Policy options for strengthening evidence-informed health policy-making in Iran: overall SASHA project findings.

BACKGROUND: The institutionalization of evidence-informed health policy-making (EIHP) is complex and complicated. It is complex because it has many players and is complicated because its institutionalization will require many changes that will be challenging to make. Like many other issues, strengthening EIHP needs a road map, which should consider challenges and address them through effective, harmonized and contextualized strategies. This study aims to develop a road map for enhancing EIHP in Iran based on steps of planning. METHODS: This study consisted of three phases: (1) identifying barriers to EIHP, (2) recognizing interventions and (3) measuring the use of evidence in Iran's health policy-making. A set of activities was established for conducting these, including foresight, systematic review and policy dialogue, to identify the current and potential barriers for the first phase. For the second phase, an evidence synthesis was performed through a scoping review, by searching the websites of benchmark institutions which had good examples of EIHP practices in order to extract and identify interventions, and through eight policy dialogues and two broad opinion polls to contextualize the list of interventions. Simultaneously, two qualitative-quantitative studies were conducted to design and use a tool for assessing EIHP in the third phase. RESULTS: We identified 97 barriers to EIHP and categorized them into three groups, including 35 barriers on the "generation of evidence" (push side), 41 on the "use of evidence" (pull side) and 21 on the "interaction between these two" (exchange side). The list of 41 interventions identified through evidence synthesis and eight policy dialogues was reduced to 32 interventions after two expert opinion polling rounds. These interventions were classified into four main strategies for strengthening (1) the education and training system (6 interventions), (2) the incentives programmes (7 interventions), (3) the structure of policy support organizations (4 interventions) and (4) the enabling processes to support EIHP (15 interventions). CONCLUSION: The policy options developed in the study provide a comprehensive framework to chart a path for strengthening the country's EIHP considering both global practices and the context of Iran. It is recommended that operational plans be prepared for road map interventions, and the necessary resources provided for their implementation. The implementation of the road map will require attention to the principles of good governance, with a focus on transparency and accountability. Video abstract.

In vitro characterization of 3-chloro-4-hydroxybenzoic acid building block formation in ambigol biosynthesis.

The cyanobacterium Fischerella ambigua is a natural producer of polychlorinated aromatic compounds, the ambigols A-E. The biosynthetic gene cluster (BGC) of these highly halogenated triphenyls has been recently identified by heterologous expression. It consists of 10 genes named ab1-10. Two of the encoded enzymes, i.e. Ab2 and Ab3, were identified by in vitro and in vivo assays as cytochrome P450 enzymes responsible for biaryl and biaryl ether formation. The key substrate for these P450 enzymes is 2,4-dichlorophenol, which in turn is derived from the precursor 3-chloro-4-hydroxybenzoic acid. Here, the biosynthetic steps leading towards 3-chloro-4-hydroxybenzoic acid were investigated by in vitro assays. Ab7, an isoenzyme of a 3-deoxy-7-phosphoheptulonate (DAHP) synthase, is involved in chorismate biosynthesis by the shikimate pathway. Chorismate in turn is further converted by a dedicated chorismate lyase (Ab5) yielding 4-hydroxybenzoic acid (4-HBA). The stand alone adenylation domain Ab6 is necessary to activate 4-HBA, which is subsequently tethered to the acyl carrier protein (ACP) Ab8. The Ab8 bound substrate is chlorinated by Ab10 in meta position yielding 3-Cl-4-HBA, which is then transfered by the condensation (C) domain to the peptidyl carrier protein and released by the thioesterase (TE) domain of Ab9. The released product is then expected to be the dedicated substrate of the halogenase Ab1 producing the monomeric ambigol building block 2,4-dichlorophenol.

Sarcopenia screening strategies in older people: a cost effectiveness analysis in Iran.

BACKGROUND AND OBJECTIVES: Sarcopenia is an important age-related disease which can lead to an increased risk of mortality, falls, fractures, and poor quality of life. So, timely detection can be effective in reducing the burden of disease. The aim of this study was to identify the most cost-effective strategy for sarcopenia screening in Iran. MATERIALS AND METHODS: We constructed a Markov transition model over a life-time horizon based on natural history. Compared strategies included Sarcopenia scoring assessment models (SarSA-Mod), European working group on sarcopenia in older people (EWGSOP), Mini sarcopenia risk assessment (MSRA) and SARC-F. Parameters values were extracted from primary data and the literature, and the costs and Quality-adjusted life years (QALYs) were calculated for each strategy. Sensitivity analysis of uncertain parameters was also performed to determine the robustness of the model. Analysis was performed using 2020 version of TreeAge Pro software. RESULTS: All four screening strategies increased life time QALYs. After removing dominated strategy, the incremental cost per QALY gained for sarcopenia screening varied from $1875.67 for EWGSOP to $1898.33 for MSRA. Our base-case analysis showed that the most cost-effective strategy was EWGSOP and 2nd best was SarSA-Mod with $43,414.3 and $42,663.3 net monetary benefits given one GDP per capita ($5520.311) as willingness to pay, respectively. Sensitivity analysis of model parameters also showed robustness of results. CONCLUSIONS: The results of the study, as the first economic evaluation of sarcopenia screening, showed that the EWGSOP strategy is more cost-effective than other strategies.

Systematic review and policy dialogue to determine challenges in evidence-informed health policy-making: findings of the SASHA study.

BACKGROUND: Various interventions have been undertaken in Iran to promote evidence-informed health policy-making (EIHP). Identifying the challenges in EIHP is the first step toward strengthening EIHP in each country through the design of tailored interventions. Therefore, the current study was conducted to synthesize the results of earlier studies and to finalize the list of barriers to EIHP in Iran. METHODS: To identify the barriers to EIHP in Iran, two steps were taken: a systematic review and policy dialogue. To conduct the systematic review, three Iranian databases and PubMed, Health Systems Evidence (HSE), Embase, and Scopus were searched. The reference lists of included papers and documentation from some local organizations were hand-searched. Upon conducting the systematic review, given the significance of stakeholders in clarifying the problem of EIHP, policy dialogue was used to complete the list previously extracted and to do advocacy. Selection criteria for the stakeholders included influential and informed individuals from knowledge-producing, knowledge-utilizing, and knowledge-brokering organizations. Semi-structured interviews were held with three important absent stakeholders. RESULTS: Challenges specific to Iran that were identified included the lack of integration of the health ministry and the medical universities, lack of ties between health knowledge utilization organizations, failure to establish long-term research plans, neglect of national research needs at the time of recruiting human resources in knowledge-producing organizations, and duplication and lack of coordination in routine data obtained from surveillance systems, disease registration systems, and censuses. It seems that some challenges are common across countries, including neglecting the importance of inter- and intra-disciplinary studies, the capacity of policy-makers and managers to utilize evidence, the criteria for evaluating the performance of policy-makers, managers, and academic members, the absence of long-term programmes in knowledge-utilizing organizations, the rapid replacement of policy-makers and managers, and lack of use of evaluation studies. CONCLUSIONS: In this study, we tried to identify the challenges regarding EIHP in Iran using a systematic review and policy dialogue approach. This is the first step toward determining the best interventions to improve evidence-informed policy-making in each country, because these challenges are contextual and need to be investigated contextually.

A roadmap for strengthening evidence-informed health policy-making in Iran: protocol for a research programme.

BACKGROUND: Many initiatives have been taken in the Islamic Republic of Iran to promote evidence-informed health policy-making (EIHP). However, these initiatives are not systematic. Since the implementation of EIHP is not consistent and the interventions in this regard are complex, a comprehensive plan could be a useful tool for employing initiatives to achieve and promote EIHP. Hence, this study aims to develop a roadmap for strengthening EIHP over a 3-year period in Iran. METHODS: Nine projects will be conducted to define the roadmap for strengthening EIHP. These projects include two reviews and a stakeholder analysis to identify the factors that facilitate or hinder achieving EIHP. The next study will be a qualitative study to prioritise the challenges and outline the main causes. The following steps will be a review of reviews to extract global experiences on interventions used for strengthening EIHP and two qualitative studies to examine the adoption of these interventions and develop an operational plan for strengthening EIHP in Iran. The research will be completed through conducting two qualitative-quantitative studies to design a tool for measuring EIHP and assessing EIHP in Iran at baseline. DISCUSSION: This national EIHP roadmap will surely be able to identify the gaps and bumps that might exist in the implementation plan for establishing EIHP and eliminate them as needed in the future. This roadmap can be a step in moving towards transparency and accountability in the health system and as thus towards good governance and improvement of the health system's performance. Although the plan can be a good model for developing countries and may promote the use of evidence in health policy-making, we should assume that there are some critical contextual factors that could potentially hinder the complete and successful implementation of EIHP. Thus, to enhance EIHP in these countries with a policy-making context that does not fully support the use of evidence, it is crucial to think about not only those interventions that directly address the EIHP barriers, but also some long-term strategies to make required changes in the context, both beyond and within the health system.

Discovery of a Mosaic-Like Biosynthetic Assembly Line with a Decarboxylative Off-Loading Mechanism through a Combination of Genome Mining and Imaging.

The biosynthetic gene cluster for the antiplasmodial natural product siphonazole was identified by using a combination of genome mining, imaging, and expression studies in the natural producer Herpetosiphon sp. B060. The siphonazole backbone is assembled from an unusual starter unit from the shikimate pathway that is extended by the action of polyketide synthases and non-ribosomal peptide synthetases with unusual domain structures, including several split modules and a large number of duplicated domains and domains predicted to be inactive. Product release proceeds through decarboxylation and dehydration independent of the thioesterase SphJ and yields the diene terminus of siphonazole. High variation in terms of codon-usage within the gene cluster, together with the dislocated domain organization, suggest a recent emergence in evolutionary terms.

Function of the loading module in CorI and of the O-methyltransferase CorH in vinyl carbamate biosynthesis of the antibiotic corallopyronin A.

Corallopyronin A is a promising in vivo active antibiotic, currently undergoing preclinical evaluation. This myxobacterial compound interferes with a newly identified drug target site, i.e., the switch region of the bacterial DNA-dependent RNA-polymerase (RNAP). Since this target site differs from that of known RNAP inhibitors such as the rifamycins, corallopyronin A shows no cross-resistance with other antibacterial agents. Corallopyronin A is a polyketide synthase- and nonribosomal peptide synthetase-derived molecule whose structure and biosynthesis is distinguished by several peculiarities, such as the unusual vinyl carbamate functionality whose formation involves carbonic acid as an unprecedented C1-starter unit. Using in vitro experiments the nature of this starter molecule was revealed to be the methyl ester of carbonic acid. Biochemical investigations showed that methylation of carbonic acid is performed by the O-methyltransferase CorH. These experiments shed light on the biosynthesis of the Eastern chain of α-pyrone antibiotics such as corallopyronin A.

MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors.

PURPOSE: Intracranial germ cell tumors (iGCT) comprise germinoma and non-germinoma. Their diagnosis predominantly relies on biopsy as only one-fifth of patients present with elevated biomarkers (AFP/ß-HCG) in serum or cerebrospinal fluid (CSF). MicroRNAs (miR/miRNA) have emerged as non-invasive biomarkers in extracranial GCT and may potentially facilitate non-invasive diagnosis in iGCT. METHODS: We analyzed eight miRNAs in serum and CSF from the miR-371~373- and miR-302/367-clusters and four miRNAs differentially expressed in iGCT tissue (miR-142-5p/miR-146a-5p/miR-335-5p/miR-654-3p) from eight iGCT patients (age 10-33 years) and 12 control subjects by pre-amplified RT-qPCR. MiR-30b-5p (serum) and miR-204-5p (CSF) acted as reference genes. ΔCt-values were expressed as [Formula: see text] after standardization against controls. RESULTS: Between iGCT and control patients' serum ΔCt-values of miR-371a-3p (p = 0.0159), miR-372-3p (p= 0.0095, miR-367 (p = 0.0190), miR-302a (p = 0.0381) and miR-302d-3p (p = 0.0159) differed significantly. Discriminatory pattern in CSF was similar to serum as miR-371a (p = 0.0286), miR-372-3p (p = 0.0028), miR-367-3p (p = 0.0167) and miR-302d-3p (p = 0.0061) distinguished between patients and controls. Abundant [Formula: see text] levels of each of these miRNAs were found across all serum and CSF samples including biomarker-negative patients. CONCLUSION: With the largest data set so far, we underline the suitability of miR-371a, miR-372, miR-367 and miR-302d in serum and CSF for diagnosis of iGCT, particularly in biomarker-negative germinoma. Diagnosis of iGCT by miRNA analysis is a feasible and valid approach, particularly as serum can be readily obtained by a less invasive procedure. MiRNA analysis may discriminate iGCT from other tumors with similar radiological findings and may allow to monitor response to therapy as well as early relapse during follow-up.

Potential limitations in systematic review studies assessing the effect of the main intervention for treatment/therapy of COVID-19 patients: An overview.

Background: Although several studies have assessed the safety, efficacy, and effectiveness of interventions in treating the COVID-19, many of them have limitations that can have an immense impact on their results. This study aims to assess the potential limitations in systematic reviews (SRs) that evaluate the effect of interventions on the treatment of the COVID-19. Methods: PubMed, Scopus, and Web of Sciences (WOS) databases were searched from inception to January 1, 2022. All systematic reviews investigated the effectiveness, efficacy, safety, and outcome of the main intervention (Favipiravir, Remdesivir, Hydroxychloroquine, Ivermectin, Lopinavir/Ritonavir, or Tocilizumab) for the treatment of COVID-19 patients and reported the potential limitations of the included studies. We assessed the quality of the included studies using the Quality Assessment Tool (QAT) for review articles. We conducted a content analysis and prepared a narrative summary of the limitations. Results: Forty-six studies were included in this review. Ninety one percent of the included studies scored as strong quality and the remaining (9%) as moderate quality. Only 29.7% of the included systematic reviews have a registered protocol. 26% of the included studies mentioned a funding statement. The main limitations of the included studies were categorized in 10 domains: sample size, heterogeneity, follow-up, treatment, including studies, design, definitions, synthesis, quality, and search. Conclusion: Various limitations have been reported in all the included studies. Indeed, the existence of limitations in studies can affect their results, therefore, identifying these limitations can help researchers design better studies. As a result, stronger studies with more reliable results will be reported and disseminated. Further research on COVID-19 SRs is essential to improve research quality and also, efficiency among scientists across the world.

Barriers to and Facilitators of Cervical Cancer Screening among Women in Southeast Asia: A Systematic Review.

In Southeast Asia, cervical cancer is the second most common cancer in women. Low coverage for cervical cancer screening (CCS) becomes a roadblock to disease detection and treatment. Existing reviews on CCS have limited insights into the barriers and facilitators for SEA. Hence, this study aims to identify key barriers and facilitators among women living in SEA. A systematic literature review was conducted on Pubmed, Embase, PsycINFO, CINAHL, and SCOPUS. Primary qualitative and quantitative studies published in English that reported barriers and facilitators to CCS were included. The Mix Methods Appraisal Tool was used for the quality assessment of the included studies. Among the 93 included studies, pap smears (73.1%) were the most common screening modality. A majority of the studies were from Malaysia (35.5%). No studies were from Timor-Leste and the Philippines. The most common barriers were embarrassment (number of articles, n = 33), time constraints (n = 27), and poor knowledge of screening (n = 27). The most common facilitators were related to age (n = 21), receiving advice from healthcare workers (n = 17), and education status (n = 11). Findings from this review may inform health policy makers in developing effective cervical cancer screening programs in SEA countries.

Therapeutic delivery of siRNA with polymeric carriers to down-regulate STAT5A expression in high-risk B-cell acute lymphoblastic leukemia (B-ALL).

Overexpression and persistent activation of STAT5 play an important role in the development and progression of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. Small interfering RNA (siRNA)-mediated downregulation of STAT5 represents a promising therapeutic approach for ALL to overcome the limitations of current treatment modalities such as high relapse rates and poor prognosis. However, to effectively transport siRNA molecules to target cells, development of potent carriers is of utmost importance to surpass hurdles of delivery. In this study, we investigated the use of lipopolymers as non-viral delivery systems derived from low molecular weight polyethylenimines (PEI) substituted with lauric acid (Lau), linoleic acid (LA) and stearic acid (StA) to deliver siRNA molecules to ALL cell lines and primary samples. Among the lipid-substituted polymers explored, Lau- and LA-substituted PEI displayed excellent siRNA delivery to SUP-B15 and RS4;11 cells. STAT5A gene expression was downregulated (36-92%) in SUP-B15 and (32%) in RS4;11 cells using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to ALL primary cells, siRNA-mediated STAT5A gene silencing was observed in four of eight patient cells using our leading polymeric delivery system, 1.2PEI-Lau8, accompanied by the significant reduction in colony formation in three of eight patients. In both BCR-ABL positive and negative groups, three of five patients demonstrated marked cell growth inhibition in both MTT and trypan blue exclusion assays using 1.2PEI-Lau8/siRNA complexes in comparison with their control siRNA groups. Three patient samples did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. This study supports the potential of siRNA therapy and the designed lipopolymers as a delivery system in ALL therapy.

Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines.

Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation.

Amine-terminated dendritic polymers as a multifunctional chelating agent for heavy metal ion removals.

In this study, amine-terminated hyperbranched PAMAM (polyamidoamine) polymer (AT-HBP) was synthesized as a multifunctional chelating agent to remove two heavy metal ions (Cr(III) and Cu(II)) from the simulated wastewater solutions. The AT-HBP was characterized by Fourier transformed infrared (FTIR), dynamic light scattering (DLS), and proton nuclear magnetic resonance (1H NMR) analysis. The removal process was carried out in two different methods, centrifuged process and ultrafiltration. The concentration of heavy metal ions before and after removal was measured by inductively coupled plasma (ICP) instrument. The removal processes were evaluated by changing different parameters such as solution pH, AT-HBP dosage, and metal ion concentration. To evaluate the extend of binding of heavy metal ions in the presence of AT-HBP the presence of salt in the solution was also examined on the performance of the removal system. The overall results indicated that removal percentages higher than 98% for Cr(III) and 86% for Cu(II) were achieved for heavy metal concentrations of 100 mg/L for both removal process methods. Furthermore, the function of second generation of polypropylenimine (PPI) was compared to AT-HBP. The results reveal that the removal of Cr(III) and Cu(II) ions by AT-HBP were approximately 20% and 10% higher compared to PPI, respectively. Finally, hyperbranched dendritic polymer with lower expenses to synthesize compared to dendrimer underlined favorable properties as a multifunctional chelating agent and enhancement of ultrafiltration process for wastewater treatment. Graphical abstract.

Advances in biology of acute lymphoblastic leukemia (ALL) and therapeutic implications.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and also occurs in adults. Although the outcomes of multi-agent chemotherapy regimens have greatly improved, high toxicity and relapses in many patients necessitate the development of novel therapeutic approaches. Advances in molecular profiling and cytogenetics have identified a broad range of genetic abnormalities, including gene mutations, chromosome translocations and aneuploidy, which has provided a more comprehensive understanding of the biology and pathogenesis of ALL. This understanding has also led to new targeted therapeutic approaches, including the use of selective small molecule inhibitors, nucleic acid-based therapies and immune-based therapies mediated by specific monoclonal antibodies and cellular immunotherapy, which are poised to revolutionize the treatment of various ALL subtypes. The main focus of this review is to highlight the latest advances in ALL biology, including the identification of prognostic factors and putative therapeutic targets. We also review the current status of, and ongoing progress in, the development of targeted therapies for ALL.

siRNA/lipopolymer nanoparticles to arrest growth of chronic myeloid leukemia cells in vitro and in vivo.

Therapies for the treatment of Chronic Myeloid Leukemia and other leukemias are still limited for patients at advanced stages, which allow development of point mutations in the BCR-ABL fusion gene that render CML cells insensitive to therapies. An effective non-viral delivery system based on lipopolymers is described in this study to deliver specific siRNAs to CML cells for therapeutic gene silencing. The lipopolymer, based on the lipid α-linolenic acid (αLA) substitution on low molecular weight polyethyleneimine (PEI), was used to deliver siRNA against the BCR-ABL gene and, the resultant therapeutic effect was evaluated in in vitro and in vivo CML models. The study concluded that siRNA/PEI-αLA nanoparticles enabled silencing of the BCR-ABL gene and BCR-ABL protein, which consequently reduced growth on CML K562 cells in vitro and arrested the growth of localized tumors in a localized CML mouse model. The results from this study confirmed the potential use of lipopolymers as delivery systems and are encouraging for the future design of non-viral delivery systems for the treatment of CML and other hematological malignancies resulting from gene fusions.

Co-treatment by docetaxel and vinblastine breaks down P-glycoprotein mediated chemo-resistance.

OBJECTIVES: Chemoresistance remains the main causes of treatment failure and mortality in cancer patients. There is an urgent need to investigate novel approaches to improve current therapeutic modalities and increase cancer patients' survival. Induction of drug efflux due to overexpression of P-glycoproteins is considered as an important leading cause of multidrug resistance. In this study, we investigated the role of combination treatments of docetaxel and vinblastine in overcoming P-glycoprotein mediated inhibition of apoptosis and induction of cell proliferation in human non-small cell lung carcinoma cells. MATERIALS AND METHODS: Cell proliferation and apoptosis were assessed using MTT assay and DAPI staining, respectively. P-glycoprotein expression was evaluated in gene and protein levels by Real-time RT-PCR and Western blot analysis, respectively. RESULTS: Combination treatment of the cells with docetaxel and vinblastine decreased the IC50 values for docetaxel from (30±3.1) to (15±2.6) nM and for vinblastine from (30±5.9) to (5±5.6) nM (P≤0.05). P-glycoprotein mRNA expression level showed a significant up-regulation in the cells incubated with each drug alone (P≤0.001). Incubation of the cells with combined concentrations of both agents neutralized P-glycoprotein overexpression (P≤0.05). Adding verapamil, a P-glycoprotein inhibitor caused a further increase in the percentage of apoptotic cells when the cells were treated with both agents. CONCLUSION: Our results suggest that combination therapy along with P-glycoprotein inhibition can be considered as a novel approach to improve the efficacy of chemotherapeutics in cancer patients with high P-glycoprotein expression.

Sphingosine 1-phosphate interacts with Survivin pathway to enhance tumorigenesis in cancer cells.

OBJECTIVES: Degradation of sphingosine 1-phosphate (S1P), as a bioactive lipid, or deregulation of its production involves in tumor progression, metastasis and chemoresistance. Since the tumor progression effects of S1P and its mechanism in chronic lymphoblastic leukemia and non-small cell lung cancer is not fully understood, we investigated the role and one of the mechanisms of S1P in tumor progression of SKW3 and H1299 cells. MATERIALS AND METHODS: The effects of S1P on proliferation, invasion and migration was studied using MTT assay, soft-agar colony forming assay and trans-well migration assay, respectively. In order to find out the mechanisms of S1P action, the role of S1P on expression of Survivin gene was assessed by real-time RT-PCR. RESULTS: Our results demonstrated that although invasion was shown only in H1299 cells, low concentration of S1P, especially at 1 µM, mediated proliferation and migration in both cell lines. In addition, these effects of S1P in tumor progression are S1P receptor-dependent, and Survivin plays a key role in S1P tumorigenesis. CONCLUSION: Our results confirmed the involvement of S1P and its receptors in tumor progression of SKW3 and H1299. We also investigated another mechanism of S1P involved in cell survival, tumor progression, and Survivin signaling. In conclusion, data demonstrated the importance of this molecule as a target for designing new anticancer drugs such as anti-S1P monoclonal antibody for inhibiting major downstream signaling, which plays significant role in tumorigenesis.

Combination therapy increases the efficacy of docetaxel, vinblastine and tamoxifen in cancer cells.

INTRODUCTION: Developing novel strategies to increase the efficacy of chemotherapy is an urgent need. We investigated the impact of combination therapy with docetaxel, or vinblastine with tamoxifen in inhibition of proliferation and induction of apoptosis in MDA-MB-231 and H1299 cells. MATERIALS AND METHODS: Cell proliferation was assessed by MTT assay and the percentage of apoptotic cells was measured using DAPI staining. STATISTICAL ANALYSIS: Statistical analysis was performed by one-way ANOVA using SPSS software. RESULTS: Vinblastine or docetaxel induced higher percentage of apoptosis in MDA-MB-231 cells than H1299 cells (P < 0.05). Tamoxifen exhibited the highest percentage of cell death in H1299 cells (P < 0.05). Treatment of both cell lines with combination of docetaxel and vinblastine or tamoxifen showed enhanced apoptotic and anti-proliferative effects (P < 0.05). CONCLUSION: Combination therapy of breast and lung cancer cell lines using docetaxel or vinblastine with tamoxifen synergistically increases the anti-proliferative affect of single agents.

Inhibition of survivin restores the sensitivity of breast cancer cells to docetaxel and vinblastine.

Combination therapy is considered a viable strategy to overcome the resistance to chemotherapeutics. Survivin as a member of the inhibitor of apoptosis protein (IAP) family, which is involved in resistance to various drugs. We investigated the role of combination therapy in downregulating survivin and increasing drug's efficacy in MDA-MB-231 cells. MTT assay and DAPI staining were applied to study the anti-proliferative activity and apoptosis response of the agents. Real-time RT-PCR and Western blot analysis were applied to study survivin mRNA and protein. Our findings showed that combined treatment of cells with docetaxel and vinblastine reduces survivin expression and consequently decreases the IC50 value of docetaxel from 70 to 5 nM (p < 0.05). Furthermore, combination therapy with deguelin, a survivin inhibitor, exerted a considerable enhancement in synergistic efficacy of docetaxel and vinblastine (p < 0.05). Survivin downregulation may thus be considered a potential strategy in increasing the efficacy of chemotherapeutics in cancer patients.

Sphingosin 1-phosphate contributes in tumor progression.

Sphingosine-1 phosphate (S1P) is a bioactive lipid that mediates diverse cellular responses. Signaling of S1P is carried out by a family of G-protein coupled receptors (GPCRs), which show differential expression patterns depending on tissue and cell types. Activation of S1P receptors induces signaling pathway, which can subsequently lead to physiological process. Intercellular S1P concentration is regulated and determined by several enzymes including S1P lyase, S1P kinase and S1P phosphatase. Numerous studies showed the role of S1P in malignant behavior of cancer cells including breast, lung, colon, and leukemia cell lines. In the past decade, extensive research activities have focused on elucidating S1P signaling pathway, its receptors, enzymes involved in S1P metabolism, and its performance in cancer biology. In this review, we will explain the function of S1P in tumor progression that demonstrated in past research articles and we will express its importance as a target for designing futuristic anticancer drug.