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1.
Artigo em Inglês | MEDLINE | ID: mdl-33427301

RESUMO

BACKGROUND: Vulvodynia and pudendal neuralgia comprise significant contributors to vulvar-related pain and its impact on daily life. AIM: A retrospective clinical audit was conducted at the Women's Health & Research Institute of Australia, Sydney, to determine the pattern of use and the efficacy of the application of topical amitriptyline 0.5% plus oestriol 0.03% in organogel (AOO), to the vulvar vestibule in reducing the impact of pain on daily life. MATERIALS AND METHODS: There were 1174 patients who received a script from May 2017 until February 2020: 1054 patients agreed to be contacted and had a valid email address. RESULTS: There were 376 (35.7%) patients who replied. Pain with intercourse was the main indication for use. Treatment was rated effective by 51.2% (95% CI: 35.4-66.8%) of patients less than 30 years of age, 66.7% (95% CI: 57.3-74.9%) of patients 30-50 years of age, and 58.3% (95% CI: 50.9-65.4%) in patients over 50. Stinging at the site of application was the most commonly reported side effect. CONCLUSION: Topical AOO is an effective and well-tolerated treatment for vulvar pain.

2.
Biotechnol Prog ; : e3130, 2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33491344

RESUMO

Cell culture media used in CHO-based biologic processes are typically sterile filtered to prevent microbial contamination prior to inoculation. In this study, the impact of common sterile filter throughput on a different, commercially available cell culture media was evaluated from the intermediate-adsorption fouling model of the filtration model. The key particle size range for optimum filter performance was discussed and identified by measuring the submicron order particle size distribution. It may be possible to predict the performance of filter capacity with size-exclusive separation by understanding the media particle counts and size distribution.

3.
Cancer Lett ; 497: 14-27, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33010383

RESUMO

Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth. In addition to its effect on cancer aggressiveness, Nurr1 enhanced the self-renewal ability of cells in vitro and in vivo, underscoring the importance of Nurr1 in maintaining the stemness of cancer stem-like cells (CSLCs). Mechanistically, Nurr1 independently activated the MEK/ERK and PI3K/Akt/mTOR signaling cascades. The MEK inhibitor trametinib (GSK) and PI3K/mTOR dual inhibitor dactolisib (BEZ) were shown to abrogate Nurr1-augmented tumorigenesis by upregulating p21 and p27 expression and by suppressing MMP9 and KLF4 expression. We provided further evidence that BEZ, but not GSK, could abolish Nurr1-enhanced radioresistance, suggesting its potential value for radiosensitizing CSLCs in the clinical setting. This study highlights the unprecedented roles of Nurr1 and elucidates mechanisms by which Nurr1 promotes tumor progression and radioresistance, providing a novel therapeutic strategy for cervical cancer treatment.

4.
Acta Crystallogr D Struct Biol ; 76(Pt 12): 1201-1210, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33263326

RESUMO

Adenylate-forming enzymes (AFEs) are a mechanistic superfamily of proteins that are involved in many cellular roles. In the biosynthesis of benzoxazole antibiotics, an AFE has been reported to play a key role in the condensation of cyclic molecules. In the biosynthetic gene cluster for the benzoxazole AJI9561, AjiA1 catalyzes the condensation of two 3-hydroxyanthranilic acid (3-HAA) molecules using ATP as a co-substrate. Here, the enzymatic activity of AjiA1 is reported together with a structural analysis of its apo form. The structure of AjiA1 was solved at 2.0 Šresolution and shows a conserved fold with other AFE family members. AjiA1 exhibits activity in the presence of 3-HAA (Km = 77.86 ± 28.36, kcat = 0.04 ± 0.004) and also with the alternative substrate 3-hydroxybenzoic acid (3-HBA; Km = 22.12 ± 31.35, kcat = 0.08 ± 0.005). The structure of AjiA1 in the apo form also reveals crucial conformational changes that occur during the catalytic cycle of this enzyme which have not been described for any other AFE member. Consequently, the results shown here provide insights into this protein family and a new subgroup is proposed for enzymes that are involved in benzoxazole-ring formation.

5.
Nat Commun ; 11(1): 5954, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230097
6.
Sci Rep ; 10(1): 20116, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208779

RESUMO

The adhesion of blood clots to wounds is necessary to seal injured vasculature and achieve hemostasis. However, it has not been specifically tested if adhesive failure of clots is a major contributor to rebleeding and what mechanisms prevent clot delamination. Here, we quantified the contribution of adhesive and cohesive failure to rebleeding in a rat model of femoral artery injury, and identified mechanisms that contribute to the adhesive strength of bulk clots in a lap-shear test in vitro. In the rat bleeding model, the frequency of clot failures correlated positively with blood loss (R = 0.81, p = 0.014) and negatively with survival time (R = - 0.89, p = 0.0030), with adhesive failures accounting for 51 ± 14% of rebleeds. In vitro, adhesion depended on fibrinogen and coagulation factor XIII (FXIII), and supraphysiological FXIII improved adhesive strength. Furthermore, when exogenous FXIII was topically applied into the wound pocket of rats, eleven adhesive failures occurred between eight rats, compared to seventeen adhesive failures between eight untreated rats, whereas the number of cohesive failures remained the same at sixteen in both groups. In conclusion, rebleeding from both adhesive and cohesive failure of clots decreases survival from hemorrhage in vivo. Both endogenous and exogenous FXIII improves the adhesive strength of clots.

7.
Cancers (Basel) ; 12(10)2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33086676

RESUMO

Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33079469

RESUMO

AIM: To review the clinical use and the effectiveness of tamoxifen in patients with advanced or recurrent ovarian cancer. METHODS: A retrospective review of clinical records was conducted in patients who received tamoxifen for the treatment of ovarian cancer between 2002 and 2016. We reviewed the clinical setting that it was given, duration of use, patients' tolerability, clinical benefit and progression-free survival. We also attempted to identify predictive markers for response. RESULTS: A total of 92 patients received tamoxifen during this 15-year period. The patients received a median of 2.5 lines of chemotherapy before switching to tamoxifen, and they remained on tamoxifen for a median of 5.6 months (range 0-85 months), with 24 patients receiving it for more than 12 months. Seventy-six patients continued on tamoxifen for more than 2 months. In this group, 75 patients had an evaluable response, either by CA 125 or clinically and clinical benefit rate (defined as complete, partial response and static disease) was seen in 42 patients (56%), with majority of patients having static disease. The median progression-free survival was 5.3 months (95% confidence interval, 2.6-8.1). Tamoxifen was well tolerated. Hormone receptor status was not demonstrated to predict response. CONCLUSION: Patients with advanced ovarian cancer who have failed previous lines of chemotherapy may achieve static disease with tamoxifen with minimal side effects. Tamoxifen may still have a role in the era of molecular target therapy.

9.
Am J Cancer Res ; 10(9): 2919-2932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042626

RESUMO

Targeted therapeutic agents such as poly (ADP-ribose) polymerases (PARP) inhibitors have emerged in treating cancers associated with germline BRCA mutations. Recently studies demonstrated the effectiveness of PARP inhibitors in treating patients with somatic BRCA mutations. Somatic mutations in 122 Chinese breast or ovarian cancer patients without BRCA, PTEN and TP53 mutations were screened using multigene sequencing panel. The five most frequent pathogenic or likely pathogenic mutated genes identified in breast cancer patients were PIK3CA (28.6%), TP53 (16.9%), MAP3K1 (14.3%), GATA3 (14.3%) and PTEN (5.2%). The five most frequently mutated genes identified in ovarian patients were TP53 (52.9%), KRAS (23.5%) and PIK3CA (11.8%), BRCA1 (5.9%) and RB1 (5.9%). Somatic PIK3CA and TP53 mutations were common events in both germline BRCA-negative breast and ovarian cancer patients. In contrast, somatic screening of BRCA mutations in BRCA-negative breast cancer patients has limited value. The results highlight the benefit of somatic testing to guide future research directions on other targeted therapies for breast and ovarian malignancies.

10.
Eur J Cancer Care (Engl) ; 29(6): e13325, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32888339

RESUMO

OBJECTIVE: To assess clinical and psychosocial outcomes of nurse-led follow-up in survivorship care of gynaecological malignancies. METHODS: Women with endometrial or ovarian cancer who were attending regular post-treatment follow-up at a tertiary referral centre were randomised into two groups-group-1: telephone follow-up by nurses and group-2: gynaecologists-led clinic follow-up. Women in group-1 were asked about their symptoms and quality of life (QoL) by nurses. Women in group-2 were followed up by gynaecologists and underwent symptom reviews and physical examinations. All ovarian cancer patients in both groups also had CA125 measured. All recruited women completed a QoL questionnaire (EORTC QLQ-C30), HADS-anxiety questionnaire and symptom checklist. RESULTS: 385 women (215 with endometrial and 170 with ovarian cancer) were randomised. There was no significant difference in the detection of recurrence according to the two follow-up protocols. However, women in the nurse-led arm scored higher on emotional (p = 0.023) and cognitive functioning (p = 0.012). Those in the gynaecologist-led arm scored higher on the HADS-anxiety scale (p = 0.001) and were more likely to report symptoms. CONCLUSIONS: Our results demonstrate a preliminary non-inferiority of nurse-led follow-up, with improved psychological morbidity and QoL. Thus, nurse-led follow-up can be considered an effective substitute for hospital-based care.

11.
Proc Natl Acad Sci U S A ; 117(42): 26151-26157, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32989148

RESUMO

Emerging evidence suggests a resurgence of COVID-19 in the coming years. It is thus critical to optimize emergency response planning from a broad, integrated perspective. We developed a mathematical model incorporating climate-driven variation in community transmissions and movement-modulated spatial diffusions of COVID-19 into various intervention scenarios. We find that an intensive 8-wk intervention targeting the reduction of local transmissibility and international travel is efficient and effective. Practically, we suggest a tiered implementation of this strategy where interventions are first implemented at locations in what we call the Global Intervention Hub, followed by timely interventions in secondary high-risk locations. We argue that thinking globally, categorizing locations in a hub-and-spoke intervention network, and acting locally, applying interventions at high-risk areas, is a functional strategy to avert the tremendous burden that would otherwise be placed on public health and society.


Assuntos
Controle de Doenças Transmissíveis/métodos , Doenças Transmissíveis Emergentes/prevenção & controle , Infecções por Coronavirus/prevenção & controle , Transmissão de Doença Infecciosa/prevenção & controle , Saúde Global/tendências , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Betacoronavirus , Clima , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/transmissão , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Previsões , Humanos , Cooperação Internacional , Modelos Teóricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Viagem
12.
Artigo em Inglês | MEDLINE | ID: mdl-32924254

RESUMO

AIM: High-grade vaginal intraepithelial neoplasia (VAIN) is considered to be a premalignant lesion. We conducted a 20-year retrospective observational single-center study on the effectiveness of vaginal stripping (local excision procedure) as a treatment for high-grade VAIN. METHODS: Women diagnosed with VAIN and treated with vaginal stripping performed from 1998 to 2017 at our unit were identified using the hospital computer database. Vaginal stripping was performed for high-grade VAIN after being diagnosed by colposcopy-directed biopsies. The patients were followed every 3-6 months afterward via cytology monitoring and vaginal smear. Colposcopy-guided biopsy was repeated for high-grade abnormal cytology or persistent low-grade abnormality. The residual disease and recurrence rates were determined. Risk factors for margin positivity and residual and recurrent disease were identified. The association between margin positivity and recurrence was evaluated. RESULTS: Excluding three women whose final histology were malignant, the follow-up smears and histology (if any) were traced in the remaining 111 women. The median follow-up time was 76 months. Twenty-one of them had persistent abnormal smears (14 high-grade lesions and seven low-grade lesions) during the year following the vaginal stripping. The residual disease rate was 18.9% (21/111). The recurrence rate was 7.2%. There were five women (4%) with procedure-related complications. History of hysterectomy was identified as a risk factor for recurrence. CONCLUSIONS: Vaginal stripping is a valid treatment option for VAIN. High-grade VAIN post treatment recurred up to 5 years post treatment. Regular long-term surveillance is needed.

13.
Pharmacol Res ; : 105157, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32814169

RESUMO

Increasing evidence shows that Traditional Chinese Medicine (TCM) has an obvious appeal for cancer treatment, but there is still a lack of scientific investigation of its underlying molecular mechanisms. Bitter melon or bitter gourd (Momordica charantia) is an edible fruit that is commonly consumed, and it is used to cure different diseases in various ancient folk medical practices. We report that a bioactive protein, MAP30, isolated from bitter melon seeds exhibited potent anticancer and anti-chemoresistant effects on ovarian cancer cells. Functional studies revealed that MAP30 inhibited cancer cell migration, cell invasion, and cell proliferation in various ovarian cancer cells but not normal immortalized ovarian epithelial cells. When administered with cisplatin, MAP30 produced a synergistic effect on cisplatin-induced cell cytotoxicity in ovarian cancer cells. When low doses of cisplatin and MAP30 were co-injected intraperitoneally, a remarkable reduction of tumor dissemination and tumor growth was observed in an ovarian cancer ascites mouse model. Notably, blood tests confirmed that MAP30 did not cause any adverse effects on liver and kidney functions in the treated mice. MAP30 activated AMP-activated protein kinase (AMPK) signaling via CaMKKß and induced cell cycle arrest in the S-phase. MAP30 modulated cell metabolism of ovarian cancer cells via suppression of GLUT-1/-3-mediated glucose uptake, adipogenesis, and lipid droplet formation in tumor development and progression. MAP30 also induced an increase in intracellular Ca2+ ion concentration, which triggered ROS-mediated cancer cell death via apoptosis and ferroptosis. Collectively, these findings suggest that natural MAP30 is a non-toxic supplement that may enhance chemotherapeutic outcomes and benefit ovarian cancer patients with peritoneal metastases.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32627061

RESUMO

PURPOSE: In England, community mental health rehabilitation teams play a major role in supporting people with complex mental health needs to progress from inpatient to community settings and from more to less supported accommodation. We aimed to conduct the first study to investigate longitudinal outcomes for users of a community rehabilitation team and identify service user characteristics associated with successful progress along the rehabilitation pathway. METHODS: We used routinely collected clinical outcome data relating to all 193 users of a community rehabilitation team in inner London, transferred to the team between June 2013 and May 2018, with a cut-off data-collection date of 20th June 2019. We estimated the proportion who moved on to more independent accommodation successfully, with no breakdown in the placement. We conducted multivariable Cox proportional hazard regression to investigate associations between service user characteristics at transfer and successful move-on. RESULTS: Overall, 43/193 (23%) service users achieved successful move-on during a median follow-up of 51 months (IQR 32-63). This was more likely for those who were residing in more highly supported accommodation (HR 3.90; 95% CI 2.01-7.54) and those who had better functioning (HR 1.04, 95% CI 1.02-1.06) at transfer, while those with a serious physical health condition were less likely to achieve successful move-on (HR 0.44, 95% CI 0.21-0.95). CONCLUSION: Most supported accommodation services aim to offer time-limited support, but most service users do not progress successfully to more independent accommodation within 4 years. Investment in interventions that improve functioning and physical health may facilitate successful move-on.

15.
Endocrinology ; 161(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569368

RESUMO

Ovarian-derived inhibin A and inhibin B (heterodimers of common α- and differing ß-subunits) are secreted throughout the menstrual cycle in a discordant pattern, with smaller follicles producing inhibin B, whereas the dominant follicle and corpus luteum produce inhibin A. The classical function for endocrine inhibins is to block signalling by activins (homodimers of ß-subunits) in gonadotrope cells of the anterior pituitary and, thereby, inhibit the synthesis of FSH. Whether inhibin A and inhibin B have additional physiological functions is unknown, primarily because producing sufficient quantities of purified inhibins, in the absence of contaminating activins, for preclinical studies has proven extremely difficult. Here, we describe novel methodology to enhance inhibin A and inhibin B activity and to produce these ligands free of contaminating activins. Using computational modeling and targeted mutagenesis, we identified a point mutation in the activin ß A-subunit, A347H, which completely disrupted activin dimerization and activity. Importantly, this ß A-subunit mutation had minimal effect on inhibin A bioactivity. Mutation of the corresponding residue in the inhibin ß B-subunit, G329E, similarly disrupted activin B synthesis/activity without affecting inhibin B production. Subsequently, we enhanced inhibin A potency by modifying the binding site for its co-receptor, betaglycan. Introducing a point mutation into the α-subunit (S344I) increased inhibin A potency ~12-fold. This study has identified a means to eliminate activin A/B interference during inhibin A/B production, and has facilitated the generation of potent inhibin A and inhibin B agonists for physiological exploration.

16.
Cancer Immunol Immunother ; 69(11): 2275-2289, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32504248

RESUMO

Due to its high ability to disseminate, ovarian cancer remains one of the largest threats to women's health, worldwide. Evidence showed that the immune cells infiltrating the tumor microenvironment are crucial in mediating metastasis. Therefore, it is necessary to understand which types of immune cells are involved in metastasis, and to determine the mechanisms by which they influence the process. By immunohistochemistry, we found that higher concentrations of intratumoral CD8+ T cells were found to be correlated with an advanced grade and stage of ovarian cancer. Additionally, the infiltration of stromal CD8+ T cells was also significantly higher in tissues with advanced stages and metastatic tumors. A positive correlation between the infiltration of FoxP3+ Treg cells and histological grade was also observed, regardless of location. PD-L1 expression in metastatic tumors was also higher than that in paired primary ovarian tumors. Transwell migration and invasion assays revealed the increased migration and invasion of ovarian cancer cell lines (A2780CP and ES2) and ascites-derived ovarian cancer cells following co-culturing with CD8+ T cells. Enhanced expression of MMP-9, uPA, VEGF, bFGF, IL-8, IL-10, and PD-L1 by cancer cells following co-culturing with CD8+ T cells were also detected by qPCR, ELISA or flow cytometry. In conclusion, our findings suggest that the infiltrated T cells could promote the development of ovarian cancer, and provide another mechanism of immune evasion mediated by T cells.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linfócitos do Interstício Tumoral/imunologia , Invasividade Neoplásica/patologia , Evasão Tumoral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/metabolismo , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Células Tumorais Cultivadas , Microambiente Tumoral/imunologia , Adulto Jovem
17.
Br J Cancer ; 123(5): 833-843, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32507856

RESUMO

BACKGROUND: CD109 was involved in the tumorigenesis and progression of various cancers via TGF-ß1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer. METHODS: CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray. The effects of CD109 expression were examined on migration, cell proliferation, spheroid formation and soft-agar colony-formation assay. Meanwhile, cervical cancer cell lines with high CD109 expression were chosen for the functional study using siRNA knockdown and CRISPR/Cas9 knockout. RESULTS: IHC demonstrated an upregulation of CD109 in the cell membrane of cervical squamous cell carcinoma. CD109( + ) cells isolated by flow-cytometric sorting displayed enhanced migration, cell proliferation, sphere-forming and anchorage-independent cell growth ability. In contrast, silencing of CD109 expression could reverse the in vitro and in vivo tumorigenic and aggressive properties. Furthermore, CD109 induced EGFR-mediated STAT3 phosphorylation known to be responsible for cell migration, proliferation and maintenance of CSC phenotype. CONCLUSION: Abundant CD109( + ) populations in cervical cancer cells potentially contributed to carcinogenesis and aggressiveness, whereas silencing of CD109 expression could reverse those properties. CD109 mediates cervical tumorigenicity and aggressiveness via CD109/EGFR/STAT3 signalling.

18.
Geriatr Nurs ; 41(5): 635-640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32402573

RESUMO

This was a prospective cohort design study that followed a group of older adults for up to 12 months. Two hundred and ninety-one participants with a mean age of 81.4 ± 9.1 years were recruited. Signs of aspiration were screened by the Yale Swallow Protocol. Variables investigated for risk were oromotor functions, self-perception of swallowing function, cognitive function, and medical history. Seventy participants were revisited for a follow-up aspiration screening 8 to 9 months later. Multivariate logistic regression found that male sex, need for assistance for feeding and mobility, reduced cognitive function, subjective judgement of swallowing function, and oromotor function were major variables that can be used to screen for older adults who may require referrals for swallowing assessment. Those who continue to show signs of aspiration across time exhibit a more frail profile than their counterparts who do not.

19.
J Biol Chem ; 295(23): 7981-7991, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32350111

RESUMO

Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are co-expressed exclusively in oocytes throughout most of folliculogenesis and play central roles in controlling ovarian physiology. Although both growth factors exist as homodimers, recent evidence indicates that GDF9 and BMP15 can also heterodimerize to form the potent growth factor cumulin. Within the cumulin complex, BMP15 "activates" latent GDF9, enabling potent signaling in granulosa cells via type I receptors (i.e. activin receptor-like kinase-4/5 (ALK4/5)) and SMAD2/3 transcription factors. In the cumulin heterodimer, two distinct type I receptor interfaces are formed compared with homodimeric GDF9 and BMP15. Previous studies have highlighted the potential of cumulin to improve treatment of female infertility, but, as a noncovalent heterodimer, cumulin is difficult to produce and purify without contaminating GDF9 and BMP15 homodimers. In this study we addressed this challenge by focusing on the cumulin interface formed by the helix of the GDF9 chain and the fingers of the BMP15 chain. We demonstrate that unique BMP15 finger residues at this site (Arg301, Gly304, His307, and Met369) enable potent activation of the SMAD2/3 pathway. Incorporating these BMP15 residues into latent GDF9 generated a highly potent growth factor, called hereafter Super-GDF9. Super-GDF9 was >1000-fold more potent than WT human GDF9 and 4-fold more potent than cumulin in SMAD2/3-responsive transcriptional assays in granulosa cells. Our demonstration that Super-GDF9 can effectively promote mouse cumulus cell expansion and improve oocyte quality in vitro represents a potential solution to the current challenges of producing and purifying intact cumulin.

20.
Br J Cancer ; 123(2): 275-287, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32390009

RESUMO

BACKGROUND: Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process. METHODS: Ovarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed. RESULTS: We demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH-CD44- subsets exerted the opposite effects. CONCLUSION: Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.

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