an immune … Continue reading →... Read more »

Wu J, Yang J, Yang K, Wang H, Gorentla B, Shin J, Qiu Y, Que LG, Foster WM, Xia Z.... (2014) iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. The Journal of clinical investigation, 124(4), 1685-98. PMID: 24614103  

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