Betaine–N-Heterocyclic Carbene Interconversions of Quinazolin-4-One Imidazolium Mesomeric Betaines. Sulfur, Selenium, and Borane Adduct Formation

Reaction of N-alkylated imidazoles with 2-chloro-4-quinazolinone gave mesomeric betaines, 2-(1-alkyl-1H-imidazolium-3-yl)quinazolin-4-olates, for which three tautomeric forms of N-heterocyclic carbenes (NHCs) can be formulated, in addition to an anionic NHC after deprotonation. The NHC tautomers were trapped with sulfur, selenium, triethylborane, and triphenylborane as thiones, selenones and borane adducts, respectively. We obtained two isomers of the cyclic borane adducts, diazaboroloquinazolinones with [1,5-a] and [5,1-b]-type fusion between the quinazolinone and the diazaborole rings. They correspond to two different NHC tautomers and to the anionic NHC derived thereof. The third NHC tautomer was trapped as a non-cyclic adduct with tris(pentafluorophenyl)borane by coordination to the quinazoline oxygen atom. 2D 1H-15N HMBC experiments of 15N-labeled quinazolinone fragments, quantitative measurements of long-range 1H-15N coupling constants (JHN), and five X-ray single crystal analyses have been carried out for the structure elucidations and to gain insight into the NMR spectroscopic properties of these compounds. © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.Russian Foundation for Basic Research, RFBR: 17-03-01029Deutscher Akademischer Austauschdienst, DAADMinistry of Education and Science of the Russian Federation, Minobrnauka: 4.6351.2017/8.9This work was supported by the Russian Ministry of Education and Science (State contract 4.6351.2017/8.9) and the Russian Foundation for Basic Research (grant 17-03-01029). Single crystal X-ray analysis of 23b was performed at the User Facilities Centers of IGIC RAS within the State Assignment on Fundamental Research to the Kurnakov Institute of General and Inorganic Chemistry. We thank the Deutscher Akademischer Austauschdienst DAAD for the financial support of the internship of S. D. at Clausthal University of Technology, Germany

Development of an evidence-based brief 'talking' intervention for non-responders to bowel screening for use in primary care:stakeholder interviews

Bowel cancer is the third most common cause of cancer death worldwide. Bowel screening has been shown to reduce mortality and primary care interventions have been successful in increasing uptake of screening. Using evidence-based theory to inform the development of such interventions has been shown to increase their effectiveness. This study aimed to develop and refine a brief evidence-based intervention for eligible individuals whom have not responded to their last bowel screening invitation (non-responders), for opportunistic use by primary care providers during routine consultations.The development of a brief intervention involving a conversation between primary care providers and non-responders was informed by a multi-faceted model comprising: research team workshop and meetings to draw on expertise; evidence from the literature regarding barriers to bowel screening and effective strategies to promote informed participation; relevant psychological theory, and intervention development and behaviour change guidance. Qualitative telephone interviews with 1) bowel screening stakeholders and 2) patient non-responders explored views regarding the acceptability of the intervention to help refine its content and process.The intervention provides a theory and evidence-based tool designed to be incorporated within current primary care practice. Bowel screening stakeholders were supportive of the intervention and recognised the importance of the role of primary care. Interviews highlighted the importance of brevity and simplicity to incorporate the intervention into routine clinical care. Non-responders similarly found the intervention acceptable, valuing a holistic approach to their care. Moreover, they expected their primary care provider to encourage participation.A theory-based brief conversation for use in a primary care consultation was acceptable to bowel screening stakeholders and potential recipients, reflecting a health promoting primary care ethos. Findings indicate that it is appropriate to test the intervention in primary care in a feasibility study

Foldamers of β-peptides : conformational preference of peptides formed by rigid building blocks : The first MI-IR spectra of a triamide nanosystem

To determine local chirality driven conformational preferences of small aminocyclobutane-1-carboxylic acid derivatives, X-(ACBA) n -Y, their matrix-isolation IR spectra were recorded and analyzed. For the very first time model systems of this kind were deposited in a frozen (~10 K) noble gas matrix to reduce line width and thus, the recorded sharp vibrational lines were analyzed in details. For cis-(S,R)-1 monomer two “zigzag” conformers composed of either a six or an eight-membered H-bonded pseudo ring was identified. For trans-(S,S)-2 stereoisomer a zigzag of an eight-membered pseudo ring and a helical building unit were determined. Both findings are fully consistent with our computational results, even though the relative conformational ratios were found to vary with respect to measurements. For the dimers (S,R,S,S)-3 and (S,S,S,R)-4 as many as four different cis,trans and three different trans,cis conformers were localized in their matrix-isolation IR (MI-IR) spectra. These foldamers not only agree with the previous computational and NMR results, but also unambiguously show for the first time the presence of a structure made of a cis,trans conformer which links a “zigzag” and a helical foldamer via a bifurcated H-bond. The present work underlines the importance of MI-IR spectroscopy, applied for the first time for triamides to analyze the conformational pool of small biomolecules. We have shown that the local chirality of a β-amino acid can fully control its backbone folding preferences. Unlike proteogenic α-peptides, β- and especially (ACBA) n type oligopeptides could thus be used to rationally design and influence foldamer’s structural preferences

Women’s subsistence strategies predict fertility across cultures, but context matters

While it is commonly assumed that farmers have higher, and foragers lower, fertility compared to populations practicing other forms of subsistence, robust supportive evidence is lacking. We tested whether subsistence activities—incorporating market integration—are associated with fertility in 10,250 women from 27 small-scale societies and found considerable variation in fertility. This variation did not align with group-level subsistence typologies. Societies labeled as “farmers” did not have higher fertility than others, while “foragers” did not have lower fertility. However, at the individual level, we found strong evidence that fertility was positively associated with farming and moderate evidence of a negative relationship between foraging and fertility. Markers of market integration were strongly negatively correlated with fertility. Despite strong cross-cultural evidence, these relationships were not consistent in all populations, highlighting the importance of the socioecological context, which likely influences the diverse mechanisms driving the relationship between fertility and subsistence

Factors associated with the efficiency of maintenance therapy in patients with metastatic colorectal cancer

Objective: to evaluate tolerability and efficacy of maintenance treatment in the absence of progression after 16 weeks of first-line therapy in patients with unresectable metastatic colon cancer.Materials and methods. We have analyzed medical case histories of patients with metastatic colorectal cancer who underwent treatment in the department of clinical pharmacology and chemotherapy of N. N. Blokhin Russian Cancer Research Center from 2007 to 2015 years. Inclusion criteria were the following: 16–24 weeks of first-line chemotherapy with no signs of progression and the inability to perform metastasectomy. Progression-free survival was the main criterion for effectiveness in our study.Results. 160 (44.5 %) of 359 treated patients met the inclusion criteria. 102 (63.7 %) patients were followed up, while the other 58 (36.3 % – comparison group) patients underwent maintenance chemotherapy. Grade I–II toxic reactions and grade III complications associated with first-line chemotherapy were insignificantly more common in the group of patients left on maintenance chemotherapy: 72.4 % and 37.9 % versus 57.8 % and 24.5 % in the comparison group, p = 0.07 and p = 0.07 respectively. The frequency of grade I–II toxic reactions and grade III complications in the second-line treatment did not differ between treatment groups (p = 0.9 and p = 0.8). The median of progression-free survival in observation group and comparison group was 4, and 6 months (odds ratio (OR) 0.6; p = 0.009), and life expectancy – 23 and 31 months (OR 0.75; p = 0.1), respectively. Statistically significant differences between groups with respect to achieving the objective response and/or normalization of carcinoembryonic antigen level were revealed: median of progression-free survival was 13 (n = 26 of 57; 45.6 %) and 4 months (n = 31 of 57, 54.4 %), respectively (HR 0.38; p = 0.002), median of life expectancy – 34 months versus 26 months (OR 0.37; p = 0.3). Conclusions. Carrying out maintenance therapy is associated with increased incidence of grade III complications during the first-line treatment, but does not affect the tolerability of the second-line treatment. Supportive chemotherapy with fluoropyrimidines remains to be the most effective in patients with favorable prognostic factors such as normalization of carcinoembryonic antigen and/or achievement of the objective response on the background of first-line chemotherapy

КЛИНИЧЕСКИЙ СЛУЧАЙ АКТИНОМИКОЗА БРЮШНОЙ СТЕНКИ И ОРГАНОВ МАЛОГО ТАЗА

The paper describes a clinical case of visceral actinomycosis in a 19-year-old female patient. The complexity of preoperative and intraoperative diagnosis is the similarity of this form of actinomycosis and the neoplastic process and abscess of the abdominal cavity and small pelvis. The disease ran involving the abdominal wall, bladder, right fallopian tube, and parametrium. The diagnosis was based on the histological findings of specimens obtained during the first surgery. On day 18 after the first surgery, there was a need for relaparotomy. Postoperatively, the patient received combination therapy, long-term antibiotic therapy, and immunomodulators (actinolysate). The performed treatment provided a positive effect. В статье представлен клинический случай висцерального актиномикоза у пациентки в возрасте 19 лет. Сложность дооперационной и интраоперационной диагностики заключалась в сходстве данной формы актиномикоза с неопластическим процессом и абсцессом брюшной полости и малого таза. Заболевание протекало с поражением брюшной стенки, мочевого пузыря, правой маточной трубы и параметрия. Диагноз установлен на основании данных гистологических исследований препаратов, полученных во время первой операции. На 18-е сутки от момента первого вмешательства возникла необходимость выполнения релапаротомии. В послеоперационном периоде пациентка получала комплексное лечение, длительную антибактериальную терапию, иммуномодуляторы (актинолизат). Проведенное лечение дало положительный эффект.

The whole genome sequence of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), reveals insights into the biology and adaptive evolution of a highly invasive pest species

The Mediterranean fruit fly (medfly), Ceratitis capitata, is a major destructive insect pest due to its broad host range, which includes hundreds of fruits and vegetables. It exhibits a unique ability to invade and adapt to ecological niches throughout tropical and subtropical regions of the world, though medfly infestations have been prevented and controlled by the sterile insect technique (SIT) as part of integrated pest management programs (IPMs). The genetic analysis and manipulation of medfly has been subject to intensive study in an effort to improve SIT efficacy and other aspects of IPM control

Факторы, ассоциированные с эффективностью поддерживающей химиотерапии при метастатическом раке толстой кишки

Objective: to evaluate tolerability and efficacy of maintenance treatment in the absence of progression after 16 weeks of first-line therapy in patients with unresectable metastatic colon cancer.Materials and methods. We have analyzed medical case histories of patients with metastatic colorectal cancer who underwent treatment in the department of clinical pharmacology and chemotherapy of N. N. Blokhin Russian Cancer Research Center from 2007 to 2015 years. Inclusion criteria were the following: 16–24 weeks of first-line chemotherapy with no signs of progression and the inability to perform metastasectomy. Progression-free survival was the main criterion for effectiveness in our study.Results. 160 (44.5 %) of 359 treated patients met the inclusion criteria. 102 (63.7 %) patients were followed up, while the other 58 (36.3 % – comparison group) patients underwent maintenance chemotherapy. Grade I–II toxic reactions and grade III complications associated with first-line chemotherapy were insignificantly more common in the group of patients left on maintenance chemotherapy: 72.4 % and 37.9 % versus 57.8 % and 24.5 % in the comparison group, p = 0.07 and p = 0.07 respectively. The frequency of grade I–II toxic reactions and grade III complications in the second-line treatment did not differ between treatment groups (p = 0.9 and p = 0.8). The median of progression-free survival in observation group and comparison group was 4, and 6 months (odds ratio (OR) 0.6; p = 0.009), and life expectancy – 23 and 31 months (OR 0.75; p = 0.1), respectively. Statistically significant differences between groups with respect to achieving the objective response and/or normalization of carcinoembryonic antigen level were revealed: median of progression-free survival was 13 (n = 26 of 57; 45.6 %) and 4 months (n = 31 of 57, 54.4 %), respectively (HR 0.38; p = 0.002), median of life expectancy – 34 months versus 26 months (OR 0.37; p = 0.3). Conclusions. Carrying out maintenance therapy is associated with increased incidence of grade III complications during the first-line treatment, but does not affect the tolerability of the second-line treatment. Supportive chemotherapy with fluoropyrimidines remains to be the most effective in patients with favorable prognostic factors such as normalization of carcinoembryonic antigen and/or achievement of the objective response on the background of first-line chemotherapy.Целью нашей работы явилась оценка переносимости и эффективности проведения поддерживающей терапии при отсутствии прогрессирования после 16 нед 1-й линии терапии у больных метастатическим неоперабельным раком толстой кишки.Материалы и методы. Нами проанализированы истории болезни пациентов с метастатическим раком толстой кишки, который получали лечение в отделении клинической фармакологии и химиотерапии РОНЦ им. Н. Н. Блохина с 2007 по 2015 г. Критериями включения больных в анализ явились: проведение 16–24 нед химиотерапии 1-й линии без признаков прогрессирования и невозможность выполнения метастазэктомии. Основным критерием эффективности в нашем исследовании явилась выживаемость без прогрессирования.Результаты. Критериям включения соответствовали 160 (44,5 %) из 359 пролеченных больных. Под дальнейшим наблюдением оставлены 102 (63,7 %) пациента, еще 58 (36,3 % – группа сравнения) проводили поддерживающую химиотерапию. Токсические реакции I–II степени и осложнения III степени на 1-й линии химиотерапии статистически незначимо чаще отмечались в группе пациентов, оставленных на поддерживающей химиотерапии: 72,4 и 37,9 % против 57,8 и 24,5 % в группе сравнения, р = 0,07 и p = 0,07 соответственно. Частота токсических реакций I–II степени и осложнений III степени во 2-й линии лечения не различалась между сравниваемыми группами (р = 0,9 и p = 0,8). Медиана выживаемости без прогрессирования в группах наблюдения и сравнения составила 4 и 6 мес (отношение рисков (ОР) 0,6; р = 0,009), а продолжительности жизни – 23 и 31 мес (ОР 0,75; р = 0,1) соответственно. Выявлены статистически значимые различия в эффективности поддерживающей терапии: медиана выживаемости без прогрессирования составила 13 (n = 26 из 57; 45,6 %) и 4 мес (n = 31 из 57; 54,4 %) соответственно (ОР 0,38; р = 0,002), медиана продолжительности жизни – 34 мес против 26 мес (ОР 0,37; р = 0,3).Выводы. Проведение поддерживающей химиотерапии ассоциировано с увеличением частоты развития осложнений III степени в процессе 1-й линии лечения, но не влияет на переносимость 2-й линии. Поддерживающая химиотерапия фторпиримидинами наиболее эффективна у пациентов с такими благоприятными прогностическими факторами как нормализация уровня раковоэмбрионального антигена и/или достижение объективного эффекта в процессе 1-й линии химиотерапии