RIPK3 unterdrückt die Entstehung von Kras-getriebenen Adenomen und Adenokarzinomen der Lunge

Lung cancer has the highest mortality of all cancer entities with 1.6 million deaths each year (The Cancer Genome Atlas Research, 2014). Despite substantial efforts and improvements in understanding the molecular underpinnings of lung cancer, the molecular heterogeneity of this disease renders treatment options insufficient for the majority of patients. Despite the availability of targeted drugs for specific patient subtypes such as those harboring defined driver mutations and the incorporation of immune-oncological treatment strategies, most patients experience resistance/relapse within several months to years. This exemplified the critical unmet medical need to identify alternative approaches for lung cancer treatment. As cancer develops by acquiring molecular capabilities that serve as milestones for carcinogenesis, an essential requirement for transformation is the sustained survival of cells despite the presence of cellular stress that impedes on their integrity. Blockade of programmed cell death not only protects cancer cells from self-inflicted death but also protects the tumors against the toxicity of many anti-cancer agents. Understanding the molecular mechanisms of programmed cell death and their blockade in cancer, therefore, provides an important avenue to explore for developing novel therapeutic strategies. Apart from apoptosis being the major form of programmed cell death, we are interested in investigating immunogenic cell deaths i.e. necroptosis whose role remains elusive in lung adenocarcinoma (LUAD). Necroptosis proceeds independent of caspases and occurs downstream of signaling through the death receptors such as tumor necrosis factor receptor (TNFR) or the Toll-like receptor (TLR) families, amongst others. One of the principal components of necroptosis, receptor-interacting protein kinase 3 (RIPK3), plays a vital role in inflammatory signaling and cell death pathways. In the framework of this thesis, a detailed investigation of the role of Ripk3 in lung tumorigenesis has been carried out. Using gene-targeted mouse models, primary murine and human lung cancer samples and available gene expression data sets, we set out to study the contribution of RIPK3 to pulmonary adenoma or adenocarcinoma formation. We found that Ripk3 is a tumor suppressor in murine lung tumorigenesis as it restricts tumor progression in Kras-driven tumors. Analogously, the analysis of TCGA gene expression data of LUAD patients indicates that RIPK3 expression reduces compared to healthy controls, an observation also confirmed by immunohistochemistry of human LUAD patient samples from tumor lesion at the protein level. To decipher the underlying mechanism, we find that Ripk3 leads to an immunogenic tumor microenvironment as Ripk3 drives immune cell (B cells and T cells) infiltration to rescue the tumor tissue. Moreover, Ripk3 deficiency leads to an increase in arginase1+ macrophages in the advanced stage. This may explain the increase in tumor burden (M2 pro-tumorigenic activity) as well as a decrease in T cell infiltration (arginase inhibits T cell propagation) in the lesion. Overall, this study determines the potential of RIPK3 as a tumor suppressor in lung tumorigenesis and sets the stage for future investigations into the capability of Ripk3 activator together with immunotherapy as therapeutics.Unter allen Krebserkrankungen hat Lungenkrebs mit 1,6 Millionen Toten im Jahr die höchste Mortalität (The Cancer Genome Atlas Research, 2014). Trotz substantieller Bemühungen und wesentlicher Fortschritte im Verständnis der molekularen Grundlagen von Lungenkrebs bedingt die hohe Heterogenität an Mutationen oftmals den Misserfolg der zur Verfügung stehenden Behandlungsmöglichkeiten. Obwohl spezifische Medikamente für Patienten-Subtypen mit beispielsweise definierten Driver-Mutationen verfügbar sind und immuntherapeutische Strategien Eintritt in die Behandlung gefunden haben, erfahren ein Großteil der Patienten innerhalb von Monaten bis Jahren ein Rezidiv oder haben mit Resistenzen zu kämpfen. Da Krebs durch die Anhäufung von fehlregulierten Mechanismen entsteht, die als Meilensteine für die Tumorgenese dienen, ist das erhaltene Überleben von Zellen in Anwesenheit von zellulärem Stress, die deren Integrität beeinträchtigt, eine essentielle Voraussetzung für deren Entwicklung zu Tumorzellen. Die Blockade des programmierten Zelltods schützt die Tumorzellen nicht nur vor internen Faktoren, die zu Zelltod führen, sondern auch gegen externe Faktoren und die Toxizität vieler antitumoraler Agenzien. Ein besseres Verständnis von den molekularen Mechanismen des programmierten Zelltods und dessen Blockade in Krebs kann somit einen wichtigen Beitrag zur Entwicklung von neuen therapeutischen Ansätzen leisten. Wir sind neben der Apoptose, der Hauptform des programmierten Zelltodes, interessiert an der Untersuchung des immunogenen Zelltods, zu dem unter anderem die Nekroptose gehört, dessen Rolle im Adenokarzinom der Lunge (LUAD) unklar ist. Nekroptose läuft unabhängig von Caspasen ab und findet nachgeschaltet an die Aktivierung von Todesrezeptoren wie zum Beispiel dem Tumornekrosefaktor-Rezeptor (TNFR) oder der Rezeptoren der Toll-like-Rezeptor-(TLR)-Familie statt. Eine der wesentlichen Komponenten von Nekroptose ist die receptor interacting protein kinase 3 (RIPK3), die eine unverzichtbare Rolle in den Signalwegen von Entzündung und Zelltod spielt. Im Rahmen dieser Arbeit wurde eine detaillierte Analyse der Bedeutung von RIPK3 in der Tumorgenese der Lunge durchgeführt. Für diese Untersuchung des Beitrags von RIPK3 zur Entstehung von pulmonalen Adenomen und Adenokarzinomen werden genetisch-modifizierte Mausmodelle, Proben von primär murinen und humanen Lungenkarzinomen und öffentlich verfügbare Genexpressionsdatensätze herangezogen. Wir konnten zeigen, dass RIPK3 als Tumorsuppressor in der murinen Tumorgenese der Lunge insofern fungiert, als es die Tumorprogression in kras-getriebenen Tumoren hemmt. Analog zeigt eine Analyse der TCGA-Genexpressionsdaten von Lungenadenokarzinomen, dass die mRNA-Expression von RIPK3 im Vergleich zu gesunden Kontrollen vermindert ist. Dies ist eine Beobachtung, die mittels Immunhistochemie an humanen Lungenadenokarzinomen auf dem Proteinlevel bestätigt werden konnte. In Bezug auf den zugrunde liegenden Mechanismus konnten wir nachweisen, dass RIPK3 zu einem immunogenen Tumor-Microenvironment führt, indem es zur Rekrutierung von B- und T-Lymphozyten führt. Darüber hinaus führt die Abwesenheit von RIPK3 im fortgeschrittenen Stadium zu einem Anstieg an arginase1+ Makrophagen. Dies könnte den assoziierten Anstieg der Tumorlast (Tumorgenese-fördernde Aktivität von M2) und auch die Reduktion der T-Zell-Infiltration (Inhibition der T-Zell-Ausbreitung durch die Arginase) erklären. Insgesamt bekräftigt diese Studie das Potenzial von RIPK3 als Tumorsuppressor in der Tumorgenese des Adenokarzinoms der Lunge. Sie bietet eine Grundlage für zukünftige Untersuchungen in Bezug auf eine mögliche RIPK3-Aktivierung und immuntherapeutische Ansätze

Role of hysterosalpingography in evaluation of tubal factors and its comparison with sonosalpingography

Background: Laparoscopy is considered as the gold standard for assessment of tubal factors of infertility, although because of its invasive nature, cost and the need for anaesthesia and hospitalization, HSG seems to be a basic routine procedure for tubal factors. Currently with the availability of the ultrasonography machines with very good resolution, SSG can be simultaneously practiced with ultrasonography during day 7-9 of the menstrual cycle to assess tubal patency. Hence, the present study was designed to compare the accuracy of HSG with SSG for evaluation of tubal factor infertility.Methods: This was a prospective cross-sectional study of 100 consecutive women with primary or secondary infertility without active pelvic infection, selected from OPD of Department of Obstetrics and Gynaecology, Acharya Vinoba Bhave Rural Hospital associated with Datta Meghe Institute of Medical Sciences University, Sawangi (Meghe), Wardha over a period of two years from September 2014 to August 2016.Results: In the present study for diagnosing tubal patency SSG had sensitivity of 88.64%, specificity of 75%, positive predictive value of 96.29% and negative predictive value of 47.36% and diagnostic accuracy of 87%, while HSG had sensitivity of 94.32%, specificity of 83.33%, positive predictive value of 97.64% and negative predictive value of 66.66% and diagnostic accuracy of 93%.Conclusions: Initial assessment of tubal patency by HSG is better than SSG as an indirect, outdoor, non-invasive procedure although with minimal radiation hazards. It allows documentation of tubal patency enables detection of several tubal lesions and permits assessments of the fine intratubal architectural details as well as little uterine pathology. It will help in reducing the number of laparoscopic procedures and their related complications and health care costs for confirmation of tubal patency

Treatment dilemma in an adolescent girl with idiopathic intracranial hypertension presenting with abnormal uterine bleeding and severe anemia

Abnormal uterine bleeding (AUB), specifically heavy menstrual bleeding (HMB) is a frequent complaint for adolescents. Idiopathic intracranial hypertension (IIH) is a syndrome of raised intracranial pressure, in the absence of any evidence of an intracranial space occupying lesion. Female sex, obesity and polycystic ovarian disease are known risk factors associated with IIH. This case report depicts the unusual case of an 18-year-old girl with IIH who presented with HMB for 28 days with severe anemia with Hb of 5.5 gm%. Urgent ophthalmic and neurological review was taken in view of IIH. Prompt treatment of AUB was done with blood transfusion, hemostatics, and orally administered iron supplements. Despite medical treatment for AUB, patient continued to bleed and hence after multidisciplinary discussion and informed consent she was started on low dose progesterone. Symptoms improved rapidly and she was discharged in a stable condition with tapering doses of medication and regular follow- up advice. Treatment of AUB in adolescents with IIH is a dilemma for physicians. To date, there is no direct evidence suggesting either implantable or oral contraceptives as a cause for IIH but few studies have closely linked oestrogen containing oral contraceptive pills and some levonorgestrel implants in IIH and hence these should be avoided

To Follow the Rules or Break Them: A Rule Following Perspective

Because most security breaches are caused by human error, employees are perceived as the first line of defense against threats. Accordingly, organizations invest in information security policy (ISP) creation, implementation, and training initiatives. However, despite a vast stream of research, employee compliance with the information security policy remains an issue. We argue that it is not enough to study the motivations behind ISP compliance, since the motivation for adaptive behavior (ISP compliance) may be different from maladaptive behaviors (avoidance and non-compliance); therefore, we take a rule-following perspective to study both. We argue that when the requirements of ISP disrupt their work, employees face rule tension. In response to rule tension, they are less likely to exhibit adaptive behaviors and more likely to exhibit maladaptive behaviors. In addition, we propose that two common governance approaches - (1) command-and-control, and (2) self-regulatory approach moderate the relationship between rule tension and adaptive and maladaptive behaviors in the context of ISP rule-following

Extraction and characterization of silk sericin

Study compares the quality and quantity of sericin obtained from four sources, namely mulberry silk cocoons, silk flats, reeling silk waste and woven silk fabric. Sericin has been extracted using the conventional HTHP machine as well as IR heating machine. Results show that among the four sources, the maximum yield of sericin (28%) is obtained from silk fabric followed by 25% sericin obtained from silk flats. IR machine extraction gives ~13 times higher yield of sericin as compared to that obtained by HTHP at 1000C for 60 min. Sample obtained from IR extraction is also compared with the standard sample in terms of its physical properties, morphological structure, protein quality, protein structure, molecular weight and thermal behaviour using various analytical methods. The study proposes a protocol for assessing the quality of sericin protein. Since the source as well as the method of extraction can affect the properties of sericin, this protocol can be used to assess and determine the quality parameters of various sericin samples

IMPACT OF IT PRODUCT COMPATIBILITY INITIATIVES ON THE MARKET VALUE OF FIRMS

Product compatibility is becoming increasingly important especially in the IT industry due to a high level of network effect in this industry. This study empirically examines the business value of IT product compatibility initiatives with respect to the nature of the compatibility achieved (i.e., horizontal compatibility, vertical compatibility) and the type of focal product (i.e., software, hardware) for which compatibility is achieved. Using event study methodology, this paper investigates the market reaction to announcements of compatibility initiatives over a three-year period. The results show that business announcements associated with horizontal compatibility yield higher abnormal returns than the ones with vertical compatibility. Also compatibility initiatives for software products tend to be associated with a more positive stock market reaction than those for hardware products. Our findings reveal the nuances in IT product compatibilities and the need to develop a richer theory to enhance our understanding of the various IT compatibilities. Our findings also provide business insights to strategic planners and help them understand how and when to invest in IT product compatibilities to obtain positive reactions from investors

Recent progress on sugarcane-bagasse based lactic acid production: technical advancements, potential and limitations

India is the largest producer of sugarcane in Asia and its sugar industry represents the second largest agro-based industry. Sugarcane bagasse (SCB), a major waste from sugar industries, is indisputably lignocellulosic biomass (LCB) embedding ∼60 % carbohydrates, making it a renewable source of fermentable sugars. Despite its unique chemical composition, SCB is primarily used for co-generation. The enormous potential of SCB can be unleashed, if sugar platform is created using biochemical route. Sugars serve as feedstock for fermentative production of several renewable fuels and chemicals, considered as key drivers for rapid industrialization. US Department of Energy has projected lactic acid (LA) as one of the top biomass-derived platform chemicals owing to its diverse applications and multi-billion-dollar market. Currently, the industrial production of LA is predominated by microbial fermentation (∼90 %) which principally uses the starchy or sugar-rich edible feedstocks. If its low-cost manufacturing relying on LCB is enabled, it can be a boon for emerging economies like India, strategically strengthening their socio-economic status. The present review showcases the technical advances made in exploiting the biochemical route towards commercial realization of LA production with SCB as the feedstock. It comprehensively discusses strategies developed in the area of pretreatment, saccharification and fermentation, bridging the gap between lab-scale and industrial LA production. It gives a glimpse on downstream processing of SCB-derived LA, which is still in its nascent stage and briefly talks about our perspective on LA as preferred choice for scale-up in “sugar industry” over other bio-based fuels and chemicals

A clinical study of association of maternal height and estimated foetal weight on mode of delivery

Background: Maternal height and antenatal estimated fetal weight can affect mode of delivery. The aims and objective of this study were to study the association between the mode of delivery and maternal height and estimated foetal weight.Methods: 240 full term primigravida women without any obstetric and medical complications who were admitted in Acharya Vinoba Bhave Rural Hospital Wardha for delivery were randomly selected for study. After delivery 138 women who underwent caesarean delivery formed the study group and 102 women who underwent vaginal delivery formed control group. These two groups were compared for their maternal heights and antenatal estimated foetal weight (by Johnson’s formula).Results: In present study (1) Mean height of women in study group was 147 cm while that in control group was 155 cm. (2) Out of 49 short statured women (height ≤ 145 cm) 47 (95.91%) had emergency caesarean section and 2(4.08%) women were delivered vaginally. (3) Estimated foetal weight in study group was 2956 grams while that in control group was 2845 grams.Conclusions: We conclude that short statured women with larger baby size has higher incidence of emergency caesarean delivery

Optimization of parameters for application of sericin on cotton knits

In this study, a process has been developed for durable coating of sericin on cotton knits. Treated samples are tested for wicking, stiffness, moisture vapour transmission rate and air permeability. Results show that cotton knits become more hydrophilic on application of sericin. Air and water vapour transmission improve, thus making the cotton sample suitable for applications in skin moisturizing and skin healing. These results indicate that sericin can be used to develop a durable finish on cotton for use in medical and sports garments

MIS-aligned Student Perspectives of Outsourcing and Offshoring

Outsourcing and offshoring (sourcing) aspects of IS functions have been common organizational activities for decades.However, the landscape is evolving. Organizations are shifting from primarily single vendor-client sourcing relationshipstoward innovative multi-vendor relationships integrated into organizational strategic plans. Current students are tomorrow’sleaders, and as such it is critical that IS programs teach cutting edge strategic sourcing concepts. We analyzed studentperceptions of the pros and cons of sourcing and found that current students largely anchor to a limited number of conceptsthat may be outdated and not representative of today’s competitive sourcing landscape. Current organizational trends insourcing require a different skill set for IS managers than those required in the past. More must be done to inform students ofcurrent trends in order to prepare them for the skills needed to be effective in their future IS roles. A framework of requiredskills for future IS managers is offered