Playing on the dark side: Smyd3 acts as a cancer genome keeper in gastrointestinal malignancies

The SMYD3 methyltransferase has been found overexpressed in several types of cancers of the gastrointestinal (GI) tract. While high levels of SMYD3 have been positively correlated with cancer progression in cellular and advanced mice models, suggesting it as a potential risk and prognosis factor, its activity seems dispensable for autonomous in vitro cancer cell proliferation. Here, we present an in-depth analysis of SMYD3 functional role in the regulation of GI cancer progression. We first describe the oncogenic activity of SMYD3 as a transcriptional activator of genes involved in tumorigenesis, cancer development and transformation and as a co-regulator of key cancer-related pathways. Then, we dissect its role in orchestrating cell cycle regulation and DNA damage response (DDR) to genotoxic stress by promoting homologous recombination (HR) repair, thereby sustaining cancer cell genomic stability and tumor progression. Based on this evidence and on the involvement of PARP1 in other DDR mechanisms, we also outline a synthetic lethality approach consisting of the combined use of SMYD3 and PARP inhibitors, which recently showed promising therapeutic potential in HR-proficient GI tumors expressing high levels of SMYD3. Overall, these findings identify SMYD3 as a promising target for drug discovery

FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs

Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs. FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes. Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases

The art of rhinoplasty: researching technical and cultural foundations of western world rhinosurgery, from the middle ages to the renaissance

The analysis of the written sources allowed to follow the gradual development of every new technique in the field of rhinoplasty but also to understand the value of this surgery in those ancient times, highlighting a deep connection between traumatologic surgery of the nose and the development of modern ‘‘aesthetic and reconstructive’’ Rhinosurgery. Specifically, we analyzed the techniques described by less known surgeons to emphasize their cultural and surgical value. As a matter of fact, the descriptions offered by these authors clearly show the importance of rhinoplasty as a cardinal and autonomous practice since Antiquity, also clarifying the persistence and development of specific techniques for this surgical practice in the History of medicine. In the manuscript, the contributions of the Italian surgeons, such as Brancas and Vianeos families, are highlighted, demonstrating their influence on the progress of this surgical specialty in the Early Modern Age. Finally, we deepen the description of Gaspare Tagliacozzi’s work, pointing out the topics and controversial debates arising from his techniques and innovations in ‘‘rhinosurgery’’ and also in the field of tissue transplantation, laying the foundations of modern Plastic Surgery. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266

The medical historical cultural foundations of western nasal surgery from ancient greece to the middle ages

The manuscript aims to clarify the origins of Western rhinosurgery through the ancient texts of the greatest physicians of the past, up to the Byzantine Era, focusing on the "exchange of knowledge" between peoples. This excursus is carried out by quoting the texts of the greatest doctors of the past, such as Hippocrates, Galen and Celsus and by analysing the works of Byzantine authors such as Oribasius, Aetius, Antillus, which, more than others, represent the moment of fusion and interpenetration of Ancient Medical knowledge, paving the way for the Medieval Scholae Medicae in the West. The aim, therefore, is to fill that sort of "great gap" (from the foundation of Constantinople in the 4th century AD to the early Arab culture in the 11th century AD) due to the fact that figures such as Branca, Vianeo and, finally, Tagliacozzi, are considered direct actors of a recovery of the "ancient knowledge" of classic authors. This literature tends to less evaluate, instead, that important and huge cultural exchange -literally osmotic- in medical and surgical knowledge between peoples and civilizations, that find a trait d'union in the application of medical knowledge and surgical practical techniques matured in the Byzantine, Arab and Early Medieval period. In final analysis, through the History of Rhinosurgery, this paper aims to highlight how Western medical knowledge is made up of the ensemble of cultures which are apparently distant and different from each other, which merge themselves in a truly universal and transcultural knowledge: the Medical knowledge

Minimally Invasive Surgical Treatment of Migraine

Migraine headache (MH) is a very common disorder affecting 10–12% of the world’s adult population. The first line therapy for migraine is usually a combination of conservative treatments but some patients seem to be refractory. For this group of patients, the minimally invasive surgical treatment of migraine might offer a solution. Migraine is usually caused by extracranial sensitive nerve compression due vascular, fascial or muscular structures nearby. The aim of migraine surgery is to relieve such compression at specific trigger points located in the occipital, temporal and frontal regions. From June 2011 until July 2019, we performed MH decompression surgeries in over 269 patients with either frontal, occipital, or temporal migraine trigger sites. In the occipital and temporal areas, nerve decompression was achieved by occipital and superficial temporal artery ligation, respectively. In patients suffering from frontal headache we performed both endoscopic nerve decompression and transpalpebral decompression. Among patient suffering from occipital migraine, 95% of them showed improvement of their condition, with 86% reporting complete relief. As concern temporal migraine, positive outcome was achieved in 83% of the patients (50% complete elimination and 33% partial improvement). In patient suffering from frontal migraine, positive results were observed in 94% of the patients (32% complete elimination, 62% partial improvement). Migraine is a common and debilitating condition that can be treated successfully with minimally invasive surgical procedure especially for those patients non-responding to medical therapies

PODRIJETLO TRANSFUZIJE KRVI

This paper deals with the literary debate on the first experiments regarding blood transfusion on human beings between 1667 and 1668 in Europe, with particular attention to the less-known experimental research, carried out in Italy. The authors examine the details of the experimental developments, focusing on the techniques and instruments used by physicians involved in this new surgical approach, with special attention to the Italian debate and experimentations. The article suggests that transfusion was considered a part of what we could call “emergency surgery”. In this framework, Italian transfusional pioneers played a central role in the improvement and transmission of a discipline that was still in its dawning throughout Europe. Moreover, the manuscript highlights the contribution of the “chirurgia infusoria” as an innovative therapeutic system for an immediate and rapid recovery. From this perspective, blood transfusion represents a surgical practice for reanimation and resuscitation. The objective of this work was to analyze the importance of foreign literature and the English and French disputes presented by Davia in Italy, which made them known. Despite foreign prohibition in Italy, experiments with animal-to-human transfusions continued after 1648. A papal bull excommunicating scientists for conducting such research has never been found.Ovaj članak bavi se književnom raspravom o prvim eksperimentima vezanim uz transfuziju krvi na ljudima između 1667. i 1668. u Europi, s posebnim osvrtom na manje poznata eksperimentalna istraživanja provedena u Italiji. Autori ispituju detalje eksperimentalnog razvoja, fokusirajući se na tehnike i instrumente kojima se koriste liječnici uključeni u ovaj novi kirurški pristup, s posebnim osvrtom na talijansku raspravu i eksperimente. U članku se sugerira da se transfuzija smatra dijelom onoga što bismo mogli nazvati “hitnom operacijom”. U tom su okviru talijanski pioniri transfuzije imali važnu ulogu u poboljšanju i prenošenju discipline koja je još uvijek bila u nastajanju diljem Europe. Štoviše, članak ističe doprinos “chirurgiainfusoria” kao inovativnoga terapijskog sustava za trenutačan i brzi oporavak. Iz te perspektive, transfuzija krvi kirurška je praksa za reanimaciju i oživljavanje. Cilj je ovog rada bio analizirati važnost strane literature i engleskih i francuskih rasprava koje je Davia predstavio u Italiji, čime su oni postali poznati. Unatoč stranoj zabrani u Italiji, eksperimenti s transfuzijama sa životinje na čovjeka nastavljeni su i nakon 1648. Papinska bula koja je ekskomunicirala znanstvenike zbog provođenja takva istraživanja nikada nije pronađena

Chasing the Foxo3: Insights into its new mitochondrial lair in colorectal cancer landscape

Colorectal cancer (CRC) poses a formidable challenge in terms of molecular heterogeneity, as it involves a variety of cancer-related pathways and molecular changes unique to an individual’s tumor. On the other hand, recent advances in DNA sequencing technologies provide an unprecedented capacity to comprehensively identify the genetic alterations resulting in tumorigenesis, raising the hope that new therapeutic approaches based on molecularly targeted drugs may prevent the occurrence of chemoresistance. Regulation of the transcription factor FOXO3a in response to extracellular cues plays a fundamental role in cellular homeostasis, being part of the molecular machinery that drives cells towards survival or death. Indeed, FOXO3a is controlled by a range of external stimuli, which not only influence its transcriptional activity, but also affect its subcellular localization. These regulation mechanisms are mediated by cancer-related signaling pathways that eventually drive changes in FOXO3a post-translational modifications (e.g., phosphorylation). Recent results showed that FOXO3a is imported into the mitochondria in tumor cells and tissues subjected to metabolic stress and cancer therapeutics, where it induces expression of the mitochondrial genome to support mitochondrial metabolism and cell survival. The current review discusses the potential clinical relevance of multidrug therapies that drive cancer cell fate by regulating critical pathways converging on FOXO3a

Apc splicing mutations leading to in-frame exon 12 or exon 13 skipping are rare events in fap pathogenesis and define the clinical outcome

Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in APC exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature meta-analysis of APC splicing mutations. We found that 119 unique APC splicing mutations, including the one described here, have been reported in FAP patients, 69 of which have been characterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with four mutations causing skipping of exon 12 or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and five mutations leading to skipping of exon 5, 7, 8, or (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations causing skipping of exon 12 or 13 considered in this study cluster with the AFAP phenotype and reveal a potential molecular mechanism of pathogenesis in FAP disease

CD90 is regulated by notch1 and hallmarks a more aggressive intrahepatic cholangiocarcinoma phenotype

Background: Intrahepatic Cholangiocarcinoma (iCCA) is characterized by a strong stromal reaction playing a role in tumor progression. Thymus cell antigen 1 (THY1), also called Cluster of Differentiation 90 (CD90), is a key regulator of cell–cell and cell–matrix interaction. In iCCA, CD90 has been reported to be associated with a poor prognosis. In an iCCA PDX model, we recently found that CD90 was downregulated in mice treated with the Notch γ-secretase inhibitor Crenigacestat. The study aims to investigate the role of CD90 in relation to the NOTCH pathway. Methods: THY1/CD90 gene and protein expression was evaluated in human iCCA tissues and xenograft models by qRT-PCR, immunohistochemistry, and immunofluorescence. Notch1 inhibition was achieved by siRNA. THY1/CD90 functions were investigated in xenograft models built with HuCCT1 and KKU-M213 cell lines, engineered to overexpress or knockdown THY1, respectively. Results: CD90 co-localized with EPCAM, showing its epithelial origin. In vitro, NOTCH1 silencing triggered HES1 and THY1 down-regulation. RBPJ, a critical transcriptional regulator of NOTCH signaling, exhibited putative binding sites on the THY1 promoter and bound to the latter, implying CD90 as a downstream NOTCH pathway effector. In vivo, Crenigacestat suppressed iCCA growth and reduced CD90 expression in the PDX model. In the xenograft model, Crenigacestat inhibited tumor growth of HuCCT1 cells transfected to overexpress CD90 and KKU-M213 cells constitutively expressing high levels of CD90, while not affecting the growth of HuCCT1 control cells and KKU-M213 depleted of CD90. In an iCCA cohort, patients with higher expression levels of NOTCH1/HES1/THY1 displayed a significantly shorter survival. Conclusions: iCCA patients with higher NOTCH1/HES1/THY1 expression have the worst prognosis, but they are more likely to benefit from Notch signaling inhibition. These findings represent the scientific rationale for testing NOTCH1 inhibitors in clinical trials, taking the first step toward precision medicine for iCCA