Immune checkpoints in targeted-immunotherapy of pancreatic cancer: New hope for clinical development

Immunotherapy has been recently considered as a promising alternative for cancer treatment. Indeed, targeting of immune checkpoint (ICP) strategies have shown significant success in human malignancies. However, despite remarkable success of cancer immunotherapy in pancreatic cancer (PCa), many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far. In this process, immunosuppression in the tumor microenvironment (TME) is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method. In this paper, the latest findings on the ICPs, which mediate immunosuppression in the TME have been reviewed. In addition, different approaches for targeting ICPs in the TME of PCa have been discussed. This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.

Anti-Mucin1 aptamer-conjugated chitosan nanoparticles for targeted co-delivery of docetaxel and IGF-1R siRNA to SKBR3 metastatic breast cancer cells

Background: Targeted co-delivery of siRNA and a chemotherapeutic drug is an attractive approach to cancer drug design and treatment. This study was carried out to design an anti-Mucin1 aptamer [Apt]-conjugated chitosan nanoparticle [NP] for targeted co-delivery of insulin-like growth factor receptor 1 [IGF-1R] Silencer siRNA and docetaxel [DTX] to SKBR3 cells

Methods: Characterization of nano-drugs, cellular uptake of NPs, cell viability, and gene expression studies were evaluated based on metastatic breast cancer cells

Results:The results of this study showed that NPs had spherical and smooth morphology with 110-118 nm in size and had positive zeta potential [12-14 mV]. siRNA and DTX were considerably loaded into NPs. The appropriate conjugation of the Apt to the NPs was affirmed by gel electrophoresis. The Apt-conjugated NPs were observed to enhance the cellular uptake of NPs into the SKBR3 cells. Although the combination treatment significantly decreased the cell viability of SKBR3 cells, the augmentative effect was observed when Apt was conjugated to NPs. Furthermore, Apt-conjugated NPs dramatically reduced the genetic expression of IGF-1R, signal transducers and activators of transcription 3 [STAT3], matrix metalloproteinases [MMP9], and vascular growth factor [VEGF]

Conclusion: The targeted NPs may augment the targeting of pathways involved in tumorigenesis and metastasis of breast cancer. Therefore, more animal model experiments are needed to further clarify the efficacy and safety of this functionalized nanodrug

Variable localization of Toll-like receptors in human fallopian tube epithelial cells / 대한생식의학회지

OBJECTIVE: To determine the localization, expression, and function of Toll-like receptors (TLRs) in fallopian tube epithelial cells. METHODS: The localization of TLRs in fallopian tube epithelial cells was investigated by immunostaining. Surprisingly, the intensity of staining was not equal in the secretory and ciliated cells. After primary cell culture of fallopian tube epithelial cells, ring cloning was used to isolate colonies of ciliated epithelial cells, distinct from non-ciliated epithelial cells. The expression of TLRs 1–10 was examined by quantitative real-time polymerase chain reaction, and protein localization was confirmed by immunostaining. The function of the TLRs was determined by interleukin (IL)-6 and IL-8 production in response to TLR2, TLR3, TLR5, TLR7, and TLR9 ligands. RESULTS: Fallopian tube epithelial cells expressed TLRs 1–10 in a cell-type-specific manner. Exposing fallopian tube epithelial cells to TLR2, TLR3, TLR5, TLR7, and TLR9 agonists induced the secretion of proinflammatory cytokines such as IL-6 and IL-8. CONCLUSION: Our findings suggest that TLR expression in the fallopian tubes is cell-type-specific. According to our results, ciliated cells may play more effective role than non-ciliated cells in the innate immune defense of the fallopian tubes, and in interactions with gametes and embryos.

[Behavioral effects of electromagnet field with low frequency on reserpine-treated mice]

Background: As depression is one of the common diseases in the world and because of the lack of proper response via usual medications, using electromagnet fields [EMF], as an alternative treatment, has become noticeable. Thus, in the present study, the effect of EMF with low frequencies was investigated on the treatment of depression

Materials and methods: The experimental study was carried out on 32 male mice [albino, mean weight of 30g] after their adaptation in animal house. The animals were classified into 4 groups [n=8]. All 4 groups were injected with high dose of reserpine [5 mg/kg] i.p. and from those, 3 groups exposed with EMF [10, 25, and 50 HZ frequencies, respectively, with intense 250 micro T] for one week, 30 minutes daily. In all 3 groups, the signs of depression [sedation, righting reflexes and swimming], diarrhea, eyes hemorrhage, and feet and hands hemorrhage were observed and compared with control group [those without exposing to EMFs]

Results: Reserpine-induced depression caused sedation, righting reflex disorders, swimming difficulty, diarrhea and eye bleeding. The sedation in 10 and 25 HZ was significantly decreased. EMF in all frequencies decreased sings significantly, particularly in 25 HZ frequency. In swimming, EMF with 10 Hz was the most effective frequency

Conclusion: The findings showed that using EMES in low frequency can reduce most signs of reserpine-induced depression

Correlation between major depressive disorder and circulating natural killer cells

Background: major depressive disorder is a mental disorder characterized by a pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Depression is associated with multiple immunological disorders. Aim of the present study was to determine correlation between percentage of circulating NK cells and major depressive disorder

Materials and Methods: patients older than 18 years with the desire to participate were enrolled in this study. For depression evaluation, we used the Hamilton Depression Rating Scale and for determination of percentage of NK cells in peripheral blood, flow cytometry method was used

Results: our results showed that in patients with major depressive disorder, numbers of circulating NK cells have significantly reduced

Conclusion: according to our findings, depression is associated with "immune suppression". NK cells are important in early phase of immunological surveillance versus viral infections and tumors. Indeed, depressive patients are susceptible to cancers and infections

[Survey on intra-peritoneal injection of mercuric chloride on blood albumin and liver enzymes]

The rapid development of the mining and industry activities increased and many toxic metals in the environment of the earth's crust has been dissipated and has taken risks to human exposure, inhalation. Today evidence of many diseases associated with environmental factors harmful to repellent Bio systems is increasing gradually, The majority of these factors were man-made and the activities associated with heavy metals was a major threat for human health. Mercury has the most toxic non-radioactive element that was already known. The purpose of this study was to investigate the effect of mercuric chloride intra peritoneally on blood albumin and some liver enzymes. In this study, 30 male Wistar rats randomized selected into 6 groups [1 control group, and experimental groups of 1, 2, 3, 4, 5]. In control group adequate serum physiology, and in experimental groups a dose of mercuric chloride infused into peritoneal cavity for 7 days. The amount of mercuric chloride infused were 1 mg/kg in 1[st] group, 2 mg/kg in group 2, 5 mg/kg in group 3, 7 mg/kg in group 4, and 10 mg/kg in the fifth group every other day for 7 days. After the 7 days blood samples, were tested and analyzed. In this study, there was a significant relation between decrease in albumin levels in experimental groups compared to the control group and a there was significant relation increase in the amount of transaminases; SGOT and SGPT in the experimental group. This study showed that intra peritoneal injection of mercuric chloride causes the balance were increased, of liver enzymes and serum albumin levels

[CAM visual stimulation with conventional method of occlusion treatment in amblyopia: a randomized clinical trial]

The application of CAM visual stimulation returns to the date of more than fifty years ago. However, the reports of previous studies in this field vary from no effect to significant effects of this method in amblyopia treatment. The purpose of this study was to determine the effect of CAM visual stimulation along with conventional occlusion therapy in anisometropic amblyopic children. Forty amblyopic children aged 4 to 6 years old with no previous treatment were enrolled in this randomized clinical trial study. The subjects were randomly assigned in two different groups. The group 1 included conventional occlusion therapy and group 2 includes occlusion therapy with complementary CAM visual stimulation. In terms of visual acuity and stereopsis improvement and reduction of amblyopia severity, two groups were compared using the repeated measure ANOVA and LSD Post Hoc tests. In group 1 including conventional occlusion therapy, visual acuity improved from 0.444 +/- 0.077 logMAR to 0.138 +/- 0.023 logMAR, i.e., improvement of 0.306 logMAR [P<0.001] whereas in group 2 including complementary CAM usage, visual acuity improved from 0.398 +/- 0.075 logMAR to 0.047 +/- 0.022 logMAR, i.e., improvement of 0.351 logMAR [P<0.001]. Regarding Stereopsis, the improvements were 157 [from 258 +/- 34 to 101 +/- 13 seconds of arc, P<0.001] and 171 [from 237 +/- 33 to 66 +/- 12 seconds of arc, P<0.001] for groups 1 and 2 respectively. All subjects of group 2 gained the normal vision at the end of the treatment period, whereas only 47% of subjects of group 1 could achieve this level of vision in that time. Improvement of visual acuity in group 2 was significantly better than group 1 [P<0.05]. Using of CAM visual stimulation along with conventional occlusion will further improve visual acuity and stereopsis in amblyopic children. These findings recommended the CAM visual stimulation as an accompanying and complementary method in amblyopia treatment

Comparing the effect of interavitreal bevacizumab in visual acuity of ischemic and non-ischemic diabetic macular edema

The paper tries to examine the effect of avastin on visual acuity in patients with Ischemic and non-ischemic diabetic macular edema which was estimated convenient, inexpensive, safe, and quick in contrast to laser or deep vitrectomy. In this clinical trial study, patients with clinically significant macular edema [CSMA] were subjected to fluorescein angiography [FA] and people whose foveal avascular zones [FAZ] were over 1000 micro m were defined as ischemic diabetic macular edema. Patients were divided into two ischemic and non-ischemic groups. The best corrected visual acuity [BCVA] and the central macular thickness [CMT] in all eyes were measured and recorded by optical coherence tomography [OCT]. All patients received 3 vitreous injections of bevacizumab [avastin] at 1-month intervals. One month after the third injection, BCVA and CMT were measured again and patient's information was compared before and after the injection. Out of 87 eyes [66 patients], 23 eyes [26.4%] belonged to ischemic group and 64 eyes [73.6%] belonged to non-ischemic group. In ischemic group, BCVA improved from 0.653 +/- 0.309 LogMAR to 0.404 +/- 0.255 LogMAR [p=0.001], while no significant change was seen in non-ischemic group [from 0.881 +/- 0.332 to 0.879 +/- 0.378]. In ischemic group, CMT was increased from 362.9 +/- 34.66 to 278.76 +/- 45.57 and in non-ischemic group it was enhanced from 353.47 +/- 67.61 to 239.87 +/- 55.44 [p=0.001]. In spite of the great impact of vitreous injection of avastin in reducing the central macular thickness in both ischemic and non-ischemic groups and sensible improvement of patients' visibility, the visibility itself was not improved considerably in ischemic group

[ relationship between soluble serum HLA-G and ICSI success rates]

Pregnancy is a successful transplantation. Factors evading rejection of the fetus by the mother's immune system are poorly understood and success rate and maintenance of embryos in assisted reproductive technologies [ART] may also depend on the same factors. The molecules of HLA-G are non-classical major histocompatibility complex class I antigens that have recently attracted attention in regards to pregnancy. The aim of the present study was to determine the concentration of HLA-G and its correlation with success or failure rates of ICSI. Serum samples of 107 women who were undergoing ICSI [the case group] were collected before and 14 days after embryo transfer, as were serum samples of 24 women with normal pregnancy [the control group] in the first trimester of pregnancy. Soluble HLA-G1 and G5 isoforms and the total sHLA-G were assayed by sandwich ELISA. Nonparametric Kolmogorov-Smirnov [K-S], Mann Whitney U and Wilcoxon tests were used for statistical analysis. No significant differences were observed in clinical variables including age, infertility duration and treatment regimen between the control and the case groups. Levels of sHLA-G1 and sHLA-G5 and the total sHLA-G prior and after ICSI in the control group, respectively, were 47.4 +/- 62.8 U/ml, OD: 1.47 +/- 0.58 prior and 59.6 +/- 69.5 U/ml, OD: 1.38 +/- 0.57 after ICSI. In the non-pregnant group, the values respectively were 35.7 +/- 55.2 U/ml, OD: 1.37 +/- 0.45 prior and 39.7 +/- 57.2 U/ml, OD: 1.31 +/- 0.46 after ICSI, corresponding to the control group; 53.16 +/- 47.92 U/ml and OD: 1.29 +/- 0.49. No significant statistical differences were found between the pregnant, nonpregnant and the control groups. No significant changes in the serum levels of sHLAG1 and sHLA-G5 isoforms and the total sHLA-G were observed following embryo transfer. No significant correlation was found between sHLA-G and the success of pregnancy in women undergoing ART. It seems that serum HLA-G has no prognostic value in the prediction of ICSI failure

[ implication of health belief model in planning educational programmes for preventing HIV/AIDS among university students]

To plan an educational program to prevent HIV/AIDS among university students based on Health Belief Model [HBM]. This descriptive cross-sectional study was conducted in Tehran University in academic year of 2004-2005. The instrument used was a questionnaire including demographic information, knowledge questions, health belief model constructs [perceived severity, perceived susceptibility, perceived benefits and barriers] and attitude towards HIV/AIDS patients, high risk behaviors questionnaire and intention to take HIV test. The participants were selected through stratified and systematic methods. Data were analyzed performing Chi-square test, Pearson correlation and one was ANOVA. In all 664 students participated in the study. The mean age was 18.74 +/- 8/1. according to self report,%4.1 were smoker,%2.9 used substance drugs,%1.5 suffered from sexual transmitted disease and HIV/AIDS.%26.4 believed that their knowledge is insufficient.%71.1 believed in having low risk of being infected. Almost all of the participants were highly aware of HIV/AIDS. The results also indicated that there was a significant relationship between the participants' knowledge and their perceived severity and susceptibility and benefits in term of willing to take the test. Lack of HIV voluntary counseling and testing center and feat of the test results were the main barriers of HIV test. The findings suggest that we need to educate and raise the people consciousness about the perceived benefits of HIV test, the way of giving the test results, and the contact details and services for voluntary counseling and testing centers

In vitro fertilized embryos do not secrete detectable HLA-G on day two

Pregnancy is a successful transplantation. The factors evading rejection of the fetus are poorly understood. Recently an interest has grown, in HLA-G molecules as one of these factors. Since these antigens are mainly expressed on the surface of cytotrophoblasts that are in direct contact with maternal tissues, it has been suggested that these molecules may have a role in induction of immune tolerance in mothers. To find the association of soluble HLA-G [sHLA-G] and the success of pregnancy with intracytoplasmic sperm injection [ICSI] procedure. In this study, the supernatant of 287 individually cultured embryos corresponding to 96 women under ICSI procedure were assayed for soluble HLA-G1 and G5 by a sandwich ELISA. Clinical pregnancy successfully occurred in 30 of candidates. No differences in clinical parameters [age, infertility duration, stimulation regimen] were observed between pregnant and nonpregnant women under ICSI procedure. None of the embryo supernatants in either group showed any detect-able sHLA-G molecules. Our results showed that detectable level of sHLA-G is not produced by day 2 embryos and such a measurement may not provide reliable information for embryo selection and estimation of pregnancy success

Deltamethrin-impregnated bed nets and curtains in an anthroponotic cutaneous leishmaniasis control program in northeastern Iran

Anthroponotic cutaneous leishmaniasis [ACL] has long been a significant public health problem in northeastern Iran. The objective of this study was to determine the efficacy of deltamethrin-impregnated vs. nonimpregnated bed nets [NIBs] and curtains [NICs] in ACL control. Deltamethrin-impregnated bed nets [IBs] and curtains [ICs] with 25 mg ai/m[2] were distributed among 160 households in one district and NIBs and NICs were distributed among the same number of households in another district. A third district with a similar numbers of households served as a control. Health education messages were disseminated to ensure the population's complicance with the proper use of bed nets and curtains. Sticky paper traps were used to assess the effect of insecticide-impregnated bed nets and curtains on the density of Phlebotomus sergenti. Deltamethrin susceptibility and also bioassay tests were carried out on the species by WHO standard method. Case findings were done by house-to-house visits once a season and all the inhabitants of the selected households in each district were examined. IBs and ICs provided good protection against sandfly bites and reduced the transmission of ACL in the intervention district, while NIBs and NICs provided no protection. There was no significant difference in monthly density of P. sergenti indoors and outdoors among the districts [P>0.05]. This species was susceptible to delta-methrin in the field population in the area. Bioassays confirmed that the nets treated with deltamethrin remained effective for more than 3 months. Personal protection is an effective and sustainable means of preventing and controlling ACL and can reduce dependence on insecticides. We encourage the use of IBs and ICs to control ACL in other high-risk areas of Iran and Afghanistan during the active season of sandflies

new epidemic focus of zoonotic cutaneous leishmaniasis in central Iran

Background: Reports from the health center of Yazd province of increasing cutaneous leishmaniasis [CL] cases led us to carry out an epidemiological study using standard techniques in Ardakan County, central Iran, during 2001

Patients and Methods: Data was collected on the prevalence of scars and ulcers over a period of 14 months among 621 households in three villages around Ardakan County. Smears were prepared by scraping the edges of the ulcers. We collected the same data on all school children aged 7 to 11 years old in the area. To determine the reservoir host of the disease, rodents and dogs were caught and examined. Sandflies were collected biweekly from indoor and outdoor locations in the study area, and then identified. Parasites isolated from human and rodents were characterized by RAPD-PCR technique

Results: The prevalence of scars and ulcers were 30.4% and 24.6%, respectively, in 3024 individuals in the three villages. Individuals 10 to 14 years of age were the most highly infected age group, with a rate of 28.4%. Males and females were equally infected. Examination of 892 students in primary schools showed a rate of 22.9% for scars and 23.7% for ulcers. Meriones libycus [42.2%] and Rhombomys opimus [57.8%] were present around the villages. Both were infected with Leishmania. Three of 19 M. libycus [15.7%] and 3 out of 26 R. opimus [11.5%] had positive results. The active season of sandflies was late April to late November. Phlebotomus papatasi and Sergentomyia sintoni were the dominant species indoors and outdoors. Natural leptomonad infection was found in P. caucasicus and S. sintoni from gerbil and Jird burrows

Conclusion: Based on this survey, there is an epidemic of zoonotic CL in the area, with Leishmania major as the agent, M. libycus and R. opimus as the reservoir hosts, and most probably Phlebotomus papatasi as the vector because about 77% of indoor sandflies were of this species