bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison between Minimally Invasive Plate Osteosynthesis and Conventional Open Plating for Midshaft Clavicle Fractures: A Systematic Review and Meta-Analysis
Authors: Zhao Enzhe , Zhang Rui , Wu Dou , Guo Yao , Liu Qiang
Published: October 2019

Objective. The aim of this study was to compare the functional outcome and complications in midshaft clavicle fractures receiving minimally invasive plate osteosynthesis and conventional open plating. Methods. Relevant studies were searched in the databases of Medline, EMBASE, Cochrane Library, Ovid, and Web of Science from inception to March 1, 2019. Pooled data were analyzed with Cochrane Collaboration’s Review Manager 5.3. Results. A total of 7 studies were included, of which 2 were randomized controlled trials, 3 were retrospective cohort studies, and 2 were prospective cohort studies including 316 patients. No statistical differences in functional outcome (weighted mean difference [WMD] = 0.99, P=0.12), operation time (WMD = −10.44, P=0.07) and time to bone union (WMD = −0.23, P=0.70) were observed between the two groups. However, minimally invasive plate osteosynthesis reduced rates of skin numbness (odds ratio (OR) = 0.25, 95% CI : 0.13 to 0.48; P<0.0001) and complications (OR = 0.33, 95% CI : 0.16 to 0.71; P=0.005) compared with conventional open plating. Conclusion. This systematic review and meta-analysis found no differences in terms of functional outcomes, operation time, and fracture healing time between minimally invasive plate osteosynthesis and conventional open plating. However, minimally invasive plate osteosynthesis had apparent advantages in rates of skin numbness and complications.
Estimation Method of Inundation Extent Based on Mathematical Morphology
Authors: Li Jianxun , Lai Kin Keung , Safonov Paul
Published: October 2019

Estimation of inundation extent is critical for the flood control system. It helps decision‐maker determine the scope of damage to save residents’ lives and property. In this paper, we analyzed the drawbacks of two kinds of methods of inundation estimation, hydrodynamic method and space‐filling method, and divided inundation extent into water‐body extent and water‐invasion extent for the purpose of enhancing estimation accuracy. Based on Mathematical Morphology, an inundation estimation method suitable for flood mapping around natural and artificial lakes was put forward by integrating remote sensing (RS) data and digital elevation model (DEM) data. This method consists of three aspects, including the subdivision of water‐body extent, the deduction of water‐invasion extent which is viewed as the expansion of water‐body extent, and the smoothing the boundaries of water‐invasion extent. With subdividing DEM data horizontally into cross sections to build equiangular subsets, the expansion operation was implemented by structuring elements which were established based on set operations and scalar flexibilities. Thus, water‐invasion extent was easily described by the structuring elements under given water volume, so that inundation extent was conveniently estimated by spatial data. The experiment results show that the method has the advantages of high accuracy and expressiveness and low time consumption. It had been used to analyze the inundation caused by the water conservancy project named Hanjiang‐to‐Weihe River Water Transfer Project in China. The method served as decision support for building an efficient emergency response mechanism and helped implement flood disaster forecast and simulation.
Static Magnetic Field Induced Neural Stem/Progenitor Cell Early Differentiation and Promotes Maturation
Authors: Ho Shih-Yin , Chen I-Chun , Chen Yi-Jyun , Lee Chien-Hsing , Fu Chao-Ming , Liu Fei-Chih , Liou Horng-Huei
Published: October 2019

The potential impacts of magnetic field exposures on brain development have raised public concern. In the present study, we aimed to investigate the biophysical effects of moderate-intensity (0.5 T, Tesla) static magnetic field (SMF) on mice neural progenitor cells (mNPCs). Our results showed that the SMF exposure increased the number of neurosphere formation and enhanced proliferative activity in mNPCs. In addition, our flow cytometry data demonstrated that the proportions of S phase and G2/M phase mNPCs were remarkably increased following 5 days of SMF exposure. Moreover, the level of a mitotic regulatory protein, cyclin B, was upregulated after SMF exposure. Furthermore, the mNPCs exposed to SMF exhibited a significant increase in Sox2 expression. When mNPCs were induced to differentiation, our immunofluorescence assay revealed that the percentage of neurons (Tuj-1-positive cells) but not astrocyte (s100β-positive cells) was significantly higher and displayed morphological complexity in the SMF group. Finally, our electrophysiological results demonstrated the mNPC-derived neurons from the SMF group showing a significantly increased in input resistance, which indicated more functional maturation. Based on these findings, it appears reasonable to suggest that SMF exposure could affect normal neurogenesis and promote neural lineage differentiation as well as neuronal maturation.
BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents
Authors: Kanakkanthara Arun , Kurmi Kiran , Ekstrom Thomas L. , Hou Xiaonan , Purfeerst Emma R. , Heinzen Ethan P. , Correia Cristina , Huntoon Catherine J. , O'Brien Daniel , Wahner Hendrickson Andrea E. , Dowdy Sean C. , Li Hu , Oberg Ann L. , Hitosugi Taro , Kaufmann Scott H. , Weroha S. John , Karnitz Larry M.
Published: October 2019

BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression.

Significance:

Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer.
Lucitanib for the Treatment of HR+/HER2− Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study
Authors: Hui Rina , Pearson Alex , Cortes Javier , Campbell Christine , Poirot Camille , Azim Hatem A. , Fumagalli Debora , Lambertini Matteo , Daly Fergus , Arahmani Amal , Perez-Garcia José , Aftimos Philippe , Bedard Philippe L. , Xuereb Laura , Scheepers Elsemieke D. , Vicente Malou , Goulioti Theodora , Loibl Sibylle , Loi Sherene , Pierrat Marie-Jeanne , Turner Nicholas C. , Andre Fabrice , Curigliano Giuseppe
Published: October 2019

Purpose:

The FGFR1 gene is amplified in 14% of patients with HR+/HER2− breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed.

Patients and Methods:

Patients with HR+/HER2− metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 amplified, (ii) FGFR1 nonamplified, 11q13 amplified, and (iii) FGFR1 and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC.

Results:

Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%–35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%–18%) and 15% (95% CI, 6%–34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers.

Conclusions:

Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR+/HER2− MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high FGFR1 amplification or expression might derive greater benefit.
On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors
Authors: Morschhauser Franck , Machiels Jean-Pascal , Salles Gilles , Rottey Sylvie , Rule Simon A.J. , Cunningham David , Peyrade Frederic , Fruchart Christophe , Arkenau Hendrik-Tobias , Genvresse Isabelle , Liu Li , Köchert Karl , Shen Kui , Kneip Christoph , Peña Carol E. , Grevel Joachim , Zhang Jun , Cisternas Galia , Reschke Susanne , Granvil Camille , Awada Ahmad
Published: October 2019

The PI3K inhibitor copanlisib has efficacy and manageable safety in patients with indolent lymphoma and solid tumors. Pharmacodynamic effects relative to copanlisib dose and plasma exposure were evaluated. Patients with lymphoma or solid tumors received copanlisib 0.4 or 0.8 mg/kg on days 1, 8, and 15 of a 28-day cycle. Primary variables were maximum changes in phosphorylated AKT (pAKT) levels in platelet-rich plasma (PRP) and plasma glucose. Other evaluations included PI3K signaling markers and T-lymphocytes in paired tumor biopsies, the relationship between estimated plasma exposure and pharmacodynamic markers, response, and safety. Sixty-three patients received copanlisib. PRP pAKT levels showed sustained reductions from baseline following copanlisib [median inhibition: 0.4 mg/kg, 73.8% (range −94.9 to 144.0); 0.8 mg/kg, 79.6% (range −96.0 to 408.0)]. Tumor pAKT was reduced versus baseline with copanlisib 0.8 mg/kg in paired biopsy samples (P < 0.05). Dose-related transient plasma glucose elevations were observed. Estimated copanlisib plasma exposure significantly correlated with changes in plasma pAKT and glucose metabolism markers. There were two complete responses and six partial responses; seven of eight responders received copanlisib 0.8 mg/kg. Adverse events (all grade) included hyperglycemia (52.4%), fatigue (46.0%), and hypertension (41.3%). Copanlisib demonstrated dose-dependent pharmacodynamic evidence of target engagement and PI3K pathway modulation/inhibition in tumor and immune cells. Results support the use of copanlisib 0.8 mg/kg (or flat-dose equivalent of 60 mg) in solid tumors and lymphoma, and provide a biomarker hypothesis for studies of copanlisib combined with immune checkpoint inhibitors (NCT03711058).
PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages
Authors: Avasarala Sreedevi , Wu Pei-Ying , Khan Samia Q. , Yanlin Su , Van Scoyk Michelle , Bao Jianqiang , Di Lorenzo Alessandra , David Odile , Bedford Mark T. , Gupta Vineet , Winn Robert A. , Bikkavilli Rama Kamesh
Published: October 2019

Increased expression of protein arginine methyl transferase 6 (PRMT6) correlates with worse prognosis in lung cancer cases. To interrogate the in vivo functions of PRMT6 in lung cancer, we developed a tamoxifen-inducible lung-targeted PRMT6 gain-of-function mouse model, which mimics PRMT6 amplification events in human lung tumors. Lung-targeted overexpression of PRMT6 accelerated cell proliferation de novo and potentiated chemical carcinogen (urethane)-induced lung tumor growth. To explore the molecular mechanism/s by which PRMT6 promotes lung tumor growth, we used proteomics-based approaches and identified interleukin-enhancer binding protein 2 (ILF2) as a novel PRMT6-associated protein. Furthermore, by using a series of in vitro gain-of-function and loss-of-function experiments, we defined a new role for the PRMT6–ILF2 signaling axis in alternate activation of tumor-associated macrophages (TAM). Interestingly, we have also identified macrophage migration inhibitory factor, which has recently been shown to regulate alternate activation of TAMs, as an important downstream target of PRMT6–ILF2 signaling. Collectively, our findings reveal a previously unidentified noncatalytic role for PRMT6 in potentiating lung tumor progression via the alternate activation of TAMs.

Implications:

This is the first study to demonstrate an in vivo role for PRMT6 in lung tumor progression via the alternate activation of TAMs.
Increased Incidence of Thyroid Disease in Patients with Alopecia Areata: A Systematic Review and Meta-Analysis
Authors: Xin Caihong , Sun Xin , Lu Li , Yang Rong , Shan Ling , Wang Yang
Published: October 2019

Background: Alopecia areata (AA) is a common, clinically heterogeneous, immune-mediated, nonscarring hair loss disease with a pathogenesis that is not fully understood. The prevalence of thyroid disease is likely increased among individuals with AA. However, this association remains controversial. Objective: To evaluate the risk of thyroid disease in patients with AA. Methods: We performed a systematic review by searching both English and Chinese literature databases. Random- or fixed-effects models were used to summarize the association between thyroid disease and AA. Results: In total, 17 articles were included in this meta-analysis, with 2,850 AA cases and 4,667 controls. Overall, the prevalence of thyroid disease in patients with AA was significantly increased compared with that in controls (odds ratios 3.66, 95% confidence intervals 2.90–4.61). Conclusions: The results suggest that AA patients should be screened for thyroid disease.
Predictive Power of Liver Maximum Function Capacity Test in Transjugular Intrahepatic Portosystemic Shunt Patients: A Pilot Study
Authors: Reichert Matthias Christian , Schulz Antje , Massmann Alexander , Buecker Arno , Glanemann Matthias , Lammert Frank , Malinowski Maciej
Published: October 2019

Background: Transjugular intrahepatic shunt (TIPSS) is placed in patients with variceal bleeding, refractory ascites, and for other indications. Postprocedural liver function-associated complications (LFAC), including hepatic encephalopathy (HE) and liver failure, represent a major setback. Current methods to predict complications are insufficient. Objectives: We investigated in a pilot study of patients prior TIPSS placement whether the risk of LFAC correlates with the functional reserve of the liver, as assessed by liver maximum function capacity (LiMAx) test. Methods: Prospectively we included patients prior TIPSS placement between June 2016 and November 2017 at Saarland University Medical Center. LiMAx was conducted before and after TIPSS placement. Patients with HE prior TIPSS, as well as other factors predisposing to HE, including concomitant sedative drugs, current bacterial infections and sepsis, were excluded. Overt HE (OHE), LiMAx, and laboratory values were assessed before and after TIPSS placement. Data were analyzed in multivariate regression and AUROC models. Results: Mean age was 60 ± 8 years. Patients (n = 20) were mainly men (65%), and presented predominantly with Child-Pugh class B (90%). Indications for TIPSS were most commonly refractory ascites or recurrent variceal bleeding. In total, 40% of the patients developed LFAC after TIPSS placement. Expectedly, LiMAx decreased and serum bilirubin increased after TIPSS. LiMAx drop ≥20% was the only parameter predicting the development of LFAC after TIPSS in multivariate regression and AUROC analysis. Conclusions: In multivariate regression models and AUROC analysis, a drop in LiMAx predicted the development of LFAC after TIPSS placement. Additional larger studies assessing OHE and early liver failure separately are warranted.
Epicardial Fat Thickness in Children with Subclinical Hypothyroidism and Its Relationship to Subclinical Atherosclerosis: A Pilot Study
Authors: Farghaly Hekma Saad , Metwalley Kotb Abbass , Raafat Duaa Mohamed , Algowhary Magdy , Said Ghada Mohamed
Published: October 2019

Background/Aims: Thyroid hormones (TSH) play a key role in the working of the cardiovascular system, with direct effects on cardiac function, vascular system, and atherosclerotic factors. Epicardial adipose tissue, the visceral fat of the heart, has emerged as a new cardiometabolic risk marker because of its close anatomical proximity to the myocardium and coronary artery. This study aimed to evaluate epicardial fat thickness (EFT) in children with subclinical hypothyroidism (SH) and its relation to early atherosclerotic changes. Methods: The study included 32 children with SH due to autoimmune thyroiditis and 32 healthy children matched for age and gender as control group. Patients and controls underwent anthropometric evaluation and measurement of fasting lipids, glucose, insulin, homeostasis model assessment for insulin resistance and high-sensitivity C-reactive protein (hs-CRP). TSH, free thyroxine (FT4 and FT3) and antithyroid autoantibodies (antithyroid peroxidase and thyroglobulin antibodies) were also measured. Conventional echo­cardiography was used to assess EFT. Noninvasive ultrasound was used to measure carotid intima-media thickness and brachial artery flow-mediated dilation (FMD) responses. Results: Compared to controls, patients had higher atherogenic index (AI) and hs-CRP (p = 0.001 for each). Conventional echocardiography revealed that patients with SH had higher EFT (p = 01) and significantly lower FMD response compared with the control (p = 0.001). In multivariate analysis, EFT values were significantly correlated with TSH (OR 1.2; 95% CI 1.04–1.34; p = 0.01), hs-CRP (OR 1.1; 95% CI 1.09–1.14; p = 0.001, AI (OR 1.6; 95% CI 1.17–2.03; p = 0.001), and FMD response (OR 2.4; 95% CI 1.14–2.53; p = 0.01). Conclusions: Our study demonstrated that EFT is higher in children with SH compared with controls and associated with FMD responses. Measurement of EFT by echocardiography in children with SH may help to identify those at high risk of developing subclinical atherosclerosis.
Prolonged Response to Regorafenib in a Patient with Iodine Refractory Thyroid Cancer
Authors: Wong Selina K. , Chu Quincy S.C. , Spratlin Jennifer L. , Sangha Randeep , McEwan Alexander J.B. , Morrish Donald W. , Arndt Diane , Sergenson Gwen , Cleton Adriaan , Huang Funan , Sawyer Michael B.
Published: October 2019

Thyroid cancer is the most common type of endocrine malignancy. Cornerstones of thyroid cancer treatment include surgery, radioactive iodine ablation, and thyroid stimulating hormone suppression. The National Comprehensive Cancer Network guidelines recommend two tyrosine kinase inhibitors for thyroid cancer patients who are non-responsive to iodine: sorafenib and lenvatinib. Another oral kinase inhibitor, regorafenib, is not considered standard of care treatment for differentiated thyroid cancer. The chemical structures of regorafenib and sorafenib differ by a single fluorine atom. Given the significant improvement in progression-free survival (PFS) of sorafenib compared to placebo demonstrated in the phase 3 DECISION trial, we report on a patient with iodine-refractory follicular thyroid cancer treated with regorafenib as part of a phase 1 clinical trial. A 75 year old woman was diagnosed with follicular thyroid carcinoma in 2006 and initiated on treatment with regorafenib in 2011. She has completed 76 cycles with stable disease and pulmonary metastases 34% smaller than baseline.
Clinical Management of Acinic Cell Carcinoma of the Lacrimal Gland
Authors: Anesi Alexandre , Negrello Sara , Lucchetti Donatella , Pollastri Giuseppe , Trevisiol Lorenzo , Badiali Licia , Lazzerini Andrea , Cavallini Gian Maria , Chiarini Luigi
Published: October 2019

To report a case of acinic cell carcinoma occurred in the lacrimal gland. A 59-year-old man was admitted because of sudden blurring of vision, progressive proptosis of the left eye, and mild double vision in left and down directions of the gaze (Hess-Lancaster test). His medical history detailed controlled bilateral keratoconus and open angle glaucoma. On examination, the best corrected visual acuity decreased from 8/20 till 1/50 in one week. There was a swelling of the left upper eyelid. A hard and tender mass was palpated in the superior temporal left orbit. Ultrasound scan showed an extraconal solid mass, situated in the superior lateral corner of the orbit. Computed tomography and magnetic resonance imaging (MRI) revealed a mass of two centimeters in diameter, with round well-defined outline, within the lacrimal gland. We performed an enucleoresection of the mass, via a coronal approach and a lateral orbitotomy by a piezosurgical device. The lesion appeared nodular, brownish, measuring about 2 × 1.5 cm. Histopathological findings were consistent with acinic cell carcinoma with a microcystic, focally papillary-cystic growth of pattern. Follow-up MRI outcomes led to removal of the residual lacrimal gland for suspicion of recurrence. No tumor recurrences where detected at 7-year follow-up.
Paeoniflorin on Rat Myocardial Ischemia Reperfusion Injury of Protection and Mechanism Research
Authors: Wu Fubin , Ye Binhua , Wu Xiandan , Lin Xian , Li Yanyan , Wu Yongning , Tong Linping
Published: October 2019

Objective: To study the myocardial benefit effect and mechanism of paeoniflorin on myocardial ischemia reperfusion injury (MIRI) in rats. Methods: Hundred SD rats were randomly divided into 5 groups: sham group, model group, Paeoniflorin (15 mg/kg) group, Paeoniflorin (30 mg/kg) group, and Paeoniflorin (60 mg/kg) group. Myocardial ischemia reperfusion model was established in each group except the sham group. The myocardial infarction and morphological changes were measured by the TTC staining and HE staining respectively. Myocardial caspase-3 was detected by immunohistochemistry. In addition, the protein levels of Bcl-2 and Bax and the expression ratio of p-erk, p-jnk, and p-p38 were detected by Western blot. Myocardial superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were measured by the assay kit. Results: Paeoniflorin (30 mg/kg) and Paeoniflorin (60 mg/kg) can obviously alleviate myocardial infarction caused by MIRI (p < 0.05). HE staining showed that the myocardial morphology in the treatment group was obviously better than that in the model group. WB and immunohistochemistry showed that Paeoniflorin (30 mg/kg) and Paeoniflorin (60 mg/kg) can significantly increase the reduced protein level of bcl-2 (p < 0.05) and reduce the increased protein level of caspase3, bax ­p-erk, p-jnk, and p-p38 caused by MIRI (p < 0.05). The activity of SOD was increased and the level of MDA was decreased after Paeoniflorin treatment. Conclusion: Paeoniflorin preconditioning has a protective effect on MIRI in rats. Its mechanism is related to reducing oxidative stress and apoptosis by inhibiting the expression of apoptosis-related signaling pathway.
Стратегія інфузійної терапії в гострому періоді політравми з використанням неінвазивного моніторингу гемодинаміки
Authors: Matolinets N. V. , Pidhirnyi Ja. M. , Netliukh A. M.
Published: October 2019

Мета роботи: встановити ефективність неінвазивного моніторингу серцевого викиду для вибору технології інфузійної терапії в гострому періоді політравми.

Матеріали і методи. Обстежено 50 пацієнтів із політравмою, госпіталізованих у відділення анестезіології та інтенсивної терапії (ВАІТ) КНП “КЛШМД м. Львова”. Середній вік постраждалих складав (48,4±5,2) року. У 25 пацієнтів основної групи проводили моніторинг показників центральної гемодинаміки за допомогою модуля esCCO, інтегрованого в монітор пацієнта Life Scope фірми Nihon Kohden (Японія). Пацієнта вважали сприйнятливим до волемічної терапії та продовжували поповнення об’єму циркулюючої крові, якщо інфузійні болюси в об’ємі 500–1000 мл збалансованих кристалоїдних розчинів викликали достовірне підвищення серцевого викиду і ударного об’єму. У контрольній групі (n=25) для порівняльного аналізу реєстрували тільки традиційні показники – артеріальний тиск (АТ), ЕКГ, насичення крові киснем (сатурація крові – SpO2) за допомогою багатофункціональних моніторів Philips IntelliVue (MP20).

Результати досліджень та їх обговорення. У пацієнтів основної групи добовий об’єм інфузії був меншим і склав (4666,7±120,3) мл, відрізняючись достовірно від об’єму інфузії (p<0,05), застосованого в контрольній групі. Серцевий викид (СВ) при госпіталізації в основній групі становив (4,06±0,10) л/хв, тобто вихідний рівень був статистично значуще нижчим відносно контрольної групи (р<0,05 – 4,40±0,07 л/хв), через 12 год лікування СВ продовжував статистично значуще зростати і порівняно з терміном 6 год вірогідно зріс – (5,30±0,06) л/хв (p<0,01), а через 24 год спостерігалась, на відміну від контрольної групи, статистично значуща динаміка зростання СВ до (5,63±0,08) л/хв із наближенням до норми. Протягом перших 12 год в контрольній групі добовий діурез склав (887,5±95,3) і зріс до (1987,5±257,3) мл до 24 год (приріст діурезу протягом першої доби 91,7 мл/год), а в основній групі (942,9±75,1) (р>0,5) та (2585,7±101,0) мл (р<0,05), відповідно, приріст діурезу 136,9 мл/год.
Лікування синдрому Міріззі
Authors: Rusyn V. I. , Rumiantsev K. E. , Pavuk F. M.
Published: October 2019

Мета роботи: визначення способу лікування спонтанних внутрішніх біліарних нориць (СВБН) при синдромі Міріззі (СМ).

Матеріали та методи. Проведено ретроспективний аналіз результатів лікування 8200 пацієнтів із жовчнокам’яною хворобою в Закарпатській обласній клінічній лікарні ім. Андрія Новака (ЗОКЛ) з 1997 до 2018 р. Із загальної кількості у 199 пацієнтів спостерігали СВБН. Частота, з якою траплялися СВБН, склала 2,4 %.

Результати досліджень та їх обговорення. Пацієнтам із СМ 1 типу виконували холецистектомію із зашиванням широкої і короткої міхурової протоки. У 30 хворих із СМ 2 типу виконали холецистектомію від дна з висіканням норицевого ходу і зашиванням дефекту в загальній жовчній протоці (ЗЖП) на Т-подібній трубці. У 14 хворих із СМ 3 типу варіантом вибору була холецистектомія з пластикою ЗЖП залишками стінки жовчного міхура (ЖМ) і зовнішнім дренуванням Т-подібною трубкою. У 9 хворих із синдромом Міріззі 4 типу виконали холецистектомію “від дна” із повним пересіканням ЗЖП. Дев’ятнадцяти хворим із холедохо-дуоденальними норицями 1 типу виконано ендоскопічну папілофістулотомію з метою надійного дренування ЗЖП, евакуації конкрементів з неї і ліквідації внутрішнього отвору нориці. Метою операції при спонтанних внутрішніх біліарних норицях є видалення жовчного міхура, забезпечення відтоку жовчі у просвіт травної трубки і пасажу хімусу по ній. При наявності нориці в порожнистому органі виконується її висікання з ушиванням отвору, окремих випадках резекційні способи ліквідації нориць.
Можливості радикального лікування папілярних карцином щитоподібної залози методом мініінвазивної хірургії
Authors: Guda B. B. , Kovalenko A. E. , Taraschenko Yu. M.
Published: October 2019

Мета роботи: розробити та ретроспективно оцінити результати хірургічного методу міні-доступу до щитоподібної залози у хворих з диференційованим тиреоїдним раком.

Матеріали і методи. Проаналізовано результати обстеження та хірургічного лікування 60 хворих із папілярними карциномами щитоподібної залози, прооперованих із застосуванням мініінвазивного методу, який полягає в зменшенні хірургічного розрізу до 2,5–3 см на рівні нижнього краю перешийка щитоподібної залози. Оцінювання результатів удосконаленого методу проводили за такими критеріями: кількість днів перебування у стаціонарі, частота ускладнень (однобічне транзиторне пошкодження зворотного гортанного нерва, транзиторна гіпокальціємія, кровотеча), стан післяопераційних рубців.

Результати досліджень та їх обговорення. Запропонований спосіб міні-доступу при хірургічному втручанні на щитоподібній залозі за її пухлинної патології є менш травматичним, більш радикальним та абластичним порівняно з традиційним. Частота післяопераційних ускладень не відрізнялася від такої при операціях із використанням звичайного доступу, водночас у жодному випадку не спостерігали у післяопераційному періоді випадків кровотечі. При оцінюванні стану післяопераційних рубців встановлено, що у всіх хворих кількість балів, які були нараховані за Stony Brook, була не нижче 3. Зменшення довжини розтину має позитивний не тільки косметичний, а й психологічний ефекти, комфортний для пацієнтів, створює умови для кращої реабілітації пацієнтів усіх вікових категорій.
Чи є альтернатива радикальній цистектомії при лікуванні хворих на м’язoво-інвазивний низькодиференційований рак сечового міхура?
Authors: Yakovlev P. G.
Published: October 2019

Мета роботи: оцінити поширеність застосування органозберігальних хірургічних методик у комплексі із періопераційною терапією як альтернативу радикальній цистектомії (РЦЕ) в лікування хворих на вперше виявлений низькодиференційований (G3) уротеліальний м’язово-інвазивний рак сечового міхура (МІРСМ) та визначити їх вплив на результати загальної виживаності. Матеріали і методи. Ретроспективно проаналізовано 309 історій хвороб пацієнтів, прооперованих протягом 2004–2017 рр. із приводу уротеліального G3 МІРСМ, а саме, клінічна стадія, застосовані методи хірургічного лікування: РЦЕ або органозберігальна операція (трансуретральна або відкрита резекція), періопераційна променева (ДПТ) та хіміотерапія (ПХТ); результати виживаності. Результати досліджень та їх обговорення. Виконано 109 (35,3 %) РЦЕ та 200 (64,7 %) органозберігальних операцій. П’ятирічна загальна виживаність для стадій II, III та IV для хворих після РЦЕ склала 43 %, 37 % та 10 %, після ТУР – 58 %, 27 %, та 19 % і після резекції сечового міхура 53 %, 42 % та 40 %.
Загоєння різаних ран шкірних покривів під впливом нановмісних біодеградуючих ранових покриттів
Authors: Popadyuk O. Y.
Published: October 2019

Мета роботи: дослідити вплив нановмісних біодеградуючих ранових покриттів на загоєння неускладнених різаних ран шкірних покривів в експерименті in vivo.

Матеріали і методи. Дослідження проводили із застосуванням біодеградуючої полімерної плівки насиченої нанооксидом цинку та розчином гідратованого фулерену С60 та ранового покриття Curasorb Zn на 53 морських свинках у клініко-біологічній базі “Віварій” ДВНЗ “Івано-Франківський національний медичний університет” з дотриманням санітарно-гігієнічних норм та правил Європейської конвенції про захист хребетних тварин. Термін спостереження – 3, 7, 4 та 21 доби. Виконували планіметричні, патоморфологічні та мікробіологічні дослідження.

Результати досліджень та їх обговорення. Морфологічно на третю добу у всіх дослідних групах спостерігали масивні ділянками некрозу, крововиливи та набряк субепітеліальних м’яких тканин. Площа ранової поверхні у тварин ІІ групи зменшилась на 17,8 %, що є кращим результатом порівняно з І групою, а у тварин ІІІ групи площа рани до 3-ї доби зменшилась на 25,8 %. Утворення грануляційної тканини на 7-му добу в ІІІ групі тварин відбувалося активніше, ніж у тварин ІІ групи, що проявлялося більшою кількістю новоутворених капілярів та менш вираженою запальною інфільтрацією зони оперативного втручання. На 14-ту добу експерименту в І дослідній групі площа ран становила (148,9±8,5) мм2, що вказувало на зменшення площі на 70,4 %. У ІІ групі на 14-ту добу площа ран зменшилась на 90,4 %, а у ІІІ групі була повна епітелізація.
Перші результати застосуваня мультимодальної анестезії при оперативних втручаннях на органах грудної клітки
Authors: Chubar I. V. , Nikolenko P. Y.
Published: October 2019

Мета роботи: продемонструвати один із варіантів збалансованої анестезії при виконанні оперативних втручань на органах грудної клітки.

Матеріали і методи. В дослідженні опрацьовано 152 випадки аналгезії, які розділено на три групи: основна – 85 пацієнтів (запропонована методика) та дві групи порівняння по 37 та 30 хворих, відповідно. Оперативні втручання на органах грудної клітки виконують при однобічній ШВЛ (інтубація правого чи лівого головних бронхів), яку досягли шляхом інтубації ендотрахеальною трубкою № 7 – № 7,5 на usb-SMART камері, приєднаній до електронних засобів візуалізації (в нашому випадку ноутбук). ШВЛ проводили за допомогою апарата “Blizar” в режимі контрольованої апаратної вентиляції (CMV). Після завершення основних хірургічних маніпуляцій ЕТТ переводили у трахею і ШВЛ проводили у звичному режимі. В період з 01.01.19 р. по 22.05.19 р. проведено 85 оперативних втручань за даною методикою (основна група). Групу порівняння склали 30 пацієнтів, оперативне втручання яким виконано за загальноприйнятою методикою тотальної внутрішньовенної анестезії з ШВЛ (використання фентанілу), третя група – фентаніл + парацетамол + лідокаїн (37 випадків). Ускладнень в кожній з груп не було.

Результати досліджень та їх обговорення. Сучасний розвиток анестезіології дає можливість для використання різних методів аналгезії. Більшість оперативних втручань на органах грудної клітки належить до складних, небезпечних, високотравматичних. Для забезпечення кращих умов виконання оперативного втручання у 80 – 90 % випадків виконується однобічна інтубація одного з головних бронхів, що вимагає від анестезіолога ретельнішого контролю глибини аналгезії та показників життєдіяльності. Останнім часом з’являється багато інформації щодо мультимодальної аналгезії, проте більшість публікацій – це використання її для купірування післяопераційного болю. В доступній нам літературі ми не знайшли інформації про використання мультимодальної аналгезії під час оперативного втручання. У сучасних умовах додатково слід враховувати фінансовий аспект – адже одна ампула наркотичного анальгетика (приклад – фентаніл) в 2,5 – 3 рази дорожча, ніж одна ампула НПЗП (приклад – налбуфін 10 мг). Це дає можливість активно і пролонговано використовувати його в поєднані з парацетамолом для купірування болю в післяопераційний період.
Comparison of Urinary Sodium and Blood Pressure Relationship From the Spot Versus 24‐Hour Urine Samples
Authors: Naser Abu Mohd , Rahman Mahbubur , Unicomb Leanne , Doza Solaiman , Anand Shuchi , Chang Howard H. , Luby Stephen P. , Clasen Thomas F. , Narayan K.M. Venkat
Published: October 2019

Background

We compared the relationship between sodium (Na) intake and blood pressure when Na intake was estimated from first‐ and second‐morning spot urine samples using the INTERSALT (International Study on Salt and Blood Pressure) formula, versus directly measured 24‐hour samples.

Methods and Results

We collected 24‐hour urine and first‐ and second‐morning voids of 383 participants in coastal Bangladesh for 2 visits. We measured participants’ blood pressure using an Omron
®
HEM–907 monitor. To assess the shape of the relationship between urinary Na and blood pressure, we created restricted cubic spline plots adjusted for age, sex, body mass index, smoking and alcohol consumption, physical activities, religion, sleep hours, and household wealth. To assess multicollinearity, we reported variance inflation factors, tolerances, and Leamer's and Klein's statistics following linear regression models. The mean daily urinary Na was 122 (SD 26) mmol/d for the first; 122 (SD 27) mmol/d for the second; and 134 (SD 70) mmol/d for the 24‐hour samples. The restricted cubic spline plots illustrated no association between first‐morning urinary Na and systolic blood pressure until the 90th percentile distribution followed by a downward relationship; a nonlinear inverse‐V‐shaped relationship between second‐morning urinary Na and systolic blood pressure; and a monotonic upward relationship between 24‐hour urinary Na and systolic blood pressure. We found no evidence of multicollinearity for the 24‐hour urinary Na model.

Conclusions

The urinary Na and systolic blood pressure relationship varied for 3 urinary Na measurements. Twenty‐four‐hour urinary Na captured more variability of Na intake compared with spot urine samples, and its regression models were not affected by multicollinearity.
Abstract 108: Reactivation of Myc Transcription in the Heart Unlocks its Proliferative Capacity
Authors: Wilson Catherine H , Bywater Megan J , Burkhart Deborah L , Sabò Arianna , Straube Jasmin , Pendino Vera , Hudson James E , Quaife-Ryan Gregory A , Porrello Enzo R , Kress Theresia R , Amati Bruno , Littlewood Trevor D , Evan Gerard I
Published: October 2019

It is unclear why some tissues are refractory to the mitogenic effects of the pleiotropic transcription factor Myc, even when its expression is deregulated. We have developed an
in vivo
model permitting determination of the early transcriptional consequences of Myc activation across all tissues of an adult mouse. Myc activation induces rapid transcriptional responses, followed by cell proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc bound DNA at open promotor and enhancer elements, in representative responsive (liver) and non-responsive (heart) tissues, but failed to induce a robust transcriptional and proliferative response in the heart. Therefore, the determinants of transcriptional responsiveness are distinct from chromatin state and DNA binding by Myc. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription may be re-engaged in mature cardiomyocytes by elevating levels of the P-TEFb, instating a profound proliferative response to Myc. These data indicate that the cardiac epigenomic architecture does not preclude Myc binding to E-boxes; rather, it is the inability of Myc to drive transcriptional output from Myc target genes that thwarts cardiomyocyte proliferation. Hence, P-TEFb activity is a key limiting determinant of whether or not an individual tissue is permissive for Myc transcriptional activation and mitogenesis. These data provide not only a greater understanding of how Myc transcriptional activity is determined in cellular contexts, they also indicate that modification of the expression levels of the transcriptional co-factor P-TEFb could be a means through which adult cardiomyocytes could be regenerated for the treatment of heart conditions.
Abstract 110: Role of Beclin1 in Regulating Parkin-mediated Mitophagy
Authors: Moreno Eileen R , Lampert Mark A , Najor Rita H , Gustafsson Åsa B
Published: October 2019

Autophagy is a cellular quality control mechanism involved in the selective elimination of damaged organelles and cytotoxic protein aggregates. Beclin1 is a component of the PI3 kinase complex that initiates autophagy in cells. Here, we have investigated the role of Beclin1 in autophagosome formation and Parkin-mediated mitophagy. Using Beclin1-deficient mouse embryonic fibroblasts (MEFs), we found that autophagosomes are still formed in the absence of Beclin1 in response to various treatments known to induce autophagy (FCCP, nutrient deprivation, rapamycin). Autophagic flux is also intact in the Beclin1-/- MEFs, indicating an alternative mechanism of autophagy is induced. Next, we examined whether elimination of mitochondria via autophagy (mitophagy) was intact in Beclin1-/- MEFs. Unexpectedly, we observed that Parkin-mediated mitophagy was significantly reduced in the absence of Beclin1. We confirmed that Parkin was recruited to depolarized mitochondria in both WT and Beclin1-/- MEFs which correlated with increased ubiquitination of mitochondrial proteins. However, high resolution imaging revealed that autophagosomes failed to sequester mitochondria that had been labeled by Parkin. We observed that Parkin was degraded in Beclin1-/- MEF’s, but not WT, after mitochondrial stress. We also found that Beclin1 selectively localized as discrete puncta on Parkin-positive mitochondria suggesting a potential role for Beclin1 in linking mitochondria to autophagosomes. In contrast to our findings in MEFs, characterization of autophagy in mice with cardiac specific deletion of Beclin1 revealed that these hearts had a reduced number of autophagosomes which correlated with a reduction in autophagic flux as indicated by accumulation of cytosolic LC3I and p62. Beclin1-deficient hearts also had significantly reduced Parkin protein levels without changes in mRNA levels, suggesting an impairment in mitophagy. Overall, these findings suggest Beclin1 is required for the proper targeting of mitochondria into autophagosomes and that the adult heart is dependent on Beclin1 to induce formation of autophagosomes.
Abstract 117: A Novel Ubiquitination Dependent Pathway Regulating Myocardial Necroptosis and Ischemic Injury
Authors: Guo Xiaoyun , Yin Haifeng , Chen Yi , Hong Siqi , He Hui , Zeng Yachang , Steinmetz Rachel , Liu Qinghang
Published: October 2019

Objective:
Necroptosis is a new caspase-independent, regulated form of necrosis, which has recently been implicated in ischemic cardiac injury and remodeling. This study aims to determine a novel ubiquitination-dependent mechanism that regulates necroptosis in the heart and the implications of necroptosis signaling in the setting of ischemic injury and remodeling.

Methods and Results:
Here we identified a novel ubiquitination-dependent mechanism mediated by the E3 ubiquitin ligase TRAF2 (TNF receptor associated factor-2) and the deubiquitinase CYLD (cylindromatosis), which critically regulates myocardial necroptosis and pathological remodeling. TRAF2 and CYLD specifically regulate K63-linked protein ubiquitination, which regulates signal transduction but not proteasomal degradation. Intriguingly, CYLD is up-regulated, but TRAF2 is down-regulated, in the heart after ischemia-reperfusion injury. We found that wild-type TRAF2 inhibits, whereas the ligase inactive mutant TRAF2-ΔRING promotes cardiomyocyte necroptosis. Importantly, acute deletion of TRAF2 in the adult heart in
Traf2
fl/fl
-MerCreMer mice induces severe dilated cardiomyopathy and lethal heart failure by promoting myocardial necroptosis. Conversely, AAV9-mediated TRAF2 gene transfer significantly attenuates ischemic-reperfusion injury. On the other hand, CYLD overexpression promotes, whereas CYLD deletion inhibits cardiomyocyte necroptosis.
In vivo
, genetic ablation of CYLD in
Cyld-/-
mice attenuates ischemic myocardial injury and adverse remodeling by suppressing myocardial necroptosis. Mechanistically, TRAF2 and CYLD opposingly regulate K63-linked polyubiquitination of TAK1 (TGFβ-activated kinase 1), TAK1-RIP1 interaction, and the formation of RIP1-RIP3 necrosome. These results thus identify a ubiquitination-dependent mechanism of necroptosis mediated by TRAF2 and CYLD, providing a new paradigm of necroptosis signaling.

Conclusion:
The E3 ligase TRAF2 and the deubiquitinase CYLD, as a suppressor and an activator of necroptosis respectively, opposingly regulate myocardial homeostasis, ischemic injury, and remodeling, thus representing promising therapeutic targets for heart disease.
Abstract 121: Precision Intervention of Cardiac Remodeling Based on Cellular Composition Principles Uncovered by Single-Cell Transcriptomics
Authors: Yu Peng , Ren Zongna , Wang Li
Published: October 2019

Stress-induced cardiac remodeling forms the foundation of many cardiac diseases, yet little is known about the spatiotemporal interplay amongst cell types underlying the pathological progression of the heart from normal to a diseased state, at single-cell resolution. Here, we analyzed 11,492 single cells, including both cardiomyocytes (CMs) and non-cardiomyocytes (NCMs), at different stages in a mouse model of pressure overload-induced cardiac remodeling, and identified a full list of factors and signaling pathways important for disease progression. Through constructing cell crosstalk maps, we revealed sequential switching in NCM subtype (fibroblasts, macrophages, and endothelial cells) utilization at different stages of cardiac remodeling. Intriguingly, stage-specific pharmacological inhibition of macrophage subtype switch dramatically retarded heart transition from adaptive to a maladaptive state. Consistently, alterations of cardiac remodeling related-genes were highly conserved in human samples. Together, our study not only characterizes the molecular features of different cell types and identifies crucial factors underlying cardiac remodeling, but may also have important implications for stage- and cell type-specific precise intervention in cardiac diseases.
Abstract 142: New Approach for Directly Reprogrammed Endothelial Cells
Authors: Lee Sangho , Chen Dandan , Yoon Young-sup
Published: October 2019

Rationale:
For therapeutic neovascularization through cell therapy to treat cardiovascular diseases, recently, we successfully generated reprogrammed ECs, directly from human dermal fibroblasts (HDF) with the ETV2 transcription factor. Although functional ECs were generated, ETV2 was delivered lentiviral vector, which is clinically unsuitable.

Objective:
In this study, we aimed to generate clinically compatible rECs, by employing an adenoviral vector to minimize genetic integration. Furthermore, to prolong the cell retention and improve cell survival, we applied synthetic biomaterial, polypeptide amphiphile (PA) nanomatrix gel and tested for experimental cell therapy in animal models.

Methods and Results:
After we transduced HDFs with Ad-
ETV2
(Ad-
ETV2
-HDF), EC gene expression was measured by qRT-PCR and flow cytometry. We found that Ad-
ETV2-
HDFs displayed a cobblestone-like morphology and showed notable induction of EC genes (CDH5, KDR, PECAM1). Flow cytometry analysis showed peak expression of CDH5 and KDR at D6 and continuous increase of PECAM1 over 9 days. Also, Ad-
ETV2
-HDFs took up acetylated LDL and bound lectin, suggesting that these cells possess functional EC characteristics. To enrich cells showing EC characters, Ad-
ETV
2-HDFs were sorted for KDR by FACS at day 6. qRT-PCR showed substantial enrichment of EC-specific gene expression in KDR
+
cells. Only KDR
+
cells (reprogrammed ECs, rECs) formed tube-like structures on Matrigel. In addition, immunostaining confirmed high expression of EC marker proteins in rECs. Next, we tested the functionality of rECs in hindlimb ischemia mouse model. At 4 weeks after injection of 4 x 10
5
rECs into the ischemic hindlimb, we observed rECs incorporated into host blood vessels or resided perivascular regions. Furthermore, we found more rECs in the tissues and were directly incorporated into the vessels when they were encapsulated in PA nanomatrix gel compared to bare rEC-injected mice.

Conclusions:
Together, these data strongly support the generation of Ad-
ETV2
-induced rECs (Ad-rECs) and enhanced retention of rECs by PA nanomatrix gel in tissue. With this study, we can develop advanced concept and techniques for clinical application of rECs and establish a new platform for future cell therapy.