19 research outputs found
Changes in the Penile Arteries of the Rat after Fractionated Irradiation of the Prostate: A Pilot Study
No full textIntroduction. External beam radiotherapy for prostate cancer leads to erectile dysfunction in 36%-43% of patients. The underlying mechanism is largely unknown, although some clinical studies suggest that the arterial supply to the corpora cavernosa is responsible. Two animal experimental studies reported on the effects of a single fraction of prostate irradiation on the penile structures. However, irradiation in multiple fractions is more representative of the actual clinical treatment. Aim. The present prospective, controlled study was initiated to investigate the effect of fractionated prostate irradiation on the arteries of the corpora cavernosa. Main Outcome Measures. Histological evaluation of the penile tissue in comparison with control rats at 2, 4, and 9 weeks after irradiation. Methods. The prostate of twelve rats was treated with external beam radiation in 5 daily fractions of 7.4 gray. Three control rats were treated with sham irradiation. Prostatic and penile tissue was evaluated for general histology (hematoxylin-eosin). The penile tissue was further evaluated after combined staining for collagen (resorcin fuchsin) and alpha-smooth muscle actin (SMA) (Biogenex). Results. The prostate showed adequate irradiation with fibrosis occurring at 9 weeks after irradiation. The corpora cavernosa showed arteries that had developed loss of smooth muscle cells expressing SMA, thickening of the intima, and occlusions. All the control rats maintained normal anatomy. Conclusion. This is the first animal experimental study that demonstrates changes in the arteries of the corpora cavernosa after fractionated irradiation to the prostatic area. The preliminary data suggests that erectile dysfunction after radiotherapy might be caused by radiation damage to the arterial supply of the corpora cavernosa. van der Wielen GJ, Vermeij M, de Jong BWD, Schuit M, Marijnissen J, Kok DJ, van Weerden WM, and Incrocci L. Changes in the penile arteries of the rat after fractionated irradiation of the prostate: A pilot study. J Sex Med 2009;6:1908-1913
Comparison of PSMA- and GRPR-targeting radiotracers in prostate cancer samples of different disease stages:is there a role for GRPR-targeting radiotracers?
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Darolutamide does not interfere with OATP-mediated uptake of docetaxel
Get PDFThe addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug–drug interaction was identified
The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.
Get PDFAs 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
NEUROBIOLOGICAL EFFECTS OF DHEA IN FEMALES WITH SPECIAL REFERENCE TO SEXUAL FUNCTION: FINDINGS FROM IN-VIVO AND HUMAN STUDIES
No full textDehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, together represent the most abundant steroid hormones in the human body. Nonetheless, their physiological significance, their mechanisms of action and their possible roles in human disease are not well understood. Highlighting the potential health significance of DHEA and DHEAS, concentrations of these hormones in humans typically decrease steadily with age, approaching a nadir at about the time many diseases of aging become markedly more prevalent. There is growing evidence in the literature that a low DHEAS level, negatively correlates with the domains of sexual function in pre and postmenopausal women to a greater extent than testosterone levels. Biological actions of DHEA(S) involve neuroprotection, neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion, as well as anti-oxidant, anti-inflammatory and anti-glucocorticoid effects. In addition, DHEA affects neurosteroidogenis and endorphin synthesis/release. We demonstrated in a model of ovariectomized rats that DHEA therapy increases proceptive behaviors, already after 1 week of treatment, affecting central function of sexual drive. In women, the analyses of clinical outcomes are far from being conclusive and many issues should still be addressed. Although DHEA preparations have been available in the market since the 1990s, there are very few definitive reports on the biological functions of this steroid, and it is still the case that its regulation is unclear and its mechanisms of action largely yet to be established. We demonstrate that one year DHEA administration at the dose of 10 mg provided a significant improvement in comparison with vitamin D in sexual function and in frequency of sexual intercourse in early postmenopausal women. Among symptomatic women, the spectrum of symptoms responding to DHEA requires further investigation, to define the type of sexual symptoms (e.g. decreased sexual function or hypoactive sexual desire disorder) and the degree of mood/cognitive symptoms that could be responsive to hormonal treatment. In this regard, our findings are promising, although they need further exploration with a larger and more representative sample size
Homeostase glicêmica em ratas com perda de função ovariana e tratadas com glicocorticoide
Get PDFDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação Multicêntrico em Ciências Fisiológicas, Florianópolis, 2015.O glicocorticoide (GC) é amplamente aplicado na clínica para o tratamento de doenças inflamatórias. Seu uso prolongado repercurte sobre a homeostase glicêmica podendo levar a resistência periférica à insulina (RI). Mulheres na transição de segunda para a terceira idade iniciam um processo natural de falha ovariana, a menopausa. Na menopausa há ganho de peso e modificações na distribuição da gordura, especialmente na região visceral. A associação entre GCs e menopausa não está bem estabelecida na literatura. Assim, avaliamos as repercussões da perda de função ovariana associada ao tratamento com GC sobre parâmetros relacionados à homeostase glicêmica. Para tanto, ratas Wistar (28 dias de vida) foram submetidas à falha ovariana por meio da administração de 4-vinilciclohexeno diepóxido (4-VCD), i.p. (VCD) ou receberam somente veículo (CTL) e 168 dias após foram tratadas com dexametasona (1 mg/kg, p.c., i.p.) por 5 dias consecutivos (DEX e VCD+DEX) ou veículo (CTL e VCD). O grupos DEX e VCD+DEX demonstraram redução da massa corporal e da ingestão alimentar durante tratamento com dexametasona (pAbstract : Glucocorticoids (GC) are widely applied in clinic for the treatment of inflammatory diseases. Its prolonged use influences the glucose homeostasis and may lead to insulin resistance (IR). Women in transition from natural reproductive life to menopause begin a natural process of ovarian failure. In this case, there are weight gain and changes in fat distribution, especially in the visceral region. The association between GCs and menopause is not well established in the literature. We evaluated the impact of the loss of ovarian function associated with GC treatment on parameters related to glucose homeostasis. Wistar rats (28 days old) underwent ovarian failure by administration of 4-vinylcyclohexene diepoxide (4-VCD) i.p. (VCD), while controls received vehicle (CTL). After 168 days rats were treated with dexamethasone (1 mg / kg bw, i.p.) for 5 consecutive days (DEX and VCD+DEX) or vehicle (CTL and VCD). The DEX and VCD+DEX groups showed reduced body weight and food intake during treatment with dexamethasone (p<0.05). The rats treated with dexamethasone showed an increase in glycemia, insulinemia, triglyceridemia and hepatic glycogen content vs. their respective control groups (p<0.05) and there is no effect of treatment with 4-VCD per se. Treatment with 4-VCD does not alter insulin sensitivity, whereas the groups treated with dexamethasone showed a reduction in insulin sensitivity compared to their respective controls (p<0.05). The VCD group exhibited impaired glucose tolerance (GTT ip.) vs. CTL group (p<0.05) and intolerance present in the DEX group was not enhanced by treatment with 4-VCD (VCD+DEX). In oral glucose challenge treatment with 4-VCD did not promote changes in VCD and VCD+DEX groups compared to their respective controls. Treatment with 4-VCD caused no change in the mass of ß cells in the VCD group, but prevented the compensatory increase (VCD+DEX group) occurred in the DEX group. The GC treatment resulted in a marked increase in plasma progesterone values vs. CTL (p<0.05) group. We conclude that treatment with 4-VCD does not cause alterations in the basal metabolic parameters, but causes glucose intolerance. Treatment with 4-VCD dos not predisposes rats to additional metabolic dysfunctions caused by the GC treatment, except for the attenuation of the increase in mass of ß cells induced by administration of dexamethasone
Defining the challenges and opportunities for using patient-derived models in prostate cancer research
No full textBACKGROUND: There are relatively few widely used models of prostate cancer compared to other common malignancies. This impedes translational prostate cancer research because the range of models does not reflect the diversity of disease seen in clinical practice. In response to this challenge, research laboratories around the world have been developing new patient-derived models of prostate cancer, including xenografts, organoids, and tumor explants. METHODS: In May 2023, we held a workshop at the Monash University Prato Campus for researchers with expertise in establishing and using a variety of patient-derived models of prostate cancer. This review summarizes our collective ideas on how patient-derived models are currently being used, the common challenges, and future opportunities for maximizing their usefulness in prostate cancer research. RESULTS: An increasing number of patient-derived models for prostate cancer are being developed. Despite their individual limitations and varying success rates, these models are valuable resources for exploring new concepts in prostate cancer biology and for preclinical testing of potential treatments. Here we focus on the need for larger collections of models that represent the changing treatment landscape of prostate cancer, robust readouts for preclinical testing, improved in vitro culture conditions, and integration of the tumor microenvironment. Additional priorities include ensuring model reproducibility, standardization, and replication, and streamlining the exchange of models and data sets among research groups. CONCLUSIONS: There are several opportunities to maximize the impact of patient-derived models on prostate cancer research. We must develop large, diverse and accessible cohorts of models and more sophisticated methods for emulating the intricacy of patient tumors. In this way, we can use the samples that are generously donated by patients to advance the outcomes of patients in the future
Pendular Nystagmus; Horizontal Gaze Palsy
No full textHorizontal Pendular Nystagmus; Horizontal Gaze Palsy; Preservation of Convergence; Normal Vertical Gaze; Optokinetic Nystagmus Absent; Horizontal Vestibular Ocular Reflex AbsentJiggly eyesThe patient is a 29 year old retarded man with a rare autosomal recessive disorder characterized by congenital absence of conjugate horizontal eye movements, preservation of vertical gaze and convergence and horizontal pendular nystagmus. Ocular motility examination: Conjugate horizontal pendular nystagmus Absent horizontal gaze (saccadic and pursuit eye movements) Absent horizontal vestibular ocular reflex Absent optokinetic nystagmus (OKN) Normal vertical gaze Preservation of convergence Neurological examination: Normal. Congenital horizontal gaze palsy (HGP) is one of several genetic disorders of eye and lid control that are believed to result from cranial nuclear maldevelopment. Among these entities, the most closely related to HGP are Duane retraction syndrome and Mobius syndrome. Abnormal development of the abducens nucleus plays a crucial role in the pathogenesis of both these entities, as well as of HGP. These disorders, referred to as Congenital Cranial Disinnervation Syndrome, have the following features: • They are present at birth • Usually non-progressive • Have an autosomal inheritance pattern, that may occur sporadically. • May result from primary disinnervation, from failed or misguided development of neurons or • Result from aberrant innervation during development (i.e. secondary disinnervation). Brain MRI was not available in this case. Brain MRI in a 13 year old girl with HGP and progressive scoliosis (HGPPS) revealed: 1. A hypoplastic pons in which the posterior two-thirds were split into two halves by a midsagittal cleft extending ventrally from the fourth ventricular floor, generating a split pons sign on axial images. 2. The facial colliculi were absent, and the fourth ventricular floor was tent shaped. 3. The medulla was also hypoplastic and showed a butterfly configuration. 4. The inferior olivary nuclei were prominent with respect to the pyramids, and the prominence of the gracile and cuneate nuclei on the posterior aspect of the medulla was absent. The pathogenesis of the absence of horizontal gaze remains speculative. It may arise from aberrant supranuclear input onto the abducens motoneurons by axons from the pontine paramedian reticular formation that cannot cross the midline, and inability of the developing axons in the medial lateral fasciculus to cross the midline, and/or from lack of midline crossing by developing pontine neurons normally destined to cross. Children with congenital absence of conjugate horizontal eye movements may adopt several adaptive strategies to compensate for their deficit. They substitute rapid head movements (head saccades) for eye saccades to change gaze rapidly. When the head is restrained, they may use their intact vergence system to move both eyes into adduction and then cross-fixate, using the right eye to view objects seen on the left and vice versa. Additional signs reported in this syndrome include: Horizontal, elliptical or pendular nystagmus, as in this case Head shaking Intermittent slow blinking of one or both eyes Retraction of the non-fixing eye during vergence movements. Facial contraction with myokymia Progressive scoliosis which becomes disabling (Review ID162-7 Horizontal Gaze Palsy and Progressive Scoliosis alongside this case).This patient with a congenital cranial disinnervation syndrome had: Congenital horizontal pendular nystagmus Absent conjugate horizontal gaze (saccades and pursuit) Absent horizontal vestibular ocular reflex Absent optokinetic nystagmus Normal vertical gaze Plaitakis et al studied two brothers affected by HGPPS and homozygous for the E919K mutation of the ROBO3 gene. In addition to severe kyphoscoliosis and absence of conjugate lateral eye movements, the brothers had congenital horizontal pendular nystagmus, the pathology of which remains unclear. Vertical OKNs were preserved, the vestibulocular reflex (VOR) was present in the vertical but not in the horizontal plane. Cold and warm caloric irrigation of the ears was performed. Cold water abolished the nystagmus of the ipsilateral eye. Conversely, warm water increased nystagmus of the ipsilateral eye The authors concluded that the monocular effects of caloric stimulation are consistent with a lack of crossing of brainstem vestibular pathways. They presumed that the loss of voluntary conjugate horizontal eye movements is on a similar basis.No neuroimaging studies are available in this patient. MRI Images obtained in a 13 year old girl with HGPPS and early onset thoracolumbar scoliosis showed: Figure 1A. Sagittal T1-weighted image of the brain shows depression of the floor of the fourth ventricle (arrowhead). The pons and medulla oblongata have a reduced volume. Figure 1B. Axial T2-weighted image at the level of the medulla oblongata shows rectangular configuration of the medulla. The floor of the fourth ventricle is tent shaped (arrows), with missing prominence of the cuneate and gracile nuclei. The inferior olivary nuclei (IO) are prominent with respect to the pyramids (P). Figure 1C. Axial T2-weighted image at the level of the pons shows absence of the facial colliculi, with tent shaped configuration of the floor of the fourth ventricle (arrows). A deep midsagittal cleft extends ventral from the fourth ventricular floor, producing the split pons sign (arrowhead). Figure 2. MRI of the spine showing prominent scoliosis. Courtesy Andrea Rossi, M.D.Brainstem hypoplasiaLinkage studies have localized a mutation of the ROBO 3 gene on chromosome 11q23 -25 which is important for hindbrain midline axon crossing.Genetic disorder Mutation of the ROBO 3 gene on chromosome 11q23-q25.1. Bosley TM, Salih MA, Jen JC, Lin DD, Oystreck D, Abu-Amero KK, MacDonald DB, al Zayed Z, al Dhalaan H, Kansu T, Stigsby B, Baloh RW. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology. 2005;64:1196-1203. http://www.ncbi.nlm.nih.gov/pubmed/15824346 2. Engle EC, Leigh RJ. Genes, brainstem development and eye movements. Neurology 2002;59:304-305. http://www.ncbi.nlm.nih.gov/pubmed/12177361 3. Jen J, Coulin CJ, Bosley TM Salih MAM, Sabatti C, Nelson SF, Baloh RW. Familial horizontal gaze palsy with progressive scoliosis maps to chromosome 11q23-25. Neurology 2002;59:432-435. http://www.ncbi.nlm.nih.gov/pubmed/12177379 4. Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rüb U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004 Jun 4;304(5676):1509-1513. http://www.ncbi.nlm.nih.gov/pubmed/15105459 5. Kruis JA, Houtman WA, Van Weerden TW. Congenital absence of conjugate horizontal eye movements. Doc Ophthalmol. 1987; 67:13-18. http://www.ncbi.nlm.nih.gov/pubmed/3428093 6. Pieh C, Lengyel D, Neff A, Fretz C, Gottlob I. Brainstem hypoplasia in familial horizontal gaze palsy and scoliosis. Neurology. 2002;59:462-463. http://www.ncbi.nlm.nih.gov/pubmed/12177390 7. Plaitakis A, Tzagournissakis M, Christodoulou P, Jen JC, Baloh RW. Vestibular modification of congenital pendular nystagmus in HGPPS with the ROBO3 mutation (abstract). Neurology 2005;64(suppl 1):A33. 8. Rossi A, Catala M, Biancheri R, Di Comite R, Tortori-Donati P. MR imaging of brain-stem hypoplasia in horizontal gaze palsy with progressive scoliosis. Am J Neuroradiol. 2004;25:1046-1048. http://www.ncbi.nlm.nih.gov/pubmed/15205146 9. Sharpe JA, Silversides JL, Blair RD. Familial paralysis of horizontal gaze. Associated with pendular nystagmus, progressive scoliosis, and facial contraction with myokymia. Neurology 1975;25:1035-1040. http://www.ncbi.nlm.nih.gov/pubmed/1237821 10. Sicotte NL, Plaitakas A, Salamon G, et al. Brainstem axon crossing defects in horizontal gaze palsy with progressive scoliosis assessed with diffusion tensor imaging and neurophysiological testing. Neurology 2005;64(Suppl1):A2. 11. Thomsen M, Steffen H, Sabo D, Niethard FU. Juvenile progressive scoliosis and congenital horizontal gaze palsy. J Pediatr Orthop B 1996;5:185-189. http://www.ncbi.nlm.nih.gov/pubmed/8866284 12. Yee RD, Duffin RM, Baloh RW, Isenberg SJ. Familial congenital paralysis of horizontal gaze. Arch Ophthalmol. 1982;100:1449-1452. http://www.ncbi.nlm.nih.gov/pubmed/7115172 13. Zweifach PH, Walton DS, Brown RH. Isolated congenital horizontal gaze paralysis. Occurrence of the near reflex and ocular retraction on attempted lateral gaze. Arch Ophthalmol 1969;81:345-350. http://www.ncbi.nlm.nih.gov/pubmed/577429
The future of patient-derived xenografts in prostate cancer research
No full textPatient-derived xenografts (PDXs) are generated by engrafting human tumours into mice. Serially transplantable PDXs are used to study tumour biology and test therapeutics, linking the laboratory to the clinic. Although few prostate cancer PDXs are available in large repositories, over 330 prostate cancer PDXs have been established, spanning broad clinical stages, genotypes and phenotypes. Nevertheless, more PDXs are needed to reflect patient diversity, and to study new treatments and emerging mechanisms of resistance. We can maximize the use of PDXs by exchanging models and datasets, and by depositing PDXs into biorepositories, but we must address the impediments to accessing PDXs, such as institutional, ethical and legal agreements. Through collaboration, researchers will gain greater access to PDXs representing diverse features of prostate cancer.</p
