[Research progress of alpha-fetoprotein vaccine in hepatocellular carcinoma].

Hepatocellular carcinoma (HCC) is the fifth world's largest malignant tumor, which seriously endangers human health. The commonly used treatment effects are not satisfactory and the mortality rate is still high. Therefore, there is an urgent need for effective adjuvant treatment to improve patient survival. Alpha-fetoprotein (AFP) acts as the most common tumor marker used for HCC diagnosis. Studies have shown that alpha-fetoprotein can self-induce T cells in patients with hepatocellular carcinoma, and its immunogenic antigenic epitopes provide new ideas for the study of AFP vaccine. Presently, a variety of AFP vaccines have been developed, such as DC vaccine, DNA vaccine, and peptide vaccine, which have been successfully applied to HCC mouse model and phase I /II clinical trials, with evident results. This article discusses the molecular mechanism, categories and application prospects of AFP vaccine in HCC.

Cost-effectiveness analysis of ramucirumab treatment for patients with hepatocellular carcinoma who progressed on sorafenib with α-fetoprotein concentrations of at least 400 ng/ml.

Objective: This study aimed to compare the cost-effectiveness of ramucirumab versus placebo for patients with hepatocellular carcinoma who progressed on sorafenib with α-fetoprotein concentrations (AFP) of at least 400 ng/ml in the United States.Methods: A Markov model was constructed to assess the cost-effectiveness of ramucirumab. Health outcomes were measured as quality-adjusted life years (QALYs). With TreeAge software, the disease process was modeled as three health states: progression-free survival (PFS), progressive disease (PD), and death. Costs were extracted from the REACH-2 trial, and utility was derived from published literature. Incremental cost-effectiveness ratios (ICERs) were calculated to compare ramucirumab with placebo. Probabilistic sensitivity analyses were developed to examine the robustness of the results.Results: In the base case analysis, ramucirumab therapy had a cost of $55,508.41 and generated 0.54 QALYs, while placebo therapy had a cost of $761.09 and generated 0.47 QALYs, leading to an additional $54,747.32 in costs and 0.07 QALYs. The ICER was $782,104.57 per QALY, which was much higher than the willingness-to-pay threshold of $100,000 per QALY. According to sensitivity analyses, the utility of PD in the two groups was the dominant parameter influencing the ICER.Conclusion: Although ramucirumab was associated with prolonged survival for patients with advanced hepatocellular carcinoma who progressed on sorafenib treatment with an AFP of at least 400 ng/ml, it is not a cost-effective treatment from a United States payer perspective.

[Engineering of a System for the Production of Mutant Human Alpha-Fetoprotein in the Methylotrophic Yeast Pichia pastoris].

A system for the production of mutant recombinant human alpha-fetoprotein (rhAFPO) lacking the glycosylation site has been engineered in the yeast Pichia pastoris. A strain of the methylotrophic yeast Pichia pastoris GS 115/pPICZ?A/rhAFP0, which produces unglycosylated rhAFPO and secretes it to the culture medium, has been constructed. Optimization and scale-up of the fermentation technology have resulted in an increase in the rhAFP0 yield to 20 mg/L. A scheme of isolation and purification of biologically active rhAFP0 has been developed. The synthesized protein has the antitumor activity, which is analogous to the activity of natural human embryonic alpha-fetoprotein.

Effect of Alpha-Fetoprotein on Lifespan of Old Mice.

Alpha-fetoprotein (AFP) is one of the best-known embryo-specific proteins. It is used to diagnose fetal abnormalities and tumors of the gastrointestinal tract and liver. AFP has pronounced immunotropic and detoxifying effect and a direct apoptotic effect on tumor cells. The treatment of mice at the oldest age in our experiments with AFP dramatically increased the survival and markedly increased the relative weight of immunotropic organs, apparently due to the general effect of AFP in improving functions of tissues and detoxifying actions. It also improved appearance and the relative weight of internal organs with a reduced age of autoaggression.

In vitro hepatic differentiation of human endometrial stromal stem cells.

Human endometrial stromal stem cells (hESSCs) can differentiate into mesodermal and ectodermal cellular lineages in the endometrium. However, whether hESSCs can differentiate into functional hepatic-like cells is unknown. In this study, we developed a multiple-step induction protocol to differentiate hESSCs into functional hepatic-like cells in vitro. Endometrial stromal cells were isolated by magnetic affinity sorting using anti-epithelial cell adhesion molecule-coated Dynabeads. The enriched hESSCs were analyzed by flow cytometry and were able to differentiate into osteoblasts or adipocytes under proper induction media. To differentiate into hepatic-like cells, hESSCs were cultured in a stepwise system containing hepatocyte growth factor, fibroblast growth factor-4, oncostatin M, and trichostatin A for a total of 24 d. The hepatic-like cell differentiation was analyzed by confocal microscopy and immunocytochemical staining. Glycogen storage, cellular urea synthesis, and ammonia concentrations were measured. Hepatic-like cells were successfully generated from hESSCs and were identified by their epithelial-like shape characteristics and expression of specific biomarkers albumin and cytokeratin 8 accompanied with a reduction of alpha-fetoprotein and alpha-smooth muscle actin expression. The hepatic-like cells generated were functional as evidenced by urea synthesis and glycogen storage. Our study demonstrated that hESSCs were able to differentiate into hepatic-like cells in vitro. Thus, endometrial stromal cells may be used as an easily accessible alternative source of stem cells for potential therapeutic applications in liver disease.

Specific antitumor immunity induced by cross-linking complex heat shock protein 72 and alpha-fetoprotein.

Hepatocellular carcinoma (HCC) is one of the most common malignancies over the world. Alpha-fetoprotein (AFP) is an oncofetal protein during HCC development that could generate weaker and less reproducible antitumor protection, and it may serve as a target for immunotherapy. Therefore, it is imperative to enhance its immunogenicity and develop therapeutic vaccines to eliminate AFP-expressing tumors. In this study, by way of glutaraldehyde cross-linking, we constructed a potential therapeutic protein complex vaccine, heat shock protein 72 (HSP72)/AFP. Our results demonstrated that AFP and HSP72 synergistically exhibited significant increases in AFP-specific CD8(+) T cell responses and impressive antitumor effects against AFP-expressing tumors. Priming mice with the reconstructed vaccine, we elicited robust strong protective immunity. Our study suggests that a tumor vaccine by cross-linking tumor antigen and HSP72 is a promising approach for cancer therapy.

Targeted delivery of anti-cancer growth inhibitory peptides derived from human alpha-fetoprotein: review of an International Multi-Center Collaborative Study.

The alpha-fetoprotein derived growth inhibitory peptide (GIP) is a 34-amino acid peptide composed of three biologically active subfragments. GIP-34 and its three constituent segments have been synthesized, purified, and studied for biological activity. The GIP-34 and GIP-8 have been characterized as anticancer therapeutic peptides. An multicenter study was initiated to elucidate the means by which these peptide drugs could be targeted to tumor cells. The study first established which cancer types were specifically targeted by the GIP peptides in both in vitro and in vivo investigations. It was next demonstrated that radiolabeled peptide ((125)I GIP-34) is specifically localized to rodent breast tumors at 24 h post-injection. The radionuclide studies also provided evidence for a proposed cell surface receptor; this was confirmed in a further study using fluorescent-labeled GIP-nanobeads which localized at the plasma membrane of MCF-7 breast cancer cells. Finally, it was readily demonstrated that GIP conjugated to either fluorescein or doxorubicin (DOX) underwent tumor cell uptake; subsequently, DOX-GIP conjugates induced cytotoxic cell destruction indicating the utility of GIP segments as cancer therapeutic agents. Following a discussion of the preceding results, a candidate cell surface receptor family was proposed which correlated with previous published reports for a putative AFP/GIP receptor.

AFPep, a novel drug for the prevention and treatment of breast cancer, does not disrupt the estrous cycle or fertility in rats.

Pregnancy lowers the risk of breast cancer, largely attributable to alpha-fetoprotein (AFP). A small AFP-derived peptide (AFPep) which mimics the active site of AFP has been developed and may be useful for decreasing the risk of breast cancer for women. AFPep has been shown previously to stop the growth of estrogen-dependent human breast cancer xenografts in mice and prevent carcinogen-induced breast cancer in a rat model. Since AFPep disrupts an estrogen-responsive pathway, it is essential to assess its effects on the female reproductive cycle and fertility. Ten cycling female Sprague-Dawley rats (age 81 days) were given 100 microg AFPep in saline s.c. daily for 20 days. A second group of ten rats was given 50 microg tamoxifen s.c. daily and a third group received saline only. Vaginal smears were obtained twice per day and stained to assess estrous cycle phase. After completion of estrous cycle assessment (five cycles, 21 days), rats were maintained on drug and allowed to mate. Effects on birth of offspring and maternal body weights were assessed. AFPep had no significant effect on the incidence or duration of any estrous cycle phase, and no effect on reproductive potential or maternal body mass. Tamoxifen significantly increased the length of diestrus, locking the cycle in this phase for most animals. Only half of the tamoxifen-treated rats mated, and none became pregnant. Tamoxifen significantly slowed the rate of body mass increase. In rats, AFPep has no toxicity and no effect on female reproduction. This molecule may be developed into an attractive modality for prevention of breast cancer in women.

In vivo targeted gene delivery by cationic nanoparticles for treatment of hepatocellular carcinoma.

BACKGROUND: Transgene expression in vivo for therapeutic purposes will require methods that allow for efficient gene transfer into cells. Although current vector technologies are being improved, the development of novel vector systems with improved targeting specificity, higher transduction efficiencies and improved safety is necessary. METHODS: Asialoglycoprotein receptor-targeted cationic nanoparticles for interleukin (IL)-12 encapsulation (NP1) or adsorption (NP2) have been formulated by blending poly(D,L-lactic-co-glycolic) acid (PLGA) (50 : 50) with the cationic lipid 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP) and the ligand asialofetuin (AF), by using a modified solvent evaporation process. RESULTS: We present a novel targeted lipopolymeric vector, which improves significantly the levels of luciferase gene expression in the liver upon i.v. administration. Targeted-NP2 particles showed a five- and 12-fold higher transfection activity in the liver compared to non-targeted (plain) complexes or naked pCMV DNA, respectively. On the other hand, BNL tumor-bearing animals treated with AF-NP1 containing the therapeutic gene IL-12, showed tumor growth inhibition, leading to a complete tumor regression in 75% of the treated mice, without signs of recurrence. High levels of IL-12 and interferon-gamma were detected in the sera of treated animals. Mice survival also improved considerably. Tumor treatment with AF-NP2 formulations lead only to a retardation in the tumor growth. CONCLUSIONS: In the present study, we have developed an efficient targeted non-viral vector for IL-12 gene transfer in hepatocellular carcinoma in vivo, by employing non-toxic cationic PLGA/DOTAP/AF nanoparticles. These results demonstrate for the first time that this cationic system could be used successfully and safely for delivery of therapeutic genes with antitumor activity into liver tumors with targeting specificity.

Alpha-fetoprotein and other tumour-associated antigens for immunotherapy of hepatocellular cancer.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer death, with few treatment options for advanced disease. OBJECTIVES: Here, we review the aetiology of HCC and focus on recent data on tumour-associated antigens (TAA) for HCC, their functions and potential use as immunological targets for immune-based therapy for HCC. In addition, we examine some aspects of antigen presentation within the liver. RESULTS/CONCLUSIONS: alpha-Fetoprotein (AFP) has been investigated for many years as a TAA, and has been tested in recent clinical trials. More recently, additional TAA have been identified and new therapeutic approaches have been investigated which may be testable clinically in this difficult disease setting.

Transplantation of embryonic stem cell-derived endodermal cells into mice with induced lethal liver damage.

ESCs are a potential cell source for cell therapy. However, there is no evidence that cell transplantation using ESC-derived hepatocytes is therapeutically effective. The main objective of this study was to assess the therapeutic efficacy of the transplantation of ESC-derived endodermal cells into a liver injury model. The beta-galactosidase-labeled mouse ESCs were differentiated into alpha-fetoprotein (AFP)-producing endodermal cells. AFP-producing cells or ESCs were transplanted into transgenic mice that expressed diphtheria toxin (DT) receptors under the control of an albumin enhancer/promoter. Selective damage was induced in the recipient hepatocytes by the administration of DT. Although the transplanted AFP-producing cells had repopulated only 3.4% of the total liver mass 7 days after cell transplantation, they replaced 32.8% of the liver by day 35. However, these engrafted cells decreased (18.3% at day 40 and 7.9% at day 50) after the cessation of DT administration, and few donor cells were observed by days 60-90. The survival rate of the AFP-producing cell-transplanted group (66.7%) was significantly higher in comparison with that of the sham-operated group (17.6%). No tumors were detected by day 50 in the AFP-producing cell-transplanted group; however, splenic teratomas did form 60 days or more after transplantation. ESC transplantation had no effect on survival rates; furthermore, there was a high frequency of tumors in the ESC-transplanted group 35 days after transplantation. In conclusion, this study demonstrates, for the first time, that ESC-derived endodermal cells improve the survival rates after transplantation into mice with induced hepatocellular injury. Disclosure of potential conflicts of interest is found at the end of this article.

Marcadores tumorales serológicos en cirugía hepatobiliopancreática / Serological tumor markers in hepatobiliopancreatic surgery

Los marcadores tumorales son, en general, proteínas que se asocian a enfermedades malignas. Pueden detectarse en sangre periférica y son útiles para el cribado, el diagnóstico, la estadificación, el pronóstico y el seguimiento de estas enfermedades.También pueden servir para detectar la presencia de metástasis ocultas, monitorizar la respuesta al tratamiento y descubrir recurrencias.En el presente artículo se exponen los principales marcadores tumorales serológicos usados en cirugía hepatobiliopancreática. La alfafetoproteína es el marcador más útil en el hepatocarcinoma, especialmente para el diagnóstico y la detección de las recurrencias tras el tratamiento. El antígeno carcinoembrionario será util en los casos de metástasis hepáticas de cáncer colorrectal. El CA 19.9 puede ayudar en el diagnóstico diferencial de las tumoraciones pancreáticas. El antígeno carcinoembrionario, el CA 19.9 y el CA 125 pueden ser útiles en casos de tumores de las vías biliares (AU)

[Effect of biological preparation alfetin in infiltrative pulmonary tuberculosis]. / Vliianie biopreparata al'fetina na infil'trativnyi tuberkulez legkikh.

The authors evaluated influence of Alfetin new Russian biologic preparation on pulmonary surfactant system and phospholipid metabolism in workers at risk of occupational pneumoconiosis, who suffer from infiltrative pulmonary tuberculosis. Considering positive changes in serum phospholipids subunits under alfetin treatment, the authors proved membrane protective effect of the drug. Alfetin was proved to weaken toxic effects of tuberculostatic drugs on lung surfactant.

Supplemental transcatheter arterial chemoembolization through a collateral omental artery: treatment for hepatocellular carcinoma.

PURPOSE: To evaluate the therapeutic efficacy and safety of supplemental transcatheter arterial chemoembolization (TACE) through the extrahepatic collateral omental artery (OA) for the treatment of hepatocellular carcinoma (HCC). METHODS: We studied 21 patients with extrahepatic collaterals of the OA, among 1,512 patients with HCC who had undergone angiography. HCCs supplied by collateral OAs were located at: segment IV in seven, segment V in five, segment III in three, segment VI in three and segment VIII in three patients (Couinaud classification of segments). On preoperative CT scans, every HCC was abutting the liver surface. Adjacent omental infiltration or engorgement was noted in 11 patients. Celiac and hepatic arteriograms showed hypertrophy of the feeding OA in all patients. TACE of the OA was performed in 19 patients with an emulsion of iodized oil and doxorubicin hydrochloride. Embolization with gelatin sponge particles was added in five patients. RESULTS: Collaterals of the OA to the HCC were found on the first to seventeenth sessions of TACE. On follow-up CT scans, five patients showed complete uptake of iodized oil in the tumor. Partial uptake of iodized oil was noted in 13 patients and no uptake in one patient. There was no serious complication that related to the omental embolization, such as omental or bowel ischemia. The cumulative survival rates from the time of the TACE of the OA were 81% at 6 months and 68% at 12 months. CONCLUSION: TACE of the OA is safe and has a potential therapeutic effect in the treatment of HCC.

Anti-prostate cancer and anti-breast cancer activities of two peptides derived from alpha-fetoprotein.

A chemically synthesized 34-amino-acid peptide and a select analog have been studied to determine their activities against the growth of prostate and breast cancer tumors. It was of interest to determine if the peptide has anti-prostate cancer activity. Previously, the peptide was shown to inhibit the growth of breast cancer tumor cells. The peptide inhibited the growth of both breast and prostate tumors. A novel experimental design for the peptide was in a study in which a time-release pellet was used to give daily peptide doses to mice that were subjected to a breast cancer tumor. The peptide was effective in inhibiting the growth of tumors in the mice. The 2 C-->2 A analog peptide, in which the two cysteines were replaced by alanines, was also active in inhibition of the growth of prostate and breast cancer cell lines and in an in vivo assay against breast cancer. A scrambled amino acid sequence of the peptide was used as a control in these tumor studies, and it had virtually no anti-cancer activity.

Utilidad de la alfafetoproteína sérica materna como parámetro de riesgo del embarazo / Utility of maternal serum alpha-fetoprotein as a risk marker of the pregnancy

Objetivos: Demostrar que las embarazadas con valores elevados, sin justificación aparente, de alfafetoproteína sérica tienen un riesgo mayor de resultados perinatales adversos.Sujetos y métodos: Se estudiaron 43.424 gestantes desde el segundo trimestre del embarazo hasta el parto. Se calculó el riesgo relativo entre los valores de alfafetoproteína en suero materno (AFPSM) y los resultados perinatales siguientes: partos pretérminos, muertes fetales anterior y posterior a la semana 28 de gestación, y recién nacidos con bajo peso.Resultados: Se estudió la influencia de las concentraciones de AFPSM sobre 4 resultados perinatales adversos, observándose en todos ellos una diferencia significativa entre el grupo de gestantes considerado control (AFPSM 2,5 MDM). Se observó un mayor riesgo relativo en las gestantes con muerte fetal anterior a la semana 28 de gestación.Conclusiones: Se ha comprobado que existe una relación entre los valores elevados de AFPSM y el riesgo de un resultado perinatal adverso. Sin embargo, la AFPSM no se puede considerar un marcador de cribado adecuado, por su baja sensibilidad, para seleccionar gestantes con un riesgo elevado de un resultado adverso. (AU)

T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein.

alpha fetoprotein (AFP)-derived peptide epitopes can be recognized by human T cells in the context of MHC class I. We determined the identity of AFP-derived peptides, presented in the context of HLA-A*0201, that could be recognized by the human (h) T cell repertoire. We screened 74 peptides and identified 3 new AFP epitopes, hAFP(137-145), hAFP(158-166), and hAFP(325-334), in addition to the previously reported hAFP(542-550.) Each possesses two anchor residues and stabilized HLA-A*0201 on T2 cells in a concentration-dependent class I binding assay. The peptides were stable for 2-4 h in an off-kinetics assay. Each peptide induced peptide-specific T cells in vitro from several normal HLA-A*0201 donors. Importantly, these hAFP peptide-specific T cells also were capable of recognizing HLA-A*0201(+)/AFP(+) tumor cells in both cytotoxicity assays and IFN-gamma enzyme-linked immunospot assays. The immunogenicity of each peptide was tested in vivo with HLA-A*0201/K(b)-transgenic mice. After immunization with each peptide emulsified in CFA, draining lymph node cells produced IFN-gamma on recognition of cells stably transfected with hAFP. Furthermore, AFP peptide-specific T cells could be identified in the spleens of mice immunized with dendritic cells transduced with an AFP-expressing adenovirus (AdVhAFP). Three of four AFP peptides could be identified by mass spectrometric analysis of surface peptides from an HLA-A*0201 human hepatocellular carcinoma (HCC) cell line. Thus, compelling immunological and physiochemical evidence is presented that at least four hAFP-derived epitopes are naturally processed and presented in the context of class I, are immunogenic, and represent potential targets for hepatocellular carcinoma immunotherapy.

Seguimiento evolutivo del disgerminoma ovárico con beta-hCG / Evolutive follow up of an ovarian dysgerminoma with beta-hCG

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Trompa de falopio accesoria / Accessory Fallopian tube

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Antitumor activity of alpha fetoprotein and epidermal growth factor conjugates in vitro and in vivo.

Conjugates of carminomycin (Cm) with alpha-fetoprotein (AFP) and epidermal growth factor (EGF) were prepared and their cytotoxic activities were studied in vitro. Both conjugates showed cytotoxic activity which exceeded that of free Cm in tumor cell cultures of MCF-7, SKOV3, QOS, P388 and B16 cells. The antitumor effects of the conjugates were studied in vivo in mice with subcutaneous tumors of B16 and P388 cells. The Cm-AFP and Cm-EGF conjugates inhibited tumor growth and noticeably increased the mean life span in experimental animals. Our results suggest that the therapeutic activity of Cm can be significantly enhanced by conjugation to AFP or EGF.