Evolution of the sperm aster after microinjection of isolated human sperm centrosomes into meiotically mature human oocytes

This study examined the feasibility of isolating and transferringthe centrosome-containing region of spermatozoa to mature humanoocytes. The findings demonstrate that individual sperm centrosomescan be transferred and are capable of nucleating maternal tubulinto form a well-developed sperm aster in the recipient oocyte.The results are discussed with respect to centrosome functionin early human development and applications in clinical in-vitrofertilization in the treatment of certain forms of male factorinfertility.     

The Noscapine Chronicle: A Pharmaco‐Historic Biography of the Opiate Alkaloid Family and its Clinical Applications

Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable “Renaissance drug” worthy of commemoration. Perhaps the only facet of noscapine's profile more astounding than its versatility is its virtual lack of side effects and addictive properties, which distinguishes it from other denizens of Papaver somniferum. This review intimately chronicles the rich intellectual and pharmacological history behind the noscapine family of compounds, the length of whose arms was revealed over decades of patient scholarship and experimentation. We discuss the intriguing story of this family of nontoxic alkaloids, from noscapine's purification from opium at the turn of the 19th century in Paris to the recent torrent of rationally designed analogs with tremendous anticancer potential. In between, noscapine's unique pharmacology; impact on cellular signaling pathways, the mitotic spindle, and centrosome clustering; use as an antimalarial drug and cough suppressant; and exceptional potential as a treatment for polycystic ovarian syndrome, strokes, and diverse malignancies are catalogued. Seminal experiments involving some of its more promising analogs, such as amino‐noscapine, 9‐nitronoscapine, 9‐bromonoscapine, and reduced bromonoscapine, are also detailed. Finally, the bright future of these oftentimes even more exceptional derivatives is described, rounding out a portrait of a truly remarkable family of compounds.     

Cover Image,Volume 40, Issue 4

The abysmal success rate of anticancer drugs in clinical trials, is in part, attributable to discordance between cultured cancer cells and patient tumors. While tumors in vivo, display a lower mitotic index, patient tumors portray much higher centrosomal aberrations, relative to in vitro cultured cells. The microenvironment too differs considerably between the in vitro and in vivo scenarios. Notably, another hallmark of cancer, hypoxia, is not recapitulated in cell lines cultured under normoxic conditions. These observations raise the possibility that hypoxia may be the missing link that explains the discordance between cell biological phenomena in vitro versus physiological conditions. Further, the interplay between hypoxia and centrosome amplification (CA) is relatively understudied. Recent research from our laboratory, geared toward examining the biological link between the two, has uncovered that hypoxia induces the expression of proteins (Plk4, Aurora A, Cyclin D) implicated in CA, in a hypoxia-inducible factor 1α (HIF-1α)-dependent context. Our studies evidence that hypoxia fuels CA that underlie intratumoral heterogeneity and metastatic potential of cancer cells. Given the advent of HIF-1α inhibitors, this research has ramifications in aiding patient risk stratification and designing new cancer drug therapies to facilitate clinical decision-making.     

中心体在肿瘤发生及治疗中的作用

中心体维持细胞形态和染色体的准确分离,与损伤修复系统协同应对DNA损伤,维护基因组的稳定性。中心体结构或功能异常与非整倍体及肿瘤发生密切相关,抑制中心体蛋白可诱导肿瘤细胞凋亡,将成为肿瘤治疗的新策略。     

STK15在恶性肿瘤中的研究进展

中心体这一微小的细胞器，在有丝分裂中对维持细胞的极性及染色体分离具有重要的调节作用。目前的研究表明中心体异常在人类恶性肿瘤中普遍存在。作为一种中心体相关激酶，STK15与恶性肿瘤的发生之间存在着极其密切的联系，其活性的改变会引起中心体扩增、染色体不稳定及细胞的转化。本文主要介绍目前STK15在部分人类恶性肿瘤中的研究进展。     

Aurora A激酶研究进展

Aurora A激酶是进化上保守的有丝分裂丝/苏氨酸激酶Aurora激酶家族成员之一,在细胞内随细胞周期的变化呈动态分布,它广泛的参与了细胞周期不同阶段的各种事件,并在人类多种恶性肿瘤的发生发展过程中起到了至关重要的作用,因而很有可能成为一个极具前途的恶性肿瘤的分子治疗靶点。     

Aggresome-related biogenesis of Lewy bodies

Neurodegenerative disorders such as Parkinson's disease (PD) and 'dementia with Lewy bodies' (DLB) are characterized pathologically by selective neuronal death and the appearance of intracytoplasmic protein aggregates (Lewy bodies). The process by which these inclusions are formed and their role in the neurodegenerative process remain elusive. In this study, we demonstrate a close relationship between Lewy bodies and aggresomes, which are cytoplasmic inclusions formed at the centrosome as a cytoprotective response to sequester and degrade excess levels of potentially toxic abnormal proteins within cells. We show that the centrosome/aggresome-related proteins gamma-tubulin and pericentrin display an aggresome-like distribution in Lewy bodies in PD and DLB. Lewy bodies also sequester the ubiquitin-activating enzyme (E1), the proteasome activators PA700 and PA28, and HSP70, all of which are recruited to aggresomes for enhanced proteolysis. Using novel antibodies that are specific and highly sensitive to ubiquitin-protein conjugates, we revealed the presence of numerous discrete ubiquitinated protein aggregates in neuronal soma and processes in PD and DLB. These aggregates appear to be being transported from peripheral sites to the centrosome where they are sequestered to form Lewy bodies in neurons. Finally, we have shown that inhibition of proteasomal function or generation of misfolded proteins cause the formation of aggresome/Lewy body-like inclusions and cytotoxicity in dopaminergic neurons in culture. These observations suggest that Lewy body formation may be an aggresome-related event in response to increasing levels of abnormal proteins in neurons. This phenomenon is consistent with growing evidence that altered protein handling underlies the etiopathogenesis of PD and related disorders.     

Pregnancy from intracytoplasmic sperm injection of a sperm head and detached tail

OBJECTIVE: To evaluate sperm ultrastructure and the efficacy of intracytoplasmic sperm injection (ICSI) with careful positioning of the sperm midpiece next to the sperm head in a patient with easily decapitated sperm syndrome. DESIGN: In vitro fertilization case report with retrospective sperm ultrastructure analysis. SETTING: In vitro fertilization clinic and andrology laboratory. PATIENT(S): A couple seeking treatment for diminished ovarian reserve and male factor infertility using donor oocyte IVF. INTERVENTION(S): Motile sperm inadvertently decapitated during micromanipulation were used for a modified ICSI procedure in which the midpiece was carefully positioned proximal to the sperm head. Sperm were also analyzed by transmission electron microscopy (TEM). MAIN OUTCOME MEASURE(S): Fertilization rate, embryo development, pregnancy, and the incidence of normal sperm ultrastructure. RESULT(S): The ICSI resulted in a fertilization rate of 63% and embryo development of good to moderate quality of 36% of the embryos. Transfer of two embryos resulted in a pregnancy and birth of a healthy child. Normal sperm centrosomes were identified retrospectively. CONCLUSION(S): Pregnancy can result in patients where the sperm are decapitated during immobilization before ICSI if normal centrosomes are present and the head and midpiece are positioned closely together.     

Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers

Over-expression of a centrosomal serine/threonine kinase, STK15/BTAK, induces centrosome amplification, which results in chromosomal instability (CIN) in cell culture. In the present study, we investigated the correlation of STK15/BTAK mRNA expression with CIN and various clinicopathological factors in human breast cancer. STK15/BTAK mRNA levels were quantified by real-time PCR, and CIN values were determined by FISH analysis of chromosomes 1, 11 and 17 using centromeric probes. STK15/BTAK mRNA levels (0.310 +/- 0.413, mean +/- SD, n = 47) in breast cancers were significantly (p < 0.01) higher than those in normal breast tissues (0.044 +/- 0.029, n = 9). Furthermore, breast cancers were divided into 3 groups (low, intermediate and high) according to STK15/BTAK mRNA expression levels. CIN values of the low-expression group (27.9 +/- 12.6%, n = 18) were significantly (p < 0.01) higher than those of normal breast tissues (9.2 +/- 2.6%, n = 6), and those of the high-expression group (38.0 +/- 12.7%, n = 14) were significantly (p < 0.05) higher than those of the low-expression group. STK15/BTAK mRNA expression showed a significant (p < 0.05) correlation with high histological grade and negativity of estrogen and progesterone receptors. Our results demonstrate that STK15/BTAK mRNA is over-expressed in the majority of breast cancers and its over-expression is significantly associated with CIN, implicating STK15/BTAK in carcinogenesis through induction of CIN. STK15/BTAK mRNA levels might be useful as an indicator of poor prognosis and resistance to endocrine therapy.