Rectosigmoid Adenocarcinoma Presenting As Nine Days of Constipation.

We report the case of a 56-year-old male presenting with nine days of constipation and absence of flatus without any improvement and who had received conservative management after recent admission at an external hospital. Upon further investigation, the patient was diagnosed with rectosigmoid adenocarcinoma and was successfully surgically treated without any perioperative complications. This case highlights the importance of early detection and interventions necessary to prevent progression of colorectal adenocarcinoma. Easily manageable symptoms such as constipation may require further evaluation by implementing a constipation scoring system to avoid missed diagnoses such as cancer and metastasis. Therefore, the association between constipation and colorectal carcinoma warrants further research investigations as well as clinician awareness to prevent life-threatening complications.

Stable and persistent male-like behavior during male-to-female sex change in the common clownfish Amphiprion ocellaris.

Many fish species exhibit natural sex change as part of their life, providing unique opportunities to study sexually-differentiated social behaviors and their plasticity. Past research has shown that behavioral sex change in the female-to-male (protogynous) direction occurs rapidly and well before gonadal sex change. However, little is known about the timecourse of behavioral sex change in male-to-female (protandrous) sex-changing species, limiting our ability to compare patterns of behavioral sex change across species and identify conserved or divergent underlying mechanisms. Using the protandrous sex changing anemonefish Amphiprion ocellaris, we assessed behavior (aggression and parental care) and hormones (estradiol and 11-ketotestosterone) in fish over six months of sex change, and compared those fish against their non-changing partners as well as control males and females. Contrary to expectations, we found that sex-changing fish displayed behavior that was persistently male-like, and that their behavior did not become progressively female-like as sex change progressed. Hormones shifted to an intermediate profile between males and females and remained stable until gonads changed. These results support a new perspective that the timecourse for protandrous sex change in anemonefish is completely distinct from other well-established models, such that behavioral sex change does not occur until after gonadal sex change is complete, and that sex-changing fish have a stable and unique behavioral and hormonal phenotype that is distinct from a male-typical or female-typical phenotype. The results also identify aspects of sex change that may fundamentally differ between protandrous and protogynous modes, motivating further research into these remarkable examples of phenotypic plasticity.

Metabolomic profiling of stool of two-year old children from the INSIGHT study reveals links between butyrate and child weight outcomes.

BACKGROUND: Metabolomic analysis is commonly used to understand the biological underpinning of diseases such as obesity. However, our knowledge of gut metabolites related to weight outcomes in young children is currently limited. OBJECTIVES: To (1) explore the relationships between metabolites and child weight outcomes, (2) determine the potential effect of covariates (e.g., child's diet, maternal health/habits during pregnancy, etc.) in the relationship between metabolites and child weight outcomes, and (3) explore the relationship between selected gut metabolites and gut microbiota abundance. METHODS: Using 1 H-NMR, we quantified 30 metabolites from stool samples of 170 two-year-old children. To identify metabolites and covariates associated with children's weight outcomes (BMI [weight/height2 ], BMI z-score [BMI adjusted for age and sex], and growth index [weight/height]), we analysed the 1 H-NMR data, along with 20 covariates recorded on children and mothers, using LASSO and best subset selection regression techniques. Previously characterized microbiota community information from the same stool samples was used to determine associations between selected gut metabolites and gut microbiota. RESULTS: At age 2 years, stool butyrate concentration had a significant positive association with child BMI (p-value = 3.58 × 10-4 ), BMI z-score (p-value = 3.47 × 10-4 ), and growth index (p-value = 7.73 × 10-4 ). Covariates such as maternal smoking during pregnancy are important to consider. Butyrate concentration was positively associated with the abundance of the bacterial genus Faecalibacterium (p-value = 9.61 × 10-3 ). CONCLUSIONS: Stool butyrate concentration is positively associated with increased child weight outcomes and should be investigated further as a factor affecting childhood obesity.

Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders.

Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes.

Impact of bisphenol-A and synthetic estradiol on brain, behavior, gonads and sex hormones in a sexually labile coral reef fish.

Endocrine disrupting chemicals, such as bisphenol A (BPA) and ethinylestradiol (EE2), are detected in the marine environment from plastic waste and wastewater effluent. However, their impact on reproduction in sexually labile coral reef fish is unknown. The objective of this study was to determine impacts of environmentally relevant concentrations of BPA and EE2 on behavior, brain gene expression, gonadal histology, sex hormone profile, and plasma vitellogenin (Vtg) levels in the anemonefish, Amphiprion ocellaris. A. ocellaris display post-maturational sex change from male to female in nature. Sexually immature, male fish were paired together and fed twice daily with normal food (control), food containing BPA (100 µg/kg), or EE2 (0.02 µg/kg) (n = 9 pairs/group). Aggression toward an intruder male was measured at 1, 3, and 6 months. Blood was collected at 3 and 6 months to measure estradiol (E2), 11-ketotestosterone (11-KT), and Vtg. At the end of the study, fish were euthanized to assess gonad morphology and to measure expression of known sexually dimorphic genes in the brain. Relative to control, BPA decreased aggression, altered brain transcript levels, increased non-vitellogenic and vitellogenic eggs in the gonad, reduced 11-KT, and increased plasma Vtg. In two BPA-treated pairs, both individuals had vitellogenic eggs, which does not naturally occur. EE2 reduced 11-KT in subordinate individuals and altered expression of one transcript in the brain toward the female profile. Results suggest BPA, and to a lesser extent EE2, pollution in coral reef ecosystems could interfere with normal reproductive physiology and behavior of the iconic sexually labile anemonefish.

A novel neurotensin/xenin fusion peptide enhances ß-cell function and exhibits antidiabetic efficacy in high-fat fed mice.

Neurotensin and xenin possess antidiabetic potential, mediated in part through augmentation of incretin hormone, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), action. In the present study, fragment peptides of neurotensin and xenin, acetyl-neurotensin and xenin-8-Gln, were fused together to create Ac-NT/XN-8-Gln. Following assessment of enzymatic stability, effects of Ac-NT/XN-8-Gln on in vitro ß-cell function were studied. Subchronic antidiabetic efficacy of Ac-NT/XN-8-Gln alone, and in combination with the clinically approved GLP-1 receptor agonist exendin-4, was assessed in high-fat fed (HFF) mice. Ac-NT/XN-8-Gln was highly resistant to plasma enzyme degradation and induced dose-dependent insulin-releasing actions (P<0.05 to P<0.01) in BRIN-BD11 ß-cells and isolated mouse islets. Ac-NT/XN-8-Gln augmented (P<0.001) the insulinotropic actions of GIP, while possessing independent ß-cell proliferative (P<0.001) and anti-apoptotic (P<0.01) actions. Twice daily treatment of HFF mice with Ac-NT/XN-8-Gln for 32 days improved glycaemic control and circulating insulin, with benefits significantly enhanced by combined exendin-4 treatment. This was reflected by reduced body fat mass (P<0.001), improved circulating lipid profile (P<0.01) and reduced HbA1c concentrations (P<0.01) in the combined treatment group. Following an oral glucose challenge, glucose levels were markedly decreased (P<0.05) only in combination treatment group and superior to exendin-4 alone, with similar observations made in response to glucose plus GIP injection. The combined treatment group also presented with improved insulin sensitivity, decreased pancreatic insulin content as well as increased islet and ß-cell areas. These data reveal that Ac-NT/XN-8-Gln is a biologically active neurotensin/xenin fusion peptide that displays prominent antidiabetic efficacy when administered together with exendin-4.

Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.

Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.

PURPOSE: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. EXPERIMENTAL DESIGN: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing. RESULTS: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. CONCLUSIONS: This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.

Individual and combined effects of GIP and xenin on differentiation, glucose uptake and lipolysis in 3T3-L1 adipocytes.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP), released postprandially from K-cells, has established actions on adipocytes and lipid metabolism. In addition, xenin, a related peptide hormone also secreted from K-cells after a meal, has postulated effects on energy regulation and lipid turnover. The current study has probed direct individual and combined effects of GIP and xenin on adipocyte function in 3T3-L1 adipocytes, using enzyme-resistant peptide analogues, (d-Ala2)GIP and xenin-25-Gln, and knockdown (KD) of receptors for both peptides. (d-Ala2)GIP stimulated adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes over 96 h, with xenin-25-Gln evoking similar effects. Combined treatment significantly countered these individual adipogenic effects. Individual receptor KD impaired lipid accumulation and adipocyte differentiation, with combined receptor KD preventing differentiation. (d-Ala2)GIP and xenin-25-Gln increased glycerol release from 3T3-L1 adipocytes, but this lipolytic effect was significantly less apparent with combined treatment. Key adipogenic and lipolytic genes were upregulated by (d-Ala2)GIP or xenin-25-Gln, but not by dual peptide culture. Similarly, both (d-Ala2)GIP and xenin-25-Gln stimulated insulin-induced glucose uptake in 3T3-L1 adipocytes, but this effect was annulled by dual treatment. In conclusion, GIP and xenin possess direct, comparable, lipogenic and lipolytic actions in 3T3-L1 adipocytes. However, effects on lipid metabolism are significantly diminished by combined administration.

Ψ-Xenin-6 enhances sitagliptin effectiveness, but does not improve glucose tolerance.

Recent studies have characterised the biological properties and glucose-dependent insulinotropic polypeptide (GIP) potentiating actions of an enzymatically stable, C-terminal hexapeptide fragment of the gut hormone xenin, namely Ψ-xenin-6. Given the primary therapeutic target of clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor drugs is augmentation of the incretin effect, the present study has assessed the capacity of Ψ-xenin-6 to enhance the antidiabetic efficacy of sitagliptin in high fat fed (HFF) mice. Individual administration of either sitagliptin or Ψ-xenin-6 alone for 18 days resulted in numerous metabolic benefits and positive effects on pancreatic islet architecture. As expected, sitagliptin therapy was associated with elevated circulating GIP and GLP-1 levels, with concurrent Ψ-xenin-6 not elevating these hormones or enhancing DPP-4 inhibitory activity of the drug. However, combined sitagliptin and Ψ-xenin-6 therapy in HFF mice was associated with further notable benefits, beyond that observed with either treatment alone. This included body weight change similar to lean controls, more pronounced and rapid benefits on circulating glucose and insulin as well as additional improvements in attenuating gluconeogenesis. Favourable effects on pancreatic islet architecture and peripheral insulin sensitivity were more apparent with combined therapy. Expression of hepatic genes involved in gluconeogenesis and insulin action were partially, or fully, restored to normal levels by the treatment regimens, with beneficial effects more prominent in the combination treatment group. These data demonstrate that combined treatment with Ψ-xenin-6 and sitagliptin did not alter glucose tolerance but does offer some metabolic advantages, which merit further consideration as a therapeutic option for type 2 diabetes.

Exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice.

BACKGROUND: Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination. METHODS: Therefore, to prolong the biological action profile of the recently characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized as direct comparator peptides. RESULTS: All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin. CONCLUSION: This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes.

Xenin-25 is a 25-amino acid peptide hormone co-secreted from the same enteroendocrine K-cell as the incretin peptide glucose-dependent insulinotropic polypeptide. There is no known specific receptor for xenin-25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin-25 focussed on effects related to gastrointestinal transit and satiety. However, xenin-25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta-cell survival. Accordingly, the beneficial impact of xenin-25, and related analogues, has been assessed in animal models of diabetes-obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin-25, particularly xenin-8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi-acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes-obesity.

Ultraviolet light and melanoma.

Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Tobacco-Cessation Interventions and Attributes of Individual and Organizational Excellence in Acute Care.

BACKGROUND: Despite years of reducing tobacco use, few studies describe to what extent evidence-based tobacco-cessation interventions are a standard of acute and critical care nursing practice using the US Public Health Service 5 A's framework: ask, advise, assess, assist, and arrange. OBJECTIVES: To identify relationships between the 5 A's framework, attributes of individual and organizational excellence, and intention to integrate tobacco-cessation interventions as a standard of daily practice among nurses. METHODS: Nurses attending the American Association of Critical-Care Nurses National Teaching Institute were invited to complete a 21-item survey. Data were gathered in Boston, Orlando, and Chicago in a 3-year period. Descriptive statistics and logistic regression were used for data analysis. RESULTS: Among 1773 completed surveys, nurses from organizations with standing orders for tobacco dependence were 5 times more likely to have high confidence in their 5 A's skills (odds ratio, 5.037; 95% CI, 3.429-7.400; P < .001) and 3.4 times more likely to have high intentions to integrate tobacco cessation into their daily practice (odds ratio, 3.421; 95% CI, 1.765-6.628; P < .001). Nurses with certifications were more likely to want to learn how to integrate tobacco-cessation interventions (odds ratio, 1.676; 95% CI, 0.990-2.836; P = .05). CONCLUSIONS: Opportunities abound to create strategies leveraging attributes of nursing and organizational excellence to promote evidence-based approaches to improve health outcomes in acutely and critically ill tobacco-dependent populations.

Early removal of urinary catheter after surgery requiring thoracic epidural: a prospective trial.

OBJECTIVES: To prevent urinary retention, urinary catheters commonly are removed only after thoracic epidural discontinuation after thoracotomy. However, prolonged catheterization increases the risk of infection. The purpose of this study was to determine the rates of urinary retention and catheter-associated infection after early catheter removal. DESIGN: This study described a prospective trial instituting an early urinary catheter removal protocol compared with a historic control group of patients. SETTING: The protocol was instituted at a single, academic thoracic surgery unit. PARTICIPANTS: The study group was comprised of patients undergoing surgery requiring thoracotomy who received an intraoperative epidural for postoperative pain control. INTERVENTIONS: An early urinary catheter removal protocol was instituted prospectively, with all catheters removed on or before postoperative day 2. Urinary retention was determined by bladder ultrasound and treated with recatheterization. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were urinary retention rate, defined as bladder volume>400 mL, and urinary tract infection rate. Results were compared with a retrospective cohort of 210 consecutive patients who underwent surgery before protocol initiation. Among the 101 prospectively enrolled patients, urinary retention rate was higher (26.7% v 12.4%, p = 0.003), while urinary tract infection rate improved moderately (1% v 3.8%, p = 0.280). CONCLUSIONS: Early removal of urinary catheters with thoracic epidurals in place is associated with a high incidence of urinary retention. However, an early catheter removal protocol may play a role in a multifaceted approach to reducing the incidence of catheter-associated urinary tract infections.

Temporal variation in the distribution of hyaluronic acid, CD44s, and CD44v6 in the human endometrium across the menstrual cycle.

Tissues undergoing rapid growth and regeneration contain hyaluronic acid (HA) as a prominent component of the extracellular matrix. The physiologic role of HA is partly mediated by its relationship with CD44, its major cell surface receptor. Given the extensive remodeling of the endometrium during the menstrual cycle, the authors sought to determine whether these changes are related to the levels of HA, CD44s, and CD44v6 in the endometrium. Archival paraffin embedded cell blocks from 10 cases of proliferative endometrium and 20 cases of secretory endometrium were retrieved from the surgical pathology files. Specimens from the secretory phase were subdivided into three categories: early secretory (day 15-18), mid-secretory (day 19-23), and late secretory (day 24-28). All cases were stained for hyaluronic acid, CD44s, and CD44v6. Sections from umbilical cord, tonsil, and squamous cell carcinoma served as positive controls for HA, CD44s, and CD44v6, respectively. Positive staining was defined as droplet to diffuse intracytoplasmic or extracellular staining for HA and uniform membranous staining for CD44. During the proliferative phase, the endometrial glands and the stroma were both negative for CD44s and CD44v6 in all cases. In the secretory phase, the endometrial glands were negative for CD44s in all cases, but CD44v6 was expressed in 12 (60%) of cases. In contrast, the stromal cells expressed CD44s in 18 (90%) cases and were negative for CD44v6 in all cases. HA staining was present in the endometrial stroma throughout the menstrual cycle but was most intense (3+) and diffuse during the midsecretory phase. There was perivascular staining for HA throughout the cycle; it was most intense adjacent to the spiral arterioles in the secretory phase. These data indicate temporal and geographic differences in HA and CD44 staining in the endometrium in concert with the menstrual cycle. The timing of peak staining of HA and CD44s in the stroma and the upregulation of CD44v6 in secretory glands are coincident with the period in which the endometrium is most receptive to embryo implantation. Whether these changes are mere hormonal consequences or actually help modulate the cyclical changes in the endometrium warrants further study.

Expression of hyaluronic acid and its receptors, CD44s and CD44v6, in normal, hyperplastic, and neoplastic endometrium.

The interaction between epithelial tumor cells and their surrounding stroma is important in tumor progression and metastasis. This is accomplished through a number of transmembrane receptors that interact with stromal extracellular matrix molecules. One of these receptors, CD44, binds to extracellular matrix component hyaluronic acid (HA). The purpose of this study was to evaluate the significance of HA, CD44s, and CD44v6 in benign, hyperplastic, atypical, and malignant endometrial epithelia. Archival paraffin-embedded cell blocks from proliferative endometrium (n = 11), secretory endometrium (n = 12), simple hyperplasia (n = 13), complex hyperplasia without atypia (n = 9), complex hyperplasia with atypia (n = 17), and adenocarcinoma (n = 21) were stained for HA, CD44s, and CD44v6. HA was detected throughout the normal menstrual cycle but was more intense during the secretory phase. Only during the secretory phase was CD44s expressed in the stromal cells in 11 cases (92%), whereas CD44v6 was detected in glandular epithelium in 9 (75%). CD44s was expressed in the glandular epithelium in 2 (15%) cases of simple hyperplasia, 4 (44%) of complex hyperplasia without atypia, 14 (82%) of complex hyperplasia with atypia, and in 16 (76%) of adenocarcinoma. CD44v6 was expressed in the glandular epithelium in 1 (11%) case of complex hyperplasia without atypia, 17 (100%) cases of complex hyperplasia with atypia, and in 18 (86%) cases of adenocarcinoma, but in none of the cases of simple hyperplasia. The endometrial stromal cells expressed CD44v6 in 1 (8%) case of simple hyperplasia, 6 (67%) of complex hyperplasia without atypia, 8 (47%) of complex hyperplasia with atypia, and in 3 (14%) of adenocarcinoma. We concluded that in the normal menstrual cycle, the timing of peak staining of HA and CD44s in the stroma and the up-regulation of CD44v6 in secretory glands are coincident with the period in which the endometrium is most receptive to embryo implantation. HA is more abundant in the stroma adjacent to the tumor, suggesting that interactions between tumor cells and stromal HA promote tumorigenesis. With progression from hyperplasia and with increasing atypia to adenocarcinoma, levels of stromal HA, glandular CD44v6, and glandular and stromal CD44s all increase. Thus, HA and CD44 are both involved in the development and progression of endometrial cancer.

Synthesis and biological properties of novel glucocorticoid androstene C-17 furoate esters.

A series of novel corticosteroid derivatives featuring C-17 furoate ester functionality have been synthesised. Profiling in vitro and in vivo has resulted in the identification of a compound with a longer duration of action and a lower oral side effect profile in rodents compared to budesonide.