The Expression of Estrogen Receptor Subtypes in Prolactinomas and Their Relationship to Tumor Biological Behavior

Dopamine agonists （DA） are a first-line therapy for prolactinomas （PA）. However, nearly 10% of prolactinomas do not respond to DA therapy. A considerable number of studies have shown that estrogen plays an important role in the development of prolactinomas. However, the expression of estrogen receptors （ER） in prolactinomas has not been fully explored. Accordingly, we examined the levels of ESR1 and its subtypes A5-DeI-ESR1 and ESR2 mRNA in prolactinomas. In the present study,

Monitoring of Biological Responses of Tumor Cells after Irradiation with ^(99m)Tc-MIBI——An In Vitro Study

To explore the possibility to employ 99m Tc MIBI to monitor biological response of tumor cells after irradiation and to observe the relation between the radiation doses and the uptake levels of 99m Tc MIBI in tumor cells, the cells were irradiated with a single dose of 2 Gy, 10 Gy and 20 Gy respectively. The uptake of 99m Tc MIBI in each dosage group was determined before and 24, 48, 72 h after irradiation respectively. Apoptosis index , plating efficiency of tumor cells was simultaneously determined. There was a positive correlation between uptake levels of 99m Tc MIBI and AI. A negative correlation was noted between the uptake levels and PE . It is suggested that 99m Tc MIBI may be used as a tracer to monitor the change of viability state of tumor cells after being irradiated with different doses.

Spinal cord biological safety of image-guided radiation therapy versus conventional radiation therapy

Tumor models were simulated in purebred Beagles at the T9-10 levels of the spinal cord and treated with spinal image-guided radiation therapy or conventional radiation therapy with 50 or 70 Gy total radiation. Three months after radiation, neuronal injury at the T9-10 levels was observed, including reversible injury induced by spinal image-guided radiation therapy and apoptosis induced by conventional radiation therapy. The number of apoptotic cells and expression of the proapoptotic protein Fas were significantly reduced, but expression of the anti-apoptotic protein heat shock protein 70 was significantly increased after image-guided radiation therapy compared with the conventional method of the same radiation dose. Moreover, the spinal cord cell apoptotic index positively correlated with the ratio of Fas/heat shock protein 70. These findings indicate that 3 months of radiation therapy can induce a late response in the spinal cord to radiation therapy; image-guided radiation therapy is safer and results in less neuronal injury compared with conventional radiation therapy.

Evaluation of treatment response for breast cancer:are we entering the era of "biological complete remission"?

Breast cancer is one of the most common malignancies in women. The post-operative recurrence and metastasis are the leading causes of breast cancer-related mortality. In this study, we tried to explore the role of circulating tumor cell （CTC） detection combination PET/CT technology evaluating the prognosis and treatment response of patients with breast cancer; meanwhile, we attempted to assess the concept of ＂biological complete remission＂ （bCR） in this regard. A 56-year-old patient with breast cancer （T2N1M1, stage IV left breast cancer, with metastasis to axillary lymph nodes and lungs） received 6 cycles of salvage treatment with albumin-bound paditaxd plus eapecitaabine and trastuzumah. Then, she underwent CTC detection and PET/CT for efficacy evaluation. CTC detection combination PET/CT is useful for the evaluation of the biological efficacy of therapies for breast cancer. The bCR of the patient appeared earlier than the conventional clinical imaging complete remission and promised the histological （pathological） complete remission. The integrated application of the concepts including bCR, imageological CR, and histological CR can achieve the early and prognosis of breast cancer. accurate assessment of biological therapeutic reponse and

Hepatoma cell line HepG2.2.15 demonstrates distinct biological features compared with parental HepG2

AIM:To investigate the biological features of hepatitis B virus(HBV)-transfected HepG2.2.15 cells. METHODS:The cell ultrastructure,cell cycle and apoptosis,and the abilities of proliferation and invasion of HBV-transfected HepG2.2.15 and the parent HepG2 cells were examined by electron microscopy,flow cytometry, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and trans-well assay.Oncogenicity of the two cell lines was compared via subcutaneous injection and orthotopic injection or implantation in nude mice,and the pathological analysis of tumor formation was performed.Two cytoskeletal proteins were detected by Western blotting. RESULTS:Compared with HepG2 cells,HepG2.2.15 cells showed organelle degeneration and filopodia disappearance under electron microscope.HepG2.2.15 cells proliferated and migrated slowly in vitro,and hardly formed tumor and lung metastasis in nude mice.Flow cytometry showed that the majority of HepG2.2.15 cells were arrested in G1 phase,and apoptosis was minor in both cell lines.Furthermore,the levels of cytoskeletal proteins F-actin and Ezrin were decreased in HepG2.2.15 cells. CONCLUSION:HepG2.2.15 cells demonstrated a lower proliferation and invasion ability than the HepG2 cells due to HBV transfection.

Risk of infections associated with biological treatment in inflammatory bowel disease

Tumor necrosis factor-α (TNF-α) inhibitors are biological agents introduced in the late 1990s for the treatment of different immune-mediated diseases as inflammatory bowel disease, rheumatoid arthritis and psoriasis. The most commonly used TNF-α antagonists are infliximab, adalimumab, and certolizumab pegol, and though highly effective in lowering inflammation, the efficacy must be weighed against the potential for adverse events. The treatment-induced immunosuppression is suspected to increase the risk of infections, including the risk of reactivation of latent tuberculosis, as the TNF-α cytokine plays an important role in the immune function. In this topic highlight a short overview of the infection risk associated with TNF-α inhibiter therapy is outlined with a focus on the overall risk of serious infections, mycobacterial infection and latent viral infections.

Relationship between phenotypes of cell-function differentiation and pathobiological behavior of gastric carcinomas

AIM: To reveal the correlation between the functional differentiation phenotypes of gastric carcinoma cells and the invasion and metastasis by a new way of cell-function classification.METHODS:Surgically resected specimens of 361 gastric carcinomas(GC) were investigated with enzyme-, mucin-, and tumor-related marker immunohistochemistry. According to the direction of cell-function differentiation, stomach carcinomas were divided into five functionally differentiated types. RESULTS: (1) Absorptive function differentiation type (AFDT): there were 82 (22.7%) patients including 76 (92.7%) aged 45 years. Sixty-nine (84.1%) cases belonged to the intestinal type. Thirty-eight (46.3%) expressed CD44v6 and 9 (13.6%) of 66 male patients developed liver metastasis.The 5-year survival rate of patients in this group (58.5%) was higher than those with the other types (P【0.01). (2) Mucin secreting function differentiation type (MSFDT): 54 (15%) cases. Fifty-three (98.1%) tumors had penetrated the serosa, 12 (22.2%) expressed ER and 22 (40.7%) expressed CD44v6. The postoperative 5-year survival rate was 28.6%. (3) Absorptive and mucin-producing function differentiation type (AMPFDT): there were 180 (49.9%) cases, including 31 (17.2%) aged younger than 45 years. The tumor was more common in women (62, 34.4%,) and expressed more frequently estrogen receptors (ER) (129, 81.7%) than other types (P【0.01). Ovary metastasis was found in 12 (19.4%) out of 62 female subjects. The patients with this type GC had the lowest 5-year survival rate (24.7%) among all types. (4) Specific function differentiation type (SFDT): 13 (3.6%) cases. Nine (69.2%) tumors of this type derived from APUD system, the other 4 (30.7%) were of different histological differentiation. Sixty per cent of the patients survived at least five years. (5) Non-function differentiation type (NFDT): 32 (8.9%) cases. Nineteen (59.4%) cases had lymph node metastases but no one with liver or ovary metastasis. The 5-year survival rate was 28.1%. CONCLUSION: This new cell-function classification of GC is helpful in indicating the characteristics of invasion and metastasis of GC with different cell-function differentiation phenotypes. Further study is needed to disclose the correlation between the cell-functional differentiation phenotypes and the relevant genotypes and the biological behavior of gastric carcinoma.

Deterministic Parsing Model of the Compound Biological Effectiveness (<i>CBE</i>) Factor for Intracellular ¹⁰Boron Distribution in Boron Neutron Capture Therapy

Purpose: In defining the biological effects of the 10B(n, α)7Li neutron capture reaction, we have previously developed a deterministic parsing model to determine the Compound Biological Effectiveness (CBE) factor in Borono-Phenyl-Alanine (BPA)-mediated Boron Neutron Capture Therapy (BNCT). In present paper, we demonstrate that the CBE factor is directly and unambiguously derivable by the new formula for any case of intracellular 10Boron (10B) distribution, which is founded on this model for tissues and tumor. Method: To determine the CBE factor, we derive the following new calculation formula founded on the deterministic parsing model with three constants, CBE0, F, n and the eigen value Nth/Nmax. where, Nth and Nmax are the threshold value of boron concentration of N and saturation boron density in tissues and tumor. In order to determine these constants and the eigen values, iterative calculation technique was employed for the CEB factor and Nmax data set previously reported. Results and Conclusion: From the iterative calculation results, it is clear that the calculated CBE factor values obtained are almost identical to the original CBE factors and there is a good correlation between the original CBE factors and Nth/Nmax, when CBE0, F and n are given as 0.5, 8 and 3, respectively. These constants provide a better understanding of different types of intracellular10B distribution.

Determination of the Compound Biological Effectiveness (CBE) Factors Based on the <i>ISHIYAMA-IMAHORI</i>Deterministic Parsing Model with the Dynamic PET Technique

Purpose: In defining the biological effects of the 10B(n, α)7Li neutron capture reaction, we have proposed a deterministic parsing model (ISHIYAMA-IMAHORI model) to determine the Compound Biological Effectiveness (CBE) factor in Borono-Phenyl-Alanine (BPA)-mediated Boron Neutron Capture Therapy (BNCT). In present paper, we demonstrate a specific method of how the application of the case of application to actual patient data, which is founded on this model for tissues and tumor. Method: To determine the CBE factor, we derived the following new calculation formula founded on the deterministic parsing model with three constants, CBE0, F, n and the eigen value Nth/Nmax.? (1), where, Nth and Nmax are the threshold value of boron concentration of N and saturation boron density and CBE0, F and n are given as 0.5, 8 and 3, respectively. In order to determine Nth and Nmax in the formula, sigmoid logistic function was employed for 10B concentration data, Db(t) obtained by dynamic PET technique. (2), where, A, a and t0 are constants. Results and Conclusion: From the application of sigmoid function to dynamic PET data, it is concluded that the Nth and Nmax for tissue and tumor are identified with the parameter constants in the sigmoid function in Equation (2) as: (3). And the calculated CBE factor values obtained from Equation (1), with Nth/Nmax.

Post-operative abdominal complications in Crohn's disease in the biological era: Systematic review and meta-analysis

AIM: To perform a systematic review and meta-analysis on post-operative complications after surgery for Crohn's disease(CD) comparing biological with no therapy.METHODS: Pub Med, Medline and Embase databases were searched to identify studies comparing postoperative outcomes in CD patients receiving biological therapy and those who did not. A meta-analysis with a random-effects model was used to calculate pooled odds ratios(OR) and confidence intervals(CI) for each outcome measure of interest. RESULTS: A total of 14 studies were included for metaanalysis, comprising a total of 5425 patients with CD 1024(biological treatment, 4401 control group). After biological therapy there was an increased risk of total infectious complications(OR = 1.52; 95%CI: 1.14-2.03, 8 studies) and wound infection(OR = 1.73; 95%CI: 1.12-2.67; P = 0.01, 7 studies). There was no increased risk for other complications including anastomotic leak(OR = 1.19; 95%CI: 0.82-1.71; P = 0.26), abdominal sepsis(OR = 1.22; 95%CI: 0.87-1.72; P = 0.25) and re-operation(OR = 1.12; 95%CI: 0.81-1.54; P = 0.46) in patients receiving biological therapy. CONCLUSION: Pre-operative use of anti-TNF-α therapy may increase risk of post-operative infectious complications after surgery for CD and in particular wound related infections.

Advances in biological immunotherapy for gastric cancer:a mini-review

Gastric cancer immunotherapy refers to the use of biological technology to mobilize the immune function so that the body has a natural anti-cancer ability.It can be induced in vitro by collecting immune cells and cancer cells from patients with gastric cancer to form specific immune cell groups.Besides,a large number of these immune cell groups are cultured,separated,and then reinfused into patients,to achieve high efficiency,eliminate tumors and mobilize immune mechanisms in patients.In theory,this method can cure tumors because the principle of immunotherapy is to stimulate the body's autoimmune response.However,for some special populations,there may be more severe side effects.At present,the prediction,prevention,and treatment of this severe side effect are not complete.The immunotherapy of gastric cancer has not yet reached the full promotion,but it is a good treatment direction.It can be used clinically with chemotherapy and radiotherapy,surgery and traditional Chinese medicine cooperate,thereby achieving significant curative effects,and even curing gastric cancer.

Topical biological agents targeting cytokines for the treatment of dry eye disease

Because inflammation plays a key role in the pathogenesis of dry eye disease and Sjogren's syndrome, topical anti-inflammatory agents such as corticosteroids and cyclosporine A have been used to treat inflammation of the ocular surface and lacrimal gland. Systemic biological agents that target specific immune molecules or cells such as tumor necrosis factor(TNF)-α, interferone-α, interleukin(IL)-1, IL-6, or B cells have been used in an attempt to treat Sjogren's syndrome. However, the efficacy of systemic biological agents, other than B-cell targeting agents, has not yet been confirmed in Sjogren's syndrome. Several studies have recently evaluated the efficacy of topical administration of biological agents targeting cytokines in the treatment of dry eye disease. Topical blockade of IL-1 by using IL-1 receptor antagonist could ameliorate clinical signs and inflammation of experimental dry eye. Using a mouse model of desiccating stress-induced dry eye, we have demonstrated that topical application of a TNF-α blocking agent, infliximab, could improve tear production and ocular surface irregularity, decrease inflammatory cytokines and Th-1 CD4+ cells on the ocular surface, and increase gobletcell density in the conjunctiva. Although controversy still remains, the use of topical biological agents targeting inflammatory cytokines may be a promising therapy for human dry eye disease.

Is non-biological treatment of rheumatoid arthritis as good as biologics?

The management of rheumatoid arthritis(RA) in the past three decades has undergone a paradigm shift from symptomatic relief to a "treat-to-target" approach. This has been possible through use of various conventional and biologic disease modifying anti-rheumatic drugs(DMARDs) which target disease pathogenesis at a molecular level. Cost and infection risk preclude regular use of biologics in resource-constrained settings. In therecent years, evidence has emerged that combination therapy with conventional DMARDs is not inferior to biologics in the management of RA and is a feasible cost-effective option.

Recombination Mutant Human Tumor Necrosis Factor Combined with Chemotherapy in the Treatment of Advanced Cancer

Objective: Past studies showed that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. The objective of present study is to evaluate the therapeutic effects and adverse reactions of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy in patients with advanced malignant tumor. Methods: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients. rmhTNF was injected intramuscularly to the trial group at a dose of 4×106 U/m2, from the 1st to 7th days, the 11th to 17th days combined with chemotherapy course. The chemotherapy plan was as follows: CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. Results: In the trial group there was 1 CR case and 12 PR cases, and the response rate was 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate in the trial group was significantly higher than that in the control group (P=0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those in the control groups. After the treatment the KPS was 89.00±9.92 in the trial group, and 84.17±8.84 in the control group, with a significant difference between the two groups (P=0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable. Conclusion: The administration of rmhTNF in combination with general chemotherapy is an effective and secure means in treating advanced malignant tumor.

Circulating tumor cell isolation:the assets of filtration methods with polycarbonate track-etched filters

Circulating tumor cells （CTCs） arise from primary or secondary tumors and enter the bloodstream by active or passive intravasation. Given the low number of CTCs, enrichment is necessary for detection. Filtration methods are based on selection of CTCs by size using a filter with 6.5 to 8 pm pores. After coloration, collected CTCs are evaluated according to morphological criteria. Immunophenotyping and fluorescence in situ hybridization techniques may be used. Selected CTCs can also be cultivated in vitro to provide more material. Analysis of genomic mutations is difficult because it requires adapted techniques due to limited DNA materials. Filtration-selected CTCs have shown prognostic value in many studies but multicentric validating trials are mandatory to strengthen this assessment. Other clinical applications are promising such as follow-up, therapy response prediction and diagnosis. Microfluidic emerging systems could optimize filtration-selected CTCs by increasing selection accuracy.

Radiobiological response of human hepatoma and normal liver cells exposed to carbon ions generated by Heavy Ion Research Facility in Lanzhou

Human hepatoma and normal liver cells were irradiated with 12C6+ ion beams (LET = 96.05 keV/μm) and γ-rays at Heavy Ion Research Facility in Lanzhou (HIRFL). The chromatid breaks and break types were detected using the premature chromosome con- densation technique. Our experimental results showed that chromatid breaks seem to have a good relation with 12C6+ absorbed dose and 12C6+ are more effective to induce chromatid breaks as compared to the γ-rays. For 12C6+ ion irradiation the major break was isochromatid break, while chromatid breaks were dominant for γ-ray irradiation. We also observed that the Relative Biology Effectiveness (RBE) of 12C6+ ion is about 2.5 times higher than that of γ-rays.

DNA ploidy and c-Kitmutation in gastrointestinal stromal tumors

AIM: To investigate the prognostic significance of c-Kitgen emutation and DNA ploidy in gastointestinal stromal tumors (GISTs).METHODS: A total of 55 cases of GISTs were studied for the expression of c-Kit by immunohistochemistry, and the c-Kit gene mutations in exons 9, 11, 13, and 17 were detected by polymerase chain reaction-single strand confirmation polymarphism (PCR-SSCP) and denaturing high performance liquid chromatography (D-HPLC) techniques. DNA ploidy was determined by flow cytometry.RESULTS: Of the 55 cases of GISTs, 53 cases (96.4%) expressed c-Kit protein. The c-Kit gene mutations of exons 11 and 9 were found in 30 (54.5%) and 7 cases (12.7%),respectively. No mutations were found in exons 13 and 17.DNA aneuploidy was seen in 10 cases (18.2%). The c-Kit mutation positive GISTs were larger in size than the negative GISTs. The aneuploidy tumors were statistically associated with large size, high mitotic counts, high risk groups, high cellularity and severe nuclear atypia, and epithelioid type.There was a tendency that c-Kit mutations were more frequently found in aneuploidy GISTs.CONCLUSION: DNA aneuploidy and c-Kit mutations can be considered as prognostic factors in GISTs.

Study on combined assay for serum tumor markers in patients,with hepatic carcinoma

INTRODUCTIONSince the hepatic solid-occupying lesion (HSOL) wasfound by both ultrasonoscopy (US) and computed tomography(CT).If the customary alpha-fetoprotin (AFP) standard fordiagnosis primary hepatic carcinoma is used,those cancerswith lower AFP concentration may miss the diagnosis.Onthe other hand,the use of the standard:AFP-positive(≥20μg/L)+HSOL=primary hepatocellular carcinoma(PHCC),may yield false positive results.In order to ele-vate both the preoperative and differential diagnosis levels forhepatic carcinoma,we assayed combindedly the preoperativelevels of serum AFP,carbohydrate antibody (CA) 19-9 andcarcinoembryonic antigen (CEA) in the patients with HSOL.

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn's disease patients

AIM:To investigate the correlation between the appearance of skin lesions and concentration of interleukin(IL)-17A,IL-23 and interferon-γ(IFN-γ)in Crohn’s disease(CD)patients during anti-tumor necrosis factor-α(TNF-α)therapy METHODS:A prospective study included 30 adult patients with CD of Caucasian origin(19 men and 11women;mean age±SD 32.0±8.6 years)during biological therapy with anti-TNF-αantibodies from January2012 to March 2013.Eighteen patients were treated with infliximab,seven with adalimumab and five withcertolizumab.Inclusion criteria were exacerbation of the underlying disease,Crohn’s Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies.Patients with a history of psoriasis,atopic dermatitis and other autoimmune skin lesions were excluded from the study.The control group consisted of 12 healthy subjects.A diagnostic survey was carried out,blood tests and careful skin examination were performed,and the serum levels of IL-17,IL-23 and IFN-γwere measured using an enzyme-linked immunosorbent assays technique.Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by antiTNF-αtherapy.RESULTS:Skin manifestations occurred in 18 of CD patients during the anti-TNF-αtherapy(60%),in the average time of 10.16±3.42 mo following the beginning of the 52-wk treatment cycle.Skin lesions observed in CD patients during biological therapy included psoriasiform lesions(44.4%),and eczema forms lesions(22.2%).In CD patients with drug induced skin lesions significantly higher levels of hemoglobin(13.3±1.5 g/dL vs 10.8±1.9 g/dL,P=0.018)and hematocrit(39.9%±4.5%vs 34.3%±5.4%,P=0.01),as well as a significantly lower level of platelets(268±62×103/μL vs 408±239×103/μL,P=0.046)was observed compared with CD patients without skin manifestations.The concentrations of IL-17A and IL-23in CD patients with skin lesions developed under antiTNF-αtherapy were significantly higher compared to those in patients without lesions(IL-17A:39.01±7.03pg/mL vs 25.71±4.90 pg/mL,P=0.00004;IL-23:408.78±94.13 pg/mL vs 312.15±76.24 pg/mL,P=0.00556).CONCLUSION:Skin lesions in CD patients during bio-logical therapy may result from significantly increased concentrations of IL-17A and IL-23,which are strongly associated with TNF-α/Th1 immune pathways.

Biomedical overview of melanin.1.Updating melanin biology and chemistry,physico-chemical properties,melanoma tumors,and photothermal therapy

Melanins(eumelanin,pheomelanin,and allomelanin)represent a very,if not themost,important group of biological pigments.Their biological roles are multiple,from photoprotection to antioxidant activity,heavy metal disposal or the myriad uses of color in organisms across all Phyla.In the first part of this review,eumelanin biology and some chemical aspects will be presented,as well as key physico-chemical features that make this biological pigment so interesting.The principal characteristics of the melanocyte,the melanin-synthesizing cell in mammals,will also be introduced.Transformed melanocytes are the cause of one of the most devastating known cancers:the malignant melanoma.Epidemiology and molecular signaling aspects will be presented next,as well as the principal advances in promising oncotherapies designed and applied for the treatment of melanoma.In particular,on account of the photo-physical properties of melanin,special details will be provided regarding the use of photothermal therapy for melanoma treatment.