CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers

CD133/prominin-1 is a pentaspan transmembrane glycoprotein overexpressed in various solid tumours including colorectal and glioblastomas. CD133 was found here to be highly expressed in >or=50% of pancreatic, gastric and intrahepatic cholangiocarcinomas. Quantitative flow cytometric analysis showed that a panel of established hepatocellular, pancreatic and gastric cancer cell lines expressed CD133 at levels higher than normal epithelial cells or bone marrow progenitor cells. A murine anti-human CD133 antibody (AC133) conjugated to a potent cytotoxic drug, monomethyl auristatin F (MMAF), effectively inhibited the growth of Hep3B hepatocellular and KATO III gastric cancer cells in vitro with IC(50) values of 2-7 ng ml(-1). MMAF induced apoptosis in the cancer cells as measured by caspase activation. The anti-CD133-drug conjugate (AC133-vcMMAF) was shown to internalise and colocalised with the lysosomal marker CD107a in the sensitive cell lines. In contrast, in the resistant cell line Su.86.86, the conjugate internalised and colocalised with the caveolae marker, Cav-1. Addition of ammonium chloride, an inhibitor of lysosomal trafficking and processing, suppressed the cytotoxic effect of AC133-vcMMAF in both Hep3B and KATO III. Anti-CD133-drug conjugate treatment resulted in significant delay of Hep3B tumour growth in SCID mice. Anti-CD133 antibody-drug conjugates warrant further evaluation as a therapeutic strategy to eradicate CD133+ tumours.     

A principal calling: professionalism and health care services

As heath care professionals, our "product" is clinical service. We demonstrate professionalism by attitudes, knowledge, and behaviors that reflect a multi-faceted approach to the standards, regulations, and principles underlying successful clinical practices. The issues facing practitioners who work in health care environments are complex, forming an infrastructure for conducting clinical and business operations. Issues discussed include: clinical quality and outcomes management; patient safety and medical errors; accreditation and compliance. A thorough knowledge of these topics forms the context within which we integrate our services with the larger health care community. In this age of accountability, inquiry, introspection and integrity are the keys to professionalism. LEARNING OUTCOMES: As a result of this activity, the reader will be able to: (1) discuss basic points related to the complex requirements and issues facing clinical practitioners today; (2) understand the components of "professional" practice within the health care community; (3) integrate quality management, regulatory compliance, and accreditation standards into every clinical practice. Profession: A calling requiring specialized knowledge and often long and intensive academic preparation; a principal calling, vocation, or employment. Professionalism: The conduct, aims, or qualities that characterize or mark a profession or professional person. -Webster's New Collegiate Dictionary.     

Anatomic M-mode echocardiography: A new approach to assess regional myocardial function--A comparative in vivo and in vitro study of both fundamental and second harmonic imaging modes.

OBJECTIVE: To evaluate the accuracy of anatomic M-mode echocardiography (AMM). METHODS: Eight phantoms were rotated on a device at different insonation depths (IDs) in a water beaker. They were insonated with different transducer frequencies in fundamental imaging (FI) and second harmonic imaging (SHI), and the diameters were assessed with conventional M-mode echocardiography (CMM) and AMM with the applied angle correction (AC) after rotation. In addition, left ventricular wall dimensions were measured with CMM and AMM in FI and SHI in 10 volunteers. RESULTS: AC had the greatest effect on the measurement error in AMM followed by ID (AC: R2 = 0. 295, ID: R2 = 0.268; P <.0001). SHI improved the accuracy, and a difference no longer existed between CMM and AMM with an AC up to 60 degrees. In vivo the limit of agreement between AMM and CMM was -1.7 to +1.8 mm in SHI. CONCLUSION: Within its limitations (AC < 60 degrees; ID < 20 cm), AMM could be a robust tool in clinical practice.     

胫后血管逆行皮瓣修复足部肿瘤性软组织缺损

目的探讨足部软组织肿瘤扩大切除术后出现缺损的修复方法.方法自1989年10月～2001年10月,应用胫后血管逆行岛状皮瓣修复15例足部软组织肿瘤扩大切除术后的缺损.结果15例患者随访12～84个月,平均38个月.胫后血管逆性岛状皮瓣完全成活,并且无局部复发.结论小腿内侧胫后血管逆行岛状皮瓣修复足部肿瘤性软组织缺损是理想的选择.具有就近取材、皮肤色泽结构相似,操作简单的特点.     

Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models

Cyclin D1 is one of the most commonly overexpressed oncogenes in breast cancer, with 45–50% of primary ductal carcinomas overexpressing this oncoprotein. Targeted deletion of the gene encoding cyclin D1 demonstrates an essential role in normal mammary gland development while transgenic studies provide evidence that cyclin D1 is a weak oncogene in mammary epithelium. In a recent exciting development, Yu et al. demonstrate that cyclin D1-deficient mice are resistant to mammary carcinomas induced by c-neu and v-Ha-ras, but not those induced by c-myc or Wnt-1. These findings define a pivotal role for cyclin D1 in a subset of mammary cancers in mice and imply a functional role for cyclin D1 overexpression in human breast cancer.     

Frequent loss of estrogen receptor-beta expression in prostate cancer.

The role of estrogen and its receptors in the etiology and progression of prostate cancer (PC) is poorly understood. In normal and malignant human prostate, estrogen receptor-alpha is expressed only in the stroma, whereas estrogen receptor-beta (ERbeta) is present in both normal stroma and epithelium. Because loss of ERbeta expression is associated with prostate hyperplasia in ERbeta-null mice, this study determined patterns of ERbeta expression in normal, hyperplastic, and malignant human prostate and associations with clinical outcome. Five normal prostates from organ donors and 159 radical prostatectomy specimens from patients with clinically localized PC were assessed for ERbeta expression using immunohistochemistry. ERbeta-positivity was defined as > or =5% of cells demonstrating nuclear immunoreactivity. All of the five normal prostates showed strong ERbeta-nuclear staining in >95% of the epithelium and 35% of the stromal cells. The number of ERbeta-positive cases declined to 24.2% (38/157) in hyperplasia adjacent to carcinoma and 11.3% (18/159) in PCs. ERbeta-positivity was related to decreased relapse-free survival (log-rank P = 0.04). Thus, loss of ERbeta expression is associated with progression from normal prostate epithelium to PC, whereas those cancers that retained ERbeta expression were associated with a higher rate of recurrence. These data identify the need to further investigate the potential role of ERbeta in the regulation of prostate epithelial cell proliferation and the functional consequences of decreased ERbeta expression in the evolution of PC.     

Evaluating the Impact of Overactive Bladder on Sexual Health in Women: What Is Relevant?

IntroductionTo assess sexual health, relevant, valid, and reliable questionnaires need to be used.AimTo assess the relevance and content validity of three sexual health questionnaires in women with overactive bladder (OAB) and urinary incontinence.Main Outcome MeasuresSexual Quality of Life Questionnaire––Female (SQoL‐F), Sexual Function Questionnaire (SFQ), and Pelvic Organ Prolapse–Incontinence Sexual Function Questionnaire (PISQ).MethodsWomen with OAB and urinary incontinence were recruited from five urology clinics in the United States; those who were interested in participating were mailed questionnaire packets with instructions. Each questionnaire item was followed by three questions regarding the understandability, relevance, and impact of bladder condition when responding to the question. Patients returned the completed questionnaires by mail; clinical information was obtained from chart review.ResultsA total of 129 patients (74% response) returned the questionnaires. The mean age was 56 years; 78% were white; 64% were married. In this sample, 64% had urge incontinence; 32% had mixed incontinence; and 4% had stress incontinence. Participants experienced bladder symptoms for a mean of 12.2 years with the following treatments: surgery (43%), bladder training (26%), exercise/biofeedback (42%), and medications (67%). SQoL‐F items were understood by more than 97% of the respondents, more than 89% for SFQ, and more than 82% for PISQ. There were two SQoL‐F items, one SFQ item, and 11 PISQ items that less than 60% of the respondents deemed relevant to their bladder condition. Correlations among questionnaire items and relevance to bladder condition ranged from 0.04 to 0.64 for the SQoL‐F, 0.04 to 0.47 for the SFQ, and 0.01 to 0.58 for the PISQ.ConclusionWomen with OAB found the majority of items on all three questionnaires to be relevant to their bladder condition. Of these questionnaires, the SQoL‐F had the highest understandability, fewest questions considered irrelevant, and correlated well with OAB symptoms. Coyne KS, Margolis MK, Brewster‐Jordan J, Sutherland SE, Bavendam T, and Rogers RG. Evaluating the impact of overactive bladder on sexual health in women: What is relevant? J Sex Med 2007;4:124–136.