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Minimally invasive robotic surgery offer benefits such as reduced physical trauma, faster recovery and lesser pain for the patient. For these procedures, visual and haptic feedback to the surgeon is crucial when operating surgical tools without line-of-sight with a robot. External force sensors are biased by friction at the tool shaft and thereby cannot estimate forces between tool tip and tissue. As an alternative, vision-based force estimation was proposed. Here, interaction forces are directly learned from deformation observed by an external imaging system. Recently, an approach based on optical coherence tomography and deep learning has shown promising results. However, most experiments are performed on ex-vivo tissue. In this work, we demonstrate that models trained on dead tissue do not perform well in in vivo data. We performed multiple experiments on a human tumor xenograft mouse model, both on in vivo, perfused tissue and dead tissue. We compared two deep learning models in different training scenarios. Training on perfused, in vivo data improved model performance by 24% for in vivo force estimation.

Insulin resistance is the hallmark of Type 2 Diabetes and is still an unmet medical need. Insulin resistance lies at the crossroads of non-alcoholic fatty liver disease, obesity, weight loss and exercise resistance, heart disease, stroke, depression, and brain health. Insulin resistance is purely nutrition related, with a typical molecular disease food intake pattern. The insulin resistant state is accessible by TyG as the appropriate surrogate marker, which is found to lead the personalized molecular hepatic nutrition system for highly efficient insulin resistance remission. Treating insulin resistance with a molecular nutrition-centered approach shifts the treatment paradigm of Type 2 Diabetes from management to cure. This allows remission within five months, with a high efficiency rate of 85%. With molecular intermittent fasting a very efficient treatment for prediabetes and metabolic syndrome is possible, improving the non-alcoholic fatty liver disease (NAFL) state and enabling the body to lose weight in a sustainable manner., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Due to the frequency and severity of cold symptoms in children, and the risk of associated complications, effective treatments are urgently needed. Here we evaluated the safety profile and treatment benefits of Echinacea in children with acute cold and flu symptoms. Methods: A total of 79 children (4-12 years) were randomized to a treatment regimen of three or five times daily Echinaforce Junior tablets (total of 1200 or 2000 mg Echinacea extract, EFJ) for the prospective treatment of upcoming cold and flu episodes at first signs. Parents recorded respiratory symptoms daily during episodes in their child and physicians and parents subjectively rated tolerability. Results: EFJ was used to treat 130 cold episodes in 68 children and was very well tolerated by more than 96% positive physician's ratings. EFJ-treated cold episodes lasted 7.5 days on average, with nine out of 10 episodes being fully resolved after 10 days. Five EFJ tablets daily reduced the average episode duration by up to 1.7 days ( p < 0.02) in comparison to three EFJ tablets daily regimen. Effective symptom resolution finally contributed to a low antibiotic prescription rate in this study of 4.6%. Conclusions: EFJ tablets present a valuable option for the treatment of acute cold episodes in children showing a wide safety margin and increased therapeutic benefits at five tablets daily.

The melanocytic lineage, which is prominently exposed to ultraviolet radiation (UVR) and radiation-independent oxidative damage, requires specific DNA-damage response mechanisms to maintain genomic and transcriptional homeostasis. The coordinate lineage-specific regulation of intricately intertwined DNA repair and transcription is incompletely understood. Here we demonstrate that the Microphthalmia-associated transcription factor (MITF) directly controls general transcription and UVR-induced nucleotide excision repair by transactivation of GTF2H1 as a core element of TFIIH. Thus, MITF ensures the rapid resumption of transcription after completion of strand repair and maintains transcriptional output, which is indispensable for survival of the melanocytic lineage including melanoma in vitro and in vivo. Moreover, MITF controls c-MYC implicated in general transcription by transactivation of far upstream binding protein 2 (FUBP2/KSHRP), which induces c-MYC pulse regulation through TFIIH, and experimental depletion of MITF results in consecutive loss of CDK7 in the TFIIH-CAK subcomplex. Targeted for proteasomal degradation, CDK7 is dependent on transactivation by MITF or c-MYC to maintain a steady state. The dependence of TFIIH-CAK on sequence-specific MITF and c-MYC constitutes a previously unrecognized mechanism feeding into super-enhancer-driven or other oncogenic transcriptional circuitries, which supports the concept of a transcription-directed therapeutic intervention in melanoma.

Here we describe the establishment and characterization of an AR+, PSMA+, ERG+, PTEN -/- , CHD1 +/- patient-derived xenograft (PDX) model termed 'C5', which has been developed from a 60 years old patient suffering from castration-resistant prostate cancer (CRPC). The patient underwent radical prostatectomy, showed early tumor marker PSA recurrence and, one year after surgery, abiraterone resistance. Subcutaneous C5 tumors can be serially transplanted between mice and grow within ~90 days to 1.5-2 cm³ tumors in SCID Balb/c mice (take rate 100%), NOD-scid IL2Rg null (NSG) mice (100%) and C57BL/6 pfp -/- /rag2 -/- mice (66%). In contrast, no tumor growth is observed in female mice. C5 tumors can be cryopreserved and show the same growth characteristics in vivo afterwards. C5 tumor cells do not grow stably in vitro, neither under two- nor three-dimensional cell culture conditions. Upon serial transplantation, some C5 tumors spontaneously disseminated to distant sites with an observable trend towards higher metastatic cell loads in scid compared to NSG mice. Lung metastases could be verified by histology by means of anti-PSMA immunohistochemistry, exclusively demonstrating single disseminated tumor cells (DTCs) and micro-metastases. Upon surgical resection of the primary tumors, such pulmonary foci rarely grew out to multi-cellular metastatic colonies despite doubled overall survival span. In the brain and bone marrow, the metastatic cell load present at surgery even disappeared during the post-surgical period. We provide shallow whole genome sequencing and whole exome sequencing data of C5 tumors demonstrating the copy number aberration/ mutation status of this PCa model and proving genomic stability over several passages. Moreover, we analyzed genomic and transcriptomic alterations during metastatic progression achieved by serial transplantation. This study describes a novel PCa PDX model that enables future research on several aspects of metastatic PCa, particularly for the AR+ , ERG+ , PTEN -/- PCa subtype.

We investigated the functional role of CEACAM1 in a spontaneous metastasis xenograft model of human melanoma in scid mice using BRAF wildtype MeWo cells with and without RNAi mediated knockdown of CEACAM1. Tumors from the xenograft model were subjected to whole genome expression analysis and metastasis was quantified histologically. Results and identified markers were verified using tissue samples of over 100 melanoma patients. Knockdown of CEACAM1 prolonged the animals' survival by significantly reducing subcutaneous growth of MeWo tumors and spontaneous lung metastasis. Microarray analysis revealed a strong influence of CEACAM1 knockdown on the network of EMT associated genes in the xenograft tumors (e.g. downregulation of BRAF, FOSL1, NRAS and TWIST). IGFBP7 and Latexin (highest up- and downregulated expression in microarray analysis) were found to be associated with longer and shorter survival, respectively, of melanoma patients. High FOSL1 and altered TWIST1 expression were found to be correlated with shortened survival in the cohort of melanoma patients. After a stepwise selection procedure combining above markers, multivariate analysis revealed IGFBP7, Latexin and altered TWIST to be prognostic markers for death. CEACAM1 could be a target for melanoma therapy as an alternative to (or in combination with) immune checkpoint and BRAF inhibitors.

Purpose: To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients., Experimental Design: Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfp(-/-)/rag2(-/-) mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples., Results: PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of β1,6-N-acetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [β(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival., Conclusion: We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of β(1,6)-branched oligosaccharides for prostate cancer progression.

Although survival rates of colon cancer patients diagnosed at an early stage (T1-2N0M0; Dukes A) vary considerably according to the studies cited, several studies indicate development of distant metastases already occurring in a considerable percentage of these patients leading to the death of the patients. This particular high risk group cannot be identified properly as no marker exists to identify these patients. As the Wnt/Win pathway plays a crucial role in metastasis formation in colorectal carcinoma, we analysed whether the transcription factor brachyury critically involved in this pathway may predict metastasis formation in these patients. The expression of brachyury-homologous (T) was immunohistochemically analysed in 748 patients and the data were correlated with classical and newer prognostic markers in colorectal cancer. Early stages colorectal cancer patients (T1-2N0M0, Dukes A) showed a significantly decreased survival when brachyury was expressed in the tumour tissue while no correlation was observed in later tumour stages. Hence a subset of colorectal cancers exists in which the ability to metastasise is already present at early stages of tumour growth and this high risk group can now be detected by immunohistochemistry., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In situ hearts and isolated cardiomyocytes from heterozygous connexin 43-deficient (Cx43+/-) mice cannot be protected by ischemic preconditioning or diazoxide. We have now addressed the role of connexin 43 in ischemic postconditioning (PC). Wild type (WT) and Cx43+/- mice were subjected to 30 min coronary occlusion and 120 min reperfusion, with and without a PC protocol of three cycles of 10 s coronary occlusion/10 s reperfusion. Infarct size (TTC staining) was reduced by PC from 54+/-5 to 37+/-3% of area at risk in WT. Likewise, infarct size was reduced by PC from 53+/-4 to 34+/-3% of area at risk in Cx43+/-. We conclude that connexin 43 is no prerequisite for PC's protection. To this end, the signal transduction of ischemic preconditioning and postconditioning differs.

Background: In spinal cord injuries disturbed defecation, constipation and their concomitant disorders are frequent clinical symptoms. They may severely impair the quality of life of the affected patients. The presented case study and two more case reports, summarized in table form, outline therapeutic difficulties and therapy options in the treatment of constipation in paraplegic patients., Case Report: A 69-year-old male patient with tetraplegia below C4 suffered from disturbed defecation, constipation with recurrent co-prostasis and pronounced meteorism which impeded breathing. Padma Lax was applied for several months, and constipation and the concomitant meteorism were noticeably reduced., Conclusion: The herbal preparation based on a formula from Tibetan Medicine may offer new therapeutic options in the care and treatment of patients with severe constipation. This report could also give first indications for controlled clinical studies in tetraplegic patients.

The peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor that plays a regulatory role in cell differentiation and proliferation. PPARgamma was first detected in adipocytes, however, it has been shown that this receptor is also expressed in normal as well as tumor cells including malignant colonic epithelial cells. In this study, the effect of the PPARgamma agonist RO205-2349, a recently developed thiazolidinedione, on tumor growth was evaluated. For this purpose, human colon cancer cells (HT29) were grown in severe combined immunodeficient mice. Under daily RO205-2349 treatment (50 mg/kg/day) a significantly reduced tumor weight became evident after 3 weeks. In the control (n = 10) and treatment (n = 10) groups the mean tumor weights were 0.45 and 0.16 g, respectively. The mean percentages of apoptotic cells were 0.8 and 2.7% in the control and treatment groups, respectively, and the cell diameter measured on average 11.4 and 9.4 microm. In contrast, cell proliferation and differentiation, which are considered to be influenced by the PPARgamma, remained unaffected as could be seen by Ki-67 and carcinoembryonic antigen immunoreactivity indicating that increased rate of apoptosis and cell shrinkage are responsible for the differences in tumor growth. Hence, in this human/mouse xenograft model, mechanisms other than the classical activation of PPARgamma are likely reasons causing limited tumor growth., (Copyright 2004 Elsevier Ireland Ltd.)

The subcompartmentalization of the white pulp in the spleen is the result of interactions of specific resident stromal cells and migrating subtypes of lymphocytes. Because carbohydrate residues of cell membranes and extracellular matrices are involved in cell-cell and cell-matrix interactions, they were investigated in rat spleen by a broad panel of lectins. Splenic macrophages, which were also demonstrated by Perls' Prussian blue reaction, were labeled selectively by most mannose-specific lectins and gave the characteristic distribution patterns in all splenic (sub)compartments. One recently isolated lectin, Chelidonium majus agglutinin (CMA), visualized predominantly central arterioles, the reticular meshwork (RM) in the periarteriolar lymphatic sheaths (PALS), the circumferential reticulum cells limiting PALS and follicles, and some follicular dendritic cells (FDCs) in white pulp. The endothelial cells of venous sinuses in red pulp were also labeled by CMA and, if frozen sections were used, CMA also labeled the macrophages of the red pulp. Compared to CMA, the monoclonal antibody CD11, which can be used only in frozen sections, stained almost solely the fibrous (extracellular) component of the RM. Because CMA stains the reticulum cells in particular, it is better suited to visualize the stromal architecture of splenic white pulp than the monoclonal antibody. Because CMA can be applied to paraffin-embedded material, it is a particularly useful tool to study the splenic stromal architecture in archival material.

The Askin tumor is one of a group of small round cell tumors and is found mainly in the thoraco-pulmonary region of children and young adults. The treatment of the patient and the differentiation of this tumor from other small round cell tumors, especially Ewing's sarcoma and neuroblastoma by light microscopy, immunohistochemical methods, and electron microscopy is discussed.

At the beginning of the 20th century the veterinary relations between Turkey and Germany intensified at the military level. After the Balkan Wars there were urgent attempts to reorganize the army, which lead to the visit of a German military mission under General L. von Sanders, who was appointed to review the army. Along with other members of the German military mission A. Thieme (1881-1949) belonged to the staff of the Turkish Army's Supreme Command as orderly officer and as advisory army veterinarian. During the First World War (1914-1918) there were 44 German veterinary officers, 23 in Turkish and 21 in German uniform. The veterinary officers in Turkish formations were assigned to the military mission, where the veterinary major Dr. K. Dreyer served as official adviser. Moreover mixed German-Turkish special units were formed under German leadership in Turkey, which included German veterinary officers in German uniform. The higher salaries were paid to the German veterinary officers than their Turkish colleagues by the Turkish government. As far as can gathered three German officers perished in Turkey.

The ability of prenatal cerebral tissue to bind different lectins was analyzed using cryostat sections of mouse brains. It was shown that the immature cells within the embryonic cell layers possess receptors for different lectins in varying amounts. Of all lectins tested, only PNL, RCL and LPL were bound on the outer cell membranes to a considerable degree. Although the labeling patterns of PNL and RCL are similar, the latter is additionally well detectable on the wall of cerebral blood vessels. Cells of the ventricular layer are moderately labeled by PNL, which recognizes beta-D-galactosyl (1-3)-N-acetyl-D-galactosamine, but heavily labeled by LPL which binds to terminal sialic acid residues. Cells of the intermediate layer, on the other hand, are heavily stained PNL and only faintly by LPL. Hence it is suggested that the process of migration might be correlated to the removal of terminal sialic acid moieties from cell surface glycoconjugates, resulting in an exposure of the penultimate galactosyl residues.

To characterize the relative toxicity of different bile salts, isolated hepatocytes were incubated with different concentrations of one bile salt or with identical concentrations of different bile salts and their conjugates. Incubation lasted for 1 hr; samples were taken at intervals and studied for enzyme release, urea synthesis and stimulation by glucagon, and by electron microscopy. While the trihydroxylated bile salt, taurocholate, did not produce alterations at concentrations up to 1,500 microM, the dihydroxylated salts, chenodeoxy- and deoxycholate, caused enzyme release and membrane lysis, and inhibited urea synthesis at concentrations above 500 microM. In contrast, ursodeoxycholate was ineffective at concentrations up to 1,500 microM. Conjugation of these bile salts did not result in significant differences with the exception of deoxycholate conjugates which induced enzyme leakage more rapidly. Studies of lipid membrane vesicles revealed corresponding alterations. The monohydroxylated salt, taurolithocholate, caused cellular damage as indicated by enzyme loss and impairment of hormonal sensitivity of cells at low concentrations (30 to 100 microM). Dihydroxylated salts produced a different time course of membrane leakage, ultrastructural changes and release of volume marker and lipid in liposomes, suggesting a possible different mechanism of damage induced by this bile salt. Both systems can readily be used to study bile salt membrane interactions.

Up till emybryonic day (ED) the 13 the prenatal histogenesis of rat mesencephalic roof is characterized by an exclusive proliferation of ventricular cells. Then the first differentiating postmitotic cells are found above the ventricular layer, so that proliferation and differentiation occur simultaneously. On ED 15 a lamination typical for embyronic CNS with ventricular, subventricular, intermediate layers and stratum zonale can be observed in the area of presumptive colliculus superior. A definite demarcation between ventricular and subventricular layers, however, is only possible by means of autoradiograpahic methods. At the end of gestation the lamination of adult colliculus superior is already noticeable. During early prenatal development, cells which originate on one single day can autoradiographically be demonstrated in different cell layers and particularly over the whole width of the intermediate layer, while towards the end of gestation time of cell origin and location inside the mesencephalic roofs are closely correlated: cells that originate on ED 13 can be found predominantly in deeper cell layers (stratum griseum profundum, lower stratum griseum intermedium), while cells originating on EDs 15 and 17 are on ED 21 situated in the upper cell layers (upper stratum griseum intermedium, stratum griseum superficiale). This results in an inside-outside gradient of cell origin, which corresponds to an inside-outside gradient of cell differentiation. Besides, a rostro-caudal and a lateromedial gradient can be observed. On ED 13 a median ventriculaar formation (MVF) can be distinguished displaying a significantly lower mitotic activity than the cells of the neighbouring ventricular layer as could be demonstrated by autoradiographic investigation. This difference is even more pronounced in latter embryonic stages. From ED 17 on the cells of this particular structure are arranged in a typical onion-like pattern. Towards the end of gestation the MVF expands considerably as compared with the surrounding ventricular layer. As long-time experiments with 3H-thymidine reveala this increase in area is brought about by the immigration of numerous ventricular cells which originated on earlier embryonic days. The apical processes of the cells of the MVF form a thick fibre bundle which can be followed upwards to the stratum zonale. Ulstructurally these strictly parallel arranged fibers mainly resembly astroglial processes, but possess, in contrast to the latter, numerous microtubules. Because of their morphological characteristics a classification of these cells as tanycytes appears justified. The MVF is compared with similar structures in other regions of the CNS and its possible function as a guide for migrating preneurons is discussed.