Retrospektive Analyse über die Zuordenbarkeit von Adenokarzinomen des rektosigmoidalen Übergangs zum proximalen Rektum oder Sigma

Hintergrund: Adenokarzinome im distalen Colon sigmoideum oder proximalen Rektum werden im klinischen Alltag häufig als Karzinome des rektosigmoidalen Übergangs beschrieben. Geklärt werden sollte die Frage, ob diese Tumore dem Sigma bzw. dem proximalen Rektum zugeordnet werden sollten oder sie eine eigenständige Tumorlokalisation darstellen. Material und Methoden: Es erfolgte eine retrospektive Analyse von insgesamt 185 Patienten, welche konsekutiv von 2004 bis 2008 aufgrund eines Adenokarzinoms im Sigma (SI 85 Patienten), rektosigmoidalen Übergang (RS 36 Patienten) oder des proximalen Rektumdrittels (PR 64 Patienten) reseziert wurden. Erhoben und analysiert wurden alle klinischen und histopathologischen Parameter. Tumorrezidive und Überleben wurden mittels standardisierter Patientenbefragung evaluiert. Ergebnisse: Patienten der SI-Gruppe zeigten einen höheren präoperativen Gewichtsverlust als Patienten der RS- und PR-Gruppe (SI 16/85 Patienten (18,8%) vs. RS 2/36 Patienten (5,6%) vs. PR 4/64 Patienten (6,3%), p=0,03). Verglichen zu Tumoren im SI und RS erfolgte in der PR-Gruppe häufiger eine neoadjuvante und adjuvante Therapie. Im RS lag häufiger eine T4-Situation vor als in beiden anderen Gruppen (SI 13/85 Patienten (15,3%), RS 9/36 Patienten (25,0%), PR 5/64 Patienten (7,8%); p = 0,07). Im RS war eine lymphogene Metastasierung häufiger, dies jedoch nicht statistisch signifikant zu den anderen Lokalisationen. Patienten mit Tumoren im RS wiesen signifikant häufiger eine synchrone Fernmetastasierung auf (SI 23/85 Patienten (27,1%), RS 13/36 Patienten (36,1%), PR 8/64 Patienten (12,5%), p=0,02), was an der signifikant höheren Rate an Leberfiliae lag. Auch Lungenfiliae und Peritonealcarcinosen traten in der RS-Gruppe vermehrt auf, dies jedoch nicht statistisch signifikant. In der Histopathologie zeigten Karzinome im SI öfter ein exulzerierendes, im RS und PR häufiger ein polypös-exophytisches Wachstumsmuster. Keine Unterschiede zwischen den Gruppen gab es hingegen in der Lymph- und Blutgefäßinvasion sowie im Differenzierungsgrad und der Tumorverschleimung. Das Follow-up lag im Median bei 36 (0 - 76) Monaten. Sowohl Lokalrezidive (SI 0%, RS 10%, PR 7,5%) als auch metachrone Fernmetastasen (SI 3,2%, RS 10%, PR 13,2%) waren im RS und dem PR häufiger. Schlussfolgerung: Karzinome des rektosigmoidalen Übergangs weisen sowohl Charakteristika des Sigmas als auch des proximalen Rektums auf. Sie ließen sich in unserer Analyse keiner der beiden Lokalisationen eindeutig zuordnen. Dies könnte mit der inhomogenen präoperativen Tumorlokalisierung assoziiert sein. Präoperativ sollte eine exakte endoskopische Höhenlokalisation des Tumorunterrands mit Zuordnung des Tumors zum Sigma oder proximalen Rektum erfolgen und dementsprechend die Therapie durchgeführt werden

Uptake and absorption of fluoranthene from spiked microplastics into the digestive gland tissues of blue mussels, Mytilus edulis L.

The present work intended to investigate the fate of contaminant-loaded microplastics if ingested by benthic filter feeder Mytilus edulis under laboratory conditions. In the course of a 7-day experiment the mussels were exposed to PVC microplastics in a size range >40 mm, in doses of 2000 particles L_1 (11.56 mg L_1). Particles were either virgin or loaded with one of four different nominal concentrations of the polycyclic aromatic hydrocarbon (PAH) fluoranthene (500, 125, 31.25 and 7.8125 mg g_1). Verification of fluoranthene concentrations on the particles provided evidence of the high absorptive capacity of PVC for this PAH, indicating that comparable particles may serve as considerable accumulation sites for high concentrations of hydrophobic contaminants in the aquatic environment. Analysis of digestive gland tissues via polarised light microscopy revealed the occurrence of particles and particle aggregates within stomach and intestines of all mussels treated with microplastics, thus making the xenobiotic bioavailable. Results of contaminant analysis in mussel tissues via equilibrium sampling point to a considerable capability of microplastics for the accumulation of hydrophobic contaminants from the environment and their potential to act as vehicles for the transport of theses contaminants into organismal tissues. of fluoranthene concentrations on the particles provided evidence of the high absorptive capacity of PVC for this PAH, indicating that comparable particles may serve as considerable accumulation sites for high concentrations of hydrophobic contaminants in the aquatic environment. Analysis of digestive gland tissues via polarised light microscopy revealed the occurrence of particles and particle aggregates within stomach and intestines of all mussels treated with microplastics, thus making the xenobiotic bioavailable. Results of contaminant analysis in mussel tissues via equilibrium sampling point to a considerable capability of microplastics for the accumulation of hydrophobic contaminants from the environment and their potential to act as vehicles for the transport of theses contaminants into organismal tissues. © 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY licens

Integrated Molecular Profiling as an Approach to Identify PI3K Inhibitor Resistance Mechanisms

The identification of drug resistance pathways and approaches to target these pathways remains a significant and important challenge in cancer biology. Here, we address this challenge in the context of ongoing efforts to advance phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of PI3K-aberrant cancers. While PI3K inhibitors have had tremendous success in some diseases, such as breast cancer, early clinical trials in other malignancies, such as head and neck squamous cell carcinoma (HNSCC), have not had the same level of success. Since HNSCC and other cancers display relatively high PI3K pathway alteration rates (>45%), these underwhelming results suggest that additional or unexpected factors may contribute to the lower response rates. Here, we highlight some of the emerging functional genomic and sequencing approaches being used to identify predictive biomarkers of PI3K inhibitor response using both cancer cell lines and clinical trial specimens. Importantly, these approaches have uncovered both innate genetic and adaptive mechanisms driving PI3K inhibitor resistance. In this chapter, we describe recent technological advances that have revolutionized our understanding of PI3K inhibitor resistance pathways in HNSCC and highlight how these and other approaches lay the groundwork to make significant strides in our understanding of molecular pharmacology in the cancer field

Проблемы технического нормирования шумовых характеристик текстильных машин

Для целей оценки соответствия шумовых характеристик машин требованиям санитарных норм предложено использовать обобщенные предельно допустимые шумовые характеристики, которые задают предельно допустимые характеристики для близких по типу машин, объединенных в группы с учетом характерной плотности их установки и условий эксплуатации. Для уточненного определения этих характеристик целесообразно использовать методику, учитывающую звукопоглощение и рассеяние шума поверхностью машин, плотность тел рассеяния в поперечном сечении производственного помещения и его акустические и геометрические характеристики.For the purposes of assessing the compliance of noise characteristics of machines with the requirements of sanitary standards, it is suggested to use generalized maximum permissible noise characteristics that set the maximum permissible characteristics for similar machines, grouped together, taking into account the characteristic density of their installation and operating conditions. For an accurate definition of these characteristics, it is advisable to use a technique that takes into account the sound absorption and noise scattering by the machine surface, the density of scattering bodies in the cross section of the production room and its acoustic and geometric characteristics

Fatal attraction of Caenorhabditis elegans to predatory fungi through 6-methyl-salicylic acid

Salicylic acid is a phenolic phytohormone which controls plant growth and development. A methyl ester (MSA) derivative thereof is volatile and involved in plant-insect or plant-plant communication. Here we show that the nematode-trapping fungus Duddingtonia flagrans uses a methyl-salicylic acid isomer, 6-MSA as morphogen for spatiotemporal control of trap formation and as chemoattractant to lure Caenorhabditis elegans into fungal colonies. 6-MSA is the product of a polyketide synthase and an intermediate in the biosynthesis of arthrosporols. The polyketide synthase (ArtA), produces 6-MSA in hyphal tips, and is uncoupled from other enzymes required for the conversion of 6-MSA to arthrosporols, which are produced in older hyphae. 6-MSA and arthrosporols both block trap formation. The presence of nematodes inhibits 6-MSA and arthrosporol biosyntheses and thereby enables trap formation. 6-MSA and arthrosporols are thus morphogens with some functions similar to quorum-sensing molecules. We show that 6-MSA is important in interkingdom communication between fungi and nematodes

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological-or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca(2+)calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction

Epstein-Barr virus and human papillomavirus serum antibodies define the viral status of nasopharyngeal carcinoma in a low endemic country

Epstein-Barr virus (EBV) causes nasopharyngeal carcinoma (NPC) in endemic regions, where almost every tumor is EBV-positive. In Western populations, NPC is rare, and human papillomavirus infection (HPV) has been suggested as another viral cause. We validated multiplex serology with molecular tumor markers, to define EBV-positive, HPV-positive, and EBV-/HPV-negative NPCs in the United Kingdom, and analyzed survival differences between those groups. Sera from NPC cases (N = 98) and age- and sex-matched controls (N = 142) from the Head and Neck 5000 clinical cohort study were analyzed. IgA and IgG serum antibodies against 13 EBV antigens were measured and compared with EBER in situ hybridization (EBER-ISH) data of 41 NPC tumors (29 EBER-ISH positive, 12 negative). IgG antibodies to EBV LF2 correctly diagnosed EBV-positive NPCs in 28 of 29 cases, while all EBER-ISH negative NPCs were seronegative to LF2 IgG (specificity = 100%, sensitivity = 97%). HPV early antigen serology was compared to HPV molecular markers (p16 expression, HPV DNA and RNA) available for 41 NPCs (13 positive, 28 negative). Serology matched molecular HPV markers in all but one case (specificity = 100%, sensitivity = 92%). EBV and HPV infections were mutually exclusive. Overall, 67% of the analyzed NPCs were defined as EBV-positive, 18% as HPV-positive and 14% as EBV/HPV-negative. There was no statistical evidence of a difference in survival between the three groups. These data provide evidence that both, EBV-positive and HPV-positive NPCs are present in a low incidence country, and that EBV and HPV serum antibodies correlate with the viral status of the tumor.</p

Mutations in POLE and survival of colorectal cancer patients – link to disease stage and treatment

Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase ϵ (POLE). Data on the clinical implications of these findings as to whether these mutations define a unique CRC entity with distinct clinical outcome are lacking. We performed Sanger sequencing of the POLE exonuclease domain in 431 well-characterized patients with microsatellite stable (MSS) CRCs of a population-based patient cohort. Mutation data were analyzed for associations with major epidemiological, clinical, genetic, and pathological parameters including overall survival (OS) and disease-specific survival (DSS). In 373 of 431 MSS CRC, all exons of the exonuclease domain were analyzable. Fifty-four mutations were identified in 46 of these samples (12.3%). Besides already reported EDMs, we detected many new mutations in exons 13 and 14 (corresponding to amino acids 410–491) as well as in exon 9 and exon 11 (corresponding to aa 268–303 and aa 341–369). However, we did not see any significant associations of EDMs with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, KRAS, and BRAF mutations. While with a median follow-up time of 5.0 years, survival analysis of the whole cohort revealed nonsignificantly different adjusted hazard ratios (HRs) of 1.35 (95% CI: 0.82–2.25) and 1.44 (0.81–2.58) for OS and DSS indicating slightly impaired survival of patients with EDMs, subgroup analysis for patients with stage III/IV disease receiving chemotherapy revealed a statistically significantly increased adjusted HR (1.87; 95%CI: 1.02–3.44). In conclusion, POLE EDMs do not appear to define an entirely new clinically distinct disease entity in CRC but may have prognostic or predictive implications in CRC subgroups, whose significance remains to be investigated in future studies

Chlamydia trachomatis genotypes in a cross-sectional study of urogenital samples from remote Northern and Central Australia

his is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Abstract OBJECTIVES: The objective was to determine the frequency of trachoma genotypes of Chlamydia trachomatis-positive urogenital tract (UGT) specimens from remote areas of the Australian Northern Territory (NT). SETTING: The setting was analysis of remnants of C. trachomatis positive primarily UGT specimens obtained in the course of clinical practice. The specimens were obtained from two pathology service providers. PARTICIPANTS: From 3356 C. trachomatis specimens collected during May 2012-April 2013, 439 were selected for genotyping, with a focus on specimens from postpubescent patients, in remote Aboriginal communities where ocular trachoma is potentially present. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the proportion of successfully genotyped UGT specimens that were trachoma genotypes. The secondary outcome measures were the distribution of genotypes, and the frequencies of different classes of specimens able to be genotyped. RESULTS: Zero of 217 successfully genotyped UGT specimens yielded trachoma genotypes (95% CI for frequency=0-0.017). For UGT specimens, the genotypes were E (41%), F (22%), D (21%) and K (7%), with J, H and G and mixed genotypes each at 1-4%. Four of the five genotyped eye swabs yielded trachoma genotype Ba, and the other genotype J. Two hundred twenty-two specimens (50.6%) were successfully genotyped. Urine specimens were less likely to be typable than vaginal swabs (p<0.0001). CONCLUSIONS: Unlike in some other studies, in the remote NT, trachoma genotypes of C. trachomatis were not found circulating in UGT specimens from 2012 to 2013. Therefore, C. trachomatis genotypes in UGT specimens from young children can be informative as to whether the organism has been acquired through sexual contact. We suggest inclusion of C. trachomatis genotyping in guidelines examining the source of sexually transmitted infections in young children in areas where trachoma genotypes may continue to circulate, and continued surveillance of UGT C. trachomatis genotypes