Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

Polarisation vision in the dark: green-sensitive photoreceptors in the nocturnal ball-rolling dung beetle Escarabaeus satyrus.

Many insects utilise the polarisation pattern of the sky to adjust their travelling directions. The extraction of directional information from this sky-wide cue is mediated by specialised photoreceptors located in the dorsal rim area (DRA). While this part of the eye is known to be sensitive to the ultraviolet, blue or green component of skylight, the latter has only been observed in insects active in dim light. To address the functional significance of green polarisation sensitivity, we define the spectral and morphological adaptations of the DRA in a nocturnal ball-rolling dung beetle-the only family of insects demonstrated to orient to the dim polarisation pattern in the night sky. Intracellular recordings revealed polarisation-sensitive green photoreceptors in the DRA of Escarabaeus satyrus. Behavioural experiments verified the navigational relevance of this finding. To quantify the adaptive value of green sensitivity for celestial orientation at night, we also obtained the polarisation properties of the night sky in the natural habitat of the beetle. Calculations of relative photon catch revealed that under a moonlit sky the green-sensitive DRA photoreceptors can be expected to catch an order of magnitude more photons compared with the UV-sensitive photoreceptors in the main retina. The green-sensitive photoreceptors - which also show a range of morphological adaptations for enhanced sensitivity - provide E. satyrus with a highly sensitive system for the extraction of directional information from the night sky.

multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results.

Genome-wide association studies (GWAS) have successfully identified over two hundred thousand genotype-trait associations. Yet some challenges remain. First, complex traits are often associated with many single nucleotide polymorphisms (SNPs), most with small or moderate effect sizes, making them difficult to detect. Second, many complex traits share a common genetic basis due to 'pleiotropy' and and though few methods consider it, leveraging pleiotropy can improve statistical power to detect genotype-trait associations with weaker effect sizes. Third, currently available statistical methods are limited in explaining the functional mechanisms through which genetic variants are associated with specific or multiple traits. We propose multi-GPA-Tree to address these challenges. The multi-GPA-Tree approach can identify risk SNPs associated with single as well as multiple traits while also identifying the combinations of functional annotations that can explain the mechanisms through which risk-associated SNPs are linked with the traits. First, we implemented simulation studies to evaluate the proposed multi-GPA-Tree method and compared its performance with existing statistical approaches. The results indicate that multi-GPA-Tree outperforms existing statistical approaches in detecting risk-associated SNPs for multiple traits. Second, we applied multi-GPA-Tree to a systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and to a Crohn's disease (CD) and ulcertive colitis (UC) GWAS, and functional annotation data including GenoSkyline and GenoSkylinePlus. Our results demonstrate that multi-GPA-Tree can be a powerful tool that improves association mapping while facilitating understanding of the underlying genetic architecture of complex traits and potential mechanisms linking risk-associated SNPs with complex traits.

GPA-Tree: statistical approach for functional-annotation-tree-guided prioritization of GWAS results.

MOTIVATION: In spite of great success of genome-wide association studies (GWAS), multiple challenges still remain. First, complex traits are often associated with many single nucleotide polymorphisms (SNPs), each with small or moderate effect sizes. Second, our understanding of the functional mechanisms through which genetic variants are associated with complex traits is still limited. To address these challenges, we propose GPA-Tree and it simultaneously implements association mapping and identifies key combinations of functional annotations related to risk-associated SNPs by combining a decision tree algorithm with a hierarchical modeling framework. RESULTS: First, we implemented simulation studies to evaluate the proposed GPA-Tree method and compared its performance with existing statistical approaches. The results indicate that GPA-Tree outperforms existing statistical approaches in detecting risk-associated SNPs and identifying the true combinations of functional annotations with high accuracy. Second, we applied GPA-Tree to a systemic lupus erythematosus (SLE) GWAS and functional annotation data including GenoSkyline and GenoSkylinePlus. The results from GPA-Tree highlight the dysregulation of blood immune cells, including but not limited to primary B, memory helper T, regulatory T, neutrophils and CD8+ memory T cells in SLE. These results demonstrate that GPA-Tree can be a powerful tool that improves association mapping while facilitating understanding of the underlying genetic architecture of complex traits and potential mechanisms linking risk-associated SNPs with complex traits. AVAILABILITY AND IMPLEMENTATION: The GPATree software is available at https://dongjunchung.github.io/GPATree/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A snapshot of pediatric inpatients and outpatients with COVID-19: a point prevalence study from Turkey.

This multi-center point prevalence study evaluated children who were diagnosed as having coronavirus disease 2019 (COVID-19). On February 2nd, 2022, inpatients and outpatients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were included in the study from 12 cities and 24 centers in Turkey. Of 8605 patients on February 2nd, 2022, in participating centers, 706 (8.2%) had COVID-19. The median age of the 706 patients was 92.50 months, 53.4% were female, and 76.7% were inpatients. The three most common symptoms of the patients with COVID-19 were fever (56.6%), cough (41.3%), and fatigue (27.5%). The three most common underlying chronic diseases (UCDs) were asthma (3.4%), neurologic disorders (3.3%), and obesity (2.6%). The SARS-CoV-2-related pneumoniae rate was 10.7%. The COVID-19 vaccination rate was 12.5% in all patients. Among patients aged over 12 years with access to the vaccine given by the Republic of Turkey Ministry of Health, the vaccination rate was 38.7%. Patients with UCDs presented with dyspnea and pneumoniae more frequently than those without UCDs (p < 0.001 for both). The rates of fever, diarrhea, and pneumoniae were higher in patients without COVID-19 vaccinations (p = 0.001, p = 0.012, and p = 0.027).  Conclusion: To lessen the effects of the disease, all eligible children should receive the COVID-19 vaccine. The illness may specifically endanger children with UCDs. What is Known: • Children with COVID-19 mainly present with fever and cough, as in adults. • COVID-19 may specifically threaten children with underlying chronic diseases. What is New: • Children with obesity have a higher vaccination rate against COVID-19 than children without obesity. • Among unvaccinated children, fever and pneumoniae might be seen at a higher ratio than among vaccinated children.

Evaluation of 601 children with multisystem inflammatory syndrome (Turk MISC study).

PURPOSE: Due to its link with the 2019 coronavirus, the multisystem inflammatory syndrome in children (MISC) has garnered considerable international interest. The aim of this study, in which MISC patients were evaluated multicenter, and the data of the third period of the Turk-MISC study group, to compare the clinical and laboratory characteristics and outcomes of MISC patients who did and did not require admission to an intensive care unit (ICU). METHODS: This retrospective multicenter observational study was carried out between June 11, 2021, and January 01, 2022. The demographics, complaints, laboratory results, system involvements, and outcomes of the patients were documented. RESULTS: A total of 601 patients were enrolled; 157 patients (26.1%) required hospitalization in the intensive care unit (ICU). Median age was 8 years (interquartile range (IQR) 4.5-11.3 years. The proportion of Kawasaki disease-like features in the ICU group was significantly higher than in the non-ICU group (56.1% vs. 43.2% p = 0.006). The ICU group had considerably lower counts of both lymphocytes and platelets (lymphocyte count 900 vs. 1280 cells × µL, platelet count 153 vs. 212 cells × 103/ µL, all for p< 0.001). C-reactive protein, procalcitonin, and ferritin levels were significantly higher in the ICU group (CRP 164 vs. 129 mg/L, procalcitonin 9.2 vs. 2.2 µg/L, ferritin 644 vs. 334 µg/L, all for p< 0.001). Being between ages 5-12 and older than 12 increased the likelihood of hospitalization in the ICU by four [95% confidence intervals (CI)1.971-8.627] and six times (95% CI 2.575-14.654), respectively, compared to being between the ages 0-5. A one-unit increase in log D-dimer (µg/L) and log troponin (ng/L) was also demonstrated to increase the need for intensive care by 1.8 (95% CI 1.079-3.233) and 1.4 times (95% CI 1.133-1.789), respectively.     Conclusion: By comparing this study to our other studies, we found that the median age of MISC patients has been rising. Patients requiring an ICU stay had considerably higher levels of procalcitonin, CRP, and ferritin but significantly lower levels of lymphocyte and thrombocyte. In particular, high levels of procalcitonin in the serum might serve as a valuable laboratory marker for anticipating the need for intensive care. WHAT IS KNOWN: • Lymphopenia and thrombocytopenia were an independent predictor factors in patients with MISC who needed to stay in intensive care unit. • The possibility of the need to stay in the intensive care unit in patients with MISC who had Kawasaki disease-like findings was controversial compared with those who did not. WHAT IS NEW: • A one-unit increase log D dimer and log troponin was demonstrated to require for intensive care unit by 1.8 and 1.4 times, respectively. • Serum procalcitonin levels had the best performance to predict stay in the intensive care unit stay.

Does prolonged prone position affect intracranial pressure? prospective observational study employing Optic nerve sheath diameter measurements.

BACKGROUND: Our aim in this observational prospective study is to determine whether the prone position has an effect on intracranial pressure, by performing ultrasound-guided ONSD (Optic Nerve Sheath Diameter) measurements in patients with acute respiratory distress syndrome (ARDS) ventilated in the prone position. METHODS: Patients hospitalized in the intensive care unit with a diagnosis of ARDS who were placed in the prone position for 24 h during their treatment were included in the study. Standardized sedation and neuromuscular blockade were applied to all patients in the prone position. Mechanical ventilation settings were standardized. Demographic data and patients' pCO2, pO2, PaO2/FiO2, SpO2, right and left ONSD data, and complications were recorded at certain times over 24 h. RESULTS: The evaluation of 24-hour prone-position data of patients with ARDS showed no significant increase in ONSD. There was no significant difference in pCO2 values either. PaO2/FiO2 and pO2 values demonstrated significant cumulative increases at all times. Post-prone SPO2 values at the 8th hour and later were significantly higher when compared to baseline (p < 0.001). CONCLUSION: As a result of this study, it appears that the prone position does not increase intracranial pressure during the first 24 h and can be safely utilized, given the administration of appropriate sedation, neuromuscular blockade, and mechanical ventilation strategy. ONSD measurements may increase the safety of monitoring in patients ventilated in the prone position.

Antibiotic associated diarrhea in outpatient pediatric antibiotic therapy.

BACKGROUND: Antibiotic-associated diarrhea is one of the most frequent side effects of antimicrobial therapy. We assessed the epidemiological data of antibiotic-associated diarrhea in pediatric patients in our region. METHODS: The prospective multi-center study included pediatric patients who were initiated an oral antibiotic course in outpatient clinics and followed in a well-established surveillance system. This follow-up system constituded inclusion of patient by the primary physician, supply of family follow-up charts to the family, passing the demographics and clinical information of patient to the Primary Investigator Centre, and a close telephone follow-up of patients for a period of eight weeks by the Primary Investigator Centre. RESULTS: A result of 758 cases were recruited in the analysis which had a frequency of 10.4% antibiotic-associated diarrhea. Among the cases treated with amoxicillin-clavulanate 10.4%, and cephalosporins 14.4% presented with antibiotic-associated diarrhea. In the analysis of antibiotic-associated diarrhea occurrence according to different geographical regions of Turkey, antibiotic-associated diarrhea episodes differed significantly (p = 0.014), particularly higher in The Eastern Anatolia and Southeastern Anatolia. Though most commonly encountered with cephalosporin use, antibiotic-associated diarrhea is not a frequent side effect. CONCLUSION: This study on pediatric antibiotic-associated diarrhea displayed epidemiological data and the differences geographically in our region.

Effectiveness of Training: Airway Management of Tracheostomized Pediatric Patients by Pediatric Residents and Anesthesiology Residents.

To evaluate the effect of training on increasing baseline knowledge of pediatrics and anesthesia residents about airway management of pediatric patients with tracheostomy. It is a prospective, descriptive, before and after survey study. A questionnaire was conducted to measure the baseline knowledge of pediatrics and anesthesia residents about airway management in patients with pediatric tracheotomy. The same questionnaire was repeated after the education. Of the 63 participants, 42 were pediatric residents and 21 were anesthesiology residents. While the number of participants who answered the cuff part, inner cannula part, obturator part and balloon part of the tracheostomy tube correctly before the training was 27, 4, 10, and 12, respectively, these numbers increased to 53, 52, 57, and 55 after the training. There was a statistically significant improvement after the training in the correct response of the cuff, inner cannula, obturator, and balloon sections. A statistically significant improvement was observed in the answers received after the training for all 7 questions regarding the clinical scenario of accidental decannulation and tracheostomy bleeding compared to the pre-training. There was a statistical improvement in part where the participants rated themselves. In conclusion, training increases the ability of healthcare professionals to cope with life-threatening complications related to pediatric tracheotomy. A standardized education program on pediatric tracheostomy should be included in the routine programs of associated departments such as emergency medicine, anesthesia, and pediatrics residencies.

Evaluation of the effects of three natural products and a hemostatic agent on wound healing: an experimental study.

BACKGROUND: People have used many natural materials such as plant leaves, roots, liquids derived from plants, and animal products to treat wounds throughout history. It can be said that the research on wound care in recent years have focused on traditional and natural products again. This study aimed to investigate the effects of sweetgum oil, propolis, silk protein, and Ankaferd Blood Stopper (ABS) on wound healing in an experimental excisional wound model. METHODS: : Including 36 Balb/c inbreed mice in the study were divided equally into four groups. Two circular excisional wounds were created on the dorsal skin of mice under anesthesia using a punch biopsy device. The wounds of the first group of mice were topically dressed with sweetgum oil, the second group mice with propolis, the third group mice with silk protein, and the fourth group mice with ABS daily. Tissue samples were taken from the wounds of mice on the 7th and 14th day of wound formation, and histological examinations were performed. On the 14th day, the wounds created in all mice were healed, and the experiment was terminated. RESULTS: Mice in the silk protein group had faster wound healing. There was no statistical difference between the groups in immunohistochemical examinations. In the ABS group, the findings of the inflammatory process were more prominent. DISCUSSION: In conclusions, propolis, sweetgum oil, silk protein, and ABS positively affect different parameters in wound healing and support wound healing.

Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia.

Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged <60 years) with CN-AML, who were comprehensively characterized with regard to clinical outcome. We used available genomic databases and stringent filters to annotate genetic variants unequivocally located in the non-coding transcriptome of AML patients. We detected 981 variants, which are recurrently present in lncRNA that are expressed in leukemic blasts. Among these variants, we identified a cytosine-to-thymidine variant in the lncRNA RP5-1074L1.4 and a cytosine-to-thymidine variant in the lncRNA SNHG15, which independently associated with longer survival of CN-AML patients. The presence of the SNHG15 cytosine-to-thymidine variant was also found to associate with better outcome in an independent dataset of CN-AML patients, despite differences in treatment protocols and RNA sequencing techniques. In order to gain biological insights, we cloned and overexpressed both wild-type and variant versions of the SNHG15 lncRNA. In keeping with its negative prognostic impact, overexpression of the wild-type SNHG15 associated with higher proliferation rate of leukemic blasts when compared with the cytosine-to-thymidine variant. We conclude that recurrent genetic variants of lncRNA that are expressed in the leukemic blasts of CN-AML patients have prognostic and potential biological significance.

The interplay of directional information provided by unpolarised and polarised light in the heading direction network of the diurnal dung beetle Kheper lamarcki.

The sun is the most prominent source of directional information in the heading direction network of the diurnal, ball-rolling dung beetle Kheper lamarcki. If this celestial body is occluded from the beetle's field of view, the distribution of the relative weight between the directional cues that remain shifts in favour of the celestial pattern of polarised light. In this study, we continue to explore the interplay of the sun and polarisation pattern as directional cues in the heading direction network of K. lamarcki. By systematically altering the intensity and degree of the two cues, we effectively change the relative reliability as they appear to the dung beetle. The response of the beetle to these modifications allows us to closely examine how the weighting relationship of these two sources of directional information is influenced and altered in the heading direction network of the beetle. We conclude that the process by which K. lamarcki relies on directional information is very likely done based on Bayesian reasoning, where directional information conveying the highest certainty at a particular moment is afforded the greatest weight.

Genetic analysis of a malignant meningioma and associated metastases.

To identify genes altered in a highly aggressive metastatic meningioma primary as well as its metastases. Exome sequencing of a primary anaplastic meningioma and metastatic lesions in which DNA could be extracted and compared to germline DNA. Genetic analysis of the metastatic sites found 31 common mutations among the primary tumor and two metastatic sites. Additionally, genetic mutations were identified which were either infrequently (MUC3A, ALDH1A3, HOXA1) or not at all previously described in meningiomas (CASS4, CMKLR1). Exome sequencing of a metastatic meningioma and its distant metastases outside the CNS identified mutations that were not previously well described.

Multiple sclerosis attack case presenting with pseudo-vestibular neuritis.

PURPOSE: Pseudo-vestibular neuritis is a clinical diagnosis for patients presenting with acute vestibular syndrome due to a central pathology. CASE REPORT: We reported a case of multiple sclerosis characterized by pseudo-vestibular neuritis. Our case was a 32-year-old male patient. The patient, who was diagnosed with multiple sclerosis in September 2019, came to the emergency clinic in January 2020 with the complaint of severe vertigo, vomiting-nausea. A newly developed demyelinating plaque was detected in the left vestibular nucleus in cranial MRI. The patient had no hearing loss. On examination of the patient, nystagmus findings supporting peripheral vestibular involvement were present on the left side. Neurologic examination showed left-sided hyperactive deep tendon reflexes, Achilles clonus, dysmetria, ataxia to the left and plantar reflex with extensor response on the left. Video head impulse test and cervical evoked myogenic potential tests were performed. Vestibular hypofunction was present on the left side. Steroid pulse therapy was administered as 1000 mg/day, i.v for 7 days. After treatment, his complaints decreased. In addition, there was an improvement in examination findings. CONCLUSION: Multiple sclerosis is shown to be an etiological factor in patients with pseudo-vestibular neuritis.

Comparison of pregnant women's anxiety, depression and birth satisfaction based, on their traumatic childbirth perceptions.

This study was conducted to identify and compare pregnant women's anxiety, depression, and birth satisfaction levels based on their traumatic childbirth perceptions. This study used a cross-sectional design. The data were collected at two stages, namely, the prenatal and postpartum stages. First, the Traumatic Childbirth Perception Scale, the Beck Anxiety Inventory, and the Beck Depression Inventory were applied to the pregnant women. Next, in the postpartum period, the Childbirth Information Form and the Birth Satisfaction Scale-Revised were applied. It was found that the participants with high levels of traumatic childbirth perception had higher mean anxiety and depressive symptom scores (26.13 ± 11.30 and 16.16 ± 9.02, respectively), whereas the participants with low levels of traumatic childbirth perception had a higher mean birth satisfaction score (17.50 ± 4.91). The findings indicated that high levels of traumatic childbirth perception may lead to have anxiety and depression, while low levels of traumatic childbirth perception may enhance their birth satisfaction. IMPACT STATEMENTWhat is already known on this subject? In the literature, it is stated that the perception of a traumatic birth can lead to permanent or long-term negative consequences in women's lives, negatively affecting their future health, subsequent birth experiences, and family relationships.What do the results of this study add? In this study, 37.7% of the participants were found to have high levels of traumatic childbirth perception. It was determined that the anxiety and depression levels of the participants with high levels of perception of traumatic birth were higher, and the levels of birth satisfaction were higher in the pregnant women with low levels of perception of traumatic birth. The results indicated that severe depressive symptoms, severe anxiety, and low levels of birth satisfaction were likely to raise traumatic childbirth perception levels in pregnant women.What are the implications of these findings for clinical practice and/or further research? The care to be given under the leadership of midwifery professionals is important in terms of reducing pregnant women's perceptions of a traumatic birth, anxiety, and depression levels and increasing their levels of birth satisfaction.

Investigating the relationship between the depression levels of midwives and nurses and their emotional labor and secondary traumatic stress levels in the COVID-19 pandemic period with structural equation modelling.

In this study, it was aimed to investigate the relationship between depression levels in midwives and nurses and their emotional labor and secondary traumatic stress levels in the COVID-19 pandemic process structural equation modelling. This cross-sectional study was conducted with 313 midwives and nurses. According to the model formed based on the presence of depression, as the Emotional Labor scores of the participants increased, their Beck Depression scores decreased 0.947-fold, while as their Secondary Traumatic Stress Scale scores increased, their Beck Depression scores increased 1.116-fold. It was determined that the scores of the participants in the Emotional Labor and Secondary Traumatic Stress Scales explained 42.8% of their Beck Depression Inventory scores. It was concluded that the depression statuses of the participants were affected by their emotional labor and secondary traumatic stress statuses.

Can Ultrasound-Guided Femoral Vein Measurements Predict Spinal Anesthesia-Induced Hypotension in Non-Obstetric Surgery? A Prospective Observational Study.

Background and objectives: To investigate whether ultrasound (US)-guided femoral vein (FV) and inferior vena cava (IVC) measurements obtained before spinal anesthesia (SA) can be utilized to predict SA-induced hypotension (SAIH) and to identify risk factors associated with SAIH in patients undergoing non-obstetric surgery under SA. Methods: This was a prospective observational study conducted between November 2021 and April 2022. The study included 95 patients over the age of 18 with an American Society of Anesthesiologists (ASA) physical status score of 1 or 2. The maximum and minimum diameters of FV and IVC were measured under US guidance before SA initiation, and the collapsibility index values of FV and IVC were calculated. Patients with and without SAIH were compared. Results: SAIH was observed in 12 patients (12.6%). Patients with and without SAIH were similar in terms of age [58 (IQR: 19-70) vs. 48 (IQR: 21-71; p = 0.081) and sex (males comprised 63.9% of the SAIH and 75.0% of the non-SAIH groups) (p = 0.533). According to univariate analysis, no significant relationship was found between SAIH and any of the FV or IVC measurements. Multiple logistic regression analysis revealed that having an ASA class of 2 was the only independent risk factor for SAIH development (p = 0.014), after adjusting for age, sex, and all other relevant parameters. Conclusions: There is not enough evidence to accept the feasibility of utilizing US-guided FV or IVC measurements to screen for SAIH development in patients undergoing non-obstetric surgery under SA. For this, multicenter studies with more participants are needed.

Synergistic Induction of Apoptosis by Quercetin and Curcumin in Chronic Myeloid Leukemia (K562) Cells: II. Signal Transduction Pathways Involved.

Flavonoids are phenolic substances with chemo-preventive and chemotherapeutic properties. They are widely found in fruits and vegetables. The polyphenols quercetin and curcumin have antioxidant, anti-inflammatory, anti-carcinogenic, and pro-apoptotic properties. They were successfully used against different human cancers, especially chronic myeloid leukemia cancer cells. We have previously investigated anti-proliferative and apoptotic effects of quercetin and curcumin combination in K562 cells. Our data showed that they had beneficial synergistic effects. Based on these findings, we aimed to clarify signaling pathways involved in synergistic combination treatment with quercetin and curcumin in these cells. Proteins were investigated by Western blotting and by confocal microscopy. Changes in several genes in 10 different pathways related to cell proliferation, apoptosis, cell cycle, inflammation, hypoxia and oxidative stress were observed. Combination of quercetin and curcumin was effective on genes that were particularly related to p53, NF-κB and TGF-α pathways. Down-regulatory (CDKN1B, AKT1, IFN-γ) and up-regulatory (BTG2, CDKN1A, FAS) effects on genes and related protein expressions may provide a multi-targeted therapy potential for chronic myeloid leukemia cancer cells without affecting healthy cells.

The Turkish validity and reliability study of the London measure of unplanned pregnancy.

AIM: This study aims to adapt the London Measure of Unplanned Pregnancy (LMUP) developed by Barrett et al. to Turkish by checking its validity and reliability. METHOD: The sample of this methodological study consisted of 596 pregnant women who were referred to the antenatal outpatient clinics of a public hospital in eastern Turkey. Data were collected from those who agreed to participate in the study, by using a personal information form and the six-item LMUP. Data were analyzed using SPSS 25.0 and AMOS 24.0 statistical package programs, and statistically assessed using descriptive statistics such as number, percentage, mean and SD, language and content validity, explanatory factor analysis (EFA), confirmatory factor analysis (CFA), Cronbach's α reliability coefficient, and test-retest analysis. RESULTS: The EFA revealed that the Turkish version of the LMUP consisted of five items and one factor. The items' factor loadings were above 0.30, and explained 68.89% of the total variance. The CFA supported the one-factor structure of the scale, which was revealed by the EFA. As a result of the CFA, the fit indices were found to be very good. The Cronbach's α coefficient of the scale was determined as 0.90. CONCLUSION: The Turkish version of the LMUP is a valid and reliable instrument to evaluate unplanned pregnancy.

hsa-miR-9-3p and hsa-miR-9-5p as Post-Transcriptional Modulators of DNA Topoisomerase IIα in Human Leukemia K562 Cells with Acquired Resistance to Etoposide.

DNA topoisomerase IIα protein (TOP2α) 170 kDa (TOP2α/170) is an important target for anticancer agents whose efficacy is often attenuated by chemoresistance. Our laboratory has characterized acquired resistance to etoposide in human leukemia K562 cells. The clonal resistant subline K/VP.5 contains reduced TOP2α/170 mRNA and protein levels compared with parental K562 cells. The aim of this study was to determine whether microRNA (miRNA)-mediated mechanisms play a role in drug resistance via decreased expression of TOP2α/170. miRNA-sequencing revealed that human miR-9-3p and miR-9-5p were among the top six of those overexpressed in K/VP.5 compared with K562 cells; validation by quantitative polymerase chain reaction demonstrated overexpression of both miRNAs. miRNA recognition elements (MREs) for both miRNAs are present in the 3'-untranslated region (UTR) of TOP2α/170. Transfecting K562 cells with a reporter plasmid harboring the TOP2α/170 3'-UTR together with either miR-9-3p or miR-9-5p mimics resulted in a statistically significant decrease in luciferase expression. Mutating the miR-9-3p or miR-9-5p MREs prevented this decrease, demonstrating direct interaction between these miRNAs and TOP2α/170 mRNA. Transfection of K562 cells with miR-9-3p or miR-9-5p mimics led to decreased TOP2α/170 protein levels without a change in TOP2α/170 mRNA and resulted in attenuated etoposide-induced DNA damage (gain-of-miRNA-inhibitory function). Conversely, transfection of miR-9-3p or miR-9-5p inhibitors in K/VP.5 cells (overexpressed miR-9 and low TOP2α/170) led to increased TOP2α/170 protein expression without a change in TOP2α/170 mRNA levels and resulted in enhancement of etoposide-induced DNA damage (loss-of-miRNA-inhibitory function). Taken together, these results strongly suggest that these miRNAs play a role in and are potential targets for circumvention of acquired resistance to etoposide. SIGNIFICANCE STATEMENT: Results presented here indicate that miR-9-3p and miR-9-5p decrease DNA topoisomerase IIα protein 170 kDa expression levels in acquired resistance to etoposide. These findings contribute new information about and potential strategies for circumvention of drug resistance by modulation of microRNA levels. Furthermore, increased expression of miR-9-3p and miR-9-5p in chemoresistant cancer cells may support their validation as biomarkers of responsiveness to DNA topoisomerase II-targeted therapy.