Tanespimycin: the opportunities and challenges of targeting heat shock protein 90

Background: Heat shock protein 90 (HSP90) is the core of a multi-chaperone complex critical for the folding, trafficking, and stabilization of many client proteins that are involved in tumor cell proliferation, survival, and angiogenesis. Targeting HSP90 results in degradation of these client proteins. Objective: Data supporting the development of tanespimycin, which targets HSP90, are reviewed. Methods: Clinical data available for tanespimycin development are presented. Results: Tanespimycin can be given safely at biologically active doses with mild toxicity such as nausea, vomiting, diarrhea, and fatigue. Although single-agent studies have shown limited activity, combinations of tanespimycin with bortezomib or trastuzumab have suggested promising avenues of further evaluation in multiple myeloma and breast cancer, respectively. Conclusions: Further development of HSP90-targeted strategies include testing of novel chemical structures having better solubility and stability and the potential for oral administration. Targeting of HSP90 in combination with other heat shock proteins, such as HSP70 or HSP27, may be an alternative strategy that warrants further exploration.     

New therapeutics based on emerging concepts in pulmonary fibrosis

Introduction: Fibrosis is an irreversible pathological endpoint in many chronic diseases, including pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal condition characterized by (myo)fibroblast proliferation and transformation in the lung, expansion of the extracellular matrix, and extensive remodeling of the lung parenchyma. Recent evidence indicates that IPF prevalence and mortality rates are growing in the United States and elsewhere. Despite decades of research on the pathogenic mechanisms of pulmonary fibrosis, few therapeutics have succeeded in the clinic, and they have failed to improve IPF patient survival.

Areas covered: Based on a literature search and our own results, we discuss the key cellular and molecular responses that contribute to (myo)fibroblast actions and pulmonary fibrosis pathogenesis; this includes signaling pathways in various cells that aberrantly and persistently activate (myo)fibroblasts in fibrotic lesions and promote scar tissue formation in the lung.

Expert opinion: Lessons learned from recent failures and successes with new therapeutics point toward approaches that can target multiple pro-fibrotic processes in IPF. Advances in preclinical modeling and single-cell genomics will also accelerate novel discoveries for effective treatment of IPF.     

Tephrosin-induced autophagic cell death in A549 non-small cell lung cancer cells

Anticancer effect of tephrosin (1) has been documented; however, the molecular mechanisms underlying the cytotoxicity of tephrosin in cancer cells remain unclear. In the present paper, the proliferation inhibition rate of several cancer cells was tested using the MTT assay; cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were determined by flow cytometry; poly(ADP-ribose) polymerase (PARP) cleavage and heat shock protein 90 (Hsp90) expression were evaluated by Western blotting; autophagy was examined by confocal microscopy and light chain 3 (LC3) conversion assay. The results showed that exposure of the cells to tephrosin induced significant proliferation inhibition in a dose-dependent manner, especially on A549 with G₂/M being arrested. Tephrosin was not found to induce cell apoptosis as PARP cleavage was not detected after 24 h treatment, but the formation of acidic vesicular organelle of autophagy character was found, and autophagy was further confirmed by the increase in the ratio of LC3-II to LC3-I. It was observed that tephrosin induced ROS generation and Hsp90 expression inhibition. These results indicate that tephrosin induces A549 cancer cell death via the autophagy pathway, and the roles of ROS generation and Hsp90 expression inhibition in this process need further study in the future.     

有症状和无症状Barrett食管患者胃镜及病理检查探讨

目的观察比较有症状和无症状Barrett食管患者胃镜及病理表现。方法选取笔者所在医院诊断为Barrett食管的患者80例,根据有无临床表现将患者分为两组,每组40例,所有患者均经胃镜检查并活检,观察两组病变形态,长度,增生程度。结果Ⅰ组(无症状组)全周型比例(20%)较Ⅱ组(有症状组)(10%)显著增多(P<0.05);Ⅰ组短节段型(27.5%)较Ⅱ组(55.0%)显著减少(P<0.05);Ⅰ组超短节段型(62.5%)较Ⅱ组(32.5%)显著增多(P<0.05);Ⅰ组与Ⅱ组比较中、重度增生(10%,25%)显著减少,轻度增生(90%,75%)显著增多。结论有症状Barrett食管患者胃镜表现及病理检查较无症状患者严重,对有症状Barrett食管患者检查、诊断应更加重视,以明确诊断,指导治疗和随访。     

Treatment of skin necrosis after radiation synovectomy with yttrium-90: a case report

Chronic synovitis, unresponsive to systemic medical therapy including agents, anti-inflammatory drugs and remission-inducing agents, and intra-articular administration of corticosteroids can be treated with surgical, chemical and radiation synovectomy. We reported a case of a 23 years old male. Skin radiation necrosis (4 x 5 cm) developed after an injection of Yttrium-90 (Y-90). Full-thickness skin graft had been applied but we were not able to succeed. Skin radiation necrosis was treated with Limberg's flap. As a result we recommend flap surgery instead of skin graft in skin radiation necrosis.     

The Constipation Severity Instrument: A Validated Measure

Purpose This study was designed to develop and test the validity and reliability of the Constipation Severity Instrument. Methods Scale development was conducted in two stages: 1) 74 items were generated through a literature review and focus groups of constipated patients and medical providers; and 2) a preliminary instrument was administered to 191 constipated patients and 103 healthy volunteers. Test-retest reliability of the constipated group was assessed (N = 90). Content, convergent, divergent, and discriminant validity were evaluated by using other validated measures by performing one-way analysis of variance and Pearson correlations. Results Exploratory and confirmatory factor analysis revealed three subscales: obstructive defecation, colonic inertia, and pain. Internal consistency (α = 0.88–0.91) and test-retest reliability (intraclass correlation coefficients = 0.84–0.91) were high for all subscales. Constipated patients were grouped by Rome II criteria: functional constipation (22 percent), pelvic floor dyssynergia (15 percent), constipation predominant irritable bowel syndrome (23 percent), and no specific criteria (40 percent). Those with constipation predominant irritable bowel syndrome or pelvic floor dyssynergia scored higher on the Obstructive Defecation and Colonic Inertia subscales than those with functional constipation or no specific criteria (P = 0.001–0.058). Subjects with functional constipation had much lower scores on the pain subscale than constipation predominant irritable bowel syndrome, functional constipation, or no specific criteria (P < 0.009).The Constipation Severity Instrument subscale and total score correlated very highly with the subscales and total score of the Patient Assessment of Constipation Symptom measure. The Constipation Severity Instrument subscales discriminated well between constipated patients and healthy volunteers (P < 0.001) and demonstrated excellent divergent validity. Higher Constipation Severity Instrument scores inversely correlated with general quality of life. Conclusions The Constipation Severity Instrument is a reliable and valid instrument for assessing constipated patients. Administration of the Constipation Severity Instrument to other constipated patients will further validate its use. Supported by the University of California San Francisco Hellman Family Award for Early Career Faculty. Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 6, 2007. Reprints are not available.     

A hydrodynamic study of pleural drainage systems: some practical consequences

BACKGROUND: A pleural drainage system must be capable of efficiently evacuating the air or fluids from the pleural cavity so that adequate lung reexpansion can take place. The air flow and negative pressure of the system will depend on the particular design of each model. This experimental study analyzes the specifications and performance of the pleural drainage systems currently on the market. METHODS: Thirteen models of pleural drainage systems connected to wall suction were examined. The models were classified into the following three groups: dry systems; wet systems; and single-chamber systems. We determined the ambient air flow and the negative pressure generated according to the suction level. The components of each model are also described. RESULTS: Under normal conditions, dry (except for the Sentinel Seal; Sherwood Medical; Tullamore, Ireland), wet, and single-chamber systems reach similar air flow rates (17 to 30, 24 to 27, and 22 to 28 L/min, respectively). With higher wall suction levels, wet systems increase the air flow (26 to 49 L/min) but the negative pressure becomes unstable because of the water loss phenomenon, dry systems increase the air flow (29 to 50 L/min) without modifying the regulator pressure, and single-chamber systems also raise the air flow (45 to 51 L/min) but increase the negative pressure. When there is an air leak, dry systems (except for the Sentinel Seal) lose less negative pressure than the other systems. CONCLUSIONS: The functioning of these systems can be optimized only by applying a suitable wall suction level adjusted to each case. Although the three types of systems are capable of evacuating adequate air flow rates, the negative pressure and the capacity to maintain it in the presence of an air leak are different in each system. Being fitted with valves and not water compartments makes the dry systems the safest and the ideal for use when the patient has to be moved.     

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Src-dependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.     

Definition of disease duration in ankylosing spondylitis

Two definitions of the “disease duration” of ankylosing spondylitis (AS) have been used in the literature: (1) duration since first symptoms connected with AS and (2) duration since diagnosis of AS. To investigate how useful these definitions are for research, we reinvestigated the data of four surveys completed by patients with AS in the years since 1996. We found that the majority of the patients remembered the age at first symptoms with an accuracy of ≤1 year, and that the difference between both definitions (the delay in diagnosis) was between 9.8 and 10.4 years on average, with extreme values of more than 30 years being not very seldom. Because the error made using the duration since diagnosis as “disease duration” is much larger than the inaccuracy taken into account using the duration since first symptoms, only the duration since first symptoms connected with AS should be used as definition for the term “disease duration” of AS.     

晚期非小细胞肺癌化疗效果与化疗敏感性研究

目的：探讨分析晚期非小细胞肺癌化疗的效果以及化疗敏感性。方法随机选取2009年6月—2011年7月该院收治的100例晚期非小细胞肺癌患者的临床资料,随机分成4个小组,分别采取TP、DP、GP、NP的化疗方案,对其中的5例患者进行9mTc-MIBI 检查,观察四种化疗方案的总有效率和4组患者的生存率,观察影像检查结果中疗效和阳性之间的关系。结果TP组和DP组的治疗有效率高于GP、NP组（40.0%、40.0%vs32.0%、28.0%）,患者1年生存率也较高（44.0%、48.0%vs32.0%、32.0%)。9mTc-MIBI检查结果为阴性不能排除患病的可能。结论 TP方案和DP方案在治疗有效率以及治疗后患者的生存率上均有明显优势,即使9mTc-MIBI检查结果为阴性,仍需完善相关的检查项目或进行临床观察。