Naturally occurring benzoic acid derivatives retard cancer cell growth by inhibiting histone deacetylases (HDAC)

Histone deacetylases (HDACs), which modulate the expression of genes, are potential therapeutic targets in several cancers. Targeted inhibition of HDAC prevents the expression of oncogenes thereby help in the treatment of cancers. Hence, several pharmaceutical companies developed inhibitors of HDAC and tested them in preclinical models and in clinical trials. SAHA (suberanilohydroxamic acid) is one such HDAC inhibitor developed for treating breast and colorectal carcinomas. However, due to poor efficacy in clinical trials the utility of SAHA for treating cancers was discouraged. Similarly another HDAC inhibitor Trichostatin-A (TSA) also showed promising results in clinical trials but exhibited severe adverse effects, which dampened the interest of using this molecule for cancer treatment. Therefore, search for developing a potent HDAC inhibitor with minimal side effects still continues. Hence, in this study we have screened benzoic acid and benzoic acid derivatives with hydroxylic (-OH) groups and methoxy (-OCH3) groups for their efficacy to bind to the TSA binding site of HDAC using molecular docking studies. Molecules that showed much stronger affinity (than TSA) to HDAC were tested for inhibiting HDAC expressing cultured cancer cells. DHBA but not Dimethoxy Benzoic Acid (DMBA) inhibited HDAC activity, leading to cancer cell growth inhibition through the induction of ROS and cellular apoptosis mediated by Caspase-3. In addition, DHBA arrested cells in G2/M phase of the cell cycle and elevated the levels of sub-G0-G1 cell population. In summary, results of this study report that DHBA could be a strong HDAC inhibitor and inhibit cancer cell growth more effectively.     

Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases

Matrix metalloproteinases (MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial–mesenchymal transition (EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT) and pericyte-myofibroblast transdifferentiation. Interstitial macrophage infiltration has also been shown to correlate with the severity of kidney fibrosis in various chronic kidney diseases. MMPs secreted by macrophages, especially MMP-9, has been shown by us to be profibrotic by induction of tubular cells EMT. EMT is mainly induced by transforming growth factor-β (TGF-β). However, MMP-9 was found by us and others to be up-regulated by TGF-β1 in kidney tubular epithelial cells and secreted by activated macrophages, resulting in EMT and ultimately kidney fibrosis. Therefore, MMP-9 may serve as a potential therapeutic target to prevent kidney fibrosis in chronic kidney disease. This review, by a particular focus on EMT, seeks to provide a comprehensive understanding of MMPs, especially MMP-9, in kidney fibrosis.     

In Vitro, Animal, and Human Characterization of OPTISON Infusions for Myocardial Contrast Echocardiography

Traditionally, performing myocardial contrast echocardiography with OPTISON required maximal bolus dosing. However, sustained and consistent opacification of the myocardium would be preferable for perfusion imaging. METHODS: Images of 5 anesthetized dogs and 6 human volunteers were obtained with a second harmonic ultrasound system during bolus administration of OPTISON and 2 infusion techniques. One infusion technique used diluted OPTISON, and the other used the buoyant properties of OPTISON microspheres by placing the contrast agent between an infusion source and the intravenous site in a vertically oriented extension line (ELT). Myocardial intensities and in vitro microsphere characteristics were analyzed to assess the consistency of microsphere delivery over time. RESULTS: In addition to providing higher myocardial opacification intensity than diluted infusions, ELT infusions provided consistent microsphere concentration, phantom enhancement, and near-peak bolus-level myocardial opacification for 7 to 15 minutes. The myocardial intensity at 3 and 5 minutes in human subjects during ELT infusions (30 mL/h; 2.5 mL) was lower (220 arbitrary units [au] and 165 au, respectively) but not significantly different (P =.3 and.1, respectively) than the peak myocardial intensity (265 au) after bolus administration. CONCLUSION: This new ELT infusion method provides an acceptable alternative to bolus administration of OPTISON for prolonged myocardial opacification.     

Effects of puberty on bone age maturation in a girl after medulloblastoma therapy.

BACKGROUND: Craniospinal radiotherapy for malignant brain tumors can result in a variety of neuroendocrine disturbances, among which are the development of growth hormone deficiency and early puberty, which can markedly reduce adult height. METHODS: The authors report the case of a girl who received craniospinal radiotherapy for a medulloblastoma at the age of 3.4 years. At 9.1 years, growth hormone therapy was started, and spontaneous onset of puberty (Tanner stage B2) occurred at age 10.3 years. Interval until menarche was short, at only 0.9 years. RESULTS: Although chronologic age at appearance of Tanner stages was within the normal range, the patient showed a rapid acceleration in skeletal maturation, resulting in adult short stature. CONCLUSION: Bone age seems to be a more precise parameter for biologic maturation in some patients after craniospinal irradiation than is clinical assessment of pubertal stages. Thus, if progression of bone age and decreasing final height predictions are noted, puberty should be stopped with gonadotropin-releasing hormone analogs, even if pubertal development seems to be adequate for chronologic age, because this increases the remaining time for growth hormone treatment.     

急性淋巴细胞白血病(上)

急性淋巴细胞白血病是淋巴前体细胞异常引起的恶性疾病,儿童与成人均可能发生。儿童发病高峰2～5岁。有效治疗的稳步进展使本病在儿童中的治愈率80％以上,同时为新的治疗方案提供了良机,新方案将保留我们在白血病无病生存病例中获得的治疗经验,同时减轻当前强化治疗方案中的毒副作用。     

The role of viral load determination for the management of human immunodeficiency virus, hepatitis B virus and hepatitis C virus infection.

During the last 5 years, considerable scientific and financial efforts have been made in the development of quantitative nucleic acid detection technology. For detection of human immunodeficiency virus (HIV), quantitative culture is time consuming, cumbersome and requires appropriate laboratory safety equipment. Quantitative determination of p24 antigen by enzyme immunoassay is of limited value due to its relatively poor sensitivity. Therefore, quantitative determination of viral load using nucleic acid amplification techniques is the most accurate, prognostic marker for HIV type 1 infection, independently of the CD4+ cell count. Hepatitis B virus (HBV) is not cultivable in vitro. Serological assays allow an accurate diagnosis and follow-up of acute or chronic infection. Quantification of HBV DNA is used for the monitoring of antiviral therapy, determination of infectivity and for resolution of unclear serological profiles, e.g. isolated anti-HBc reactivity, as well as for patients in which HBV mutants are suspected. Hepatitis C virus (HCV) can only be detected by molecular based assays because no cell culture system, which permits a reliable isolation of clinical specimens, is currently available. Furthermore, early diagnosis and follow-up of infection cannot be achieved with antibody serology. The prognostic relevance of quantitative HCV RNA determination is of limited value for the long-term prognosis of chronic hepatitis C. However, viral load may predict the outcome of antiviral therapy. Genetic diversity is another challenge for HCV RNA quantification.     

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS (DISH) OF THE SPINE: A CAUSE OF BACK PAIN? A CONTROLLED STUDY

This is the first controlled study of the frequency of backpain in a European caucasian population with diffuse idiopathicskeletal hyperostosis (DISH). Elderly patients admitted to hospital for reasons other thanback pain were assessed for the presence of spinal DISH usingthe routine lateral chest radiograph films. A total of 106 probands(82 males, 24 females) with a mean age of 70 years fulfilledthe criteria for DISH as defined previously. One hundred andseventyeight patients (117 males, 61 females) not meeting thesecriteria were used as controls. The prevalence of back painwas assessed by a blinded interviewer using a structured questionnaire.Our primary hymthesis was that spinal DISH positive probandshad not had back pain more often than controls. The controlledstudy showed no statistically significant difference in painfrequency between spinal DISH positive probands and controlsat any spinal level. We conclude that back pain does not occur more often in radiographicallydefined DISH positive probands than in controls. The radiologicalfinding of spinal DISH, as far as it does not lead to stenosisof the spinal canal or dysphagia, thus seems to be a findingwithout clinical relevance. KEY WORDS: Spine, Radiographs, Pain, Osteoarthritis, Forestier's disease, Ankylosing vertebral hyperostosis