Abstract-To evaluate the clinical application of the second derivative of the fingertip photoplethysmogram waveform, we performed drug administration studies (study 1) and epidemiological studies (study 2). In study 1, ascending aortic pressure was recorded simultaneously with the fingertip photoplethysmogram and its second derivative in 39 patients with a meanϮSD age of 54Ϯ11 years. The augmentation index was defined as the ratio of the height of the late systolic peak to that of the early systolic peak in the pulse. The negative d/a reflects the late systolic pressure augmentation in the ascending aorta and may be useful for noninvasive evaluation of the effects of vasoactive agents. In study 2, the second derivative of the plethysmogram waveform was measured in a total of 600 subjects (50 men and 50 women in each decade from the 3rd to the 8th) in our health assessment center. The b/a ratio increased with age, and c/a, d/a, and e/a ratios decreased with age. Thus, the second derivative aging index was defined as b-c-d-e/a. The second derivative wave aging index (y) increased with age (x) (rϭ0.80, PϽ0.001, yϭ0.023xϪ1.515). The second derivative aging index was higher in 126 subjects with any history of diabetes mellitus, hypertension, hypercholesterolemia, and ischemic heart disease than in age-matched subjects without such a history (Ϫ0. Key Words: photoplethysmography Ⅲ second derivative wave Ⅲ augmentation index Ⅲ vasoactive agents Ⅲ vascular aging Ⅲ angiotensin Ⅲ nitroglycerin N oninvasive pulse wave analysis is useful for evaluation of vascular load and vascular aging. 1 It is usually measured at the palpable artery, including carotid, femoral, and radial arteries.2 These pulse wave tracings provide more precise information concerning blood pressure changes than systolic and diastolic pressures only. 3 The basic idea of the augmentation index was first described by Murgo et al 4 in 1980 in relation to the reflection return point in the ascending aorta. Kelly et al 2 first used the term "augmentation index" in their 1989 study evaluating age-related changes in AIs. They showed age-related increase in AIs at carotid and radial arteries. Ascending aortic pressure can be divided into 2 components at the anacrotic notch, where maximal flow velocity is observed.2 The early systolic component is caused mainly by left ventricular ejection, and the second component is augmented by peripheral reflection wave.5 PTG detects the changes in the amount of light absorbed by hemoglobin, which reflects changes in blood volume. Wiederhelm et al 6 showed pulsatile pressure changes in vessel down to metaarteriole size that corresponded to pulse tracing. PTG has been used to evaluate arterial compliance in relation to changes in the amplitude of wave, 7 but the wave contour itself is not usually used. The SDPTG has been developed to allow more accurate recognition of the inflection points on the original plethysmographic wave, ie, anacrotic or dicrotic notches. In 1972, Ozawa recorded the first and second derivative waves of P...

Meis1 and Hoxa9 expression is upregulated by retroviral integration in murine myeloid leukemias and in human leukemias carrying MLL translocations. Both genes also cooperate to induce leukemia in a mouse leukemia acceleration assay, which can be explained, in part, by their physical interaction with each other as well as the PBX family of homeodomain proteins. Here we show that Meis1-deficient embryos have partially duplicated retinas and smaller lenses than normal. They also fail to produce megakaryocytes, display extensive hemorrhaging, and die by embryonic day 14.5. In addition, Meis1-deficient embryos lack well-formed capillaries, although larger blood vessels are normal. Definitive myeloerythroid lineages are present in the mutant embryos, but the total numbers of colony-forming cells are dramatically reduced. Mutant fetal liver cells also fail to radioprotect lethally irradiated animals and they compete poorly in repopulation assays even though they can repopulate all hematopoietic lineages. These and other studies showing that Meis1 is expressed at high levels in hematopoietic stem cells (HSCs) suggest that Meis1 may also be required for the proliferation/self-renewal of the HSC.

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LAMP3 (DC-LAMP, TSC403, CD208) was originally isolated as a gene specifically expressed in lung tissues. LAMP3 is located on a chromosome 3q segment that is frequently amplified in some human cancers, including uterine cervical cancer. Because two other members of the LAMP family of lysosomal membrane glycoproteins, LAMP1 and LAMP2, were previously implicated in potentially modulating the interaction of vascular endothelial and cancer cells, we hypothesized that LAMP3 might also play an important part in metastasis. To clarify the metastatic potential of LAMP3 in cervical cancers, we transfected a LAMP3 expression vector into a human uterine cervical cancer cell line, TCS. In an in vitro invasion assay, the migration of LAMP3-overexpressing TCS cells was significantly higher than in control TCS cells. In an in vivo metastasis assay, distant metastasis was detected in 9 of 11 LAMP3-overexpressing TCS cell-injected mice and in only 1 of 11 control mice. Histologic study showed that LAMP3-overexpressing cells readily invaded into the lymph-vascular space. In clinical samples, quantitative real-time reverse transcription-PCR (RT-PCR) analyses showed that LAMP3 mRNA was significantly up-regulated in 47 of 47 (100%) cervical cancers and in 2 of 15 (13%) cervical intraepithelial neoplasias, compared with a low level of LAMP3 mRNA expressed in normal uterine cervixes. Interestingly, high LAMP3 expression was significantly correlated with the overall survival of patients with stage I/II cervical cancers. These findings indicate that LAMP3 overexpression is associated with an enhanced metastatic potential and may be a prognostic factor for cervical cancer. (Cancer Res 2005; 65(19): 8640-5)

Serum tumor markers have a major role in the screening, diagnosis, and monitoring of most of the gynecologic cancers. Ovarian cancer is one of the deadliest of the group because it is so frequently asymptomatic until it has advanced to an untreatable stage. Even serum cancer antigen-125 (CA-125), clinically one of the most reliable serum markers for ovarian cancer, is elevated in only half of early-stage still-treatable tumors. Because of the very low prevalence of ovarian cancer in the general population, at present, there is no cost-effective imaging or simple microscopic screening test for ovarian cancer as there is for breast and cervical cancers. However, recent proteomics and nucleic acid-based analyses have shown great promise for the discovery of new and more useful serum biomarkers, which cumulatively might provide such a screening tool. In this review, we will discuss both the currently used serum tumor markers for screening, diagnosis, monitoring of ovarian cancer, and the novel biomarkers that are now under investigation and validation.

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Clear cell carcinoma (CCC) of the ovary is known to be highly resistant to platinum-based chemotherapy. The purpose of our study was to identify a candidate protein that is associated with chemoresistance of CCC and to investigate the specific mechanism of chemoresistance conferred by the identified protein. Enhanced expression of Annexin A4 (Anx A4) was identified in ovarian CCC cells using 2-D differential gel electrophoresis (2D-DIGE) and mass spectrometry. Anx A4 levels were elevated in CCC cells compared with non-CCC cells as determined by real-time RT-PCR and Western blot analysis. Immunohistochemical analysis of Anx A4 was performed in 126 epithelial ovarian cancer tissue samples and demonstrated significantly elevated levels of Anx A4 protein levels in ovarian CCC tumors compared with ovarian serous and endometrioid tumors (p < 0.01). Anx A4-transfected ovarian non-CCC cells were more resistant to carboplatin (IC50 5 42 lM) compared with control cells (IC50 5 23 lM) as determined by modified MTT assay. Intracellular platinum levels were significantly lower in Anx A4-transfected cells compared with control cells after carboplatin treatment (p 5 0.0020) and after an additional 360 min of carboplatin-free incubation (p 5 0.0004), as measured by atomic absorption spectrophotometry. Expression of Anx A4 is elevated in ovarian CCC tumors and is associated with chemoresistance in cultured ovarian cancer cells. These results demonstrate that Anx A4 confers chemoresistance in ovarian cancer cells in part by enhancing drug efflux. Thus, Anx A4 may represent a novel therapeutic target of chemoresistance in patients with ovarian CCC. ' 2009 UICC

Squamous cell carcinoma (SCC) accounts for approximately 95% of the malignant tumors of the vaginal vulva and is mostly found in elderly women. The future numbers of patients with vulvar SCC is expected to rise, mainly because of the proportional increase in the average age of the general population. Two different pathways for vulvar SCC have been put forth. The first pathway is triggered by infection with a high-risk-type Human Papillomavirus (HPV). Integration of the HPV DNA into the host genome leads to the development of a typical vulvar intraepithelial neoplasia (VIN), accompanied with overexpression of p14ARF and p16INK4A. This lesion subsequently forms a warty- or basaloid-type SCC. The HPV vaccine is a promising new tool for prevention of this HPV related SCC of the vulva. The second pathway is HPV-independent. Keratinizing SCC develops within a background of lichen sclerosus (LS) through a differentiated VIN. It has a different set of genetic alterations than those in the first pathway, including p53 mutations, allelic imbalances (AI), and microsatellite instability (MSI). Further clinical and basic research is still required to understand and prevent vulvar SCC. Capsule. Two pathway for pathogenesis of squamous cell carcinoma of the value are reviewed.