高孕激素促排卵与克罗米芬微刺激方案在卵巢低储备患者取卵周期的可控性比较

目的:比较卵巢低储备患者在取卵周期采用高孕激素促排卵(progestin-primed ovarian stimulation, PPOS)方案与克罗米芬微刺激促排卵方案的临床疗效及周期可控性。方法:回顾性分析因卵巢低储备接受体外受精-胚胎移植的患者,分为PPOS方案组(试验组)和克罗米芬微刺激方案组(对照组)。观察两组患者促排卵过程的早发促黄体生成素(LH)峰比例、促排卵药物的用量及用药时间、获卵数(率)、成熟卵数(率)及胚胎实验室结局等指标。结果:共纳入972例,每组486例。试验组中早发LH峰比例明显低于对照组(6.17%vs 39.92%,P0.001)。两组患者获卵数(率)、成熟卵数、正常受精数(率)、卵裂数及有效胚胎数等指标差异均无统计学意义。试验组患者促排卵用药天数和用药量显著多于对照组,差异有统计学意义(P0.001)。结论:PPOS方案能有效抑制早发LH峰的出现,是一种适合卵巢低储备患者的促排卵方案。     

Pharmacology and clinical applications of human recombinant antithrombin

Importance of the field: Antithrombin therapy (AT) has been tested in various medical applications. With advances in genetics and biotechnology, large-scale production of human recombinant antithrombin (rhAT) is now feasible. The prospect of administering a recombinant protein rather than a pooled blood component, has rekindled interest in antithrombin therapy. However, many known properties of human pooled antithrombin (hpAT) still need to be investigated and established for rhAT.

Areas covered in this review: The manufacture and clinical pharmacology of antithrombin. The literature, evidence and our own views about the future of this drug and its potential clinical applications.

What the reader will gain: The reader will appreciate the biological rationale underpinning antithrombin administration in various clinical settings. The potential benefits and harms of the intervention are addressed. Novel future applications of recombinant antithrombin are broached.

Take home message: rhAT has been approved for its use in congenital antithrombin deficiency. rhAT has also been used off-label to treat heparin-resistance in cardiac surgery and sepsis. It is a promising adjuvant for immunosuppression in organ transplantation, and may have role as an anti-angiogenic, anti-tumor and anti-viral agent. rhAT has clear safety advantages over phAT, such as the avoidance of infection transmission.     

Farletuzumab in epithelial ovarian carcinoma

Importance of the field: Ovarian cancer is the leading cause of death from a gynecologic malignancy. Recurrence is both common and lethal, necessitating the development of novel targeted therapies. Farletuzumab (MORAb-003) is a humanized mAb with high affinity for folate receptor α (FRα), a 38 kDa GPI-anchored protein that is overexpressed in 90% of epithelial ovarian cancers.

Areas covered in this review: Preclinical and clinical trials, published or presented at national meetings from 2006 to the present, are presented in this review.

What the reader will gain: Preclinical studies have demonstrated robust antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro, inhibition of tumor growth in ovarian tumor xenografts and a safe toxicology profile in non-human primates. Phase I and II studies have demonstrated single agent and combination therapy efficacy with minimal drug-specific toxicity. The Phase III development plan in ovarian cancer patients includes combination chemotherapy studies in both platinum-sensitive (recently launched) and platinum-resistant (planned) recurrent disease.

Take home message: FRα is overexpressed in ovarian cancers but largely absent from normal tissue, making it an attractive therapeutic target. Farletuzumab is a novel inhibitor of FRα and has shown clinical efficacy in early phase trials.     

Contribution of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) use in current cancer treatment: review of clinical data

Importance of the field: Granulocyte colony-stimulating factors (G-CSFs) such as lenograstim have improved the management of cancer patient treatments for 15 years. Their use in preventing chemotherapy-induced febrile neutropenia and for progenitor-cell transplantation has been evaluated. Although the main indications are nowadays defined in academic guidelines, some changes in traditional G-CSF use are being induced by the emergence of new chemotherapy schedules and new drugs.

Areas covered in this review: Analyzing publications on G-CSFs and lenograstim identified in the PubMed database from 1985 to date, we summarise pharmacological data and clinical trials on lenograstim and discuss its effects and limits in current treatment regimens.

What the reader will gain: Lenograstim is a glycosylated form of recombinant human G-CSF, more similar to the endogenous cytokine. Clinical trials have proven its efficacy for preventing chemotherapy-induced neutropenia and for progenitor-cell transplantation, almost similar to filgrastim. Its benefit is compelling in some well-defined settings (highly myelosuppressive chemotherapy, advanced cancer, high-risk patients).

Take home message: If usual indications are well defined nowadays, further investigations are still needed to better define optimal use (optimal time to start, treatment duration) and effects on quality of life. In addition, since new strategies for cancer management are emerging, such as oral chemotherapy or targeted therapies, there is a need for clinical data to define lenograstim use in these recent settings.     

控制性超促排卵中更换不同来源卵泡刺激素对IVF-ET结局的影响

目的分析在控制性超促排卵(COH)过程中,更换卵泡刺激素(FSH)对体外受精-胚胎移植(IVF-ET)周期结局的影响。方法对本院行IVF-ET的150例患者临床资料进行回顾性分析。其中50例患者在COH中将进口基因重组促卵泡激素(rFSH)更换为国产高纯尿促卵泡激素(uFSH)(研究组),100例患者在同期全程使用rFSH行COH(对照组)。比较2组患者促排卵情况和临床相关指标的区别。结果 2组促排卵时间、FSH用量、获卵数、MⅡ期卵子数、临床结局比较无显著性差异,研究组患者较对照组明显减少了药品费用。结论 COH过程中,以uFSH代替rFSH,不影响IVF-ET的结局,且费用更低。     

Anti-Müllerian hormone levels before and after uterine artery embolization

Objective: To determine the effects of uterine artery embolization (UAE) on ovarian reserve as measured by Anti-Müllerian hormone (AMH) levels.

Material and methods: Non-randomized, observational study of 89 women 23–40 years of age who received UAE. Control hormone levels were measured prior to UAE and the first post-embolization measurement was taken at various times post-procedure (mean?=?190?±?229 days).

Results: Historical work verified by our earlier work has shown that AMH levels decline with age. Regression analysis allows us to determine whether UAE contributes to a greater decline in AMH values over that naturally occurring with aging. The effect of the procedure was found to contribute no deleterious effect to the natural decline in AMH levels. In addition, multiple blood draws were obtained from 32 patients up to 47 months post-UAE. Regression studies with these patients as their own controls showed no long-term diminishment of ovarian reserve due to the UAE procedure.

Conclusions: Earlier reported data are consistent with larger sample size. UAE does not affect ovarian reserve in women <40 as evidenced by no significant change in AMH levels after embolization. Women who are of reproductive age and have uterine fibroids can consider UAE without concern for adverse effects on their fertility.     

Hyaluronidase: a review of approved formulations,indications and off-label use in chronic pain management

Importance of the field: Hyaluronidase for injection is an adjuvant that increases the absorption and dispersion of other injected drugs or fluids (hypodermoclysis); and improves absorption of radiopaque agents in subcutaneous urography. Ovine hyaluronidase is approved for the treatment of vitreous hemorrhages.

Areas covered in this review: We review approved indications for injectable hyaluronidase and off-label uses as well as safety, efficacy and dosing information. We compare formulations made using animal tissue extracts versus the novel human recombinant type. Emphasis is on the human recombinant form and off-label uses in patients with chronic pain.

What the reader will gain: Hyaluronidase reduces the obstacle that the interstitial matrix presents to fluid and drug transfer. It is a mucolytic enzyme derived from mammalian tissue or synthesized in vitro in pure form (rHuPH20) using recombinant technology. Hyaluronidase is used off-label in chronic pain management to facilitate removal of epidural adhesions with mechanical and/or hydrostatic forces and to treat edema.

Take home message: The recently introduced rHuPH20 formulation obviates any risk of allergic reaction or prion-related illnesses. Reduction of edema by hyaluronidase and facilitation of epidural adhesioloysis may be beneficial in treating certain chronic painful conditions.     

The role of talactoferrin alfa in the treatment of non-small cell lung cancer

Importance of the field: Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in recent years.

Areas covered in this review: Talactoferrin alfa is an oral immunomodulatory agent currently in late-stage clinical trials that acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue.

What the reader will gain: Talactoferrin is a recombinant human lactoferrin that is a member of the transferrin family of iron-binding glycoproteins. Lactoferrins have multiple known biological activities including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties. This review discusses the proposed mechanism of action of talactoferrin-alfa and outlines the pre-clinical, Phase I and II data in NSCLC. The ongoing Phase III trials are discussed.

Take home message: The current role of Talactoferrin alpha in the treatment of NSCLC is described and we explore potential future roles for this drug in both early stage and advanced stage disease.     

Ofatumumab,a human anti-CD20 monoclonal antibody

Importance of the field: Since relapse of chronic lymphocytic leukemia (CLL), and refractoriness to treatment following relapse, is inevitable after initial treatment, development of novel treatment strategies is necessary.

Areas covered in this review: CD20 as a therapeutic target for CLL, successes and limitations of current anti-CD20 monoclonal antibody (mAb) therapy, and implications of preclinical and clinical developments of novel alternatives, including ofatumumab, that may enhance anti-CD20 mAb therapy are reviewed. The literature reviewed encompasses papers and congress abstracts from the past 13 years.

What the reader will gain: While rituximab combined with chemotherapy has considerably improved outcomes for some but not all CLL patients, single-agent use is limited in relapsed/refractory CLL. Novel anti-CD20 mAbs in development, such as ofatumumab, may bypass some limitations by virtue of alternative epitope binding and modified effector functions. Ofatumumab induces significant complement-dependent cell lysis in vitro, particularly in cells with low CD20 expression. The FDA recently approved ofatumumab for treatment of CLL refractory to fludarabine and alemtuzumab.

Take home message: CD20-targetting chemoimmunotherapeutic options have advanced treatment of CLL. Results for single-agent ofatumumab and other new CD20 mAbs, in different lines of therapy and in combination with chemotherapy, will guide optimal use of these alternative therapies for B-cell malignancies.     

PTH analogues and osteoporotic fractures

Importance of the field: At present there are two parathyroid hormone (PTH) analogues (PTH 1 – 34 and PTH 1 – 84) registered for the treatment of established osteoporosis in postmenopausal women (PTH 1 – 34 and PTH 1 – 84) and in men (PTH 1 – 34 only) who are at increased risk of having a fracture.

Areas covered in this review: The efficacy and safety of PTH 1 – 34 and PTH 1 – 84 in the management of osteoporosis is evaluated by reviewing published literature and presentations from scientific meetings through to 2010.

What the reader will gain: This review focuses on data on fracture risk reduction and safety endpoints of PTH analogues. The adverse reactions reported most are nausea, pain in the extremities, headache and dizziness.

Take home message: Exogenous PTH analogues, given as daily subcutaneous injections, stimulate bone formation, increase bone mass and bone strength, and improve calcium balance. In postmenopausal women with osteoporosis, PTH analogues reduced the risk of vertebral (PTH 1 – 34 and PTH 1 – 84) and non-vertebral fractures (only PTH 1 – 34). In men and women with glucocorticosteroid-induced osteoporosis, PTH 1 – 34 reduced the risk of vertebral fractures. In general, PTH analogues are well tolerated with an acceptable safety profile: they can be used for the prevention and treatment of fractures in postmenopausal women with severe, established osteoporosis.     

Mesenchymal stem cells: biological properties and clinical applications

Importance of the field: In the last decade, knowledge of mesenchymal stem cells (MSCs) has evolved rapidly; their immunomodulatory properties and paracrine interactions with specific cell types in damaged tissues and promising results in some clinical applications have made these cells an attractive option for the treatment of certain diseases.

Areas covered in this review: We present some relevant methodological issues and biological properties of MSCs, as well as clinical applications of MSC therapies with particular emphasis in the treatment of graft versus host disease (GVHD), complex perianal fistula and refractory metastatic neuroblastoma. Other topical aspects relevant to the application of cellular therapies such as biosafety studies and cellular production of MSCs are also discussed in this review.

What the reader will gain: The growing optimism regarding MSCs research is based on the promising results obtained in in vitro and in vivo studies. The rapid translational research with MSCs necessitated standardization of methodology and terminology and greater focus on other aspects such as biosafety and cellular production, especially for clinical use of MSCs.

Take home message: Much has been learned about the biology and applications of MSCs and much remains to be learned.     

The secretion of human growth hormone stimulated by human growth hormone releasing factor following severe cranio-cerebral trauma

Patients suffering from severe cranio-cerebral trauma show alterations of the secretory patterns of thyroid stimulating hormone (TSH) and human growth hormone (HGH) which may be of prognostic significance. We studied 10 patients following severe brain injury and prospectively compared a new synthetic human growth hormone releasing factor (HGHRF) test with the thyrotropin releasing hormone (TRH) test. On admission, all patients had a Glasgow Coma Scale score of 3 or 4. All patients had a low T3 syndrome. In the patients who died the TSH response after stimulation with TRH was also absent. In the patients who survived a significant TSH increase was observed (p<0.05). In comparison to the patients who died those who survived showed a significant (p<0.001) HGH increase after HGHRF stimulation. This test might be useful as an additional tool in establishing early prognosis in patients with severe brain injury.     

Naptumomab estafenatox: a new immunoconjugate

Importance of the field: New agents that specifically engage the immune system are being tested in a variety of malignancies. This review provides an overview of naptumomab, an immunotoxin, with encouraging clinical activity in Phase I trials.

Areas covered in this review: This review examines the preclinical and the published clinical data with regards to naptumomab.

What the reader will gain: This review provides the reader with an understanding of the mechanism of action, immunology, pharmacokinetics and clinical activity of this agent.

Take home message: Naptumomab has a unique mechanism of action and appears to be an active agent in the treatment of refractory solid tumors such as renal cell carcinoma.     

Gene therapy for pulmonary hypertension: prospects and challenges

Introduction: Recent evidence shows that pulmonary arterial hypertension (PAH) remains a fatal disease despite the introduction of new pharmacological treatments. New options are therefore needed and gene therapy approaches are a rational consideration based on emerging understanding of the genetic basis of PAH.

Areas covered: This review briefly discusses the recent developments in clinical management of PAH and the investigation of gene delivery techniques for pulmonary vascular disease from 1997 to 2010, relating this to improved understanding of disease pathogenesis during this period. There is a focus on bone morphogenetic protein receptor type 2, as mutations in this gene are clearly linked to disease pathogenesis and outcomes. The reader will gain insight into the gene vector strategies being used, the target cells and the specific genes being delivered as candidate therapeutic approaches for PAH.

Expert opinion: Various genes and strategies for delivery have achieved improvements in PAH in animal models, which is encouraging for the development of this technology for human application. The main limiting factor for clinical progress relates to gene delivery vector technology.     

Adenovirus vaccine immunotherapy targeting WT1-expressing tumors

Importance of the field: Tumor associated antigens (TAAs) offer specific targets for developing cancer immunotherapies. In particular, viral vectors encoding transgenic TAAs have been used in recent vaccination strategies. Wilm's Tumor gene (WT1) is a robust TAA which is overexpressed in many malignancies and has been recently used to develop a novel recombinant adenovirus (Ad-WT1) for antitumor immunotherapy.

Areas covered in this review: The lines of evidence over the past two decades leading to the development of Ad-WT1 immunotherapy are reviewed, including preclinical studies and clinical trials using WT1-based vaccines and TAA-expressing adenoviral vectors for antitumor therapy.

What the reader will gain: The fundamental immunogenic properties of WT1-based vaccines are detailed, as well as the recent progress in using adenoviral vectors for eliciting a TAA-specific immune response. The reader will also gain an understanding of the evidence supporting Ad-WT1 antitumor therapy in vivo.

Take home message: Ad-WT1 elicits a potent CD4⁺ and CD8⁺ T cell immune response and can effectively inhibit tumor growth in vivo, thus making it an important potential cancer therapy worthy of future investigation.     

Pharmacotherapy and interventional treatments for secondary hyperparathyroidism: current therapy and future challenges

Importance of the field: Chronic kidney disease is frequently complicated by secondary hyperparathyroidism, which causes bone disease and vascular calcification, leading to increased risk of morbidity and mortality.

Areas covered in this review: This review covers treatment options for secondary hyperparathyroidism in patients receiving dialysis, particularly focusing on active vitamin D derivatives, calcimimetics and direct injection therapy into parathyroid glands. In addition, the potential of gene therapy is also described.

What the reader will gain: The reader will gain a comprehensive review of the effectiveness and role of available therapies for patients with secondary hyperparathyroidism, as well as the results of observational studies that address the effect of these treatments on clinical outcomes.

Take home message: Treatment with active vitamin D derivatives and calcimimetics allows adequate control of secondary hyperparathyroidism, which it is hoped will translate into improved clinical outcomes. These treatments appear to be effective even in patients with advanced disease, but patients who develop resistance to therapy should undergo parathyroid intervention, such as surgical parathyroidectomy and direct injection therapy. Gene therapy is not applicable to humans at present, but they will help clarify the molecular pathogenesis of secondary hyperparathyroidism.     

Erythropoietin in stroke: quo vadis

Importance of the field: Recombinant erythropoietin (rEPO) failed in a recent clinical study to protect from damages induced by ischemic stroke. The lack of acute treatments in ischemic stroke and the promising outcome in numerous preclinical studies in vivo demands a more critical evaluation of the future use of EPO as an acute treatment.

Areas covered in this review: The current use and administration of rhEPO and its analogs in animal models and the future use of this cytokine in the treatment of ischemic stroke.

What the reader will gain: In this review the potential reasons for the failure of EPO in the clinical trial are analysed and whether the preclinical trials sufficiently evaluated the true potential of recombinant EPO and its analogs is assessed. Alternative methods for administration of EPO to enhance its potential as a neuroprotective drug in ischemic stroke are discussed.

Take home message: Failure in clinical trial does not necessarily indicate the lack of therapeutic potential of EPO. This review encourages further investigation of the true potential of EPO as a candidate drug for the treatment of ischemic stroke by improved preclinical experimental design and utilization of alternative administration methods.     

HER3 mRNA as a predictive biomarker in anticancer therapy

Importance of the field: Heterodimerization of human EGF receptor (HER) 2 and HER3, a co-receptor of HER2, plays an important and dominant role in the functionality and transformation of HER-mediated pathways. Understanding the role of HER3 in oncogenesis as well as its place as a target for anticancer therapy is an ongoing area of research. Determination of biomarkers for clinical benefit from agents targeting HER3 is an essential component of translating basic science into real-world effective anticancer therapies, with the aim of ensuring the patients most likely to benefit from such treatments can be identified.

Areas covered in this review: This review focuses on the targeting of HER2 and HER3 by monoclonal antibodies and the potential for HER3 mRNA levels to predict treatment outcome in ovarian cancer.

What the reader will gain: An understanding of the value of biomarkers for clinical benefit to anticancer therapy and the current status of HER3 mRNA as a biomarker for clinical benefit of the HER2–HER3 dimerization inhibitor pertuzumab.

Take home message: HER3 mRNA levels may be a biomarker for active ligand-induced HER2–HER3 signaling, with low HER3 mRNA levels correlated with clinical benefit from the HER2–HER3 dimerization inhibitor pertuzumab.     

Thyroid hormone effect on human mitochondria measured by flow cytometry

Abstract

Background: Mitochondrial function may be impaired in a number of diseases including metabolic syndrome, cardiovascular disease and endocrine disorders. Therefore it is important to be able to measure mitochondrial function in human cells. Purpose: The aim of the present study was to evaluate a method to measure mitochondrial function in human derived cells, which also would reflect regulation by thyroid hormones. Methods: The MDA-MB-231 cell line (a human breast cancer cell line) was incubated with bioactive iodothyronines (T₄, 3′-3, 5-T₃, 3, 5-T₂) 50nmol/l for 3 h. Mitochondrial membrane potentials (MMP) were measured by a flow cytometer after staining with Tetramethylrhodamine methyl ester (TMRM). Also, the effect of TRIAC (a stimulator of thyroid hormone nuclear receptors) and L-Carnitine (an inhibitor of thyroid hormone passage into the nucleus) was examined. Findings: It was possible to measure mitochondrial membrane potential (MMP) in human derived cells and to examine thyroid hormone effects using flow cytometry. Bioactive iodothyronines increased mitochondrial membrane potential. TRIAC had no effect and L-Carnitine only inhibited T₄ stimulation of membrane potential. Conclusion: Flow cytometry may be a valuable method for examining and testing mitochondrial function in human cells. Our findings demonstrate increase of mitochondrial membrane potential and an extra nuclear short time effect of 3, 5-T₂ on mitochondrial activity.