Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

Estrogen/Progesterone Receptor Expression and Cancer Antigen 125 Level as Preoperative Predictors to Estimate Lymph Node Metastasis in Endometrioid Endometrial Cancer.

Loss of estrogen receptor/progesterone receptor (ER/PR) in endometrial cancer (EC) is associated with tumor progression and poor outcomes. Elevated pretreatment cancer antigen 125 (CA 125) level is a risk factor for lymph node metastasis (LNM). We evaluated whether the combination of ER/PR expression and CA 125 level could be used as a biomarker to predict LNM. We retrospectively investigated patients with endometrioid EC who underwent complete staging surgery during January 2015 to December 2020. We analyzed ER/PR status using immunohistochemical staining, and quantified its expression using the sum of both ER/PR H-scores. Receiver operating characteristic curves were used to identify optimal cutoff values of H-score and CA 125 levels for predicting LNM. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. In 396 patients, the optimal cutoff values of the ER/PR H-score and CA 125 were 407 (area under the receiver operating characteristic curve: 0.645, P=0.001) and 40 U/mL (area under the receiver operating characteristic curve: 0.762, P<0.001), respectively. Multivariate analysis showed that CA 125 ≥40 UmL (odds ratio: 10.02; 95% CI: 4.74-21.18) and ER/PR H-score <407 (odds ratio: 4.20; 95% CI: 1.55-11.32) were independent predictors. An LNM predictive nomogram was constructed using these 2 variables and our model yielded a negative predictive value and negative likelihood ratio of 98.3% and 0.14, respectively. ER/PR expression with pretreatment CA 125 levels can help estimate LNM risk and aid in decision-making regarding the need for lymphadenectomy in patients with endometrioid EC.

Clinical practice guidelines for the prevention and treatment of osteoporosis in Taiwan: 2022 update.

Osteoporosis greatly increases the risk of fractures. Osteoporotic fractures negatively impact quality of life, increase the burden of care, and increase mortality. Taiwan is an area with a high prevalence of osteoporosis. This updated summary of guidelines has been developed by experts of the Taiwan Osteoporosis Association with the intention of reducing the risks of osteoporotic fractures and improving the quality of care for patients with osteoporosis. The updated guidelines compile the latest evidence to provide clinicians and other healthcare professionals with practical recommendations for the prevention, diagnosis, and management of osteoporosis under clinical settings in Taiwan.

Comprehensive Clinicopathologic Analysis for Mismatch Repair Protein Expression in Unselected Endometrial Carcinoma Patients With an Emphasis on the Role of MLH1 Deficiency.

Screening for mismatch repair (MMR) deficiency in unselected patients with endometrial carcinoma (EC) and the clinicopathologic descriptions of ECs with MMR deficiency have been well demonstrated in Western populations, but studies on Asian populations are relatively scarce. In this study, we described the clinicopathologic features of ECs according to MMR status in unselected Taiwanese patients. We also conducted subgroup analysis of MMR-deficient (dMMR) cases according to the presence or absence of MLH1. Patients diagnosed with ECs between January 2017 and February 2020 at our institution were included. Immunohistochemistry analysis of MLH1, PMS2, MSH2, and MSH6 proteins on endometrial primary tumors and clinicopathologic variables were assessed retrospectively. A total of 231 EC patients were enrolled, of whom 50 (21.6%) had dMMR tumors. Of these 50 cases, 39 had tumors that lacked MLH1 expression and 11 were positive for MLH1. The overall dMMR group was significantly related to older age, parity, and high histologic grade compared with the MMR-proficient (pMMR) group. ECs with MLH1 deficiency were obviously associated with several poor pathologic features, including high histologic grade, lymph node metastasis, and lymphovascular space invasion. Moreover, we first reported that parity and the late age at menopause are strongly correlated with MLH1-related dMMR EC group compared with pMMR group. In conclusion, triaging EC patients into pMMR, MLH1-related dMMR and non-MLH1-related dMMR groups by immunohistochemistry analysis may help clinicians to predict disease behavior and guide further management. The strong association between parity and MLH1-related dMMR ECs warrants further investigation on the underlying mechanism.

Maternal Metformin Treatment Reprograms Maternal High-Fat Diet-Induced Hepatic Steatosis in Offspring Associated with Placental Glucose Transporter Modifications.

Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.

Effects of Icodextrin Solution (Adept®) on Ovarian Cancer Cell Proliferation in an In Vitro Model.

Background and objective: Anti-adhesion barriers are currently used during ovarian cancer surgery to decrease adhesion-related morbidity. Adept® (4% icodextrin) solution, a liquid anti-adhesion material, has been widely used during gynecologic surgeries, though the risk of this barrier for oncologic surgery is controversial. The aim of this study was to determine the effect of Adept® solution on the proliferation of ovarian cancer cells. Materials and methods: We assessed the dose- and time-dependent effects of icodextrin on the growth and proliferation of OVCAR-3 and A2780 human ovarian tumor cell lines in vitro. Cell growth was determined by cell number counting. Expressions of cell cycle-regulation proteins (cyclin D1 and cyclin B1) were determined using Western blot analysis. Results: Adept® did not significantly increase ovarian cancer cell growth when tested at various concentrations (0, 1, 5, 10, 15, and 20%, equal to 0, 0.04, 0.2, 0.4, 0.6 and 0.8% icodextrin) and different time points (1-3 days) compared to control cells. Moreover, the protein levels of cyclin D1 and B1 were not overexpression-elevated in icodextrin-treated ovarian cancer cells, either with an increasing concentration or with an increasing treated time. These results demonstrated that Adept® does not activate the growth or proliferation of ovarian cancer cells in either a dose- or time-dependent manner. Conclusions: This study supports the use of Adept® solution as a safe anti-adhesion barrier for ovarian cancer surgery, though further in vivo studies are necessary.

Metformin ameliorates maternal high-fat diet-induced maternal dysbiosis and fetal liver apoptosis.

BACKGROUND: The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effect of maternal HFD-induced maternal hepatic steatosis and dysbiosis on the fetal liver and intestines, and the effect of prenatal metformin in a rat model. METHODS: Sprague-Dawley rats were assigned to three groups (N = 6 in each group). Before mating, the rats were randomly assigned to HFD or normal-chow diet (NCD) group for 7 weeks. After mating, the HFD group rats were continued with high-fat diet during pregnancy and some of the HFD group rats were co-treated with metformin (HFMf) via drinking water during pregnancy. All maternal rats and their fetuses were sacrificed on gestational day 21. The liver and intestinal tissues of both maternal and fetal rats were analyzed. In addition, microbial deoxyribonucleic acid extracted from the maternal fecal samples was analyzed. RESULTS: HFD resulted in maternal weight gain during pregnancy, intrahepatic lipid accumulation, and change in the serum short-chain fatty acid profile, intestinal tight junctions, and dysbiosis in maternal rats. The effect of HFD on maternal rats was alleviated by prenatal metformin, which also ameliorated inflammation and apoptosis in the fetal liver and intestines. CONCLUSIONS: This study demonstrated the beneficial effects of prenatal metformin on maternal liver steatosis, focusing on the gut-liver axis. In addition, the present study indicates that prenatal metformin could ameliorate maternal HFD-induced inflammation and apoptosis in the fetal liver and intestines. This beneficial effect of in-utero exposure of metformin on fetal liver and intestines has not been reported. This study supports the use of prenatal metformin for pregnant obese women.

Factors associated with the inconsistent diagnosis between frozen section and permanent pathologic examination in borderline ovarian tumors.

AIM: The predictive accuracy of frozen sections for borderline ovarian tumors (BOTs) is suboptimal. The aim of this study was to determine the diagnostic accuracy of BOTs and factors associated with an upgrade to a permanent pathological diagnosis of invasive carcinoma in patients diagnosed with BOTs by frozen section. METHODS: We conducted a retrospective study between 2011 and 2018 at Kaohsiung Chang Gung Memorial Hospital (KCGMH). Two hundred and twenty-five records of eligible patients with a diagnosis of BOT by frozen section or permanent diagnosis were reviewed. Positive predictive value and the diagnostic accuracy of frozen sections were calculated. Univariate and multivariate analyses were used to determine the clinicopathological factors associated with an upgrade of the diagnosis from a borderline tumor to malignancy. RESULTS: The agreement between frozen section and permanent pathological diagnoses was 63.1%, and the positive predictive value was 72.1%. The multivariate analysis revealed that CA-125 level > 136 U/mL (odds ratio [OR] = 2.96, 95% confidence interval [CI] = 1.3-6.9; p = 0.012), and tumor histologic type (clear cell/endometrioid vs. mucinous; OR:32.8, 95% CI = 6.9-154.8, p < 0.001; clear cell/endometrioid vs. serous: OR 48.1, 95% CI = 8.8-261.8, p < 0.001) were independent risk factors for an upgrade of the permanent diagnosis from a BOT to ovarian carcinoma. CONCLUSION: An elevated CA-125 level (over 136 U/mL) and tumor histologic type (clear cell and endometrioid subtypes) were associated with an upgrade in the diagnosis of ovarian tumor from a BOT on frozen section to a permanent diagnosis of malignancy.

Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice.

BACKGROUND: Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12 months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis. METHODS: Seven-week-old C57BL/6 (B6) male mice were administered HF diet for 12 months (HF group). Two other groups received HF diet for 12 months accompanied by NAC for 12 months (HFD + NAC(1-12)) or 6 months (HFD + NAC(1-6)). The control group was fed regular diet for 12 months (CD group). RESULTS: Liver steatosis was more pronounced in the HF group than in the CD group after 12 month feeding. NAC intake for 6 or 12 months decreased liver steatosis in comparison with HF diet (p < 0.05). Furthermore, NAC treatment also reduced cellular apoptosis and caspase-3 expression. In the unfolded protein response (UPR) pathway, the expression of ECHS1, HSP60, and HSP70 was decreased in the HFD group (p < 0.05) and rescued by NAC therapy. With regards to the endoplasmic reticulum (ER) stress, Phospho-PERK (p-PERK) and ATF4 expression was decreased in the HF group, and only the HFD + NAC(1-12), but not HFD + NAC(1-6) group, showed significant improvement. CONCLUSION: HF diet for 12 months induces significant liver steatosis via altered ER stress and UPR pathway activity, as well as liver apoptosis. NAC treatment rescues the liver steatosis and apoptosis induced by HF diet.

Resveratrol intake during pregnancy and lactation re-programs adiposity and ameliorates leptin resistance in male progeny induced by maternal high-fat/high sucrose plus postnatal high-fat/high sucrose diets via fat metabolism regulation.

BACKGROUND: Maternal obesity is an emerging problem in the modern world. Growing evidence suggests that intrauterine high-fat (HF) exposure may predispose progeny to subsequent metabolic challenges. Progeny born to mothers who ate an HF diet also tends to eat an HF diet when growing and aggravate metabolic issues. Thus, the generational transmission of obesity is cyclical. Developing a strategy to prevent the occurrence of metabolic syndrome related to prenatal and/or postnatal HF diet is important. In this study, the reprogramming effects of maternal resveratrol treatment for the progeny with maternal HF/postnatal HF diets were investigated. METHODS: Sprague-Dawley dams were fed either a control or a high-fat/high sucrose diet (HFHS) from mating to lactation. After weaning, the progeny was fed chow or an HF diet. Four experimental groups were yielded: CC (maternal/postnatal control diet), HC (maternal HF/postnatal control diet), CH (maternal control/postnatal HFHS diet), and HH (maternal/postnatal HFHS diet). A fifth group (HRH) received a maternal HFHS diet plus maternal resveratrol treatment and a postnatal chow diet to study the effects of maternal resveratrol therapy. RESULTS: Maternal resveratrol treatment lessened the weight and adiposity of progeny that were programmed by combined prenatal and postnatal HFHS diets. Maternal resveratrol therapy ameliorated the decreased abundance of the sirtuin 1 (SIRT1) enzyme in retroperitoneal tissue and the altered leptin/soluble leptin receptor ratio of progeny. Maternal resveratrol therapy also decreased lipogenesis and increased lipolysis for progeny. CONCLUSIONS: Maternal resveratrol intervention can prevent adiposity programmed by maternal and postnatal HFHS diets by inducing lipid metabolic modulation. This study offers a novel reprogramming role for the effect of maternal resveratrol supplements against obesity.

The influence of probiotics on genital high-risk human papilloma virus clearance and quality of cervical smear: a randomized placebo-controlled trial.

BACKGROUND: Probiotics has been shown to be effective in reducing vaginal colonization of pathogenic organisms. The aim of this study was to investigate the influence of probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on genital high-risk human papilloma virus (HR-HPV) clearance and quality of cervical smear. METHODS: This was a randomized, double-blinded, placebo-controlled trial. Women with genital HR-HPV infection were randomized into study and control groups. A probiotic or placebo preparation was administered orally (one capsule daily) until negative HR-HPV testing. A cervical smear and HR-HPV tests were performed at the beginning of the study and every 3 months thereafter until a negative result was obtained. RESULTS: A total of 121 women with genital HR-HPV infection were enrolled (62 in the study group and 59 in the control group). There was no significant difference in HR-HPV clearance rate between the two groups (58.1% vs. 54.2%). The only factor predicting HR-HPV clearance was a lower initial viral load (HR 3.214; 95% CI: 1.398, 7.392; p = 0.006). Twenty-two women had a mildly abnormal initial cervical smear and nine had an unsatisfactory smear. At 6 months follow-up, both mildly abnormal cervical smear and unsatisfactory smear rates had decreased significantly in the study group compared to the control group (p = 0.017 and 0.027). CONCLUSIONS: The application of probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 did not influence genital HR-HPV clearance, but may have decreased the rates of mildly abnormal and unsatisfactory cervical smears. TRIAL REGISTRATION: Clinicaltrials.gov NCT01599416 , May, 2012. Retrospectively registered.

Obesity programmed by prenatal dexamethasone and postnatal high-fat diet leads to distinct alterations in nutrition sensory signals and circadian-clock genes in visceral adipose tissue.

BACKGROUND: Prenatal dexamethasone treatment has been shown to enhance the susceptibility of offspring to postnatal high-fat (HF) diet-induced programmed obesity. We investigated the metabolic phenotypes, nutrient-sensing signal and circadian-clock genes in adipose tissue that are programmed by prenatal dexamethasone exposure and postnatal HF diet. METHODS: Male offspring of Sprague-Dawley rats were divided into four experimental groups: normal diet, prenatal dexamethasone exposure, postnatal HF diet, and prenatal dexamethasone plus postnatal HF diet. Postnatal HF diet was prescribed from weaning to 6 months of age. RESULTS: Prenatal dexamethasone and postnatal HF diet exerted synergistic effects on body weight and visceral adiposity, whereas prenatal dexamethasone and postnatal HF diet altered the metabolic profile and caused leptin dysregulation. Prenatal dexamethasone and postnatal HF diet distinctly influenced nutrient-sensing molecules and circadian-clock genes in adipose tissue. The mRNA expression of mTOR, AMPK-α2, PPAR-α, and PPAR-γ was suppressed by prenatal dexamethasone but enhanced by postnatal HF diet. CONCLUSION: Prenatal dexamethasone and postnatal HF treatment cause dysregulation of nutrient-sensing molecules and circadian-clock genes in visceral adipose tissue. Characterizing altered nutrient-sensing molecules and circadian-clock genes has potential therapeutic relevance with respect to the pathogenesis and treatment of prenatal stress and postnatal HF diet-related metabolic disorders.

Resveratrol ameliorates maternal and post-weaning high-fat diet-induced nonalcoholic fatty liver disease via renin-angiotensin system.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on prenatal and postnatal HF diet-induced NAFLD. METHODS: Male Sprague-Dawley rat offspring were placed in five experimental groups (n = 10-12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120. RESULTS: We found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group. CONCLUSION: Our results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.

Prenatal dexamethasone and postnatal high-fat diet have a synergistic effect of elevating blood pressure through a distinct programming mechanism of systemic and adipose renin-angiotensin systems.

BACKGROUND: Hypertension may result from high-fat (HF) diet induced-obesity and overexposure to glucocorticoids in utero. Recent studies demonstrated the potent contribution of adipose tissue's renin-angiotensin system (RAS) to systemic RAS, which plays a key role in regulating blood pressure (BP). In this study, we investigated the effects of prenatal dexamethasone (DEX) exposure and postnatal HF diet on RAS of adipose tissue. METHODS: RAS and BP of 6-month old rats exposed to prenatal DEX and/or postnatal HF diet were examined. RESULTS: Prenatal DEX plus postnatal HF exerted a synergistic effect on systolic BP. Prenatal DEX exposure suppressed plasma angiotensin (ANG) I and ANG II, whereas postnatal HF suppressed plasma ANG-(1-7) level. Prenatal DEX increased prorenin receptor and renin levels, but suppressed angiotensinogen (AGT) and angiotensin-converting-enzyme 1 (ACE1) mRNA expressions in adipose tissue. Postnatal HF increased AGT mRNA expression, but suppressed prorenin receptor, renin, ACE2, ANG II type 2 receptor (AT2R), and Mas receptor (MasR) mRNA expression levels. CONCLUSIONS: Prenatal GC exposure altered the ACE1/ANG II/ANG II type 1 receptor (AT1R) axis, whereas postnatal HF negatively impacted the ACE2/ANG-(1-7)/MasR axis. Prenatal DEX exposure and postnatal HF synergistically elevated BP through a distinct programming mechanism of systemic and adipose RAS. Adipose RAS might be a target for precise hypertension treatment.

Regulation of Leptin Methylation Not via Apoptosis by Melatonin in the Rescue of Chronic Programming Liver Steatosis.

We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14⁻21 were administered with intraperitoneal dexamethasone (DEX) or prenatal dexamethasone and melatonin between gestational day 14 and postnatal day ~120 (DEX+MEL). Chronic programming effects in the liver were assessed at day ~120. Liver steatosis increased in the DEX compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05), with no changes in cellular apoptosis. Expression of leptin and its receptor decreased in the DEX (p < 0.05) and increased in the DEX+MEL group (p < 0.05), as revealed by RT-PCR and Western blotting. Tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 expression increased in the DEX group compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05). Liver DNA methyltransferase activity and leptin methylation increased in the DEX group (p < 0.05) and decreased in the DEX+MEL group (p < 0.05), with no changes in HDAC activity. Thus, prenatal dexamethasone induces liver steatosis at ~120 days via altered leptin expression and liver inflammation without leptin resistance. Melatonin reverses leptin methylation and expression and decreases inflammation and chronic liver steatosis not via apoptosis or histone deacetylation (HDAC).

Detrimental effect of maternal and post-weaning high-fat diet on the reproductive function in the adult female offspring rat: roles of insulin-like growth factor 2 and the ovarian circadian clock.

PURPOSE: We evaluate the impact of maternal and post-weaning high-fat (HF) diet on ovarian follicular population, steroidogenesis, and gene expression with a focus on the circadian clock system and insulin-like growth factor 2 (Igf2) in adult offspring ovaries, and to elucidate whether a maternal and post-weaning diet confers similar risks. METHODS: Virgin Sprague-Dawley rats were fed with normal chow (C) diet or HF diet for 5 weeks before mating, during gestation, and lactation. Female offspring were fed with the C or HF diet from weaning to 6 months of age, resulting in four study groups (n = 6 per group): C/C, C/HF, HF/C, and HF/HF. RESULTS: Ovaries from offspring exposed to post-weaning HF diet (i.e., the C/HF and HF/HF groups) had a decrease in small follicle numbers, but with similar numbers of antral follicles and corpora lutea. Offspring from HF-fed dams (i.e., the HF/C and HF/HF groups) had increased plasma estradiol concentrations and decreased luteinizing hormone levels at 6 months of age. In addition, Igf2 and each of the circadian rhythm core genes Clock, Per1, Per2, and Per3 were increased in the ovaries of offspring exposed to maternal HF diet (both HF/C and HF/HF groups). CONCLUSIONS: Maternal and post-weaning HF diet programs the reproductive profile of the female offspring in adult life through different manners. Post-weaning HF intake resulted in the reduction of small follicles in adulthood, whereas maternal HF diet had long-term deleterious consequences on female offspring steroidogenesis and coincided with alteration of the upregulation of the imprinted gene Igf2 and changes in ovarian circadian rhythms.

N-Acetylcysteine Prevents Programmed Hypertension in Male Rat Offspring Born to Suramin-Treated Mothers.

Adulthood hypertension can be programmed by preeclampsia. Preeclampsia is associated with an imbalance in vasoactive factors, including nitric oxide (NO), hydrogen sulfide (H2S), and renin-angiotensin system (RAS). We examined whether maternal N-acetylcysteine (NAC) therapy prevented maternal suramin treatment-induced programmed hypertension in offspring and explored the effects of this therapy on NO, H2S, and RAS pathways in the kidneys. Pregnant Sprague-Dawley rats were intraperitoneally administered 60 mg/kg suramin alone on Gestational Days 10 and 11 and were treated with or without 1% NAC through drinking water during the entire pregnancy and lactation period. Male offspring were divided into four groups (n = 8-10/group): control, suramin, NAC, and suramin plus NAC. All rat offspring were euthanized at 12 wk of age. Maternal suramin treatment induced programmed hypertension in male offspring, which was prevented by maternal NAC therapy. Suramin-induced programmed hypertension was associated with increased plasma asymmetric dimethylarginine (ADMA, an NO synthase inhibitor) level, decreased plasma l-arginine-to-ADMA ratio, and decreased renal dimethylarginine dimethylaminohydrolase (an ADMA-metabolizing enzyme) activity. Protective effects of NAC against suramin-induced programmed hypertension were associated with an increase in plasma glutathione level, increase in renal 3-mercaptopyruvate sulfurtransferase level, and restoration of suramin-induced reduction in H2S synthesis in the kidneys. Suramin treatment exerted negligible effect on the RAS pathway in the adult male offspring kidneys. Our data suggested interplay among suramin, ADMA-NO pathway, and H2S synthesis pathway in programmed hypertension. Furthermore, NAC administration in pregnant rats with hypertension prevented programmed hypertension in adult offspring.

Early postnatal treatment with soluble epoxide hydrolase inhibitor or 15-deoxy-Δ(12,14)-prostagandin J2 prevents prenatal dexamethasone and postnatal high saturated fat diet induced programmed hypertension in adult rat offspring.

Prenatal dexamethasone (DEX) exposure, postnatal high-fat (HF) intake, and arachidonic acid pathway are closely related to hypertension. We tested whether a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-deoxy-Δ(12,14)-prostagandin J2 (15dPGJ2) therapy can rescue programmed hypertension in the DEX+HF two-hit model. Four groups of Sprague Dawley rats were studied: control, DEX+HF, AUDA, and 15dPGJ2. Dexamethasone (0.1mg/kg body weight) was intraperitoneally administered to pregnant rats from gestational day 16-22. Male offspring received high-fat diet (D12331, Research Diets) from weaning to 4 months of age. In AUDA group, mother rats received 25mg/L in drinking water during lactation. In the 15dPGJ2 group, male offspring received 15dPGJ2 1.5mg/kg BW by subcutaneous injection once daily for 1 week after birth. We found postnatal HF diet aggravated prenatal DEX-induced programmed hypertension, which was similarly prevented by early treatment with AUDA or 15dPGJ2. The beneficial effects of AUDA and 15d-PGJ2 therapy include inhibition of SEH, increases of renal angiotensin converting enzyme-2 (ACE2) and angiotensin II type 2 receptor (AT2R) protein levels, and restoration of nitric oxide bioavailability. Better understanding of the impact of arachidonic acid pathway in the two-hit model will help prevent programmed hypertension in children exposed to corticosteroids and postnatal HF intake.

Low-dose metronomic chemotherapy with cisplatin enhanced immunity in a murine model of ectopic cervical cancer.

Previous researchers have claimed that metronomic low-dose/dense chemotherapy can enhance the therapeutic effectiveness of cisplatin treatment in the control of cancer. Therefore, the aim of this study was to explore the effectiveness of metronomic drug delivery with regards to its effects on adaptive immunity in a murine model of ectopic cervical cancer. The effectiveness of long-term low-dose/dense cisplatin treatment in HPV E7-expressing TC-1 cells was evaluated via morphological observations. Tumour mass and survival curves were used to determine the antitumour effect against E7-expressing tumours. After experimental mice had been treated with low-dose/dense cisplatin therapy, flow cytometry was used to measure the expression of MHC class I surface antigens on cultured TC-1 cells. Splenocytes expressing both interferon (IFN)-γ and CD8 responsible for E7 antigens and the Treg population were also quantified using flow cytometry. The results indicate that in vivo treatment with metronomic cisplatin suppresses the growth of cultured TC-1 cells. An increase was also observed in the number of splenocytes expressing both IFN-γ and CD8 responsible for E7 antigens and the Treg population. These results support previous reports that metronomic low-dose/dense cisplatin chemotherapy is an effective treatment against ectopic cervical cancer with E7-expression.

Pretreatment Factors Associated with Recurrence for Patients with Cervical Cancer International Federation of Gynecology and Obstetrics Stage IB1 Disease.

BACKGROUND: Pretreatment prognostic information is lacking for patients with cervical cancer International Federation of Gynecology and Obstetrics (FIGO) stage IB1 disease. Thus, we attempted to identify a high-risk subgroup among them prior to treatment. METHODS: Cervical cancer FIGO stage IB1 patients who had received curative treatment with various modalities in our institute between January 2004 and December 2010 were enrolled. Pretreatment clinical parameters including age, squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen, hemoglobin (Hb) level, platelet count, histological type, and treatment modality were analyzed for treatment outcomes. RESULTS: One hundred ninety-seven patients were included with a median follow-up of 66 months (range 6-119 months). In Cox regression analysis, only SCC histology (HR 0.457, 95% CI 0.241-0.967, p = 0.017) was an independent factor predicting better disease-free survival (DFS). Among SCC histology, patients with an Hb level less than 12 g/dl and a SCC-Ag level more than 3 ng/ml had worse treatment outcomes. The 5-year DFS rates were 89.2, 69.3, and 44.4% for the patients at low-risk (SCC, Hb >12 g/dl, SCC-Ag ≤3 ng/ml), intermediate-risk (non-SCC), and high-risk (SCC, Hb ≤12 g/dl, SCC-Ag >3 ng/ml), respectively (p < 0.001). CONCLUSION: Non-SCC and SCC histology with both anemia and high pretreatment SCC-Ag level were associated with recurrence. Further validation studies are warranted for clarification.