Are Well Performing Catalysts for the Ring Opening Polymerization of l -Lactide under Mild Laboratory Conditions Suitable for the Industrial Process? the Case of New Highly Active Zn(II) Catalysts

Poly(lactic acid) (PLA) is one of the best candidates as a sustainable plastic material for a circular economy, being biodegradable, bio-based, recyclable, and displaying good thermal and mechanical properties. The industrial production of PLA is mainly based on the ring opening polymerization (ROP) of l-lactide (l-LA) promoted by tin(II) 2-ethylhexanoate [Sn(Oct)2] in a continuous solvent-free process operating at temperatures between 180 and 200 °C, above the melting point of the resulting isotactic polymer. Despite the huge efforts in the research of alternative catalysts based on less toxic metals, resulting in a plethora of highly active catalysts under laboratory mild conditions, very few candidates can compete with Sn(Oct)2 under industrially relevant conditions. We report a family of new Zn(II) complexes, bearing variously substituted monoanionic [N,O-] (imidazole[1,5-a]pyrid-3-yl)phenolate ligands, as catalysts for the ROP of l-LA under both mild (20 °C, solvent) and industrially relevant (190 °C, in the melt, technical grade unpurified monomer, very low catalyst loading) conditions. Interestingly, the best performing catalyst under mild conditions is the worst performing under harsh conditions, and, on the contrary, the less active catalysts under mild conditions compete well with Sn(Oct)2 under industrially relevant conditions. Kinetic and DFT mechanistic investigations shed light on the non-trivial role of the 2-pyridine substituent in the catalytic performances at different temperatures. Preliminary depolymerization tests on commercial PLLA samples suggested that the new catalysts can also be a suitable candidate for the chemical recycling of PLA under mild conditions

Study Protocol: Implementation of a Computer-Assisted Intervention for Autism in Schools: A Hybrid Type II Cluster Randomized Effectiveness-Implementation Trial

Background: The number of children diagnosed with autism has rapidly outpaced the capacities of many public school systems to serve them, especially under-resourced, urban school districts. The intensive nature of evidence-based autism interventions, which rely heavily on one-to-one delivery, has caused schools to turn to computer-assisted interventions (CAI). There is little evidence regarding the feasibility, effectiveness, and implementation of CAI in public schools. While CAI has the potential to increase instructional time for students with autism, it may also result in unintended consequences such as reduction in the amount of interpersonal (as opposed to computerized) instruction students receive. The purpose of this study is to test the effectiveness of one such CAI—TeachTown—its implementation, and its effects on teachers’ use of other evidence-based practices. Methods:This study protocol describes a type II hybrid cluster randomized effectiveness-implementation trial. We will train and coach 70 teachers in autism support classrooms in one large school district in the use of evidence-based practices for students with autism. Half of the teachers then will be randomly selected to receive training and access to TeachTown: Basics, a CAI for students with autism, for the students in their classrooms. The study examines: (1) the effectiveness of TeachTown for students with autism; (2) the extent to which teachers implement TeachTown the way it was designed (i.e., fidelity); and (3) whether its uptake increases or reduces the use of other evidence-based practices. Discussion: This study will examine the implementation of new technology for children with ASD in public schools and will be the first to measure the effectiveness of CAI. As importantly, the study will investigate whether adding a new technology on top of existing practices increases or decreases their use. This study presents a unique method to studying both the implementation and exnovation of evidence-based practices for children with autism in school settings. Trial registration: NCT02695693. Retrospectively registered on July 8, 2016

BI-69A11 enhances susceptibility of colon cancer cells to mda-7/IL-24-induced growth inhibition by targeting Akt

Background: Akt and its downstream signalling pathways contribute to the aetiology and progression of Colorectal Carcinoma (CRC). Targeting the Akt pathway is an attractive strategy but few chemotherapeutic drugs have been used to treat CRC with only limited success. BI-69A11, a small molecule inhibitor of Akt, efficiently inhibits growth in melanoma cells. Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 promotes cancer-selective apoptosis when delivered by a tropism-modified replication incompetent adenovirus (Ad.5/3-mda-7). However, Ad.5/3-mda-7 displays diminished antitumour efficacy in several CRC cell lines, which correlates with the expression of K-RAS. Methods: The individual and combinatorial effect of BI-69A11 and Ad.5/3-mda-7 in vitro was studied by cell viability, cell cycle, apoptosis and invasion assays in HT29 and HCT116 cells containing wild type or mutant K-ras, respectively. In vivo HT29 tumour xenografts were used to test the efficacy of the combination treatment. Results: BI-69A11 inhibited growth and induced apoptosis in CRC. However, combinatorial treatment was more effective compared with single treatment. This combination showed profound antitumour and anti angiogenic effects in vitro and in vivo by downregulating Akt activity. Conclusions: BI-69A11 enhances the antitumour efficacy of Ad.5/3-mda-7 on CRC overexpressing K-RAS by inducing apoptosis and regulating Akt activity thereby warranting further evaluation in treating CRC

RNA analysis of consensus sequence splicing mutations: implications for thediagnosis of Wilson disease

Wilson disease (WD) is an autosomal recessive disorder caused by a defective function of the copper-transporting ATP7B protein. This results in progressive copper overload and consequent liver, brain, and kidney damage. Approximately 300 WD-causing mutations have been described to date. Missense mutations are largely prevalent, while splice-site mutations are rarer. Of these, only a minority are detected in splicing consensus sequences. Further, few splicing mutations have been studied at the RNA level. In this study we report the RNA molecular characterization of three consensus splice-site mutations identified by DNA analysis in WD patients. One of them, c.51 + 4 A --> T, resides in the consensus sequence of the donor splice site of intron 1; the second, c. 2121 + 3 A --> G, occurred in position + 3 of intron 7; and the c.2447 + 5 G --> A is localized in the consensus sequence of the donor splice site of intron 9. Analysis revealed predominantly abnormal splicing in the samples carrying mutations compared to the normal controls. These results strongly suggest that consensus sequence splice-site mutations result in disease by interfering with the production of the normal WD protein. Our data contribute to understanding the mutational spectrum that affect splicing and improve our capability in WD diagnosis

CUP-syndrome: Inguinal high grade serous ovarian carcinoma lymph node metastases with unknown primary origin – a case report and literature review

Objective: High-grade serous ovarian carcinoma (HGSC) often presents lymph node involvement. According to the paths of lymphatic drainage, the most common site of nodal metastasis is in the aortic area. However, pelvic lymph nodes are also involved and inguinal metastases are less frequent. Methods: Our report concerns the case of a 78-year-old woman with an inguinal lymph node relapse of HGSC, with the prior positivity of a right inguinal lymph node, after the primary surgery. Ovaries and tubes were negative on histological examination. A comprehensive search of the literature published from January 2000 to October 2021 was conducted on PubMed and Scopus. The papers were selected following the PRISMA guidelines. Nine retrospective studies were evaluated. Results: Overall, 67 studies were included in the initial search. Applying the screening criteria, 36 articles were considered eligible for full-text reading of which, after applying the exclusion criteria, 9 studies were selected for the final analysis and included in the systematic review. No studies were included for a quantitative analysis. We divided the results according to the relapse location: loco-regional, abdominal, and extra-abdominal recurrence. Conclusions: Inguinal node metastasis is a rare but not unusual occurrence in HGSC. A reasonable level of suspicion should be maintained in patients with inguinal adenopathy and high CA125 values, especially in women with a history of gynecologic surgery, even in the absence of negative imaging for an ovarian origin

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Mesonephric-Like Adenocarcinomas a Rare Tumor: The Importance of Diagnosis

Mesonephric-like adenocarcinomas (MLA) are rare neoplasms that arise in the uterine body and ovary and have been added to the World Health Organisation’s recent 2020 classification of female genital cancers. The pathogenesis of MLA is unknown and it remains debated whether they represent mesonephric carcinomas (Wolffian) arising in the endometrium/ovary or endometrioid carcinomas (Müllerian) closely mimicking mesonephric carcinomas. Here we report the case of a 57-year-old woman with an initial misdiagnosis of endometrioid adenocarcinoma on diagnostic biopsy. The patient came to our clinical evaluation for the appearance of menometrorrhagia complicated by anemia for several months. Therefore, she underwent pelvic echo-flowmetry, with indication for diagnostic hysteroscopy with endometrial biopsy, which yielded a positive result for endometrioid endometrial adenocarcinoma. Following staging CT scan and targeted examinations on pulmonary findings, the patient underwent surgery with surprise of definitive diagnosis deponent for endometrial MLA. Our intention is to establish a brief review of the scientific evidence in the literature and the tools available for a correct histological diagnosis, in the light of the scant anatomopathological evidence. Our question gives rise to the motive for the publication: is immunohistochemistry the right way to resolve the diagnostic error at histology, which is usually the only source of diagnostic certainty? This case is intended to alert of diagnostic error that risked having the patient treated as a neoplasm with a favorable prognosis and low degree of aggressiveness instead of for a very aggressive and poor prognosis tumor such as MLA

Pattern of ancient goat migration revealed by AFLP molecular markers

I marcatori AFLP ricostruiscono gli spostamenti di Capra hircus al seguito delle antiche migrazioni umane. Capra hircus \ue8 adattabile a condizioni ambientali molto differenti e possiede un areale di distribuzione estremamente ampio. Studi recenti suggeriscono che la capra abbia giocato un ruolo chiave nel sostentamento delle popolazioni umane durante le migrazioni demiche verso ovest, successive alla rivoluzione agricola del Neolitico. Lo studio della variabilit\ue0 genetica di questa specie pu\uf2 quindi essere un utile strumento sia per ricostruire le antiche migrazioni umane, sia per preservare la diversit\ue0 biologica di razze storiche e localmente adattate. L\u2019analisi statistica dei marcatori AFLP effettuata su 44 razze autoctone (campionate in Europa, Medio Oriente, Anatolia) e 2 cosmopolite, affiancata da metodi di interpolazione geografica, ha permesso di evidenziare: - la peculiare composizione genetica delle razze Orobica e Tauernshecken (entrambe di origine incerta) rispetto ai popolamenti europeo e medio-orientale; - un significativo gradiente di distribuzione delle distanze genetiche tra razze che da sud-est procede verso nord-ovest, sovrapponibile al modello di variazione genetica umana, probabile traccia di almeno due differenti eventi di migrazioni umane lungo la via di espansione neolitica dell\u2019agricoltura.Domestic goat (Capra hircus) is a very adaptable and geographically spread livestock species. Recent studies on mitochondrial DNA diversity suggest that goats have been the most widely transported and traded livestock species. For this reason it is thought to have played a central role in the demic spread of agriculture during the Neolithic agricultural revolution (Luikart et al. 2001). The investigation of the evolutionary and demographic history of C. hircus may indeed shed light on human past history and migrations and contribute to explain human populations biological diversity as we observe it nowadays. Knowledge on the level and distribution of diversity within a species has also immediate importance for the management and conservation of locally adapted populations. The sustainable conservation and management of small ruminant genetic resources are addressed in the EU ECONOGENE project, that combines molecular genetics, socio-economics and geostatistics to accomplish these tasks. One of the major objectives of the project is to investigate geographic patterns of genetic variation at the individual, farm and population level. Here we present preliminary results of the analysis of the AFLP goat dataset comprising 44 autochthonous and 2 cosmopolite breeds sampled across Europe and Middle East