Frizzled7: a promising achilles' heel for targeting the Wnt receptor complex to treat cancer

Frizzled7 is arguably the most studied member of the Frizzled family, which are the cognate Wnt receptors. Frizzled7 is highly conserved through evolution, from Hydra through to humans, and is expressed in diverse organisms, tissues and human disease contexts. Frizzled receptors can homo- or hetero-polymerise and associate with several co-receptors to transmit Wnt signalling. Notably, Frizzled7 can transmit signalling via multiple Wnt transduction pathways and bind to several different Wnt ligands, Frizzled receptors and co-receptors. These promiscuous binding and functional properties are thought to underlie the pivotal role Frizzled7 plays in embryonic developmental and stem cell function. Recent studies have identified that Frizzled7 is upregulated in diverse human cancers, and promotes proliferation, progression and invasion, and orchestrates cellular transitions that underscore cancer metastasis. Importantly, Frizzled7 is able to regulate Wnt signalling activity even in cancer cells which have mutations to down-stream signal transducers. In this review we discuss the various aspects of Frizzled7 signalling and function, and the implications these have for therapeutic targeting of Frizzled7 in cancer

Non-adversarial Robustness of Deep Learning Methods for Computer Vision

Non-adversarial robustness, also known as natural robustness, is a property of deep learning models that enables them to maintain performance even when faced with distribution shifts caused by natural variations in data. However, achieving this property is challenging because it is difficult to predict in advance the types of distribution shifts that may occur. To address this challenge, researchers have proposed various approaches, some of which anticipate potential distribution shifts, while others utilize knowledge about the shifts that have already occurred to enhance model generalizability. In this paper, we present a brief overview of the most recent techniques for improving the robustness of computer vision methods, as well as a summary of commonly used robustness benchmark datasets for evaluating the model's performance under data distribution shifts. Finally, we examine the strengths and limitations of the approaches reviewed and identify general trends in deep learning robustness improvement for computer vision

Constitutional principle of equality and legal regulation of gay marriages

Pravni poretci modernih demokracija kao svoju temeljnu vrijednost postavljaju prava osoba-pojedinaca, dok je smisao, glavna ideja i cilj takvih poredaka stvaranje adekvatne društvene sredine za potpuni i slobodan razvoj svakog pojedinca. Neometani razvoj nečije osobnosti nedvojbeno uključuje jedno od najintimnijih područja života - ljubav i seksualnost, tj. nečiju seksualnu orijentaciju. Seksualne manjine su vrlo često suočene s „tolerantnim“ stavom seksualne većine koji se može opisati kao „društveni imperativ nevidljivosti“. Drugim riječima, ne samo da se osoba drugačije seksualne orijentacije ne može lako prepoznati (na stranu određeni stereotipi) i time je on ili ona faktički nevidljiva, nego i pripadnici većine često vjeruju da bi homoseksualne osobe trebale biti potpuno zadovoljne samom slobodom „da rade ono što žele u svoja četiri zida“. Stoga ostajanje nevidljivim postaje temeljni oblik zaštite koju pruža većina. Međutim, seksualna orijentacija se prestaje promatrati isključivo kao ostvarivanje seksualnih sklonosti, budući da je to karakteristika koja uključuje međuljudske odnose kao izraz osnovnih ljudskih potreba. U tom je smislu besmisleno raspravljati o tezi da se radi o osobnom izboru. Do sada je većinom prihvaćeno da pravo na osobni razvitak, kao i pravo na uspostavljanje i razvoj određenih međuljudskih odnosa, spada u domašaj zaštite - i poštivanja - privatnog života. Tako je i Europski sud za ljudska prava, kod definiranja „privatnog života“ u čl. 8 Europske konvencije, potvrdio u različitim slučajevima da ovo pravo ne obuhvaća samo osobni razvitak, nego i što je još važnije, razvitak odnosa s drugim ljudima i s vanjskim svijetom u cjelini. Rad daje teorijski okvir poimanja načela jednakosti, a zatim prelazi na kratki pregled paradigmatskih ispitivanja i pristupa koje je u tom smislu razvio američki Vrhovni sud. Slijedi analiza novije sudske prakse kako na saveznoj, tako i na državnoj razini, kao i prikaz jedne od najliberalnijih odluka u odnosu na istospolne zajednice, a koju je donio Južnoafrički Ustavni sud. Načelo jednakosti i nediskriminacije potom se analizira u relevantnim pravorijecima Europskog suda za ljudska prava te razmatra i gledište prava Europske unije. Konačno, rad se osvrće na pravni okvir suzbijanja diskriminacije i uređenja istospolnih zajednica u Republici Hrvatskoj. Istraživanje pokazuje kontinuiranu reinterpretaciju načela jednakosti u kontekstu pravnog uređenja istospolnih zajednica i ukazuje na izazove s kojima će se uskoro suočiti naš nacionalni pravni poredak na tom području.Modern democratic legal organisation holds the rights of the individual or person as its fundamental value. However, the significance, main idea and aim of such organisation is the creation of an adequate social environment for the complete and free development of each individual. Unhindered development of someone’s person undoubtedly includes one of the most intimate areas of life which includes love and sexuality or someone’s sexual orientation. Sexual minorities very often are faced with the “tolerant” attitude of the sexual majority which can be described as the social “imperative of invisibility”. In other words, not only can the person of a different sexual orientation not be easily recognised ( by certain stenotypes) and therefore he or she is factually invisible, but also those belonging to the majority often believe that homosexuals should be completely satisfied merely with the freedom “ to do whatever they like within their own four walls”. Consequently, remaining invisible becomes the basic form of protection offered by the majority. However, sexual orientation is ceasing to be considered exclusively as achieving sexual preference given that is a characteristic which includes interpersonal relations as an expression of basic personal human needs. In this sense, it is senseless to discuss the theory that it is about personal choice. Up till now, it was for the most part accepted that the right to personal development, just as the right to form and develop certain interpersonal relations, belongs to the area of protecting and respecting one’s private life. So too did the European Court of Human Rights by defining one’s “private life” in article 8 of the European Convention confirm that in various cases this right does not only include personal development, but also what is more important, the development of relations with other people and with the outside world as a whole. This paper provides the theoretical framework of comprehending the principle of equality and then goes on to a brief overview of paradigma questioning and approaches developed by the American Supreme Court. Then, an overview of more recent court practice follows both at a federal and state level, including an analysis of one of the most liberal decisions related to same sex couples brought by the South African Constitutional Court. The principle of equality and non-discrimination is then analysed in relevant European Court of Human Rights judgements taking into consideration the stance of European Union law. Finally, this paper looks at the legal framework for combating discrimination and regulating same sex relationships in the Republic of Croatia. Research shows continual reinterpretation of the principle of equality in the context of legal regulation of same sex couples and points out the challenges soon to be faced by our national legal organisation in this area

Constitutional principle of equality and legal regulation of gay marriages

Pravni poretci modernih demokracija kao svoju temeljnu vrijednost postavljaju prava osoba-pojedinaca, dok je smisao, glavna ideja i cilj takvih poredaka stvaranje adekvatne društvene sredine za potpuni i slobodan razvoj svakog pojedinca. Neometani razvoj nečije osobnosti nedvojbeno uključuje jedno od najintimnijih područja života - ljubav i seksualnost, tj. nečiju seksualnu orijentaciju. Seksualne manjine su vrlo često suočene s „tolerantnim“ stavom seksualne većine koji se može opisati kao „društveni imperativ nevidljivosti“. Drugim riječima, ne samo da se osoba drugačije seksualne orijentacije ne može lako prepoznati (na stranu određeni stereotipi) i time je on ili ona faktički nevidljiva, nego i pripadnici većine često vjeruju da bi homoseksualne osobe trebale biti potpuno zadovoljne samom slobodom „da rade ono što žele u svoja četiri zida“. Stoga ostajanje nevidljivim postaje temeljni oblik zaštite koju pruža većina. Međutim, seksualna orijentacija se prestaje promatrati isključivo kao ostvarivanje seksualnih sklonosti, budući da je to karakteristika koja uključuje međuljudske odnose kao izraz osnovnih ljudskih potreba. U tom je smislu besmisleno raspravljati o tezi da se radi o osobnom izboru. Do sada je većinom prihvaćeno da pravo na osobni razvitak, kao i pravo na uspostavljanje i razvoj određenih međuljudskih odnosa, spada u domašaj zaštite - i poštivanja - privatnog života. Tako je i Europski sud za ljudska prava, kod definiranja „privatnog života“ u čl. 8 Europske konvencije, potvrdio u različitim slučajevima da ovo pravo ne obuhvaća samo osobni razvitak, nego i što je još važnije, razvitak odnosa s drugim ljudima i s vanjskim svijetom u cjelini. Rad daje teorijski okvir poimanja načela jednakosti, a zatim prelazi na kratki pregled paradigmatskih ispitivanja i pristupa koje je u tom smislu razvio američki Vrhovni sud. Slijedi analiza novije sudske prakse kako na saveznoj, tako i na državnoj razini, kao i prikaz jedne od najliberalnijih odluka u odnosu na istospolne zajednice, a koju je donio Južnoafrički Ustavni sud. Načelo jednakosti i nediskriminacije potom se analizira u relevantnim pravorijecima Europskog suda za ljudska prava te razmatra i gledište prava Europske unije. Konačno, rad se osvrće na pravni okvir suzbijanja diskriminacije i uređenja istospolnih zajednica u Republici Hrvatskoj. Istraživanje pokazuje kontinuiranu reinterpretaciju načela jednakosti u kontekstu pravnog uređenja istospolnih zajednica i ukazuje na izazove s kojima će se uskoro suočiti naš nacionalni pravni poredak na tom području.Modern democratic legal organisation holds the rights of the individual or person as its fundamental value. However, the significance, main idea and aim of such organisation is the creation of an adequate social environment for the complete and free development of each individual. Unhindered development of someone’s person undoubtedly includes one of the most intimate areas of life which includes love and sexuality or someone’s sexual orientation. Sexual minorities very often are faced with the “tolerant” attitude of the sexual majority which can be described as the social “imperative of invisibility”. In other words, not only can the person of a different sexual orientation not be easily recognised ( by certain stenotypes) and therefore he or she is factually invisible, but also those belonging to the majority often believe that homosexuals should be completely satisfied merely with the freedom “ to do whatever they like within their own four walls”. Consequently, remaining invisible becomes the basic form of protection offered by the majority. However, sexual orientation is ceasing to be considered exclusively as achieving sexual preference given that is a characteristic which includes interpersonal relations as an expression of basic personal human needs. In this sense, it is senseless to discuss the theory that it is about personal choice. Up till now, it was for the most part accepted that the right to personal development, just as the right to form and develop certain interpersonal relations, belongs to the area of protecting and respecting one’s private life. So too did the European Court of Human Rights by defining one’s “private life” in article 8 of the European Convention confirm that in various cases this right does not only include personal development, but also what is more important, the development of relations with other people and with the outside world as a whole. This paper provides the theoretical framework of comprehending the principle of equality and then goes on to a brief overview of paradigma questioning and approaches developed by the American Supreme Court. Then, an overview of more recent court practice follows both at a federal and state level, including an analysis of one of the most liberal decisions related to same sex couples brought by the South African Constitutional Court. The principle of equality and non-discrimination is then analysed in relevant European Court of Human Rights judgements taking into consideration the stance of European Union law. Finally, this paper looks at the legal framework for combating discrimination and regulating same sex relationships in the Republic of Croatia. Research shows continual reinterpretation of the principle of equality in the context of legal regulation of same sex couples and points out the challenges soon to be faced by our national legal organisation in this area

A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells

The embryonic programme ‘epithelial–mesenchymal transition' (EMT) is thought to promote malignant tumour progression. The transcriptional repressor zinc-finger E-box binding homeobox 1 (ZEB1) is a crucial inducer of EMT in various human tumours, and was recently shown to promote invasion and metastasis of tumour cells. Here, we report that ZEB1 directly suppresses transcription of microRNA-200 family members miR-141 and miR-200c, which strongly activate epithelial differentiation in pancreatic, colorectal and breast cancer cells. Notably, the EMT activators transforming growth factor β2 and ZEB1 are the predominant targets downregulated by these microRNAs. These results indicate that ZEB1 triggers an microRNA-mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells. Alternatively, depending on the environmental trigger, this loop might switch and induce epithelial differentiation, and thus explain the strong intratumorous heterogeneity observed in many human cancers

Targeting Wnt signaling for the treatment of gastric cancer

The Wnt signaling pathway is evolutionarily conserved, regulating both embryonic development and maintaining adult tissue homeostasis. Wnt signaling controls several fundamental cell functions, including proliferation, differentiation, migration, and stemness. It therefore plays an important role in the epithelial homeostasis and regeneration of the gastrointestinal tract. Often, both hypo- or hyper-activation of the pathway due to genetic, epigenetic, or receptor/ligand alterations are seen in many solid cancers, such as breast, colorectal, gastric, and prostate. Gastric cancer (GC) is the fourth commonest cause of cancer worldwide and is the second leading cause of cancer-related death annually. Although the number of new diagnoses has declined over recent decades, prognosis remains poor, with only 15% surviving to five years. Geographical differences in clinicopathological features are also apparent, with epidemiological and genetic studies revealing GC to be a highly heterogeneous disease with phenotypic diversity as a result of etiological factors. The molecular heterogeneity associated with GC dictates that a single ‘one size fits all’ approach to management is unlikely to be successful. Wnt pathway dysregulation has been observed in approximately 50% of GC tumors and may offer a novel therapeutic target for patients who would otherwise have a poor outcome. This mini review will highlight some recent discoveries involving Wnt signaling in GC

The hepatitis B virus pre-core protein p22 activates Wnt sgnaling

An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/β-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/β-catenin transcription. The effect of p22 on TCF/β-catenin transcription was dose dependent and inhibited by dominant-negative TCF4. HBV p22 activated synthetic and native Wnt target gene promoter reporters, and TCF/β-catenin target gene expression in vivo. Importantly, HBV p22 activated Wnt signaling on its own and in addition to Wnt or β-catenin induced Wnt signaling. Furthermore, HBV p22 elevated TCF/β-catenin transcription above constitutive activation in colon cancer cells due to mutations in downstream genes of the Wnt pathway, namely APC and CTNNB1. Collectively, our data identifies a previously unappreciated role for the HBV pre-core protein p22 in elevating Wnt signaling. Understanding the molecular mechanisms of p22 activity will provide insight into how Wnt signaling is fine-tuned in cancer

Frizzled-7 is required for Wnt signaling in gastric tumours with and without Apc mutations

A subset of patients with gastric cancer have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating gastric cancer, and the specific Wnt receptor transmitting oncogenic Wnt signaling in gastric cancer is unknown. Here, we use inhibitors of Wnt/Fzd (OMP-18R5/vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures. Pharmacologic targeting of Fzd inhibited the growth of gastric adenomas in vivo. We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of gastric cancer, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of Fzd7 or treatment with vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to Apc. Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating patients with gastric cancer regardless of APC mutation status

The central role of Wnt signaling and organoid technology in personalizing anticancer therapy

The Wnt pathway is at the heart of organoid technology, which is set to revolutionize the cancer field. We can now predetermine a patient's response to any given anticancer therapy by exposing tumor organoids established from the patient's own tumor. This cutting-edge biomedical platform translates to patients being treated with the correct drug at the correct dose from the outset, a truly personalized and precise medical approach. A high throughput drug screen on organoids also allows drugs to be tested in limitless combinations. More recently, the tumor cells that are resistant to the therapy given to a patient were selected in culture using the patient's organoids. The resistant tumor organoids were then screened empirically to identify drugs that will kill the resistant cells. This information allows diagnosis in real-time to either prevent tumor recurrence or effectively treat the recurring tumor. Furthermore, the ability to culture stem cell-derived epithelium as organoids has enabled us to begin to understand how a stem cell becomes a cancer cell or to pin-point the genetic alteration that underlies a given genetic syndrome. Here we summarize these advances and the central role of Wnt signaling, and identify the next challenges for organoid technology