CAR-T cells: Early successes in blood cancer and challenges in solid tumors

New approaches to cancer immunotherapy have been developed, showing the ability to harness the immune system to treat and eliminate cancer. For many solid tumors, therapy with checkpoint inhibitors has shown promise. For hematologic malignancies, adoptive and engineered cell therapies are being widely developed, using cells such as T lymphocytes, as well as natural killer (NK) cells, dendritic cells, and potentially others. Among these adoptive cell therapies, the most active and advanced therapy involves chimeric antigen receptor (CAR)-T cells, which are T cells in which a chimeric antigen receptor is used to redirect specificity and allow T cell recognition, activation and killing of cancers, such as leukemia and lymphoma. Two autologous CAR-T products have been approved by several health authorities, starting with the U.S. Food and Drug Administration (FDA) in 2017. These products have shown powerful, inducing, long-lasting effects against B cell cancers in many cases. In distinction to the results seen in hematologic malignancies, the field of using CAR-T products against solid tumors is in its infancy. Targeting solid tumors and trafficking CAR-T cells into an immunosuppressive microenvironment are both significant challenges. The goal of this review is to summarize some of the most recent aspects of CAR-T cell design and manufacturing that have led to successes in hematological malignancies, allowing the reader to appreciate the barriers that must be overcome to extend CAR-T therapies to solid tumors successfully.

novel defensin-like peptide associated with two other new cationic antimicrobial peptides in transcriptome of the Iranian scorpion venom

Introduction: Scorpion venom is a source of bioactive peptides, and some antimicrobial peptides [AMPs] have been found in the venom gland of scorpions. Therefore, the discovery of new anti-infective agents is an essential need to overcome the problem of antibiotic resistance of clinical isolates. Here, we describe three new cationic AMPs, including meuVAP-6, meuAP-18-1, and meuPep34 from the venom gland of the Iranian scorpion, Mesobuthus eupeus

Methods: The cDNA sequences encoding all the three peptides were obtained from the cDNA library of scorpion venom gland and were deposited in the GenBank database

Results: MeuVAP-6 and meuAP-18-1 are non-disulphide-bridged antimicrobial peptides, while meuPep34 is a cysteine-rich defensin-like peptide

Discussion: All three identified AMPs are rich in arginine and tryptophan. The overall results from the length, net charge, and hydrophobicity index suggested that meuPep34 could be the most active AMPs with the potential ability of biofilm inhibition. The data from molecular characterization of identified AMPs can provide a platform for further investigations in the drug design

Molecular Characterization and Biodiversity of a Putative Chlorotoxin from the Iranian Yellow Scorpion Odontobuthus doriae

Background: Chloride channels have already been over-expressed in the different types of cancer. Chlorotoxins, as the blocking agent of these channels, have been indicated to be an effective drug against tumors. In this study, we characterized a putative chlorotoxin from a cDNA library of the venom glands obtained from the Iranian scorpion Odontobuthus doriae

Methods: A cDNA library was constructed from venom gland transcriptome of six scorpions. The cDNA encoding Odontobuthus doriae chlorotoxin was isolated from the library, and its putative peptide was characterized by some bioinformatics software such as protein blast, SignalP4.0, DISULFIND and Clustal Omega

Results: The mature Odontobuthus doriae chlorotoxin peptide has a 35-amino-acid residue and four disulfide bounds. This putative chlorotoxin is a small, compact, and stable molecule. Moreover, based on the open reading frame sequence similarity, this peptide is similar to Buthus martensii Karsch chlorotoxin-like toxin and Bml2-b neurotoxins from the Chinese scorpion Mesobuthus martensii

Conclusion: The small size of this putative chlorotoxin and its stability make it as a suitable candidate for medical and pharmacological research, especially in the cancer research

Impact of pharmaceutical impurities in ecstasy tablets: gas chromatography-mass spectrometry study

In this study, a simple and reliable method by gas chromatograph-mass spectrometry [GC-MS] was developed for the fast and regular identification of 3, 4-MDMA impurities in ecstasy tablets. In so doing, 8 samples of impurities were extracted by diethyl ether under alkaline condition and then analyzed by GC-MS. The results revealed high MDMA levels ranging from 37.6% to 57.7%. The GC-MS method showed that unambiguous identification can be achieved for MDMA from 3, 4-methylenedioxyamphetamine [MDA], Amphetamine [AM], methamphetamine [MA] and ketamine [Keta] compounds, respectively. The experimental results indicated the acceptable time window without interfering peaks. It is found that GC-MS was provided a suitable and rapid identification approach for MDMA [Ecstacy] tablets, particularly in the Forensic labs. Consequently, the intense MDMA levels would support the police to develop a simple quantification of impurity in Ecstasy tablets

Cationic immune stimulating complexes containing soluble leishmania antigens: preparation, characterization and in vivo immune response evaluation

Background: Cationic immune stimulating complexes [PLUSCOMs] are particulate antigen delivery systems. PLUSCOMs consist of cationic immunostimulatory complexes [ISCOMs] derivatives and are able to elicit in vivo T cell responses against an antigen

Objective: To evaluate the effects of PLUSCOMs containing Leishmania major antigens [SLA] on the type of immune response generated in the murine model of leishmaniasis

Methods: PLUSCOMs consisting of 1, 2-dioleoyl-3-trimethylammonium-propane [DOTAP] were used as antigen delivery system/immunoadjuvants for soluble SLA. BALB/c mice were immunized subcutaneously, three times in 2-week intervals. Footpads swellings at the site of challenge and parasite loads were assessed as a measure of protection. The immune responses were also evaluated by determination of IgG subclasses and the level of IFN- gamma and IL-4 in cultured splenocytes

Results: There was no significant difference [p<0.05] between the sizes of lesions in mice immunized with different formulations. Also, there was no significant difference in the number of parasites in the footpad or spleen of all groups compared with the control group. The highest level of IFN- gamma secretion was observed in the splenocytes of mice immunized with PLUSCOM/SLA [p<0.001] and lower amounts of IL-4 was observed in PLUSCOM group [p<0.001] as compared to negative control

Conclusion: Our results indicated that SLA in different formulations generated an immune response with mixed Th1/Th2 response that was not protective enough despite the activation of CD4+ T cells with secreting IFN- gamma in groups which received PLUSCOM with antigen

[Introducing the professional metamorphosis theory of the BSN students and its application in the nursing education]

Background and aim: Professional socialization is a critical aspect of nursing students' development. This process begins with entering into the nursing program and continues after graduation and beginning of professional practice. This paper aimed to introduce the professional metamorphosis theory of BSN students and its application in the nursing education

Materials and Methods: This study was conducted with the aim of the introduction of the professional metamorphosis theory of BSN students. For this purpose, a search was performed on scientific databases [Pub Med, CINAHL, SID and IranMedex] using the key terms "professional socialization", "professionalization", "nursing education", and " metamorphosis". Ultimately 27 scientific articles and 2 Textbooks selected and reviewed. The results were compared with the present theory

Findings: In this study, the professional metamorphosis nursing students as a grounded theory was introduced. The theory was compared with related models and theories in the nursing literature. The applications and practical suggestions were provided in the nursing education

Conclusions: This study introduced "professional metamorphosis of nursing students" as a grounded theory in the sociocultural context of the health system of Iran. The nursing students' experiences during these stages [dependence, disintegration, and integration] and surrounding professional and extra- professional contexts help the nurse educators and administrators to develop effective educational interventions

Relapse model among Iranian drug users: a qualitative study

Relapse is a common problem in drug user's rehabilitation program and reported in all over the country. An in-depth study on patients' experiences can be used for exploring the relapse process among drug users. Therefore, this study suggests a model for relapse process among Iranian drug users. In this qualitative study with grounded theory approach, 22 participants with rich information about the phenomenon under the study were selected using purposive, snowball and theoretical sampling methods. After obtaining the informed consent, data were collected based on face-to-face, in-depth, semi-structured interviews. All interviews were analyzed in three stages of axial, selective and open coding methods. Nine main categories emerged, including avoiding of drugs, concerns about being accepted, family atmosphere, social conditions, mental challenge, self-management, self-deception, use and remorse and a main category, feeling of loss as the core variable. Mental challenge has two subcategories, evoking pleasure and craving. Relapse model is a dynamic and systematic process including from cycles of drug avoidance to remorse with a core variable as feeling of loss. Relapse process is a dynamic and systematic process that needs an effective control. Determining a relapse model as a clear process could be helpful in clinical sessions. Results of this research have depicted relapse process among Iranian drugs user by conceptual model

Epidemiological review of scorpion envenomation in Iran

This epidemiological review was carried out to display the magnitude and the geographic distribution of scorpion envenomation in Iran with focus on the southwestern region of Iran, particularly. The Iranian recognized scorpions belonging to two families, including Buthidae and Scorpionidae. Buthidae family consists of 14 genuses, 26 species, and 18 sub-species, while Scorpionidae family has three genuses and four species. The lack of basic knowledge, including the geographical distribution, clinical manifestations, and specific treatments related to scorpiofauna justifies such multidisciplinary studies. The venom of two endemic Iranian scorpions, including Hemiscorpius lepturus [H. lepturus] and Odonthubuthus doriae [O.doriae] have considered as an effective source of new neurotoxin peptides for the further development of physio-pharmacological probes and designing the clinical trials. Such epidemiological information may improve the determinants of Iranian scorpion stings in order to plan and implement effective public health intervention

Dosage comparison of snake anti-venom on coagulopathy

This study was done to determine whether high or low dose of anti-snake venom [ASV] is better in coagulopathy in victims of envenoming by vipers. This retrospective study was conducted on the 154 patients [Mean age +/- SD, Range] of viper snake bites who were referred to the emergency ward of Razi Hospital, Ahvaz, Iran over 2 years period [2004 - 2006]. According to the treatment dosage the patients were divided in two groups include group 1 [78 cases], low dose regimen and group 2 [76 cases], high dose one. In group 1, the treatment was performed by administration of 4 to 6 vials of ASV through intravenous infusion. In group 2, the patients were given 5 to 10 vials of ASV as an initial dose. In low dose regimen, the number of received packed red blood cell was higher [14 vs. 3] in comparison with high dose group. The number of ASV vials the patients received was 5.5and 21.06 in group 1 and 2, respectively [5.5 +/- 1.7 vs. 21.06 +/- 10.89; p < 0.01]. The difference in frequency of coagulopathy complications, and need for using packed red blood cell were statistically significant [96.2% and 17.9% in group 1 vs. 34.2% and 3.9% in group 2, p < 0.01]. It seems that cautious usage of high dose of ASV [10 - 20 vials] without very special concerns about the cost, dose, and without hazardous side effects is essential for the routine management of sever snake envenoming

Relapse experience in Iranian opiate users: a qualitative study

To understand the relapse process, it is required to notice the clients learned behaviors and environmental contexts. We aimed to explore and describe relapse experiences of Iranian drug users. This is a grounded theory study and twenty two participants were selected using purposive sampling, snowball and theoretical sampling. After obtaining written informed consent, data gathering was done by means of in-depth semi-structured interviews. According to Strauss and Corbin three phases of open coding, axial coding and selection coding were done for qualitative analysis and continuous comparison. During the research period Guba and Lincoln criteria were used to be reassured of the accuracy and rigor of the study findings. The main categories of this study were craving and conflict, family stress and psychological indicators of relapse that emerged in three phases including recovery, tension and pre-relapse. High anxiety, withdrawal, rationalization and lying were the most common symptoms. Family reactions and social conditions play a key role in relapse. Relapse process is an active and multidimensional event in which the clients experience a psychosocial status continuum from recovery to relapse. Most psychological problems are seen in the tension phase

Effects of odontobuthus doriae scorpion venom on mouse sciatic nerve

Temporary paralysis is a rare manifestation of envenoming following the yellow Iranian scorpion, Odontobuthus doriae [O. doriae]. Thus, to elucidate the underlying mechanism, we investigated the neurotoxic effect of venom in the sciatic nerve, the possible mechanism in a mice model. The neurotoxicity and temperature effects in the venom-induced neurotoxicity were examined using the mouse sciatic nerve and mouse phrenic nerve-hemidiaphragm [MHD] preparations. O .doriae venom [1 [micro]g/mL] caused changes in the perineural waveform associated with nerve terminal action potentials. Venom affected on both negative and positive components of the waveform which is known as a compound action potential. The time-response relationship of venom-induced depression of resting membrane potential [RMP] was significant [p < 0.05]. No significant difference in augmentation was seen in room temperature in comparison with 37[degree]C. In conclusion, although there was no evidence that the venom had any specific curarizing action at the neuromuscular junction; the results suggest that the venom exerts its neuromuscular transmission on the sciatic nerve through potassium and sodium ionic-currents. Furthermore, the influence of temperature on neurotoxicity was ineffective on blockade of the neuromuscular transmission in-vitro

Two biological active fractions isolated from buthotus schach [bs] scorpion venom examined on striated muscle preparation, in-vitro

Buthotus schach is one of the most dangerous scorpions in tropical part of Iran. The effects of its crude venom at 1, 3, 10 microg/mL and its obtained fractions by gel filtrations were investigated on neuromuscular transmission. CBC and MHD indirectly and directly stimulated preparations techniques were used to study their possible pre or post junctional activities. At 3 and 10 microg/ mL [not at 1 microg/mL], BS venom caused initiall increase in twitch height followed by blockage due to large contraction that responded gradually at the same time. Contracture responses to exogenous Ach [1-2 mM, 30 sec] and Carb [30-40 microM, 60 sec] in the presence of the venom were not increased which does show no anticholinstrease effects. Furthermore Contracture response to KC1 [20-40 mM, 30 sec] does changed exposure to venom in CBC preparations. On the other hand the effects of the venom in response to directly stimulated preparations was shallower than in indirect stimulated preparations. So in agreement with KCL response BS venom affects mostly prejunctionally to facilitate the neurotransmitter release rather than postjunctionally effects. To access bioactive components, seven fractions were collected by gel filtrations techniques. Among the fractions F[6], LD[50]=21 microg < F[4], LD[50]= 35.5 microg < Venom LD[50]= 84 microg per mice were more toxic respectively. Both fractions show the same effects but stronger than venom on twitch height responses in indirectly stimulated CBC preparations. Finally, according to our results venom as well as fractions F4 and F6 act mostly prejunctionally on Ach release. More attempt is carrying out to study their effects on ion channel activities

Cytotoxic effects of two Iranian scorpions odontobuthusdoriae and bothutus saulcyi on five human cultured cell lines and fractions of toxic venom

Scorpion venom toxicity is of major concern due to its influence on human activities and public health. We investigated the in-vitro process of cell death caused by two Iranian scorpions Odontobuthus doriae and Bothutus salceyi venom on human cell lines. The aim of this study was to provide further information about triggering cell death and suggestion of methods for the elimination of unwanted cells such as tumor cells. The cytotoxicity and apoptosis induced by effect of scorpion venoms on five established eukaryotic cell lines are analyzed on different human cell lines. All cultured cell lines were incubated with varying doses of scorpion venom for 24 h at 37°C. Control culture was treated with an equal amount of SFM. The percentage of cell survival was measured using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium [MTT] colorimetric assay. Our data demonstrated that Bothutus saulcyi, does not show cytotoxic effect on any of the used cell lines. Odontobuthus doriae, however, has resulted a dose dependent cytotoxic effect with maximum at 1 ug/mL on 1321N1 glioma like cell line. Then the cytotoxic venom of O. doriae was fractionated using Sephadex G50 gel chromatography. The toxic fractions on mouse used to Cytotoxicity assay on 1321 N1 cell line and data demonstrated that, the fraction F3 showed a dose dependent Cytotoxicity assay. Further studies to explode the mode of action of these venoms are recommended and purification of the toxic fraction should be done

Effect of antibiotic therapy on asymptomatic bacteriuria in kidney transplant recipients

Asymptomatic bacteriuria is a very common complication after kidney transplantation and the need for antibiotic therapy is controversial. The aim of this study was to evaluate the effect of antibiotic therapy on the clinical course of asymptomatic bacteriuria in renal transplant recipients. In the present study, 88 kidney transplant recipients with asymptomatic bacteriuria were divided into two groups of cases and controls. The patients had been selected from among those with at least 1 year follow-up. In the case group, asymptomatic bacteriuric episodes were treated with antibiotics, and in control group, they were followed without antibiotic therapy. The follow-up period was 9 to 12 months. Bacteriuric episodes, symptomatic urinary tract infection [UTI] episodes, and changes in plasma creatinine level were recorded and compared between the two groups. The rate of bacteriuric episodes and symptomatic UTIs were not significantly different between the two groups [P >0.05]. In addition, level of plasma creatinine did not increase significantly in neither of the groups during the study [P >0.05]. It seems that treatment of asymptomatic bacteriuria in kidney recipients does not decrease the rate of UTI episodes afterwards. Asymptomatic bacteriuria does not affect renal function in short term. Thus, we can abandon antibiotic therapy, subject to careful follow-up

enhancing effect of sodium glycocholate and sodium salicylate on rats gastro-intestinal permeability to insulin

There have been numerous efforts to formulate insulin into an oral dosage form. The major problems involved with the oral administration of insulin are acidic and enzymatic decomposition by the gastric medium, and poor absorption in the small intestine due to its macromolecular structure. This study attempted to test the enhancing ability of two absorption enhancers, sodium glycocholate [Na-GC] and sodium salicylate [Na-Sal], in different parts of rat's gastrointestinal tract. The amount of insulin in each formulation was 0.6 iu/kg body weight. The concentration of enhancers [Na-Sal or Na-GC] in each formulation was 10 micro g/ml. Formulations made of insulin and enhancers were prepared and injected directly to stomach, duodenum, jejunum and ileum of anesthetized rats through an abdominal incision. Blood samples were taken at 45 and 60 min intervals. The glucose concentration was determined by the o-toluidine method. Injections [IP] of insulin and normal saline were positive and negative controls, respectively. The blood glucose concentrations showed a significant decrease [p<0.05] due to the injection of insulin into duodenum, while the effect noted in jejunum was insignificant [p>0.05]. Also, there was no anti-hyperglycemic effect accompanied by formulations administered into the stomach and ileum. It could be concluded that insulin, if formulated in a protected form to prevent acidic and enzymatic decomposition, in combination with such enhancers may overcome hyperglycemia due to insulin deficiency