Vitamin, mineral and iron supplementation in pregnancy: cross-sectional study

Aim. To assess the use of vitamin, mineral and iron supplements during pregnancy in Zagreb and Novi Sad. Methods. The study was conducted by use of a structured standardized questionnaire consisting of two parts, i. e. data obtained by maternal interview and hospital records. It is designed as a cross-sectional study in two countries (Croatia and Serbia). The study included 893 pregnant women from Zagreb and 6099 pregnant women from Novi Sad. Results. In Zagreb, pregnant women reported highest utilization of vitamin-mineral supplements (n = 508; 56.9 %), whereas in Novi Sad these supplements ranked third (n = 408; 20.3 %), following tocolytics and iron supplements. There was no statistically significant difference in the prevalence of congenital malformations between neonates at in utero exposure to vitamins, minerals and iron supplements and those without such exposure in either Zagreb or Novi Sad arm, with the exception of iron and calcium supplementation in the Zagreb arm. Conclusions. In spite of certain study limitations, the results obtained pointed to the unreasonable and potentially harmful use of these supplements in pregnant women from Zagreb

Vitamin, mineral and iron supplementation in pregnancy: cross-sectional study

Aim. To assess the use of vitamin, mineral and iron supplements during pregnancy in Zagreb and Novi Sad. Methods. The study was conducted by use of a structured standardized questionnaire consisting of two parts, i. e. data obtained by maternal interview and hospital records. It is designed as a cross-sectional study in two countries (Croatia and Serbia). The study included 893 pregnant women from Zagreb and 6099 pregnant women from Novi Sad. Results. In Zagreb, pregnant women reported highest utilization of vitamin-mineral supplements (n = 508; 56.9 %), whereas in Novi Sad these supplements ranked third (n = 408; 20.3 %), following tocolytics and iron supplements. There was no statistically significant difference in the prevalence of congenital malformations between neonates at in utero exposure to vitamins, minerals and iron supplements and those without such exposure in either Zagreb or Novi Sad arm, with the exception of iron and calcium supplementation in the Zagreb arm. Conclusions. In spite of certain study limitations, the results obtained pointed to the unreasonable and potentially harmful use of these supplements in pregnant women from Zagreb.Мета. Oцінити вживання вітаминів, а також харчових добавок, які містять мінерали і залізо, протягом вагітності жінок із Загреба та Нові-Сада. Mетоди. Дослідження проводили із використанням стандартного структурованого опитування, яке складається з двох частин: даних, одержаних під час інтерв’ю, та лікарняних записів. Воно побудовано як кроссекційне дослідження у двох країнах (Хорватії і Сербії). Досліджували 893 вагітні жінки із Загреба та 6099 вагітних жінок з Нові-Сада. Результати. У вагітних жінок із Загреба відмічено найвище вживання вітамінно-мінеральних добавок (n = 508; 56.9 %), у той час як у Нові-Саді воно виявилося в три рази нижчим (n = 408; 20.3 %), включаючи токолітики – препарати, які попереджують передчасні пологи, і добавки заліза. Не виявлено статистичено достовірних розбіжностей у частоті появи вроджених дефектів розвитку у новонароджених, які в пренатальному періоді отримували або не отримували добавки, які містять вітаміни, мінерали і залізо, в обох регіонах, за винятком добавок із залізом та кальцієм у загребській виборці. Выводы. Незважаючи на певні обмеження у дослідженні, результати свідчать про необгрунтоване та потенційно шкідливе застосування таких добавок серед вагітних жінок у Загребі.Цель. Oценить применение витаминов, а также пищевых добавок, содержащих минералы и железо, во время беременности у женщин, проживающих в Загребе и Нови-Саде. Mетоды. Исследование проводили с использованием стандартного структурированного опроса, состоящего из двух частей: данных, полученных в ходе интервью, и записей в больницах. Оно построено как кросс-секционное исследование в двух странах (Хорватии и Сербии). Исследовано 893 беременные женщины из Загреба и 6099 – из Нови-Сада. Результаты. У беременных женщин из Загреба отмечено наиболее высокое употребление витаминно-минеральных добавок (n = 508; 56.9 %), в то время как в Нови-Саде оно оказалось в три раза ниже (n = 408; 20.3 %), включая токолиты – препараты, предотвращающие преждевременные роды, и добавки железа. Не выявлено статистически достоверных различий в частоте появления врожденных дефектов развития у новорожденных, которые в пренатальном периоде получали или не получали добавок, содержащих витамины, минералы и железо, в обоих регионах, за исключением добавок с железом и кальцием в загребской выборке. Выводы. Несмотря на определенные ограничения в исследовании, результаты свидетельствуют о необоснованном и потенциально вредном применении этих добавок среди беременных женщин в Загребе

Switch from antagonist to agonist of the androgen receptor blocker bicalutamide is associated with prostate tumour progression in a new model system

Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the non-steroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention. © 1999 Cancer Research Campaig

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC

Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer

The main cause of prostate cancer-related mortality is the development of hormone-refractory disease. Circulating serum levels of IL-6 are raised in hormone-refractory prostate cancer patients and evidence from cell line studies suggests that the IL-6R/JAK/STAT3 pathway may be involved in development of this disease. In the current study we investigate if expression levels of these family members are implicated in the development of hormone-refractory prostate cancer. Immunohistochemistry using IL-6R, JAK1, STAT3, pSTAT3Tyr705 and pSTAT3Ser727 antibodies was performed on 50 matched hormone-sensitive and hormone-refractory tumours pairs. An increase in expression of cytoplasmic IL-6 receptor, with the development of hormone-refractory prostate cancer was associated with reduced time to relapse (P=0.0074) while an increase in expression of cytoplasmic pSTAT3Tyr705 was associated with reduced patient survival (P=0.0003). In addition, those patients with high expression of cytoplasmic pSTAT3Tyr705 in their hormone-refractory tumours had significantly shorter time to death from biochemical relapse and overall survival in comparison to those patients with low expression of cytoplasmic pSTAT3Tyr705 (P=0.002 and P=0.0027, respectively). Activation of STAT3, via phosphorylation is associated with reduced patient survival, suggesting that activation of the IL-6R/JAK/STAT3 pathway is involved with development of hormone-refractory prostate cancer

Application of the JA-CHRODIS Integrated Multimorbidity Care Model (IMCM) to a Case Study of Diabetes and Mental Health

The Integrated Multimorbidity Care Model (IMCM), developed by the Joint Action on Chronic Diseases and Promoting Healthy Ageing across the Life Cycle (JA-CHRODIS), proposes a set of 16 multidimensional components (i.e., recommendations) to improve the care of persons with multimorbidity in Europe. This study aimed at analyzing the potential applicability of the IMCM. We followed a qualitative approach that comprised two phases: (1) The design of a case study based on empirical clinical data, which consisted of a hypothetical woman with multimorbidity, type 2 diabetes mellitus, mental health, and associated social problems, and (2) the creation of a consensus group to gather the opinions of a multidisciplinary group of experts and consider the potential applicability of the IMCM to our case study. Experts described how care should be delivered to this patient according to each model component, suggested the use of specific rating scales and tools to assess her needs in a comprehensive and regular way, and pointed our crucial health and social resources to improve her care process. Experts also highlighted patient-centered, integrated and tailored care as one of the keystones of quality healthcare. Our results suggest that the IMCM is applicable in complex patients with multimorbidity

Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer

This study examined androgen receptor (AR) gene amplification and protein expression in 102 matched paired hormone sensitive and resistant tumours from 51 patients. AR gene amplification and X chromosome copy number were assessed by fluorescent in situ hybridisation, and protein expression was assessed by immunohistochemistry. All tumours were stained for PSA protein expression. Significantly more tumours exhibited AR amplification following the development of hormone resistance (20%, 10 out of 49) compared to matched hormone-sensitive tumours from the same patient (2%, one out of 48) (P = 0.0085). The level of AR expression was significantly higher in hormone- resistant tumours compared to matched hormone-sensitive tumours from the same patient (130, interquartile range, 55-167 vs 94.5 interquartile range, 55-120, P = 0.019). AR expression levels in hormone-resistant tumours with and without AR amplification were not significantly different. However, an increase in AR expression was seen with the development of AR amplification in paired tumours. The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance. Alternative mechanisms for modulating the function of the AR, or other signalling pathways, must be considered as key factors in the development of hormone-resistant prostate

Prevention and early detection of prostate cancer

This Review was sponsored and funded by the International Society of Cancer Prevention (ISCaP), the European Association of Urology (EAU), the National Cancer Institute, USA (NCI) (grant number 1R13CA171707-01), Prostate Cancer UK, Cancer Research UK (CRUK) (grant number C569/A16477), and the Association for International Cancer Research (AICR

Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface

Prostate cancer is a leading killer of men in the industrialized world. Underlying this disease is the aberrant action of the androgen receptor (AR). AR is distinguished from other nuclear receptors in that after hormone binding, it preferentially responds to a specialized set of coactivators bearing aromatic-rich motifs, while responding poorly to coactivators bearing the leucine-rich “NR box” motifs favored by other nuclear receptors. Under normal conditions, interactions with these AR-specific coactivators through aromatic-rich motifs underlie targeted gene transcription. However, during prostate cancer, abnormal association with such coactivators, as well as with coactivators containing canonical leucine-rich motifs, promotes disease progression. To understand the paradox of this unusual selectivity, we have derived a complete set of peptide motifs that interact with AR using phage display. Binding affinities were measured for a selected set of these peptides and their interactions with AR determined by X-ray crystallography. Structures of AR in complex with FxxLF, LxxLL, FxxLW, WxxLF, WxxVW, FxxFF, and FxxYF motifs reveal a changing surface of the AR coactivator binding interface that permits accommodation of both AR-specific aromatic-rich motifs and canonical leucine-rich motifs. Induced fit provides perfect mating of the motifs representing the known family of AR coactivators and suggests a framework for the design of AR coactivator antagonists