New angiogenic regulators produced by TAMs: perspective for targeting tumor angiogenesis

Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs

Generating and transferring grassroots innovations in a multi-actor participatory process

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Molecular cloning of KS, a novel rat gene expressed exclusively in the kidney

Molecular cloning of xKSx, a novel rat gene expressed exclusively in the kidney.BackgroundWe aimed to identify genes with kidney specific, developmentally regulated expression. Here we report the cDNA sequence and expression pattern of KS, a novel kidney-specific rat gene.MethodsA partial cDNA was identified by differential display polymerase chain reaction (PCR) of a renal cell fraction enriched for proximal tubular and renin-expressing cells. Using the partial cDNA as a probe, a rat kidney cDNA library was screened. The full-length KS sequence was obtained by PCR amplification of cDNA ends. The expression pattern of KS was investigated by Northern blot. RNA was extracted from several organs of newborn and adult rats, as well as from the kidneys of rats with altered tubular function, that is, rats that had undergone unilateral nephrectomy, unilateral ureteral obstruction, neonatal losartan treatment, and the appropriate control animals. The expression of KS was also investigated in the kidneys of rats with spontaneous or renovascular hypertension.ResultsThe KS cDNA (2426bp) contained one open reading frame encoding a predicted 572 amino acid protein. The derived peptide sequence displayed approximately 70% similarity to the hypertension-related SA gene product and approximately 50% similarity to prokaryotic and eukaryotic acetyl-CoA synthases (EC 6.2.1.1). KS was expressed in the kidney and not in any other organ assayed. KS RNA was not detected in fetal and newborn rat kidney but became apparent after one week of postnatal life. Gene expression was downregulated in rat models of altered tubular function. KS expression was decreased in spontaneously hypertensive rats but not in renovascular hypertension.ConclusionKS, a novel rat gene, exhibits a unique tissue-specific expression exclusively in mature kidneys. The data suggest KS may encode an adenosine monophosphate binding enzyme

PFKFB3 overexpression in monocytes of patients with colon but not rectal cancer programs pro-tumor macrophages and is indicative for higher risk of tumor relapse

Introduction: Circulating monocytes are main source for tumor-associated macrophages (TAMs) that control tumor growth, angiogenesis, metastasis and therapy resistance. We raised the questions how monocyte programming is affected by growing tumors localized in colon and rectal sections, and how treatment onsets affect monocyte programming in the circulation. Methods: Patients with rectal cancer and colon cancer were enrolled in the study. Peripheral blood monocytes were characterized by phenotypic analysis using flow cytometry, by transcriptomic analysis using RNA sequencing and by gene expression analysis using real-time RT-PCR. Phenotypic analysis was performed with IF/confocal microscopy. Spatial transcriptomic analysis was applied using GeoMX DSP-NGS. Results: In patients with rectal cancer, increased amount of CCR2+ monocytes was indicative for the absence of both lymphatic and hematogenous metastasis. In contrast, in patients with colon cancer CD163+ monocytes were indicative for LN metastasis. NGS analysis identified tumor-specific transcriptional programming of monocytes in all CRC patients compared to healthy individuals. The key transcriptional difference between monocytes of patients with colon and rectal cancer was increased expression of PFKFB3, activator of glycolysis that is currently considered as therapy target for major solid cancers. PFKFB3-expressing monocyte-derived macrophages massively infiltrated tumor in colon. Nanostring technology identified correlation of PFKFB3 with amount and tumor-promoting properties of TAMs in colon but not in rectal cancer. PFKFB3 was indicative for tumor relapse specifically in colon cancer. Discussion: Our findings provide essential argument towards CRC definition to cover two clinically distinct cancers – colon cancer and rectal cancer, that differentially interact with innate immunity

Первичный серологический статус и иммунологическая эффективность вакцинации против Streptococcus pneumoniae и Haemophilus influenzae типа b у детей с бронхолегочной дисплазией: когортное исследование

Background. The primary serological status of children with bronchopulmonary dysplasia (BPD) with respect to respiratory significant pathogens remains unstudied. Wherein, the efficacy of vaccination of children with BPD against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) has been studied in a small number of studies which results are contradictory.Objective. Our aim was to study the pre-vaccinal serological status with regard to S. pneumoniae and Hib and the immunological efficacy of vaccination against these infections in children with BPD.Methods. The study included children with BPD without exacerbation. The immunological efficacy of conjugate vaccines — pneumococcal 13-valent and against Haemophilus influenza type b — was assessed by the level of IgG against S. pneumoniae and Hib using the ELISA method. The level of antibodies was determined before vaccination and 1 or 3–6 months afterwards.Results. The study included 32 children with BPD, mean age at the time of determining primary serological status was 13.3±1.3 months, at the time of vaccination — 15.2±1.5 months. The mean gestational age was 28.7±0.8 weeks, the body weight at birth was 1225±180 g. Before vaccination, all children with BPD had no protective antibody titre against S. pneumoniae and Hib averaging 0.2±0.034 and 0.13±0.0106 mg/L, respectively. One month after vaccination, the level of antibodies to S. pneumoniae reached 12.9±2.34 mg/L to Hib — 3.34±0.769 mg/L.Conclusion. After immunization with a pneumococcal 13-valent conjugate vaccine and a conjugate vaccine against Haemophilus influenzae type b, the concentration of IgG against S. pneumoniae exceeded the protective level in all examined patients (100%), the concentration to Hib — in 29 (90.6%).Обоснование. Первичный серологический статус детей с бронхолегочной дисплазией (БЛД) в отношении респираторно значимых патогенов остается неизученным. При этом эффективность вакцинации детей с БЛД против Streptococcus pneumoniae и Haemophilus influenzae типа b (Hib) изучалась в небольшом числе исследований, результаты которых противоречивы. Цель исследования — изучить довакцинальный серологический статус в отношении S. pneumoniae и Hib и иммунологическую эффективность вакцинации против этих инфекций у детей с БЛД.Методы. В исследование включали детей с БЛД, вне обострения. Иммунологическую эффективность конъюгированных вакцин — 13-валентной пневмококковой и против гемофильной инфекции типа b — оценивали по уровню IgG к S. pneumoniae и Hib методом ELISA. Уровень антител определяли до вакцинации и спустя 1 и 3–6 мес.Результаты. Включено 32 ребенка с БЛД средний возраст которых на момент определения первичного серологического статуса составил 13,3±1,3 мес, на момент вакцинации — 15,2±1,5 мес. Средний гестационный возраст — 28,7±0,8 нед, масса тела при рождении — 1225±180 г. У всех детей с БЛД до вакцинации отсутствовал защитный титр антител к S. pneumoniae и Hib, составив в среднем 0,2±0,034 и 0,13±0,0106 мг/л соответственно. Через 1 мес после вакцинации уровень антител к S. pneumoniae достигал 12,9±2,34 мг/л, к Hib — 3,34±0,769 мг/л.Заключение. После иммунизации 13-валентной пневмококковой конъюгированной вакциной и конъюгированной вакциной против гемофильной инфекции типа b концентрация IgG к S. pneumoniae превышала защитный уровень у всех обследованных пациентов (100%), концентрация к Hib — у 29 (90,6%).Конфликт интересовЛ.С. Намазова-Баранова — получение исследовательских грантов от фармацевтических компаний Пьер Фабр, Genzyme Europe B.V., ООО «Астра зенека Фармасьютикалз», Gilead / PRA «Фармасьютикал Рисерч Ассошиэйтс СиАйЭс», Teva Branded Pharma ceuti cal products R&D, Inc. / ООО «ППД Девелопмент (Смоленск)», «Сталлержен С.А.» / «Квинтайлс ГезмбХ» (Австрия). М.В. Федосеенко — получение гонораров от компании Sanofi, Pfizer за чтение лекций

WSES guidelines for management of Clostridium difficile infection in surgical patients

In the last two decades there have been dramatic changes in the epidemiology of Clostridium difficile infection (CDI), with increases in incidence and severity of disease in many countries worldwide. The incidence of CDI has also increased in surgical patients. Optimization of management of C difficile, has therefore become increasingly urgent. An international multidisciplinary panel of experts prepared evidenced-based World Society of Emergency Surgery (WSES) guidelines for management of CDI in surgical patients.Peer reviewe