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TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint–dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 μmol/L GI50 value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3–TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.

TACC3 is an independent prognostic factor for breast cancer.

BO-264 impairs tumor growth better than SPL-B does at the same dose.

BO-264 significantly suppresses tumor growth in colon cancer models.

TACC3 level is critical for BO-264 response.

Synthesis of BO-264.

Supplementary Methods

Antibody list and primer sequences

TACC3 inhibition induces mitotic arrest, DNA damage and apoptosis in cell lines responsive to BO-264.

Çevresel kaos yüksek seviyede gürültülü, düzensiz, kalabalık ve çocukların kendilerini güvende hissetmelerini sağlayan rutinlerin eksik olduğu mikrosistemleri tanımlamaktadır. Mevcut çalışmalar ev ortamındaki kaosun yarattığı karmaşıklığın, öngörülemezliğin ve dikkat dağıtıcı uyaranların çok olmasının bilişsel esneklik, çalışma belleği ve ketleyici kontrol bileşenlerinden oluşan yönetici işlev gelişimi ile negatif yönde ilişkili olduğuna işaret etmektedir. Ancak, okul öncesi eğitim kurumlarındaki çevresel kaosun yönetici işlev becerileri ile ilişkisi ve ev ortamındaki çevresel kaos düzeyi ile olan etkileşimi daha önce incelenmemiştir. Bu çalışmanın amacı, evdeki ve okul öncesi eğitim kurumlarındaki çevresel kaos ile çocukların yönetici işlev becerileri arasındaki ilişkiyi araştırmaktır. Çalışmaya 244 okul öncesi dönemdeki çocuk (%50’si kız, Ortyaş = 60.89 ± 8.39 ay) ile bu çocukların anne ve öğretmenleri katılmıştır. Anne tarafından doldurulan Aile Çevresi Kaos Ölçeği (AÇKÖ) ve öğretmen tarafından doldurulan Erken Çocukluk Programlarında Yaşam Ölçeği (EÇPYÖ) aracılığıyla sırasıyla evdeki ve okul öncesi eğitim kurumundaki kaos düzeyi ölçülmüştür. Çocukların yönetici işlev becerileri dört görevden oluşan bir batarya kullanılarak doğrudan gözlem yöntemiyle değerlendirilmiştir. Korelasyona dayalı bulgular, evdeki ve okul öncesi eğitim kurumundaki çevresel kaos ile çocukların yönetici işlev becerileri arasında istatistiksel olarak anlamlı ve negatif yönde ilişki olduğunu ortaya koymuştur. Çevresel kaosun temel ve etkileşimli ilişkilerinin incelendiği düzenleyici değişken analizi bulguları, evdeki ve okul öncesi eğitim kurumundaki çevresel kaos arasında anlamlı düzeyde bir etkileşim olduğunu göstermiştir. Bu etkileşim, evdeki kaos düzeyi yüksek olan çocuklar için okul öncesi eğitim kurumlarındaki sakin, yapılandırılmış ve öngörülebilir bir çevrenin koruyucu rolüne; öte yandan ev ve okul öncesi eğitim ortamlarının her ikisinin de yüksek düzeyde kaos içermesinin “çifte olumsuzluk” oluşturarak çocuklar için yüksek risk yaratan bir durum olduğuna işaret etmiştir. Çalışmadan elde edilen bulgular, uygulamaya yönelik olarak çevresel kaos düzeyi yüksek koşullarda yaşayan çocukların yönetici işlevlerini desteklemeye yönelik müdahale programlarının nasıl geliştirilebileceğine dair tartışılmıştır. Environmental chaos refers to microsystems with high levels of noise, disorganization, crowding, and a lack of routines that make children feel safe. Available studies point out that home chaos-related commotion, unpredictability, and sources of distraction are negatively associated with the development of executive functions, which consist of the components of cognitive flexibility, working memory, and inhibitory control. Meanwhile, no study has yet examined the relationship between executive functions and child care chaos or the interaction between home and child care chaos. The present study aims to investigate the relationship of home and child care chaos with children’s executive functions. The participants involve 244 preschoolers (121 girls and 123 boys, Mage = 60.89 ± 8.39 months), as well as their mothers and teachers. Home and child care chaos were measured respectively by having mothers fill out the Confusion, Hubbub, and Order Scale (CHAOS; Matheny et al., 1995) and the teachers fill out the Life in Early Childhood Programs Scale (LECP; Kontos & Wachs, 2000). Children’s executive functions were assessed using the direct observation method with a battery of four tasks. The correlation-based findings reveal statistically significant and negative associations for home and child care chaos with children’s executive functions. The study conducted a moderation analysis to test the main and interactive relations of home and child care chaos, with the result showing a significant interaction between the chaos levels in both environments. These findings point to the protective role of a calm, structured, and predictable environment in child care for children with high levels of home chaos. On the other hand, high levels of environmental chaos both at home and child care pose the greatest risk for children by creating a double jeopardy. The study discusses these findings in terms of practical applications for intervention programs that aim to support the executive functions of children who are exposed to high levels of environmental chaos.

Objective: The aim of this study was to evaluate the care burden, psychological distress and psychiatric disorders of the companions of adult patients in the hospital. Method: This study is a cross-sectional descriptive study. A study questionnaire that included a sociodemographic information form, the Zarit Caregiver Burden Scale (ZCBS) and the Brief Symptom Inventory (BSI) were administered to the companions. Simple descriptive and inferential statistics were performed. The Mann-Whitney U test was used if comparisons between two independent groups were normal. Correlation coefficients and statistical significance were calculated by using the Spearman test for at least one normal nondistributed relationship. A multiple linear regression analysis was performed for determining factors associated with BSI scores. The type 1 error level was used as 5% for statistical significance. All P values of less than 0.05 were considered significant. Results: Three hundred companions were included in the study. Emotional commitment was the leading cause of companionship. The mean values of the companions’ ZCBS and BSI scores were 20.2 and 34.4, respectively. There was a moderately positive correlation (r=0.502) between the ZCBS and BSI scores, and it was statistically significant. ZCBS score were positively associated with BSI score. Conclusion: Psychological distress increases as the care burden of companions increases. Companions need more assistance from health care institutions, family members and the community. The support of health workers and family members reduced the companions’ care burden and psychological distress. Physicians working in the hospital should take into account that companions may be hidden patients.

Diagnosing of interstitial lung disease (ILD) is difficult and expensive. The standard diagnostical approaches to ILD are bronchoalveolar lavage, transbronchial lung biopsy, transbronchial lung cryobiopsy (TBLC) and surgical lung biopsy (SLB). SLB is gold standard for the confident diagnosis of ILD but because of the poor performance of the patients it's use is limited. We conducted a retrospective study to point out that TBLC plays an important role in diagnosis of ILD and has fewer complications and lower cost than awake video-assisted thoracic surgery (AVATS).132 patients who underwent TBLC and AVATS with a pre-diagnosis of ILD in our hospital between 2015 and 2020 were evaluated retrospectively. Diagnosis rates, complications and costs were recorded.There were no non-diagnostic materials in 44 patients in AVATS arm. Prolonged air leak was observed in 11(25.0%) of the patients, and six of them (13.6%) were discharged with Heimlich Valve (HV). Median length of stay in the hospital was 8 days, while average patient cost was $515.9 (415.2-2662.9) in the AVATS arm. Non-diagnostic material was obtained from 10 (11.3%) of 88 patients in TBLC arm. Six (6.8%) of them had pneumothorax, only one of them required a chest tube. No patient was discharged with HV (p=0.001). Median cost for each patient with a median hospital stay of 2.0 (1.0-21.0) (p0.001) days was $171.9 (80.8-1493.3) (p0.001).Although TBLC is behind AVATS in terms of diagnostic accuracy, it may be an alternative diagnostic tool in the diagnosis of interstitial lung disease due to its acceptable safety profile and cost-effectiveness.

Sir, Tuberculosis (TB) is the second most common fatal infectious disease, following human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS), in the adult population. Socio-economic deprivation, immigration, wars, omission of tuberculosis control programs, and HIV/AIDS epidemics have led to an increase in the incidence of tuberculosis. The World Health Organization (WHO) publishes a global tuberculosis report annually. The 2013 report stated that, in 2012, 8.6 million people developed TB, and 1.3 million people died from the disease, including 320,000 deaths among HIV-positive individuals.

WOS: 000461206800006, Objective: Bioimpedance spectroscopy (BIS) can be used to determine hypervolemia and malnutrition in chronic hemodialysis (HD) patients. In this prospective observational study, we investigated the survival predictability of impedance ratio (IR) calculated by BIS in HD patients (Clinical Trials Gov Identifier: NCT01468363). Materials and Methods: A total of 430 chronic HD patients, out of 500 prevalent chronic HD patients from the city of Zonguldak who met the inclusion criteria, were included in the study. With a mean follow-up of 32.2 +/- 14.4 months, BIS was performed in all patients. The IR percentage (IR%) was calculated by dividing the resistance values using the 200 kHz and 5 kHz impulses. Student's t-test, Cox regression analysis, and Kaplan-Meier survival analysis were performed, and a p

OBJECTIVES The effect of non-steroidal anti-inflammatory drugs (NSAID), mostly used for postoperative analgesic purposes for wound healing, is still a matter of debate. Our goal was to evaluate the effects of the most widely used NSAID and corticosteroids after surgical operations on tracheal wound healing in an experimental rat model. METHODS Thirty-nine male Wistar albino rats were included in this study. Tracheotomy was performed in 32 rats; then they were divided into 3 groups. After the first day, the animals in group 1 were treated with an NSAID (diclofenac 10 mg/kg/day) (NSAID, n = 12) for 7 days; the animals in group 2 were treated with a corticosteroid (dexamethasone, 2 × 0.1 mg/kg/day) (steroid, n = 10) for 7 days; the animals in group 3 (control, n = 10) were not given any medications. For a fourth group (histological control, n = 7), in order to evaluate normal morphological and histological characteristics, neither surgery nor medication was used. Five rats were eliminated from the study (2 rats in the NSAID group died and 3 rats in the steroid group developed local wound infections). The drop-out rate was 12.8%. Histological characteristics, inflammation, fibrosis, necrosis, neochondrogenesis, neovascularization and epithelization were evaluated in 34 rats. Non-parametric tests were used for statistical analysis. RESULTS Inflammation, vascularization and number of fibroblasts and chondrocytes were significantly higher in the control group than in the histological control group. There was some reduction in all parameters except vascularization in the NSAID group (P > 0.05). When the steroid group was compared to the NSAID group, inflammation (P 0.05) were more suppressed in the steroid group. The number of fibroblasts increased in the steroid group (P > 0.05). CONCLUSIONS Steroids and NSAID may have negative effects on tracheal wound healing, probably by suppressing inflammation and fibroblast proliferation. NSAID was mostly used postoperatively for analgesic purposes and should be avoided.

Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) is a microtubule-associated protein that is localized on mitotic spindles and ensures proper chromosomal segregation and microtubule stability. TACC3 is frequently amplified or mutated, and was demonstrated to be a prognostic factor in a broad spectrum of cancers which makes it a highly attractive therapeutic target. TACC3 knockdown was demonstrated to cause mitotic spindle defects and prevent proper mitotic progression causing apoptotic cell death. Inhibition of TACC3 with the currently available small molecule inhibitors, KHS101 and SPL-B, has been shown to reduce the growth of glioblastoma xenografts, and suppress tumor growth in ovarian cancer xenografts, respectively. However, none of these TACC3 inhibitors is being tested in clinics potentially due to low systemic stability or high IC50 (inhibitory concentration 50) values. Here, by combining rational drug design and screening approaches, we aimed to identify a novel and more potent TACC3 inhibitor that is effective in in vitro and in vivo systems and that can be used as a mitotic blocker in breast cancer (BC). A library of test compounds was generated by replacing certain functional groups of already available TACC3 inhibitors with their isosteric equivalents to improve potency and drug-like properties. Then, the generated compounds were tested in vitro in terms of growth inhibition in a panel of breast cancer cell lines of different breast cancer subtypes. The compounds were also compared based on their effect on the cellular processes that TACC3 is involved in, and were further compared with genomic TACC3 inhibition by siRNAs. Finally, the most promising agent was tested in vivo in terms of its anti-tumorigenic effects. BO-264 was identified as the most potent TACC3 inhibitor that effectively kills breast cancer cells of different subtypes when administered at nanomolar dose. Moreover, it demonstrated superior inhibitory effects on mitotic progression, DNA repair, and cellular viability as compared to currently available inhibitors. Oral administration of BO-264 suppressed tumor growth in breast cancer xenografts at a dose that caused no apparent toxicity. Specificity of BO-264 to TACC3 protein was tested by kinome profiling and further validated by state-of-art binding assays. Currently, we are testing the pharmacokinetics and pharmacodynamics properties and organ toxicity of our inhibitor and performing the detailed molecular characterization of BO-264-mediated anti-tumor effects. Overall, our preclinical findings suggest that our novel compound (BO-264) is potentially a specific TACC3 inhibitor, causing growth inhibition in breast cancer cell lines and xenograft models by inducing mitotic arrest, DNA damage and apoptosis. Considering the critical importance of TACC3 as a cancer biomarker and driver of disease progression, BO-264 has great potential to be used as a novel therapeutic strategy in BC. Citation Format: Ozge Akbulut, Deniz Lengerli, Ozge Saatci, Elif Duman, Urartu Seker, Burcu Caliskan, Erden Banoglu, Ozgur Sahin. A novel TACC3 inhibitor as an anti-cancer agent in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3871.

Background: This study aims to evaluate the outcomes of sublobar resections in patients with early-stage non-small cell lung cancer and to investigate the factors affecting survival. Methods: Medical files of a total of 63 patients (52 males, 11 females; mean age 64 years; range, 39 to 81 years) who underwent sublobar resection for suspected or known early-stage non-small cell lung cancer between January 2001 and August 2013 were retrospectively reviewed. Data including demographic characteristics of the patients, comorbid conditions, smoking status, surgical margin, visceral pleura invasion, distance from surgical margin to tumor, tumor size, pathological N status, cell type, tumor localization, and recurrences were recorded. Results: Survival was significantly longer in the patients with negative surgical margin for tumor (R0) than in those with positive margin (R1) (94.1 months vs. 32.2 months, p

Many synthetic materials are being used in order to reduce the frequency of prolonged air leak (PAL) in thoracic surgical practice. This study presents our experience with the topical application of acrylate co-monomer (Glubran-2) as a synthetic tissue adhesive in an attempt to decrease troublesome postoperative air leaks in patients undergoing resection for non-small cell lung carcinoma. Of the 112 patients who had undergone resection for lung carcinoma, 69 patients having lobectomy or bilobectomy were included in this study. The application group (group A) consisted of 33 patients where a synthetic tissue adhesive (Glubran-2) was used and compared with the control group (group C, n = 36) retrospectively. There was no difference between the groups regarding demographic details and operative variables. Both groups were compared in view to PAL, chest tube duration, in-hospital stay and hospital costs. There was no significant difference between group A (n = 11, 33 %) and group C (n = 6, 17 %) for the development of PAL (P = 0.11). Hospital stay was 16.1 ± 6.7 days in group A and 15.3 ± 5.8 days in group C (P = 0.66). The surgical cost was significantly higher in group A (€806 ± 127) than the group C (€624 ± 94) (P

Chylothorax is accumulation of chyle in the pleural cavity due to disruption of the thoracic duct. The causes can be classified as neoplastic, traumatic (iatrogenic or noniatrogenic), congenital, sporadic, spontaneous, and miscellaneous. A 22-year-old man with no feature in his history and family history was referred to emergency department with the case of falling from height. Abdominal computed tomogram (CT) revealed laceration of liver, grade 5 splenic laceration, fracture of the left acetabulum, and dislocation of the left hip. He was optimized for emergency splenectomy and close left hip reduction. On the 2nd day of the operation, bilateral chylotorax revealed. The treatment depends on its etiology, the amount of drainage, and the clinical picture. Treatment can be classified into 3 categories treatment of the underlying condition, conservative management (such as bed rest, nil by mouth or low fat medium chain triglycerides by mouth and total parenteral nutrition), and surgical management by ligation or clipping of the thoracic duct with open thoracotomy or video-assisted thoracoscopic surgery. The main purpose of surgical treatment is to stop the chylous leak.

Purpose of this study is to find out whether strategically oriented human resource management will lead a difference in the financial performance of company. In this study a company is accepted as strategically oriented if it provides two conditions; the company must declare their general vision, mission and values and besides the company must declare their human resource vision, mission, strategies, values and policies to their shareholders in their websites. With respect to built up model in the research, performance indicators such as pre-tax profits/ sales, pre –tax profit/ net assets, sales from production/ net assets, and gross value added/ net assets constitute the dependent variables of the research. On the other hand, independent variables are company’s general vision, mission and values, and also human resource vision, mission and values, and strategies and policies. Research population is composed of entirety of companies that take place in the 2006 list of Turkey’s Top 500 Industrial Enterprises (ISO 500). As a result of hypothesis testing, analyzed relationships are found as statistically insignificant.