Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity.

The activation of Homo sapiens Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone ONC201. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC50 = 0.79 ± 0.03 µM) and antitumor activity in vitro (IC50 = 0.038 ± 0.003 µM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo. This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.

Single-dose administration of a short-acting gonadotropin-releasing hormone agonist does not affect cycle outcome in frozen-thawed embryo transfer cycles.

OBJECTIVE: This prospective study aimed to assess the effect of short-acting gonadotropin-releasing hormone agonist (GnRHa) administration on pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles. METHODS: Patients who planned to have FET in Peking Union Medical College Hospital (China) were recruited for this study and randomly assigned into two groups. Patients in the experimental group (n = 460) received triptorelin acetate on the day of embryo transfer along with routine luteal support. Patients in the control group (n = 433) only received luteal support. One dose (0.1 mg) of a short-acting GnRHa was administered on the day of blastocyte transfer. The rates for clinical pregnancy, biochemical pregnancy, implantation, miscarriage, and ectopic pregnancy were compared between the groups. RESULTS: There were no significant differences in the number and quality of blastocytes transferred between the two groups. In the experimental and control groups, the clinical pregnancy rate was 56.3% and 50.58%, the biochemical pregnancy rate was 15.78% and 18.94%, and the median implantation rate was 39.98% and 38.01%, respectively, with no significant difference between the groups. Biochemical pregnancy and abortion and the ectopic pregnancy rate were not significantly different between the two groups. CONCLUSION: In FET cycles, a GnRHa does not affect the pregnancy outcome.

Structure-activity relationship study of DEL-22379: ERK dimerization inhibitors with increased safety.

Aberrant activation of ERK signaling pathway usually leads to oncogenesis, and small molecular agents targeting this pathway are impeded by the emergence of drug resistance due to reactivation of ERK signaling. Compound DEL-22379 has been reported to inhibit ERK dimerization which was unaffected by drug-resistant mechanism reactivating the ERK signaling. Here, we discussed a structure-activity relationship study of DEL-22379. Forty-seven analogues were designed and synthesized. Each synthesized compound was biologically evaluated for their inhibitory rates on several tumor cell lines and compounds with high inhibitory rates were further evaluated for IC50 values. The structure-activity relationship of idolin-2-one scaffold and the impact of Z/E configuration on potency were discussed. Potential safety of two synthesized analogues was investigated and in silico docking study of five compounds was performed to understand the structural basis of ERK dimerization inhibition.

Factors Associated with Effectiveness of Treatment and Reproductive Outcomes in Patients with Thin Endometrium Undergoing Estrogen Treatment.

BACKGROUND: Thin endometrium is associated with poor reproductive outcomes; estrogen treatment can increase endometrial thickness (EMT). The aim of this retrospective cohort study was to investigate the factors influencing the effectiveness of estrogen treatment and reproductive outcomes after the treatment in patients with thin endometrium. METHODS: Relevant clinical data of 101 patients with thin endometrium who had undergone estrogen treatment were collected. Possible factors influencing the effectiveness of treatment were analyzed retrospectively by logistic regression analysis. Eighty-seven infertile women without thin endometrium who had undergone assisted reproduction served as controls. The cases and controls were matched for age, assisted reproduction method, and number of embryos transferred. Reproductive outcomes of study and control groups were compared using Student's t-test and the Chi-square test. RESULTS: At the end of estrogen treatment, EMT was ≥8 mm in 93/101 patients (92.1%). Effectiveness of treatment was significantly associated with maximal pretreatment EMT (P = 0.017) and treatment duration (P = 0.004). The outcomes of assisted reproduction were similar in patients whose treatment was successful in increasing EMT to ≥8 mm and the control group. The rate of clinical pregnancy in patients was associated with the number of good-quality embryos transferred in both fresh (P = 0.005) and frozen-thawed (P = 0.000) embryo transfer cycles. CONCLUSIONS: Thinner EMT before estrogen treatment requires longer treatment duration and predicts poorer treatment outcomes. The effectiveness of treatment depends on the duration of estrogen administration. Assisted reproductive outcomes of patients whose treatment is successful (i.e., achieves an EMT ≥8 mm) are similar to those of controls. The quality of embryos transferred is an important predictor of assisted reproductive outcomes in patients treated successfully with exogenous estrogen.

[Evaluation the efficacy and safety of estradiol and drospirenone tablets in the treatment of menopausal symptoms among postmenopausal Chinese healthy women:a randomized, multi-center, double-blind, placebo-controlled clinical study].

OBJECTIVE: To study the efficacy and safety of estradiol and drospirenone tablets (Angeliq) in treatment of menopausal symptoms among postmenopausal Chinese healthy women. METHODS: Total 244 postmenopausal Chinese healthy women who had moderate to severe hot flushes were randomly assigned into estradiol and drospirenone (observation group, n = 183) or placebo group (n = 61) by the ratio of 3:1 for 16 weeks in this randomized multi-center double-blind placebo-controlled study. During the trial, the follow-up visits were conducted at week 4, 8, 12, 16 of treatment and 2 weeks after treatment respectively. Height, weight, vital signs, hot flushes, other relevant menopausal symptoms and vaginal bleeding were observed in each follow-up visit, while the clinical global impression scale was assessed at 16 weeks as well. RESULTS: It showed that hot flushes were reduced significantly more in observation group than that in placebo group (P < 0.01), although both treatments were effective. The absolute values of mean severity index of total hot flushes decreased by -0.6 ± 0.5 in observation group and -0.4 ± 0.4 in placebo group from baseline respectively, which reached significant difference (P < 0.05). However, the absolute values of mean severity index of moderate to severe hot flushes decreased by -0.6 ± 0.8 in observation group and -0.3 ± 0.6 in placebo group from baseline respectively, which had no significant difference (P > 0.05). After 16 weeks treatment, it also showed that estradiol and drospirenone had significant better efficacy than placebo on moderate to severe sweating, vaginal dryness and clinical global impression scale (P < 0.01). During the trial, blood pressure in observation group was stable. The rate of vaginal bleeding in observation group was higher than that in the placebo group, especially during the week 4 to week 8 when 48.9% (87/178) in observation group and 10.7% (6/56) in placebo group of patients bled. Although the cumulative amenorrhea rate of observation group was lower than that of placebo group in each cycle (28 days), it increased gradually along with duration of the treatment. The commonest adverse event in observation group was breast tenderness which accounted for 12.0% (22/183). The level of serum potassium was in the normal range in observation group mostly.Meanwhile, the other adverse events rate was low. Serious adverse events reported in this trial were assessed as not study drug related or as unlikely study drug related. CONCLUSION: Estradiol and drospirenone tablets which could effectively alleviate menopausal symptoms in postmenopausal Chinese healthy women is a novel hormone replacement therapy regimen with high safety and efficacy.

Social and behavior factors related to aged Chinese women with osteoporosis.

BACKGROUND: Women aged >or=65 years are screened routinely for osteoporosis in the developed world and identifying risk factors for osteoporosis should be highlighted in developing countries such as the People's Republic of China. In the present study, possible factors related to the occurrence of primary osteoporosis in aged Chinese women were explored. METHODS: On appointed attendance at a menopausal outpatient clinic, generally healthy Chinese women aged >or=65 years were requested to complete a self-administered questionnaire. Bone mineral density at the left femur region was assessed using dual-energy X-ray absorptiometry, by which subjects were categorized as osteoporotic (group A), osteopenic (group B) or normal (group C). If a prevalent spinal fracture was affirmed, patients in group B were reclassified into group A. Non-conditional logistic regression analysis was applied to the calculate odds ratio (OR) of being in group A against the other two groups in terms of social and behavior factors (including education, past occupation, work quality, marriage status, income, self-rated health status, amount of daily physical activity, cigarette smoking, time watching television, and consumption of milk, soy products and tea). RESULTS: Three hundred and twenty-four participants were eligible (77 in group A, 137 in group B, 110 in group C). There were significant differences in age, height, weight, menopausal age and years since menopause among groups. Compared with subjects with amount of daily physical activity <0.5 h in group A, the OR for women in group C was 0.357 (95% confidence interval (CI) 0.144-0.889) for 0.5-1 h, 0.314 (95% CI 0.126-0.780) for 1-2 h and 0.278 (95% CI 0.080-0.968) for >2 h of daily physical activity. When adjusted for age and weight, however, the difference was not significant. Other factors did not reach statistical significance. CONCLUSION: The development of osteoporosis in aged women was affected by both menopause and aging. The known related factors could help to identify susceptible subjects in aged Chinese women for either further assessment or treatment.

[Identification of potential neoplastic risk in gonadal development abnormality with Y chromosome of 79 cases].

OBJECTIVE: To identify the potential neoplastic risk in gonadal development abnormality with Y chromosome. METHODS: Inquiries about the illness history were made. Lymphocyte chromosomal karyotype of peripheral blood was analyzed. Sex determining region Y gene and relative steroids and enzymes were detected. Gonadal site was examined through medical imaging. Gonadal excision was performed by laparotomy or laparoscopy. Pathological examinations were done on all of the specimens. RESULTS: Among 41 cases of androgen insensitive syndrome, spermatogenic cell neoplasm occurred in 1 patient, sertoli cell tumor in 2, and interstitial cell hyperplasia in 5. Among 14 cases of 17 alpha-hydroxylase deficiency (XY) syndrome, one was sertoli cell tumor, and one was sertoli cell hyperplasia. In 4 cases of XY pure gonadal dysgenesis, one was gonadoblastoma with dysgerminoma. One of 16 cases of XO/XY gonadal dysgenesis was spermatogenic cell neoplasm with agenda cell tumor. Four cases of testes degeneration were all with dysgenetic testes. All of the gonadoblastoma and germ-cell tumor were located in the pelvis. Tumors occurred mostly during 15 years of age to 32 years. CONCLUSIONS: The gonads of XY pure gonadal dysgenesis has high risks of gonadoblastoma and germ-cell tumor. The older the onset age after puberty, the higher the malignancy risk is. Once diagnosed, bilateral gonads should be excised as soon as possible.

[Germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in China Han people].

OBJECTIVE: To detect BRCA1 and BRCA2 gene germline mutation in the Chinese breast cancer families. METHODS: Samples of peripheral blood were collected to prepare genomic DNA by conventional techniques from 15 inherited breast cancer patients from 14 breast cancer families, 76 sporadic breast cancer patients, and 100 healthy controls based on informed consent. Exons 4, 8, 11 and 18 - 20 of BRCA1, and exons 1 - 14, 17 - 24 and 27 of BRCA2, were analyzed using DNA direct sequencing. RESULTS: Six single nucleotide polymorphisms (SNPs) were found on the exon 11 of BRCA1, 2 being silent changes without change of amino acid coding, and 4 with change of amino acid coding among which 2 were polymorphic amino acid alterations and 2 were pathogenic SNPs, i.e. mutational sites. One novel BRCA1 mutation, C1196T (Pro 359 Leu), was identified in a family breast cancer patients, who was diagnosed at the age of 37. Another BRCA1 mutation, Trp 372 stop was found in a breast cancer patient who was diagnosed at the age 29. Eight SNPs were found on the exon3, 10 and 11 of BRCA2, among which 5 were silent changes and 3 were polymorphic amino acid alterations. A1093C (Asn289His) in exon 10 and A 3199G (Asn991Asp) in exon 11 being found simultaneously in the patients of 2 families but not appearing in pool DNA sample, and Asn 371 His appearing as A/C heterozygote in pool DNA sample. CONCLUSION: Two pathogenic SNPs have been found in BRCA1 and may be related to early-onset breast cancer. One of them may be a novel mutation characterized of familial breast cancer in China.

[Monitoring the breast changes of Chinese postmenopausal women under long-term hormone replacement therapy by mammary ultrasonography].

OBJECTIVE: To investigate the effects of long-term hormone replacement therapy (HRT) on the breasts of postmenopausal women using mammary ultrasonography. METHODS: An open randomized clinical study was designed. The percutaneous estradiol gel was used in a cyclic regimen combined with micronized progesterone (MP) or medroxyprogesterone acetate (MPA). Sixty healthy women (natural menopause for 1 to 5 years) were recruited and divided into four groups according to the dosage of estrogen and two kinds of progestin. All were given for 25 days per month. Mammary ultrasonography was used to observe breast glandular section thickness, breast duct width, the morphology of lobular unit and the blood flow of color Doppler imaging at baseline and every year from the second to seventh year of HRT. The serum estradiol was also measured from the 15th to 25th day of the cycle. Breast pain was recorded by the subjects. RESULTS: (1) The breast glandular section thickness after HRT was larger than that of before HRT. The breast glandular section thickness became larger gradually over time while the breast duct width became smaller over time. The breast duct width of the fifth year of HRT was significantly different from that of the sixth year (P < 0.05). (2) Twenty-two persons had new breast structure changes after HRT, and the accumulated incidence was 41.5%. New solid lesions formation occurred in five subjects (8.3%) and new cyst formation occurred in one subject (1.7%). After the second year of HRT, the serum estradiol level of the subjects with breast structure changes was higher than that of without breast structure changes and in the sixth year of HRT, and the difference was significant (P < 0.05). After the second year of HRT, the breast glandular section thickness of the subjects with breast structure changes was larger than that of without breast structure changes and in the fifth and sixth year of HRT, the difference was significant (P < 0.05). (3) After HRT, the serum estradiol level of subjects with mastalgia was higher than that of without mastalgia and in the second and sixth follow-up year, the difference was significant (P < 0.05). CONCLUSIONS: There is an increasing trend of the percentage of glandular tissues of the breast after HRT. There is an increasing trend of the serum estradiol level and the breast glandular section thickness among the subjects with the breast structure changes; there is an increasing trend of the serum estradiol level among the subjects with mastalgia. Mammary ultrasonography can be used to monitor breast structure changes and breast lesions during HRT.