Eradication of therapy-resistant human prostate tumors using a cancer terminator virus

Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-x(L). Adenovirus-mediated delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a secreted cytokine having cancer-selective apoptosis-inducing properties, profoundly inhibits prostate cancer cell growth. However, forced overexpression of Bcl-2 or Bcl-x(L) renders prostate cancer cells resistant to Ad.mda-7. We constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV generates large quantities of MDA-7/IL-24 as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal prostate epithelial cells and parental and Bcl-2- or Bcl-x(L)-overexpressing prostate cancer cells confirmed cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-x(L) cells in athymic nude mice completely eradicated not only primary tumors but also distant tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for advanced prostate cancer patients with metastatic disease.     

Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis

Pancreatic cancer is one of the deadliest of cancers. Even with aggressive therapy, the 5-year survival rate is <5%, mandating development of more effective treatments. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) shows potent antitumor activity against most cancers displaying safety with significant clinical efficacy. However, pancreatic cancer cells display inherent resistance to mda-7/IL-24 that is the result of a "protein translational block" of mda-7/IL-24 mRNA in these tumor cells. We now show that a dietary supplement perillyl alcohol (POH) has significant chemopreventive effects for pancreatic cancer and, when coupled with adenovirus-mediated mda-7/IL-24 gene therapy (Ad.mda-7), effectively eliminates s.c. and i.p. xenografts of human pancreatic cancer cells in nude mice, promoting enhanced survival. The combination of POH and Ad.mda-7 efficiently abrogates the mda-7/IL-24 protein translational block, resulting in MDA-7/IL-24 protein production and growth suppression. Of direct translational relevance, clinically achievable concentrations of POH with Ad.mda-7, both of which have been found safe and without toxic effects in human trials, were used. This novel and innovative approach combining a dietary agent and a virally delivered therapeutic cytokine provides a means of both preventing and treating human pancreatic cancer with significant clinical translational potential.     

Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764)

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.     

Massive lower gastrointestinal bleeding due to 'Dieulafoy's vascular malformation' of the jejunum: case report.

Dieulafoy reported three cases of massive gastric hemorrhage due to a dilated submucosal artery in 1898, and since then, more than 100 cases of this gastric vascular malformation have been reported in the literature. These same pathologic lesions are even a rarer occurrence in the small bowel. This article reports a 38-year-old hypotensive male who presented to the hospital after an acute onset of massive lower gastrointestinal hemorrhage; superior mesenteric angiography demonstrated an actively bleeding lesion in a proximal jejunal branch. Intraoperative small bowel endoscopy via an enterotomy demonstrated a 4 mm bleeding submucosal lesion 30 cm distal to the ligament of Treitz. A literature review revealed six other cases of Dieulafoy''s vascular malformation that occurred in the small bowel, with the lesions located in the proximal jejunum between 15 cm and 45 cm distal to the ligament of Treitz. The cause of these lesions is unknown. This case demonstrates the importance of preoperative angiography and intraoperative endoscopy when massive lower gastrointestinal hemorrhage is suspected to be from a small bowel source.     

Pelvic peritoneal defects and endometriosis: Allen-Masters syndrome revisited

The peritoneum covering the pelvic viscera is usually smooth and glistening. Defects in the pelvic peritoneum are usually presumed to be acquired. Allen and Masters described such a clinical syndrome, the anatomic cornerstone of which was laceration(s) of uterine supports with resultant defect(s) in the broad and/or uterosacral ligaments. This diagnosis has been made more often recently on the basis of laparoscopic findings alone. Twenty-five cases of pelvic peritoneal defects were documented in a series of 635 consecutive diagnostic laparoscopies done primarily for pelvic pain. None fit the criteria of the Allen-Masters syndrome. Sixty-eight percent had associated endometriosis. It is suggested that pelvic peritoneal defects may be causally related to endometriosis, the disease either attacking presumably previously altered peritoneal surfaces or causing peritoneal scarring, duplication, and reduplication secondary to the cyclic insults of the ectopic endometrium and thereby producing the appearance of traumatic lacerations. Further, it is suggested that when such defects are noted at laparoscopy, the presence of other associated pathologic abnormalities, including endometriosis, should be investigated.     

Laparoscopic Falope Ring sterilization. Two years of experience.

The most commonly utilized method of tubal sterilization via laparoscopy currently is electrocautery. Because this procedure has led to disastrous consequences in a small percentage of cases, a method of nonelectric sterilization has been sought by several investigators. The Falope-Ring sterilization technique was introduced in 1973 and a preliminary report appeared in 1974. The procedure was begun at Michael Reese Hospital in 1975 and over a 2 year period 241 cases were accumulated. The procedure was found to be a relatively simple operative technique which required decreased operating time and less pneumoperitoneum at laparoscopy. It was also found to be easily teachable. It was found to be free of immediate disastrous complications and, in a rather early evaluation, it was found to be effective. There are clear indications that this technique is a viable alternative to female tubal electrocautery.     

ESPCS与营养健康教育在更年期妇女中的研究进展

更年期是指妇女从生殖期至非生殖期的过渡阶段,当妇女进入更年期后,其生殖器官（如卵巢、子宫等）功能会明显下降,且在该阶段内会出现多种临床体征。同时随着卵巢功能下降,其体内雌激素水平也随之降低,导致妇女身体和心理功能受到不良影响,严重降低生活质量,很大程度上也会引发疾病。随着我国人口数量的增多,我国进入更年期妇女人数也逐渐增多,约1/5妇女已进入该年龄阶段。因此,在女性更年期期间保持具有良好的心理状态和营养健康对其身体健康和生活质量具有重要价值。本文对讲解-模拟-实践-沟通-支持（ESPCS）与营养健康教育在更年期妇女中的效果进行研究。     

Endometriosis in adolescents

Traditional gynecologic opinion holds that endometriosis is rare in teenagers. However, several reports of this disease in teenagers have appeared over the past four decades, and in one study of a series of endometriosis patients, teenagers accounted for 8.5% of them. With these facts in mind, 43 consecutive laparoscopies were prospectively analyzed in symptomatic teenagers. A 65% incidence of endometriosis was found. The symptoms and physical findings are analyzed. The liberal use of diagnostic laparoscopy in selected symptomatic adolescents is recommended for the early diagnosis and aggressive preventive treatment of this common and potentially crippling illness.