Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf(+/-) mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-beta signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.     

Effects of hydrogen sulfide on erectile function and its possible mechanism(s) of action

IntroductionThe current pharmacotherapy for erectile dysfunction (ED) relies significantly on the use of phosphodiesterase type 5 (PDE5) inhibitors, but quite a proportion of ED patients are resistant to this therapy, necessitating a search for an alternative treatment. We reviewed available published data to analyze current evidence of hydrogen sulfide (H₂S) as a novel pharmacotherapeutic agent with supportive role in sexual function.AimTo discuss the role of H₂S in erectile function, its possible mechanism of action, and how this knowledge may be exploited for therapeutic use.MethodsPubmed and Medline search was conducted to identify original articles and reviews.Main Outcome MeasuresData from peer‐reviewed publications.ResultsAnimal studies using different species, including in vitro study done in humans, show evidence of H₂S's pro‐erectile effects. The mechanism behind is still unclear, but evidence in literature points out the involvement of K⁺_ATP channel, modulation of protein with anti‐erectile effects, as well as involvement of the nitrergic pathway through a complex cross‐talk. A new drug called H₂S‐donating sildenafil (ACS6), which incorporated an H₂S‐donating moiety in sildenafil, has been developed. While more studies are still needed, this heralded a new pharmacotherapeutical approach, which is multipronged in nature.ConclusionsGiven the mounting evidence of H₂S's role in erectile function and how it appears to achieve its pro‐erectile effects through different mechanisms, H₂S represents a potentially important treatment alternative or adjunct to PDE5 inhibitors. Liaw RL, Srilatha B, and Adaikan PG. Effects of hydrogen sulfide on erectile function and its possible mechanism(s) of action. J Sex Med 2011;8:1853–1864.     

Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer

Tumour hypoxia is a microenvironmental factor related to poor response to radiation, chemotherapy, genetic instability, selection for resistance to apoptosis, and increased risk of invasion and metastasis. Hypoxia-regulated carbonic anhydrase IX (CA IX) has been studied in various tumour sites and its expression has been correlated with the clinical outcome. The purpose of this study was to investigate the correlation of CA IX expression with outcome in patients with invasive breast cancer. We conducted a retrospective study examining the effects of carbonic anhydrase IX (CA IX) on survival in patients with breast cancer. To facilitate the screening of multiple tissue blocks from each patient, tissue microarrays were prepared containing between two and five representative samples of tumour per patient. Immunohistochemistry was used to examine expression of CA IX in patients with breast cancer. The study includes a cohort of 144 unselected patients with early invasive breast cancer who underwent surgery, and had CA IX expression and follow-up data available for analysis. At the time of analysis, there were 28 deaths and median follow-up of 48 months with 96% of patients having at least 2 years of follow-up. CA IX was negative for 107 patients (17 deaths) and positive for 37 patients (11 deaths). Kaplan-Meier survival curves show that survival was superior in the CA IX-negative group with a 2-year survival of 97% for negatives and 83% for positives (log-rank test P=0.01). Allowing for potential prognostic variables in a Cox regression analysis, CA IX remained a significant independent predictor of survival (P=0.035). This study showed in both univariate and multivariate analysis that survival is significantly inferior in patients with tumour expressing CA IX. Prospective studies are underway to investigate this correlation in clinical trial setting.     

En plaque intradural extramedullary spinal tuberculoma and concurrent intracranial tuberculomas: paradoxical response to antituberculous therapy. Case report

Spinal intradural extramedullary tuberculoma is a rare entity. Rarer still are extensive en plaque intradural extramedullary tuberculomas occurring concurrently with multiple intracranial tuberculomas as a paradoxical response to chemotherapy for tuberculosis (TB). The authors describe the case of a 21-year-old man who was treated for tuberculous meningitis. Three months after the episode of meningitis, while undergoing chemotherapy for TB, he developed features of thoracic myelopathy. Investigations revealed an extensive en plaque intradural extramedullary lesion spanning seven segments in the lower thoracic spine. Magnetic resonance imaging of the brain revealed multiple asymptomatic intracranial tuberculomas. Even after further treatment with antituberculous chemotherapy was initiated, the lesion failed to respond. The authors performed a laminectomy and excised the en plaque intradural extramedullary lesion. The patient's condition responded well to this treatment. Although the appearance of intracranial tuberculoma as a paradoxical response to chemotherapy has been previously reported, no authors have reported on the development of an extensive en plaque intradural extramedullary tuberculoma in conjunction with asymptomatic multiple intracranial tuberculomas as a paradoxical response. In cases in which patients present with compressive myelopathy following therapy for tuberculous meningitis, it is important to consider in the differential diagnosis that intradural extramedullary tuberculoma may be a paradoxical response to chemotherapy. The authors' experience and their review of the literature indicate that surgery has a definitive role to play in the management of spinal intradural extramedullary tuberculoma.     

9‐cis retinoic acid is the ALDH1A1 product that stimulates melanogenesis

Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV‐radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV‐induced lipid aldehyde 4‐hydroxy‐2‐nonenal nor the ALDH1A1 product all‐trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9‐cis retinal and its corresponding product 9‐cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA and melanin. ALDH1A1 depletion inhibited the ability of 9‐cis retinal but not 9‐cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalysing the conversion of 9‐cis retinal to 9‐cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli's salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9‐cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9‐cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo.     

‘Brain attacks’ and acute stroke in childhood: a practical approach in a time of proposed thrombolysis

Sudden focal neurological symptoms or ‘brain attacks’ in children are a common scenario for acute paediatric care givers. A small proportion will have had a vascular stroke. Suspected stroke in adults, signalled by FAST (Face, Arms, Speech, Time) test positivity, is an accepted medical emergency. Children are rarely dealt with urgently unless there is coma. Barriers to stroke recognition and response in children are multifactorial. Childhood stroke is rare and may be ‘FAST negative’. Overall, there is low awareness, low clinical suspicion and many logistic obstacles to timely detection and aspired treatment delivery. Yet stroke continues to affect hundreds of children in the UK each year, causing life-changing disability and, in some, death. This article highlights current key recommendations for the diagnosis and management of acute stroke set out in the 2017 Royal College of Paediatrics and Child Health (RCPCH) Stroke in childhood guideline. Evidence and rationale are discussed, and important practice points offered. There is focus on arterial ischaemic stroke in light of the proposed hyperacute management pathway, which includes thrombolysis. Ongoing challenges on the ground and how these may be overcome are considered.