COMBINED INHIBITION OF DDR1 AND CDK4/6 INDUCES SYNERGISTIC EFFECTS IN ER-POSITIVE, HER2-NEGATIVE BREAST CANCER WITH PIK3CA/AKT1 MUTATIONS

COMBINED INHIBITION OF DDR1 AND CDK4/6 INDUCES SYNERGISTIC EFFECTS IN ER-POSITIVE, HER2-NEGATIVE BREAST CANCER WITH PIK3CA/AKT1 MUTATIONS Maryam Shariati, M.S. Advisory Professor: Funda Meric-Bernstam, M.D. Molecular alterations in the phosphatidylinositol 3‑kinase (PI3K)/ serine/threonine protein kinase B (AKT) signaling pathway occur frequently in estrogen receptor–positive (ER-positive) breast tumors. Patients with ER-positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer are often treated with cyclin-dependent kinase (CDK4/6) inhibitors such as palbociclib in combination with endocrine therapy. Although this is a very effective regimen, disease progression ultimately occurs in most patients. Further, the modulators of palbociclib sensitivity remain unclear. The purpose of this study was to identify synthetic lethality partners that can enhance palbociclib’s antitumor efficacy in ER-positive breast cancer with PI3K pathway alterations. Using ER-positive isogenic breast cancer cell lines, we demonstrated that the efficacy of palbociclib is attenuated in the presence of PIK3CA or AKT1 mutations. Using a shRNA library screen targeting cancer–­­­­related human kinases, we identified that downregulation of discoidin domain receptor 1 (DDR1), a tyrosine kinase active in various cancers, is synthetically lethal with palbociclib. DDR1 knockdown by shRNA markedly reduced the growth of PIK3CA and AKT1 mutant and wild-type (WT) ER-positive cell lines in vitro. In addition, DDR1 pharmacological inhibitor, 7rh benzamide, decreased cell growth and inhibited cell cycle progression in all cell lines, while selectively enhancing the sensitivity of PIK3CA and AKT1 mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest, decreasing PLK1, cyclin E2, and RB phosphorylation in PIK3CA and AKT1 mutant cell lines. In vivo, 7rh significantly enhanced the antitumor efficacy of palbociclib. Similarly, reverse phase protein array (RPPA) analysis of the xenografts revealed a greater PLK1 reduction in a combined 7rh and palbociclib treatment group. Our data indicate that DDR1 inhibition can augment the cell cycle suppressive effect of palbociclib and could be an effective targeted therapy for ER-positive, HER2-negative breast cancers with PI3K pathway activation

REGULATION OF FOXC2 EXPRESSION AND FUNCTION DURING EPITHELIAL-MESENCHYMAL TRANSITION BY GSK-3β

Metastasis is the ultimate cause for the majority of cancer-related deaths. The forkhead box transcription factor FOXC2 is known to be involved in regulating metastasis as well as a variety of developmental processes, including the formation of lymphatic and cardiovascular systems. Previous studies have shown that FOXC2 protein is localized either in the nucleus and/or in the cytoplasm of human breast tumor cells. This pattern of localization is similar to that of another forkhead family member, FOXO3a. Additionally, localization of FOXO3a is known to be differentially regulated by upstream kinase AKT. Therefore, I investigated whether FOXC2 localization could also be regulated by upstream kinases. Analysis of FOXC2 protein sequence revealed two potential phosphorylation sites for GSK-3β. Furthermore, inhibition of GSK-3βsignificantly reduces FOXC2 protein. In addition, exposure of HMLE Twist cells expressing endogenous FOXC2 to the GSK-3β inhibitor, TWS119, results in accumulation of FOXC2 protein in the cytoplasm with concomitant decrease in the nucleus in a time-dependent manner. Furthermore, continued treatment with TWS119 eventually induces epithelial morphology and decreased stem cell properties including sphere formation in these cells. Further characterization of FOXC2- GSK-3β interaction and the associated signaling cascade are necessary to determine the effect of FOXC2 phosphorylation by GSK-3β on EMT and metastasis

Staging Iranian modernity : authors in search of new forms

This dissertation calls attention to three important twentieth-century Iranian playwrights who have made extraordinary contributions to the development of modern Iranian drama and whose oeuvres reveal instances of creative encounter with modern Western dramaturgy. In place of an attempt to provide a thorough diachronic analysis of dramatic productions in the regions concerned, I focus on specific moments and key figures that exemplify major stages in the evolution of modern drama both in Iran and the West, i.e., the triumvirate aesthetic movements of Idealism, Realism, and Modernism. With the aim of re-situating modern Iranian drama within the context of international dramatic developments, the plays of Gholamhossein Sa‘edi, Akbar Radi, and Bahram Beyzaie are respectively compared with the works of Henrik Ibsen, Anton Chekhov, and Luigi Pirandello in order to detail the affinities and divergences between the two through close-readings of plays and analysis of the scholarship and historical documents that shaped the playwrights’ views about modernity. In doing so, I thus propose a reading of Iranian drama that is sensitive both to Western influences and to the transformation exerted on Western literary forms in response to local realities and needs. In order to demonstrate the rise of modern drama as a literary form that is deeply aware of modernity, I provide a historically grounded perspective on its development. Therefore, in addition to examining the specific plays, I engage with a methodology that includes reviewing historical and social circumstances that informed the playwrights’ creations. Such an approach allows for the expansion of the dominant Western cannon, Ibsen, Chekhov, and Pirandello, for instance, and for gaining new perspectives on other national literary traditions which unfortunately have mostly been omitted from the world dramatic discourse. At the same time, by linking Western dramatists to their Iranian counterparts, this dissertation aims to join the discussions on the interactions between Iranian and Western literatures and to give an account of an exchange between Iran and the West that is embedded in the development of both.Comparative Literatur

Motivational Components Involved in the Metamotivational Monitoring in Medical Students

Background: Theoretical implications of self-regulated learning emphasize that self-regulation of motivation (metamotivation) plays an important role in learning, effort, perseverance, and academic success in general. Metamotivation is how people monitor and control their motivational states to achieve their goals. Researchers believe that metamotivation includes two reciprocal processes: metamotivational monitoring, evaluating whether the person has selected the proper level (quantity) and type (quality) of motivation to perform his tasks; and metamotivational control, using the results of the monitoring phase and applying suitable strategies for adapting or changing the motivation. In metamotivational monitoring, students try to identify the declined motivational component in order to regulate its quantity and quality using motivational regulation strategies. In this field, two important questions arise: How can identify and measure the motivational components involved in metamotivational monitoring? and: Which motivational component is targeted by the medical students when they use every motivational regulation strategy? Methods: Applying a multi-stage study, motivational components involved in metamotivational monitoring were characterized and a questionnaire developed. Then, using Structural Equation Modeling, predictive relationships between motivational components and motivational regulation strategies were investigated. Results: The Motivational Components Questionnaire (MCQ) showed acceptable evidence of validity and reliability. In the Exploratory Factor Analysis, 6 factors were discovered that explained 74% of the total variance. In examining the predictive relationships, each of the four components of self-efficacy, intrinsic value, self-relevant value and promotion value were specifically predicted by two motivational regulation strategies. Conclusions: Evidence of validity and reliability of the MCQ indicates that this questionnaire can be used in medical education contexts. Health Profession Educators can improve the academic motivation of students by identifying one or more declined motivational component and teaching specific motivational regulation strategies. It is recommended to hold training courses on motivational regulation strategies for medical school faculty, study-skills advisors, and students

The effect of Syrian mesquite (Prosopis farcta) seed extract on thioacetamide-induced oxidative stress in rats

Background: This experimental study aimed at investigating the effect of Prosopis farcta seeds hydro-alcoholic extract on thioacetamide-induced oxidative stress in rats. Materials and Methods: In this study, 30 adult male rats were randomly divided into three groups: healthy control, positive control, and P. farcta- treated group received thioacetamide. The healthy control rats received normal saline orally. The positive control rats received thioacetamide (50 mg/kg IP) for three times at one-day interval (oxidative stress induction). The P. farcta seed extract (100 mg/kg) was administered orally for 21 days. At the end of the experiment, blood samples were taken from the rats' heart to separate serum and the serum catalase (CAT) and superoxide dismutase (SOD) activities were determined. After euthanasia, liver and kidney were separated to determine malondialdehyde (MDA) levels. Results: The activities of CAT and SOD were significantly lower in the thioacetamide- intoxicated group compared to those in the healthy control group (P<0.001). The treatment with P. farcta seed extract significantly increased the activities of these enzymes compared to the positive control group (P<0.001). Moreover, after three weeks of oral treatment, the P. farcta seed extract significantly reduced the liver MDA concentrations compared with the positive control rats (P<0.05). Conclusion: It can be concluded that P. farcta seed hydro-alcoholic extract can protect against thioacetamide-induced oxidative stress

Metamotivation in Medical Students: Explaining Motivation Regulation Strategies in Medical Students

BACKGROUND: Metamotivation is a process that students use to monitor their motivational states to reach their academic goals. To date, few studies have addressed the ways that medical students manage their motivational states. This study aim to identify the motivational strategies of medical students as they use the metamotivational process to monitor and control their motivational states. MATERIALS AND METHODS: This qualitative study uses directed content analysis of the narrative responses of 18 medical students to draft an in-depth and semistructured interview protocol which were conducted through WhatsApp due to social distance restrictions of COVID-19. Data were collected, encoded, and analyzed using deductive content analysis approach descripted by Elo and Kyngäs. RESULTS: Seven main themes were extracted as the motivational strategies of medical students including “regulation of value,” “regulation of situational interest,” “self-consequating,” “environmental structuring,” “efficacy management,” “regulation of relatedness,” and “regulation of situational awareness.” In this study by identifying new strategies, we provide a broader framework of metamotivational strategies in the field of the progression of learners in medical education. CONCLUSION: Medical students use a variety of strategies to regulate their academic motivation. To sustain and improve the motivation of medical students, identifying and strengthening metamotivational strategies is the first step

Frequency and Causes of Hypotonia in Neonatal Period with the Gestational Age of More Than 36 Weeks in NICU of Mofid Children Hospital, Tehran, Iran During 2012-2014

How to Cite This Article: Seyed Shahabi N, Fakhraee H, Kazemian M, Afjeh A, Fallahi M, Shariati M, Gorji F. Frequency and Causes of Hypotonia in Neonatal Period with the Gestational Age of More Than 36 Weeks in NICU of Mofid Children Hospital, Tehran, Iran During 2012-2014. Iran J Child Neurol. Winter 2017; 11(1):43-49. AbstractObjectiveHypotonia is a serious neurologic problem in neonatal period. Although hypotonia is a nonspecific clinical finding but it is the most common motor disorder in the newborn. The objective of this study was to determine the frequency of neonatal hypotonia then to ascertain of the most common causes.Materials & MethodsThis cross –sectional prospective study was carried out on the 3281 term infants hospitalized in conventional and NICU of Mofid Children Hospital, Tehran, Iran during 2012-2014. Diagnosis was made by history, physical & neurological examination and accessible diagnostic tests.ResultsFifty nine hypotonic neonates were identified, forty seven (79.66%) had central hypotonia (Hypoxic ischemic encephalopathy (n= 2), other causes of encephalopathy (n=2), intracranial hemorrhage (n=4), CNS abnormalities (n= 7), chromosomal disorders (n=4), syndromic–nonsyndromic (n=8), and metabolic diseases (n=8). Peripheral hypotonic recognized in 6 infants (10.17%); spinal muscular atrophy (n= 1), and myopathy (n= 5). Six cases (10.17%) remained unclassified. Twelve infants had transient hypotonia. In final study, 18 of 59 infants (30%) died, nearly 90% before one year of age. Twenty-eight (47%) infants found developmental disorders and only 13 (22%) infants achieved normal development in their follow up.ConclusionNeonatal hypotonia is a common event in neonatal period. A majority of diagnosis is obtained by history and physical examination. Neuroimaging, genetic and metabolic tests were also important in diagnosis. Genetic, syndromic–nonsyndromic, and metabolic disorders were the most causes of neonatal hypotonia.References1.Miller VS, Delgado M, Iannaccone ST. Neonatal hypotonia Seminar in neurology 1993; 13 (1):73-83.2. Laugal V, Cossee M, MJ. de Saint –Martin A, Echaniz- Laguna A, Mandel JL, Astruc D, Messer FMJ. Diagnostic approach to neonatal hypotonia: retrospective study on144neonates.Eur J Pediatr 2008; 167:517-523.3. Birdi K, Prasad C, Chodirker B, Chudly AE, The floppy infant: retrospective analysis of clinical experience (1990-2000) in a tertiary care facility. J Chlid Neurol 2005; 20: 803-808.4. Johnston HM.The floppy weak infant revisited. Brain Dev 2003; 25:55-58.5. Crawford TO. Clinical Evaluation of the Floppy infant. Pediatric Annal 1992;16:348-354.6. Richer LP, Shevell MI, Miller SP. Diagnostic profile of neonatal hypotonia; An 11 year study. Peditric Neurol 2001; 25:32-37.7. Paro–Panjan D. Congenital hypotonia is there an algorithm. J Child Neurology 2004;19 (6):439-442. 8. Griggs RC, Mendell JR, Miller RG. Cngenital myopathies.in: Evaluation and treatment of myopathies. Philadelphia:FA Davis C; 1995:211-469. Nada Zadeh and Louanne Hudgings. The Genetic Approach to hypotonia in the neonate. NeoReviews 2009; 10; e600-e607.10. Bodenstiener JB. The evaluation of the hypotonic infant Seminar in PediatricNeurology 2008;15:10-20.11. Dubowitz V. Thomas NH. The natural history of type 1(severe) spinal muscular dystrophy. Neuromuscular Disord. 1994;4:497-50212.12. Jimenez E, Garcia – Cazoria A, Colomer J, Nascimento A, Ieiondo M, Compistol J. Hypotonia in the neonatal period: 12 years experience.[Article in Spanish] Rev Neurol 2013 Jan16:56 (2):72-8

Comparison of Carbon Dioxide Laser With Surgical Blade for Removal of Epulis Fissuratum. A Randomized Clinical Trial

Introduction: Epulis fissuratum is often formed as a result of a poor fitting denture. The conventional treatment for this fibrous hyperplastic tissue is to excise it using a scalpel and to close the wound by a continuous or an interrupted suture. The increased utilization of lasers in dentistry also includes the utilization of carbon dioxide (CO2) lasers in place of surgical scalpels in soft tissue surgeries. The objective of this study is to assess the feasibility of utilizing CO2 laser in place of scalpel in surgical treatment of epulis fissuratum.Methods:In this clinical trial research (IRCT code: IRCT2016071124969N2), 19 patients were selected with nearly symmetrical epulis fissuratums in the anterior part of the jaws. The hyperplastic tissue was evenly divided into two sections in each patient. One section was randomly selected and cut by CO2 laser and the other section by a surgical scalpel. The wound created by the scalpel was closed by appropriate number of interrupted sutures. Surgery duration and bleeding as well as vestibular depth, re-epithelialization and edema in both sections were noted and recorded after 7 and 14 days postoperatively.Results:The time of surgery and the amount of bleeding during surgery in the laser section was less and the vestibular depth was more than surgical scalpel section (P < 0.05). Surgical scalpel wound at day seventh healed significantly better than the section treated by the CO2 laser (P< 0.05). Wound in both sections healed similarly on day 14 and no statistical difference was observed. Edema presence was also equal in both sides after 7th and 14th following the surgery.Conclusion:According to the results it could be concluded that the use of CO2 laser may result in less surgery time, less bleeding during surgery, more vestibular depth, better re-epithelialization of the wound and less need for suturing. CO2 laser may be a clinically preferred method for surgical treatment of epulis fissuratum

Increased expression of stemness genes Rex-1, Oct-4, Nanog, and Sox-2 in women with ovarian endometriosis versus normal endometrium: A case-control study

Background: Endometriosis is a common, chronic inflammatory disease which is defined as an overgrowth of endometrial tissue outside the uterine cavity. The etiology of this disease is complex and multifactorial but there is a strong evidence that supports the presence of endometrial stem cells and their possible involvement in endometriosis. Objective: In this study, we analyzed the mRNA expression of REX-1 stemness gene and reconsidered three other stemness genes SOX-2, NANOG, OCT-4 in women with endometriosis compared to normal endometrium. Materials and Methods: Ten ectopic and ten eutopic tissue samples along with 23 normal endometrium specimens were recruited in this study. The expression levels of OCT-4, NANOG, SOX-2, and REX-1 genes were evaluated by the quantitative real-time polymerase chain reaction. Results: The transcription levels of OCT-4, NANOG, and SOX-2 mRNA were significantly increased in ectopic lesions compared with eutopic and control group (p = 0.041, p = 0.035, p = 0.048), although the REX-1 mRNA increase was not significant between endometriosis and control groups. Also, there were differences in the expression level of these genes in normal endometrium during the menstrual cycles (p = 0.031, p = 0.047, p = 0.031). Conclusion: Based on our data, we confirm the dynamic role of stemness genes in proliferation and growth of normal endometrium during the menstrual cycle and conclude that differential expression n levels of these genes may contribute to the pathophysiology of endometriosis. Key words: Endometriosis, Stemness genes

Validation of the Postnatal Growth and Retinopathy of Prematurity (G-ROP) screening criteria

Background: Retinopathy of prematurity (ROP) is a leading cause of irreversible blindness in infants. The Postnatal Growth and ROP (G-ROP) study proposed new screening criteria for ROP. This study aimed to validate the G-ROP screening criteria in a group of Iranian premature infants who were treated in the neonatal intensive care unit (NICU) for at least 40 days. Methods: In this retrospective study, we extracted the data pertaining to infants admitted to the NICU from January 2020 to December 2021. We screened all the included infants for ROP based on the Iranian national screening criteria. We applied the G-ROP criteria to our study population, and if no criterion was met, the infant was exempted from ROP screening. We determined the sensitivity and specificity of the G-ROP guidelines for ROP detection, along with its capacity for predicting the requirement for ROP treatment. Moreover, we compared the G-ROP guidelines with the Iranian and North American guidelines for ROP screening. Results: A total of 166 premature infants with complete datasets were included: 130 had ROP, of whom 61 were treated. There were 109 female infants (65.7%). The mean (standard deviation [SD]) birth weight and gestational age were 1080 (256) g and 28.28 (1.97) weeks, respectively. Applying the G-ROP criteria, 127 of 130 infants with ROP were identified (sensitivity, 97.69%; 95% confidence interval [CI], 95.11% – 100%), and of 36 infants without ROP, three were correctly excluded (specificity, 8.33%; 95% CI, 0% – 17.36%). The G-ROP criteria did not fail to identify infants who required treatment for ROP (sensitivity, 100%; 95% CI, 98.29 – 100) and had a specificity of 8.69% (95% CI, 2.04% – 15.34%). Although the Iranian and North American criteria had 100% sensitivity for infants with any stage of ROP, they could not detect infants without ROP (0% specificity). Conclusions: The G-ROP screening criteria had a sensitivity of 100% in identifying infants requiring treatment for ROP in our high-risk group; however, specificity was not sufficiently high. Further studies with larger numbers of referred infants could confirm a decrease in the burden of retinal examinations using these criteria