Establishing and clinically validating a machine learning model for predicting unplanned reoperation risk in colorectal cancer.

BACKGROUND: Colorectal cancer significantly impacts global health, with unplanned reoperations post-surgery being key determinants of patient outcomes. Existing predictive models for these reoperations lack precision in integrating complex clinical data. AIM: To develop and validate a machine learning model for predicting unplanned reoperation risk in colorectal cancer patients. METHODS: Data of patients treated for colorectal cancer (n = 2044) at the First Affiliated Hospital of Wenzhou Medical University and Wenzhou Central Hospital from March 2020 to March 2022 were retrospectively collected. Patients were divided into an experimental group (n = 60) and a control group (n = 1984) according to unplanned reoperation occurrence. Patients were also divided into a training group and a validation group (7:3 ratio). We used three different machine learning methods to screen characteristic variables. A nomogram was created based on multifactor logistic regression, and the model performance was assessed using receiver operating characteristic curve, calibration curve, Hosmer-Lemeshow test, and decision curve analysis. The risk scores of the two groups were calculated and compared to validate the model. RESULTS: More patients in the experimental group were ≥ 60 years old, male, and had a history of hypertension, laparotomy, and hypoproteinemia, compared to the control group. Multiple logistic regression analysis confirmed the following as independent risk factors for unplanned reoperation (P < 0.05): Prognostic Nutritional Index value, history of laparotomy, hypertension, or stroke, hypoproteinemia, age, tumor-node-metastasis staging, surgical time, gender, and American Society of Anesthesiologists classification. Receiver operating characteristic curve analysis showed that the model had good discrimination and clinical utility. CONCLUSION: This study used a machine learning approach to build a model that accurately predicts the risk of postoperative unplanned reoperation in patients with colorectal cancer, which can improve treatment decisions and prognosis.

[Soil nematode community characteristics of alfalfa field with different growing ages in the semi-arid Loess Plateau of Central Gansu, Northwest China]. / 陇中黄土高原半干旱区不同种植年限紫花苜蓿土壤线虫群落分布特征.

To clarify the impacts of long-term alfalfa plantation on the soil nematode community, soil samples were collected from different alfalfa growing ages (2 a, 9 a, 18 a) in the semi-arid area of Loess Plateau in Central Gansu by Illumina Miseq sequencing technology. The main controlling factors affecting its community change were also explored. The results showed that soil nematode belongs to 2 classes, 7 orders, 16 families and 21 genera. Among them, Chromadorea was the dominant group (44.6%-81.4%), the relative abundance of which decreased with alfalfa growing ages. Paratylenchus, Helicotylenchus, Xiphinema, Pristionchus, Ditylenchus, Panagrolaimus, Longidorus, Aprutides, Isolaimium and Aglenchus were the special nematode species of alfalfa, among which Paratylenchus (54.1%), Helicotylenchus (23.9%) and Xiphinema (21.9%) were the dominant nematodes in 2 a, 9 a and 18 a alfalfa soil respectively. Plant-parasitic nematode was the dominant group in alfalfa soil (31.8%-67.1%), and its relative abundance decreased at first and then increased with alfalfa growing ages. Results of redundancy analysis showed that soil available phosphorus and total nitrogen were the dominant environmental factors affecting community structure of soil nematodes in the region.

[Effects of plastic film mulching patterns on maize grain yield, water use efficiency, and soil water balance in the farming system with one film used two years.] / 覆膜方式对一膜两年覆盖旱地玉米籽粒产量、水分利用效率和土壤水分平衡的影响.

The aim of this study was to develop cost-saving and efficiency-improving technologies in whole plastic mulching and double ridge-furrow maize in semi-arid region of Loess Plateau. The objective was to investigate soil water balance in farming system with one film used two years. A field experiment was conducted to investigate the effects of different mulching and tillage patterns under one film used two years conditions on the yield, economic benefits, and water use efficiency of maize. There are four treatments: Ridge-furrow planting with complete plastic film mulching, F1M; flat-planting with complete plastic film mulching, F2M; flat-planting with half plastic film mulching, F3M; and flat-planting without mulching, F4M, the control. The results showed that the F1M and F2M treatments had significant effects on the improvement of the production and efficiency compared with the control. The F1M and F2M treatments improved biomass by 32.8% and 32.9%, enhanced grain yield by 60.0% and 51.7%. Water use efficiency and rainfall use efficiency in F1M and F2M treatments were increased by 59.8%, 35.9% and 87.6%, 64.4%, respectively. Furthermore, gross output value and input-output ratio of F1M and F2M treatments under every new plastic film mulched pattern were enhanced by 51.0%, 41.2% and 15.1%, 16.2%, respectively. The production pattern on cost-saving and efficiency-increasing of the system on double ridge-furrow and flat planting with one film used two years, this pattern increased gross output value by 40.8%, 42.2%, and increased input-output ratio by 40.3%, 42.2%, respectively. Under the condition of low precipitation (606.5 mm), total water consumption of ridge-furrow and flat planting under the system of one film used within two years was 731.3 mm and 746.8 mm, the soil moisture deficit was 124.8 mm and 140.3 mm, with enhancement of 22.7% and 38.0%, respectively. The total water consumption of ridge-furrow and flat planting treatments was reduced by 28.6% and 30.0%, and the fallow efficiency was improved by 178.9% and 148.3%. In conclusion, whole plastic mulching with double ridge-furrow and flat planting farming system had positive effects on yield and water use efficiency in semi-arid region of Loess Plateau. Combined with the technology of one film used within two years, this cropping system could be cost saving and efficiency increasing. However, the water deficit under low water condition should be seriously considered in practice.

[Effect of Boron-antimony Interaction on the Uptake and Accumulation of Antimony and Boron by Rice Seedling].

Effect of interactions between boron (B) and antimony on the uptake and accumulation by rice (Oryza sativa L.) seedling was investigated in solution culture. The results showed that Sb(III) and Sb(V) could inhibit rice growth and Sb(III) was more toxic than Sb(V). Concentrations of B in rice roots and shoots were significantly affected by the addition of Sb(III) and Sb(V). The addition of 30 µmol x L(-1) Sb(III) could significantly decrease B of rice shoots and roots by 57.6% and 75.6%, and 30 µmol x L(-1) Sb(V) could decrease B of rice roots by 16.0%, compared with the control treatment, when the B concentration was 0.5 mg x L(-1). Equally, adding B also significantly affected the concentrations of Sb in rice roots and shoots. The addition of 2.0 mg x L(-1) B could decrease the concentrations of Sb in rice roots and shoots,by 39.1% and 9.2%, respectively, compared with 0.5 mg x L(-1) B, when the Sb(III) concentration was 10 µmol x L(-1). Adding 2.0 mg x L(-1) B could decreasd Sb concentrations in rice roots by 13.9%, compared with 0.5 mg x L(-1) B, when the Sb(V) concentration was 10 µmol x L(-1). Furthermore, adding B had significant effect on bioaccumulation factor and distribution ratio of Sb in rice roots and shoots. The results of the study demonstrated that Sb pollution in farmland could be alleviated by adding B fertilizer, thus protecting human health from Sb pollution.

[Soil dryness characteristics of alfalfa cropland and optimal growth years of alfalfa on the Loess Plateau of central Gansu, China].

This paper investigated soil moisture in alfalfa (Medicago sativa) cropland with different growth years (1, 3, 8, 12 and 14 years) and discussed the optimum growth years of alfalfa on the Loess Plateau of central Gansu. The results showed that the soil moisture along 0-300 cm soil profile of alfalfa croplands with different growth years was obviously lower than that of the local soil stable moisture. The soil water contents in croplands with alfalfa that had grown for 12 and 14 years were only 9.2% and 7.1% of local soil stable moisture, respectively, which were even lower than the lower limit of alfalfa growth. The average soil dryness indexes along 0-300 cm soil profile in 1, 3, 8, 12 and 14 years alfalfa croplands were 125.4%, 30.5%, 18.4%, -34.2% and -83.3% respectively. The results indicated that soil dryness occurred to varying degrees with different growth years except croplands with alfalfa grown for 1 year. With the increase of growth years of alfalfa, the soil dryness intensity increased and the soil dryness rate decreased. According to the soil moisture and alfalfa productivity results in this study, it could be concluded that the optimum growth years of alfalfa are 8-10 years in semiarid areas of the Loess Plateau.

17α-Estradiol and genistein inhibit high fat diet induced prostate gene expression and prostate growth in the rat.

PURPOSE: High dietary fat and low phytoestrogen intake are associated with prostate cancer development and progression. Our previous study showed that exposure to a high fat diet significantly increased prostate 5α-reductase-2 mRNA and prostate growth in the rat. In the current experiments we determined the effects of genistein and 17α-estradiol on the modulation of dietary fat induced prostate 5α-reductase-2 and insulin-like growth factor-1 gene expression, and prostate growth. MATERIALS AND METHODS: At weaning male ACI/Seg rats (Harlan® Sprague-Dawley®) were fed a low or a high fat diet, with or without genistein or 17α-estradiol for 2, 4 or 10 weeks. The prostate was dissected and weighed. We determined the levels of prostate 5α-reductase-2 mRNA, insulin-like growth factor-1 mRNA, dihydrotestosterone, and plasma insulin-like growth factor-1, dihydrotestosterone and testosterone. RESULTS: Two-week exposure to a high fat diet significantly increased prostate insulin-like growth factor-1 mRNA without significant changes in plasma insulin-like growth factor-1, which was blocked by genistein and 17α-estradiol. Genistein but not 17α-estradiol also inhibited prostate 5α-reductase-2 mRNA and intraprostatic dihydrotestosterone induced by the high fat diet at 2 weeks. Genistein and 17α-estradiol completely blocked high fat diet induced prostate growth at 10 weeks of dietary treatment. However, neither genistein nor 17α-estradiol had any significant effect when co-administered with the low fat diet. CONCLUSIONS: Results indicate that genistein and 17α-estradiol can inhibit dietary fat induced changes in prostate 5α-reductase-2 and insulin-like growth factor-1 gene expression, and prostate growth in the rat. This may be beneficial to prevent dietary fat associated prostate diseases such as prostate cancer.

The first successful paternity through in vitro fertilization-intracytoplasmic sperm injection with a man homozygous for the 5α-reductase-2 gene mutation.

OBJECTIVE: To report a case of successful paternity from a male homozygous for 5α-reductase-2 deficiency. DESIGN: Case report. SETTING: Academic center, division of reproductive endocrinology. PATIENT(S): A 45-year-old Dominican man and his 32-year-old wife. INTERVENTION(S): In vitro fertilization and intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Pregnancy. RESULT(S): Viable twin gestation. CONCLUSION(S): Men homozygous for 5α-reductase-2 deficiency can achieve biologic paternity through in vitro fertilization with intracytoplasmic sperm injection despite severely abnormal semen parameters.

Inhibition of aberrant androgen receptor induction of prostate specific antigen gene expression, cell proliferation and tumor growth by 17α-estradiol in prostate cancer.

PURPOSE: Androgen independent prostate cancer growth and metastasis are a major cause of prostate cancer death. Aberrant androgen receptor activation due to androgen receptor mutation is an important mechanism of androgen independence. We determined the effectiveness and mechanism of 17α-estradiol (Sigma®) in blocking aberrant androgen receptor activation due to androgen receptor mutation. MATERIALS AND METHODS: We used LNCaP and MDA Pca-2b prostatic tumor cells (ATCC®) containing a mutated androgen receptor and WT estrogen receptor ß to test 17α-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression and cell growth. Cotransfection analysis was used to further elucidate the mechanism of 17α-estradiol action. Xenograft animals with an LNCaP prostate tumor were prepared to study the in vivo effect of 17α-estradiol on tumor growth inhibition. RESULTS: In LNCaP cells 17α-estradiol produced a dose dependent inhibition of cyproterone acetate (Sigma) or dihydrotestosterone induced prostate specific antigen gene expression. In MDA Pca-2b cells 17α-estradiol inhibited cortisol (Sigma) induced prostate specific antigen expression and blocked dihydrotestosterone and cortisol induced cell proliferation in LNCaP and MDA Pca-2b cells, respectively. Cotransfection analysis showed that 17α-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression was medicated via estrogen receptors. In xenograft mice with LNCaP prostate cancer 17α-estradiol but not 17ß-estradiol (Sigma) significantly inhibited tumor growth, although each estrogen tended to decrease tumor growth. CONCLUSIONS: Results suggest that 17α-estradiol with less classic estrogenic activity is a potential therapeutic agent for androgen independent prostate cancer due to androgen receptor mutation.

[Effects of different tillage measures on upland soil respiration in Loess Plateau].

A field experiment was conducted in Lijiabu Town of Dingxi City, Gansu Province to study the soil respiration and its relations with the canopy temperature and soil moisture content in a rotation system with spring wheat and pea under effects of different tillage measures. Six treatments were installed, i.e., tillage with no straw- or plastic mulch (conventional tillage, T), tillage with straw mulch (TS), tillage with plastic mulch (TP), no-tillage (NT), no-tillage with straw mulch (NTS), and no-tillage with plastic mulch (NTP). During the growth periods of spring wheat and pea, soil respiration had different change patterns, with the peaks appeared at the early jointing, grain-filling, and maturing stages of spring wheat, and at the 5-leaf, silking, flowering and poding, in spring wheat field between treatments NTS and T, and the soil respiration rate was significantlyand maturing stages of pea. There was an obvious difference in the diurnal change of soil respiration lower in NTS than in T; while the soil respiration in pea field had less diurnal chan ge. Soil respiration rate had a significant linear relationship with the canopy temperature of both spring wheat andpea, the correlation coefficient being the highest at booting stage of spring wheat and at flowering and poding stage of pea, followed by at grain-filling stage of spring wheat and at branching stage of pea. There was also a significant parabola relationship between soil respiration rate and soil moisture content, the correlation coefficient being higher under conservation tillage than under conventional tillage, with the highest under NTS. The moisture content in 10-30 cm soil layer of spring wheat field and that in 5-10 cm soil layer of pea field had the greatest effects on soil respiration. Comparing with conventional tillage, all the five conservation tillage measures decreased soil respiration, with the best effects of no-tillage with straw mulch.

NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells.

PURPOSE: Prostate cancer is a major cause of cancer mortality in American males. Once prostate cancer has metastasized, there is currently no curative therapy available. The development of effective agents is therefore a continuing effort to combat this disease. In the present study, the effects and potential mechanisms of NSC606985 (NSC), a water-soluble camptothecin analog, in prostate cancer cells were investigated. METHODS: Prostatic tumor cells, DU-145, LNCaP and PC-3, were used for the study. Cell proliferation, cell cycle, cell apoptosis and caspase 3/7 activity were determined in the presence or absence of NSC. The levels of Bax and Bak, and the release of cytochrome c from mitochondria were analyzed by Western blot. RESULTS: Treatment with NSC at nanomolar concentrations produced a time- and dose-dependent decrease in viable cell numbers of multiple prostate cancer cells. In DU-145 cells, NSC produced a time-and dose-dependent induction of cell apoptosis and cell cycle arrest as evidenced by cell morphological changes, increases in S-phase and sub-G1 cell fractions, an elevation of caspase 3/7 activity, DNA fragmentation and apoptotic cells. NSC increased the levels of apoptotic proteins, Bax and Bak, and induced a release of cytochrome c from mitochondria to cytosol in DU-145 cells. Co-administration of Z-VAD-FMK, a pan-caspase inhibitor, blocked NSC-induced caspase 3/7 activity and cell apoptosis without affecting NSC-induced cell cycle arrest. In contrast, co-administration of a PKCdelta inhibitor, rottlerin, had no significant effect on NSC induction of caspase activity, and slightly potentiated NSC-induced cell death. Furthermore, like camptothecin, a mutation of topoisomerase 1 that prevents the binding of camptothecin to the enzyme completely abolished the NSC effect in DU-145 cells. CONCLUSION: The data obtained suggest that NSC is able to decrease cell growth, induce cell apoptosis and cause growth arrest in prostatic tumor cells, which may involve an interaction with topoisomerase 1 and an activation of mitochondrial apoptotic pathway.

[Leaf water potential of spring wheat and field pea under different tillage patterns and its relationships with environmental factors].

Based on a long-term experiment, the leaf water potential of spring wheat and field pea, its relationships with environmental factors, and the diurnal variations of leaf relative water content and water saturation deficient under different tillage patterns were studied. The results showed that during whole growth period, field pea had an obviously higher leaf water potential than spring wheat, but the two crops had similar diurnal variation trend of their leaf water potential, i.e., the highest in early morning, followed by a descent, and a gradual ascent after the descent. For spring wheat, the maximum leaf water potential appeared at its jointing and heading stages, followed by at booting and flowering stages, and the minimum appeared at filling stage. For field pea, the maximum leaf water potential achieved at squaring stage, followed by at branching and flowering stages, and the minimum was at podding stage. The leaf relative water content of spring wheat was the highest at heading stage, followed by at jointing and flowering stages, and achieved the minimum at filling stage; while the water saturation deficient was just in adverse. With the growth of field pea, its leaf relative water content decreased, but leaf water saturation deficient increased. The leaf water potential of both spring wheat and field pea had significant correlations with environmental factors, including soil water content, air temperature, solar radiation, relative air humidity, and air water potential. Path analysis showed that the meteorological factor which had the strongest effect on the diurnal variation of spring wheat' s and field pea' s leaf water potential was air water potential and air temperature, respectively. Compared with conventional tillage, the protective tillage patterns no-till, no-till plus straw mulching, and conventional tillage plus straw returning increased the leaf water potential and relative water content of test crops, and the effect of no-till plus straw mulching was most significant.

17alpha-estradiol inhibits LAPC-4 prostatic tumor cell proliferation in cell cultures and tumor growth in xenograft animals.

BACKGROUND: Blockade of androgen activity is a major effective therapy for advanced prostate cancer. Estrogen analogs have been used for prostate cancer therapy for years presumably by inhibiting testosterone biosyntheses, but with considerable adverse events due to their classic estrogenic activity. With the discovery of the estrogen receptor (ER) beta and its presence in prostate tumor cells, evaluation of estrogen analogs with less classic estrogenic activity in prostate cancer therapy is emerging. METHODS: The effects of 17alpha-estradiol (alphaE2), a stereo-isomer of 17beta-estradiol (betaE2), on dihydrotestosterone (DHT)-induced cell growth and gene expressions were examined in androgen-dependent LAPC-4 prostatic tumor cells and in LAPC-4 xenograft animals, and compared to those of betaE2. RESULTS: Both alphaE2 and betaE2 attenuated DHT induction of PSA gene expression, cell proliferation, and cell growth in cultured LAPC-4 cells. The inhibition of cell proliferation was associated with a blockade of DHT-induced cyclin A and cyclin D1 expression by alphaE2 and betaE2. In LAPC-4 xenograft mice, alphaE2 significantly inhibited tumor growth without altering the plasma testosterone level, while betaE2 failed to inhibit tumor growth even though it significantly inhibited PSA gene expression. CONCLUSION: alphaE2 is an effective agent for inhibition of DHT-induced PSA, cyclin A, cyclin D1 gene expression, and cell proliferation in LAPC-4 cells, and tumor growth in LAPC-4 xenograft mice.

Pancreaticoduodenal arterial rupture and hemoabdomen in ACI/SegHsd rats with polyarteritis nodosa.

Many lesions associated with aging have been well-characterized in various strains of rats. Although documented in Sprague-Dawley and spontaneously hypertensive rats, polyarteritis nodosa has not previously been reported in ACI/SegHsd rats. ACII SegHsd rats were maintained on high-fat (40.5%), low-fat (11.6%), and high-fat to low-fat dietary protocols to examine the correlation between dietary fat and the regulation of prostate 5alpha-reductase gene expression and prostate cancer. Seven rats died unexpectedly with hemoabdomen and rupture of the pancreaticoduodenal artery secondary to polyarteritis nodosa (PAN). The purpose of this study was to analyze the pathologic findings in these and the remaining ACI/SegHsd rats and to correlate the level of dietary fat with the presence of PAN, arterial rupture, and hemoabdomen. Approximately 65% of the rats had evidence of PAN by histopathology, with a 24% incidence of arterial rupture. Additional lesions noted included an 88% incidence of chronic progressive nephropathy (CPN) and a 32% incidence of cartilaginous foci in the aortic valve. We found no association between the percentage of dietary fat and incidence of PAN, CPN, or cardiac cartilage. Although arterial rupture is a known complication of polyarteritis nodosa in humans, this case series is the first to document arterial rupture and hemoabdomen in rats with PAN.

Inhibition of tumor growth and tumor metastasis by a Chinese herbal formula--ZYD88, in an animal model with metastatic Lewis lung carcinoma.

Tumor metastasis is the leading cause of cancer death. In the present study, we determined the effectiveness of ZYD88, a Chinese herbal formula, in the inhibition of tumor growth and distant tumor metastases to the lung and liver in an animal model with metastatic Lewis lung carcinoma (LLC). Treatment with ZYD88 in adult C57BL/6 mice with metastatic LLC produced dose-dependent deceases in primary tumor weight, the mitotic tumor cell number, microvessel density, distant tumor metastases and red blood cell immune complexes, while it significantly increased tumor necrosis, thymus cortical thickness, the thymus medullar reticular epithelial cell (REC) number, and the activity of red blood cell C3b receptors. Although cyclophosphamide inhibited tumor growth, it had no significant effects on distant tumor metastases, thymus cortical thickness, the thymus medullar REC number, red blood cell C3b receptor activity and red blood cell immune complexes. These results indicate that ZYD88 possesses significant anti-angiogenic, anti-tumor and anti-metastatic effects in this animal model, and warrants further investigation.

Effects of male sex hormones on gender identity, sexual behavior, and cognitive function.

Androgens, the male sex hormones, play an essential role in male sexual differentiation and development. However, the influence of these sex hormones extends beyond their roles in sexual differentiation and development. In many animal species, sex hormones have been shown to be essential for sexual differentiation of the brain during development and for maintaining sexually dimorphic behavior throughout life. The principals of sex determination in humans have been demonstrated to be similar to other mammals. However, the hormonal influence on sexual dimorphic differences in the nervous system in humans, sex differences in behaviors, and its correlations with those of other mammals is still an emerging field. In this review, the roles of androgens in gender and cognitive function are discussed with the emphasis on subjects with androgen action defects including complete androgen insensitivity due to androgen receptor mutations and 5alpha-reductase-2 deficiency syndromes due to 5alpha-reductase-2 gene mutations. The issue of the complex interaction of nature versus nurture is addressed.

Regulation of prostate 5alpha-reductase-2 gene expression and prostate weight by dietary fat and caloric intake in the rat.

BACKGROUND: High-fat diet is a major risk factor for prostate cancer. 5alpha-reductases are potential targets of dietary fat. METHODS: Male ACI/Seg rats given either a low-fat or a high-fat diet at weaning or adulthood were sacrificed at 2, 4, and 10 weeks after dietary treatment. Prostate 5alpha-reductase mRNAs, plasma androgens, food consumption, prostate, and body weight were determined. RESULTS: Prostate 5alpha-reductase-2 mRNA and plasma dihydrotestosterone levels were elevated at 2 weeks, and prostate weight was increased at 10 weeks in neonatal rats fed the high-fat diet. Animals fed the high-fat diet consumed more calories in the first 4 weeks. 5alpha-reductase-1 mRNA, plasma testosterone, and body weight were not different between the two dietary groups. These dietary effects were not observed in adult rats fed the same diets. CONCLUSION: A high-dietary fat and caloric intake upregulates prostate 5alpha-reductase-2 gene expression, and stimulates prostate growth in neonatal, but not adult rats.

Receptor isoform and ligand-specific modulation of dihydrotestosterone-induced prostate specific antigen gene expression and prostate tumor cell growth by estrogens.

Androgens via the androgen receptor (AR) play crucial roles in prostate physiology and pathophysiology. These androgen actions can be either inhibited or potentiated by estrogens. The mechanisms of these seemingly opposing estrogen effects are unclear. We studied the effects of estrogens on the modulation of androgen induction of prostate specific antigen (PSA) gene expression and prostate tumor cell growth. Cotransfection analyses in CV-1, DU-145, and PC-3 cells showed that dihydrotestosterone (DHT)-induced PSA transcription activity was inhibited by 17beta-estradiol, diethylstilbestrol, ICI182780, and 17alpha-estradiol, but not by tamoxifen via estrogen receptor alpha (ERalpha). In the presence of ERbeta, 17beta-estradiol and diethylstilbestrol had no significant effect, while 17alpha-estradiol inhibited and ICI182780 and tamoxifen potentiated DHT action. When both ERalpha and ERbeta were present, all ER-ligands except tamoxifen inhibited DHT action. The inhibition of DHT action by 17beta-estradiol via ERalpha was mainly dependent on the DNA binding domain, while the 17alpha-estradiol effect was mainly dependent on the ERalpha carboxyl terminus. Treatment with DHT in LAPC-4 prostate tumor cells that express a wild-type AR and both ERbeta and ERalpha greatly increased the PSA gene expression and cell growth. These DHT effects were significantly attenuated by the addition of 17alpha-estradiol, 17beta-estradiol, or cyproterone acetate in a dose-dependent manner. These results indicate that estrogens produce an ER-isoform- and ER-ligand-specific modulation of DHT induction of PSA gene expression and prostate tumor cell growth, providing a molecular basis for designing favorable agents for the prevention and control of prostate cancer.

Long-term growth hormone therapy in adulthood results in significant linear growth in siblings with a PROP-1 gene mutation.

PROP-1 gene mutations result in impaired production of GH, gonadotropins, TSH, and prolactin. We describe three adult siblings, aged 18-25 yr, with short stature, hypothyroidism, and lack of pubertal maturation, who were homozygous for 301-302delAG PROP-1 mutation. We had the unique opportunity to treat them in adulthood with GH for 4-5 yr and thyroid replacement before sex steroid replacement. Sibling 1, a female, had a chronological age (CA) of 25 yr 8 months, a bone age (BA) of 12.5 yr, and height of 128.7 cm [-5.29 sd score (SDS)]; sibling 2, a younger sister had a CA of 22 yr 5 months, a BA of 13 yr, and height of 137.5 cm (-3.94 SDS); and sibling 3, a male, had a CA of 18 yr 4 months, a BA of 11.5 yr, and height of 127.5 cm (-6.38 SDS). Despite delay in treatment and fairly advanced BA, all responded to GH and thyroid hormone therapy with a dramatic increase in linear growth: 22.3 cm for sibling 1, 22 cm for sibling 2, and 34.5 cm for sibling 3. After sex hormone replacement, siblings 1, 2, and 3 grew another 2.6, 3, and 9.5 cm to final heights of 153.6, 162.5, and 171.5 cm, respectively. In conclusion, the substantial linear growth in adult siblings with a PROP-1 mutation illustrates that despite an advanced BA, linear growth potential remains in adulthood in the setting of sex steroid deficiency.

Mutations in CYP11B1 gene: phenotype-genotype correlations.

11beta-hydroxylase deficiency, an autosomal recessive disorder, is the second most common cause of congenital adrenal hyperplasia. We studied four subjects with classic 11beta-hydroxylase deficiency and severe hypertension: a 46,XX affected subject from a Turkish family with severe ambiguity of the external genitalia and hypertension, and three affected 46,XY subjects from a Dominican kindred with isosexual precocious puberty and severe hypertension. The affected subjects had significantly elevated plasma 11-desoxycortisol, 11-desoxycorticosterone, Delta4-androstenedione, and testosterone. To determine the molecular genetic defects, genomic DNA was isolated from the leukocytes of affected subjects and their family members. The encoding region of the 11beta-hydroxylase gene (CYP11B1) was amplified by PCR with specific primers. Using single-stranded DNA conformational polymorphism (SSCP) and DNA sequencing, a nonsense mutation in exon 6 of CYP11B1 in the affected 46,XX subject from the Turkish family was identified, where a cytosine was substituted by a thymidine, resulting in the replacement of glutamine (CAG) by a stop codon (TAG) at amino acid position 338 (Q338X). In the three 46,XY Dominican boys, the mutation was also a nonsense mutation in exon 6 of CYP11B1, where a cytosine was substituted by a thymidine, resulting in the replacement of glutamine (CAG) by a stop codon (TAG) at amino acid position 356 (Q356X). Both mutations result in the biosynthesis of a truncated 11beta-hydroxylase protein with loss of enzymatic activity. Heterozygosity was determined in family members of both probands including parents and siblings. These results indicate that mutations of CYP11B1 in these subjects are responsible for their clinical syndromes.

Androgen-induced prostate-specific antigen gene expression is mediated via dihydrotestosterone in LNCaP cells.

Prostate cancer is a leading cause of cancer death in American males. Androgens play an essential role in prostate development, growth and pathogenesis of benign prostate hyperplasia, and prostate cancer. Although testosterone is the main androgen secreted from the testes, dihydrotestosterone (DHT), a more potent androgen converted from testosterone by 5alpha-reductase isozymes, type 1 and 2, is the major androgen in the prostate cells. Thus, 5alpha-reductase(s) are critical in determining androgen activity in the prostate. However, it is unclear in prostate tumor cells whether 1 or 2 5alpha-reductase isozymes are expressed and whether they are functionally important. In the present report, we studied the importance of 5alpha-reductase isozymes in the androgen induction of prostate-specific antigen (PSA) gene expression in LNCaP prostatic tumor cells. Treatment with either testosterone or DHT in LNCaP cells produced dose- and time-dependent increases in PSA levels in the cell media and in PSA messenger RNA (mRNA) levels in the cells. However, testosterone-induced but not DHT-induced PSA gene expression was significantly inhibited by finasteride, a 5alpha-reductase inhibitor, in a dose-dependent manner. Furthermore, we demonstrated for the first time that both 5alpha-reductase-1 and 5alpha-reductase-2 mRNAs were expressed in LNCaP cells using reverse transcriptase-polymerase chain reaction (RT-PCR) and RT-PCR Southern blot analysis. These results suggest that both 5alpha-reductase isozymes are present and functionally important in prostatic tumor LNCaP cells and that DHT is a major mediator of androgen induction of PSA gene expression in these cells.