bluuebunny/crossref_metadata_2025 huggingface dataset:
Splicing-accessible coding 3′UTRs control protein stability and interaction networks
Authors: Preussner Marco , Gao Qingsong , Morrison Eliot , Herdt Olga , Finkernagel Florian , Schumann Michael , Krause Eberhard , Freund Christian , Chen Wei , Heyd Florian
Published: July 2020

Background

3′-Untranslated regions (3′UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3′UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we describe a protein-coding function of 3′UTRs upon frameshift-inducing alternative splicing in more than 10% of human and mouse protein-coding genes.

Results

3′UTR-encoded amino acid sequences show an enrichment of PxxP motifs and lead to interactome rewiring. Furthermore, an elevated proline content increases protein disorder and reduces protein stability, thus allowing splicing-controlled regulation of protein half-life. This could also act as a surveillance mechanism for erroneous skipping of penultimate exons resulting in transcripts that escape nonsense mediated decay. The impact of frameshift-inducing alternative splicing on disease development is emphasized by a retinitis pigmentosa-causing mutation leading to translation of a 3′UTR-encoded, proline-rich, destabilized frameshift-protein with altered protein-protein interactions.

Conclusions

We describe a widespread, evolutionarily conserved mechanism that enriches the mammalian proteome, controls protein expression and protein-protein interactions, and has important implications for the discovery of novel, potentially disease-relevant protein variants.
Identification and comparison of proteomic and peptide profiles of mung bean seeds and sprouts
Authors: Yu Wei , Zhang Guifang , Wang Weihao , Jiang Caixia , Cao Longkui
Published: July 2020

The objectives of this study were to analyze and compare the proteomic and peptide profiles of mung bean (Vigna radiata) seeds and sprouts. Label-free proteomics and peptidomics technologies allowed the identification and relative quantification of proteins and peptides. There were 1918 and 1955 proteins identified in mung bean seeds and sprouts, respectively. The most common biological process of proteins in these two samples was the metabolic process, followed by cellular process and single-organism process. Their dominant molecular functions were catalytic activity, binding, and structural molecule activity, and the majority of them were the cell, cell part, and organelle proteins. These proteins were primarily involved in metabolic pathways, biosynthesis of secondary metabolites, and ribosome. PCA and HCA results indicated the proteomic profile varied significantly during mung bean germination. A total of 260 differential proteins between mung bean seeds and sprouts were selected based on their relative abundance, which were associated with the specific metabolism during seed germination. There were 2364 peptides identified and 76 potential bioactive peptides screened based on the in silico analysis. Both the types and concentration of the peptides in mung bean sprouts were higher than those in seeds, and the content of bioactive peptides in mung bean sprouts was deduced to be higher.
Molecular characterization of ascaridoid parasites from captive wild carnivores in China using ribosomal and mitochondrial sequences
Authors: Xie Yue , Li Yingxin , Gu Xiaobin , Liu Yunjian , Zhou Xuan , Wang Lu , He Ran , Peng Xuerong , Yang Guangyou
Published: July 2020

Background

Despite the public health importance of toxocariasis/toxascariasis, only a few species of these ascaridoid parasites from wild canine and feline carnivores have been studied at the molecular level so far. Poor understanding of diversity, host distribution and the potential (zoonotic) transmission of the ascaridoid species among wild animals negatively affects their surveillance and control in natural settings. In this study, we updated previous knowledge by profiling the genetic diversity and phylogenetic relationships of ascaridoid species among eleven wild canine and feline animals on the basis of a combined analysis of the ribosomal internal transcribed spacer region (ITS) gene and the partial mitochondrial cytochromecoxidase subunit 2 (cox2) and NADH dehydrogenase subunit 1 (nad1) genes.

Results

In total, three genetically distinct ascaridoid lineages were determined to be present among these wild carnivores sampled, includingToxocara canisinAlopex lagopusandVulpes vulpes,Toxocara catiinFelis chaus,Prionailurus bengalensisandCatopuma temminckiandToxascaris leoninainCanis lupus,Panthera tigris altaica,Panthera tigris amoyensis,Panthera tigris tigris,Panthera leoandLynx lynx. Furthermore, it was evident thatT. leoninalineage split into three well-supported subclades depending on their host species, i.e. wild felids, dogs and wolves and foxes, based on integrated genetic and phylogenetic evidence, supporting that a complex ofT. leoninaother than one species infecting these hosts.

Conclusions

These results provide new molecular insights into classification, phylogenetic relationships and epidemiological importance of ascaridoids from wild canids and felids and also highlight the complex of the taxonomy and genetics ofToxascarisin their wild and domestic carnivorous hosts.
Field safety and efficacy of an orally administered combination of sarolaner, moxidectin and pyrantel (Simparica Trio®) for the prevention of angiostrongylosis in dogs presented as veterinary patients
Authors: Becskei Csilla , Willesen Jakob L. , Schnyder Manuela , Wozniakiewicz Magda , Miroshnikova Nataliya , Mahabir Sean P.
Published: July 2020

Background

Infection with the cardiopulmonary nematode Angiostrongylus vasorum may cause severe disease in dogs, therefore prophylactic treatments are necessary to prevent infection in dogs at risk. A clinical field study was conducted to demonstrate the efficacy and safety of an oral combination of sarolaner, moxidectin and pyrantel (Simparica Trio®) for the prevention of A. vasorum infection in dogs (prevention study). A survey study was conducted concurrently to determine the infection pressure in the same areas.

Methods

Prevention and survey studies were both conducted at the same veterinary clinics in endemic hot spots for A. vasorum in Denmark and Italy. The prevention study was a randomized, placebo controlled, double masked study where 622 client-owned dogs were treated and tested at 30 days intervals for 10 months. In the survey study 1628 dogs that were at risk of infection and/or were suspected to be infected were tested by fecal and/or serological methods, and the percent of dogs positive for A. vasorum was calculated.

Results

In the prevention study, there were no adverse events related to treatment with Simparica Trio®. Two placebo-treated animals became infected with A. vasorum during the 10-month study period, while none of the dogs in the combination product-treated group became infected. In the survey study, 12.2% of the study dogs were found positive to A. vasorum, indicating high exposure to the parasite during the period of the prevention study.

Conclusions

Monthly oral treatment with the combination of sarolaner, moxidectin and pyrantel (Simparica Trio®) was 100% effective in the prevention of natural infection with A. vasorum in dogs in highly endemic areas. In endemic areas, A. vasorum occurrence in dogs at risk is considerable.
Prevalence of severe Plasmodium knowlesi infection and risk factors related to severe complications compared with non-severe P. knowlesi and severe P. falciparum malaria: a systematic review and meta-analysis
Authors: Kotepui Manas , Kotepui Kwuntida Uthaisar , Milanez Giovanni D. , Masangkay Frederick R.
Published: July 2020

Background

Plasmodium knowlesi is a potential cause of severe and fatal malaria, but comprehensive studies of its pooled prevalence and risk factors are lacking. This study aimed to explore the prevalence and risk factors related to severe P. knowlesi infection.

Methods

A systematic review was conducted by retrieving all published articles on severe P. knowlesi available in Web of Science (ISI), Scopus, and PubMed (MEDLINE). Titles, abstracts, and full-text articles were screened, and any irrelevant studies were excluded. The random-effects model was used to compute the pooled prevalence estimate of severe P. knowlesi infection by a metaprop command provided in STATA software. Differences in demographic characteristics, clinical characteristics, and laboratory data were analysed using Review Manager Version 5.3 software for patients in the following groups: 1) patients with severe and non-severe P. knowlesi infection and 2) patients with severe P. knowlesi and severe P. falciparum infection.

Results

Out of the 2382 studies retrieved from the three databases, seven studies with a total enrolment of 1124 patients with P. knowlesi infections were eligible to be included in this systematic review and meta-analysis. The pooled prevalence estimate of severe P. knowlesi infection was 19% (95% CI: 11–27%, I2 = 93.7%). Severe acute kidney injuries (AKI) (77 cases, 45.6%), jaundice (71 cases, 42%), and hyperparasitaemia (55 cases, 32.5%) were the common clinical manifestations found among patients with severe complications. In comparison to non-severe P. knowlesi infections, patients with severe P. knowlesi infections had significantly higher age, leucocyte count, and parasitaemia levels (P < 0.05). In comparison to patients with severe P. falciparum infections, patients with severe P. knowlesi infections had significantly higher age, neutrophil count, and creatinine levels (P < 0.05).

Conclusions

This systematic review and meta-analysis demonstrated a high proportion of severe P. knowlesi infections. Patients with severe P. knowlesi infections had higher age, leucocyte count, and parasitaemia levels than those with non-severe P. knowlesi infections. In addition, patients with severe P. knowlesi infections had higher age, neutrophil count, and creatinine levels than those with severe P. falciparum infections.
Vitality models found useful in modeling tag-failure times in acoustic-tag survival studies
Authors: Skalski John R. , Whitlock Steven L.
Published: July 2020

Acoustic telemetry studies often rely on the assumption that premature tag failure does not affect the validity of inferences. However, in some cases this assumption is possibly or likely invalid and it is necessary to apply a correction to estimation procedures. The question of which approaches and specific models are best suited to modeling acoustic tag failures has received little research attention. In this short communication, we present a meta-analysis of 42 acoustic tag-life studies, originally used to correct survival studies involving outmigrating juvenile salmonids in the Columbia/Snake river basin. We compare the performance of nine alternative parametric models including common failure–time/survival models and the vitality models of Li and Anderson Theor Popul Biol 76:118–131, (2009) and Demogr Res 28:341–372, (2013). The tag-life studies used acoustic tags from three different tag manufacturers, had expected lifetimes between 12 and 61 days, and had dry weights ranging from 0.22 to 1.65 g. In 57% of the cases, the vitality models of Li and Anderson Theor Popul Biol 76:118–131, (2009) and Demogr Res 28:341–372, (2013) fit the tag-failure times best. The vitality models were also the second-best choices in 17% of the cases. Together, the vitality models, log-logistic, (19%), and gamma models (14%) accounted for 90% of the models selected. Unlike more traditional failure–time models (e.g., Weibull, Gompertz, gamma, and log-logistic), the vitality models are capable of characterizing both the early onset of tag failure due to manufacturing errors and the anticipated battery life. We provide further guidance on appropriate sample sizes (50–100 tags) and procedures to be considered when applying precise tag-life corrections in release–recapture survival studies.
Self-reflection and screening mental health on Canadian campuses: validation of the mental health continuum model
Authors: Chen Shu-Ping , Chang Wen-Pin , Stuart Heather
Published: July 2020

Background

This study describes the psychometric testing of the Mental Health Continuum (MHC) model the Canadian Department of National Defense developed initially, among undergraduates of three Canadian universities. The MHC is a tool that consists of 6 items to guide students the way to attend to, or monitor, signs and behavior indicators of their mental health status and suggest appropriate actions to improve their mental health.

Methods

Online survey data were collected from 4206 undergraduate students in three universities in two Canadian provinces during the spring of 2015 and winter of 2016. Participants completed an online survey questionnaire that consisted of the MHC questionnaire, the Kessler Psychological Distress Scale (K-10), and demographic information, including age, gender, and year of study.

Results

Factor analysis using the principal components method followed by a two-step internal replication analysis showed that the MHC tool was two-dimensional and that all six domains assessed were crucial. The construct (convergent) validity of the MHC tool was tested against the K-10, and the correlation analysis results were strong overall, as well as within subgroups defined by gender, year of study, and university.

Conclusions

The MHC is a useful tool that helps college students reflect on and enhance their mental health.
Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models
Authors: Kumar Sathish , Lemere Cynthia A. , Walter Jochen
Published: July 2020

The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer’s disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct age-dependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.
BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy
Authors: Kaji Seiji , Maki Takakuni , Ueda Jun , Ishimoto Tomoyuki , Inoue Yutaka , Yasuda Ken , Sawamura Masanori , Hikawa Rie , Ayaki Takashi , Yamakado Hodaka , Takahashi Ryosuke
Published: July 2020

Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar α-synuclein-immunoreactive inclusions in oligodendrocytes. Although the myelinating process of oligodendrocytes can be observed in adult human brains, little is known regarding the presence of α-synuclein pathology in immature oligodendrocytes and how their maturation and myelination are affected in MSA brains. Recently, breast carcinoma amplified sequence 1 (BCAS1) has been found to be specifically expressed in immature oligodendrocytes undergoing maturation and myelination. Here, we analyzed the altered dynamics of oligodendroglial maturation in both MSA brains and primary oligodendroglial cell cultures which were incubated with α-synuclein pre-formed fibrils. The numbers of BCAS1-expressing oligodendrocytes that displayed a matured morphology negatively correlated with the density of pathological inclusions in MSA brains but not with that in Parkinson’s disease and diffuse Lewy body disease. In addition, a portion of the BCAS1-expressing oligodendrocyte population showed cytoplasmic inclusions, which were labeled with antibodies against phosphorylated α-synuclein and cleaved caspase-9. Further in vitro examination indicated that the α-synuclein pre-formed fibrils induced cytoplasmic inclusions in the majority of BCAS1-expressing oligodendrocytes. In contrast, the majority of BCAS1-non-expressing mature oligodendrocytes did not develop inclusions on day 4 after maturation induction. Furthermore, exposure of α-synuclein pre-formed fibrils in the BCAS1-positive phase caused a reduction in oligodendroglial cell viability. Our results indicated that oligodendroglial maturation and myelination are impaired in the BCAS1-positive phase of MSA brains, which may lead to the insufficient replacement of defective oligodendrocytes. In vitro, the high susceptibility of BCAS1-expressing primary oligodendrocytes to the extracellular α-synuclein pre-formed fibrils suggests the involvement of insufficient oligodendroglial maturation in MSA disease progression and support the hypothesis that the BCAS1-positive oligodendrocyte lineage cells are prone to take up aggregated α-synuclein in vivo.
CytoSorb removes MDMA in vitro, but is it an effective therapy in vivo?
Authors: Honore Patrick M. , Redant Sebastien , Datzmann Thomas
Published: July 2020

Background

3,4-Methylenedioxymethamphetamine intoxication can result in potentially lethal multi-organ failure, for which the current treatment is largely supportive. Recently, a report of the use of the CytoSorb device as a part of the successful treatment of a patient with 3,4-methylenedioxymethamphetamine intoxication and multi-organ failure has been described.

Main body

While 3,4-methylenedioxymethamphetamine was very effectively removed by CytoSorb in vitro, the degree of removal in the clinical setting described may have been minimal. Indeed, the therapy was started relatively late in this case, and, as the therapy is concentration dependent, the removal of 3,4-methylenedioxymethamphetamine is likely to have been limited. On the other hand, in this case, CytoSorb hemoadsorption was very effective to treat rhabdomyolysis and hyperinflammation.

Conclusion

The in vitro experimentation demonstrates that 3,4-methylenedioxymethamphetamine is effectively removed by CytoSorb. However, it is debatable whether the case report confirms the possibility of in vivo removal of 3,4-methylenedioxymethamphetamine by CytoSorb. Nevertheless, the potential of the CytoSorb device to contribute to the treatment of many critically ill patients has yet to be fully explored, and further studies are warranted.
Splenic sarcoid reaction mimicking metachronous metastasis in patients after distal gastrectomy for gastric cancer: a case report and literature review
Authors: Okada Haruhiko , Ouchi Kazutomo , Saito Tetsuya , Takahashi Yuka , Yamada Masaki , Negami Naoki , Ishido Yasunori , Yamazaki Sanae , Sato Masahiko
Published: July 2020

Background

The occurrence of sarcoid reactions has been recognized in various cancers. The common location for observing these granulomas is mainly the lymph nodes, but a rare occurrence in the spleen has been reported.

Almost all splenic sarcoid reactions associated with gastric cancer have been resected synchronously and diagnosed accidentally, and a rare metachronous occurrence of a sarcoid reaction in the spleen after distal gastrectomy can mimic cancer metastasis. We describe a rare case of a splenic sarcoid reaction recognized in a patient with gastric cancer 6 months after distal gastrectomy.

Case presentation

An 82-year-old man underwent laparoscopic distal gastrectomy for gastric cancer (T3N0M0, stage IIA). Six months after gastrectomy, CT and 18F-fluorodeoxyglucose (FDG)-PET/CT showed the appearance of a splenic mass. We diagnosed solitary splenic metastasis from gastric cancer and performed laparoscopic-assisted splenectomy. His splenic tumor was diagnosed as a sarcoid reaction by histopathological examination.

Conclusion

To our knowledge, this is the first report of a splenic sarcoid reaction recognized 6 months after distal gastrectomy for gastric cancer without any chemotherapy. The splenic sarcoid reaction and cancer metastasis to the spleen were undistinguishable from the CT and FDG-PET/CT findings. The present case and literature review showed that cases of splenic sarcoid reactions associated with gastric cancer can also be accompanied by the occurrence of these granulomas in lymph nodes. When the appearance of a solitary mass is observed in the spleen after resection of primary cancer, it is necessary to consider not only cancer metastasis but also sarcoid reactions. Retrospective histopathological confirmation of the existence of sarcoid reactions in lymph nodes from resected specimens might possibly avoid incorrect diagnosis and intervention.
In-situ simulations for COVID-19: a safety II approach towards resilient performance
Authors: Lakissian Zavi , Sabouneh Rami , Zeineddine Rida , Fayad Joe , Banat Rim , Sharara-Chami Rana
Published: July 2020

Background

COVID-19 has taken the world by surprise; even the most sophisticated healthcare systems have been unable to cope with the volume of patients and lack of resources. Yet the gradual spread of the virus in Lebanon has allowed healthcare facilities critical time to prepare. Simulation is the most practical avenue not only for preparing the staff but also for troubleshooting system’s latent safety threats (LSTs) and for understanding these challenges via Hollnagel’s safety I–II approaches.

Methods

This is a quality improvement initiative: daily in situ simulations were conducted across various departments at the American University of Beirut Medical Center (AUBMC), a tertiary medical care center in Beirut, Lebanon. These simulations took place in the hospital with native multidisciplinary teams of 3–5 members followed by debriefing with good judgment using the modified PEARLS (Promoting Excellence and Reflective Learning in Simulation) for systems integration. All participants completed the simulation effectiveness tool (SET-M) to assess the simulation. Debriefings were analyzed qualitatively for content based on the Safety Model and LST identification, and the SET-Ms were analyzed quantitatively.

Results

Twenty-two simulations have been conducted with 131 participants. SET-M results showed that the majority (78–87%) strongly agreed to the effectiveness of the intervention. We were able to glean several clinical and human factor safety I–II components and LSTs such as overall lack of preparedness and awareness of donning/doffing of personal protective equipment (PPE), delayed response time, lack of experience in rapid sequence intubation, inability to timely and effectively assign roles, and lack of situational awareness. On the other hand, teams quickly recognized the patient’s clinical status and often communicated effectively.

Conclusion

This intervention allowed us to detect previously unrecognized LSTs, prepare our personnel, and offer crucial practical hands-on experience for an unprecedented healthcare crisis.
Automated [18F]PSMA-1007 production by a single use cassette-type synthesizer for clinical examination
Authors: Naka Sadahiro , Watabe Tadashi , Kurimoto Kenta , Uemura Motohide , Soeda Fumihiko , Neels Oliver C. , Kopka Klaus , Tatsumi Mitsuaki , Kato Hiroki , Nonomura Norio , Shimosegawa Eku , Cardinale Jens , Giesel Frederik L. , Hatazawa Jun
Published: July 2020

Background

[18F]PSMA-1007, a positron emission tomography (PET) tracer, specifically targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer. PSMA-PET is effective especially for regional detection of biochemical recurrence, which significantly affects patient management. Herein, we established and optimized a one-step radiolabeling protocol to separate and purify [18F]PSMA-1007 with a CFN-MPS200 synthesizer for clinical application.

Results

A dedicated single use cassette and synthesis program for [18F]PSMA-1007 was generated using a single-step method for direct precursor radiolabeling. In the cassette, three tube types (fluoro-elastomer, PharMed® BPT, silicone) and two different precursor salts (trifluoroacetic acid or acetic acid) were compared for optimization. Furthermore, three-lot tests were performed under optimized conditions for quality confirmation. Activity yields and mean radiochemical purity of [18F]PSMA-1007 were > 5000 MBq and 95%, respectively, at the end of synthesis, and the decay-corrected mean radiochemical yield from all three cassettes was approximately 40% using a trifluoroacetic acid salt precursor. Fluoro-elastomer tubings significantly increased the amount of non-radioactive PSMA-1007 (8.5 ± 3.1 μg/mL) compared to those with other tubings (0.3 μg/mL). This reduced the molar activity of [18F]PSMA-1007 synthesized in the cassette assembled by fluoro-elastomer tubings (46 GBq/μmol) compared to that with PharMed® BPT and silicone tubings (1184 and 1411 GBq/μmol, respectively). Residual tetrabutylammonium, acetonitrile, and dimethyl sulfoxide levels were <  2.6 μg/mL, < 8 ppm, and <  11 ppm, respectively, and ethanol content was 8.0–8.1% in all three cassettes and two different salts. Higher activity yields, radiochemical purities, and decay-corrected radiochemical yields were obtained using an acetic acid salt precursor rather than a trifluoroacetic acid salt precursor (7906 ± 1216 MBq, 97% ± 0%, and 56% ± 4%). In the three-lot tests under conditions optimized with silicone cassettes and acetic acid salt precursor, all quality items passed the specifications required for human use.

Conclusions

We successfully automated the production of [18F]PSMA-1007 for clinical use and optimized synthesis procedures with a CFN-MPS200 synthesizer using a silicone cassette and acetic acid salt precursor. Cassette availability will facilitate a wide spread use of [18F]PSMA-1007-PET, leading to an effective prostate cancer management.
Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators
Authors: Moon Euy Sung , Elvas Filipe , Vliegen Gwendolyn , De Lombaerde Stef , Vangestel Christel , De Bruycker Sven , Bracke An , Eppard Elisabeth , Greifenstein Lukas , Klasen Benedikt , Kramer Vasko , Staelens Steven , De Meester Ingrid , Van der Veken Pieter , Rösch Frank
Published: July 2020

Background

Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems. Here, we report squaric acid (SA) containing bifunctional DATA5m and DOTA chelators based on UAMC1110 as pharmacophor. The novel radiopharmaceuticals DOTA.SA.FAPi and DATA5m.SA.FAPi with their non-radioactive derivatives were characterized for in vitro inhibitory efficiency to FAP and PREP, respectively and radiochemical investigated with gallium-68. Further, first proof-of-concept in vivo animal study followed by ex vivo biodistribution were determined with [68Ga]Ga-DOTA.SA.FAPi.

Results

[68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DATA5m.SA.FAPi showed high complexation > 97% radiochemical yields after already 10 min and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and DATA5m.SA.FAPi and its natGa and natLu-labeled derivatives were excellent resulting in low nanomolar IC50 values of 0.7–1.4 nM. Additionally, all five compounds showed low affinity for the related protease PREP (high IC50 with 1.7–8.7 μM). First proof-of-principle in vivo PET-imaging animal studies of the [68Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor (SUVmean of 0.75) and low background signal. Ex vivo biodistribution showed highest uptake in tumor (5.2%ID/g) at 60 min post injection with overall low uptake in healthy tissues.

Conclusion

In this work, novel PET radiotracers targeting fibroblast activation protein were synthesized and biochemically investigated. Critical substructures of the novel compounds are a squaramide linker unit derived from the basic motif of squaric acid, DOTA and DATA5m bifunctional chelators and a FAP-targeting moiety. In conclusion, these new FAP-ligands appear promising, both for further research and development as well as for first human application.
Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19?
Authors: Bonaz Bruno , Sinniger Valérie , Pellissier Sonia
Published: July 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), at the origin of the worldwide COVID-19 pandemic, is characterized by a dramatic cytokine storm in some critical patients with COVID-19. This storm is due to the release of high levels of pro-inflammatory cytokines such as interleukin (IL)-1 β, IL-6, tumor necrosis factor (TNF), and chemokines by respiratory epithelial and dendritic cells, and macrophages. We hypothesize that this cytokine storm and the worsening of patients’ health status can be dampened or even prevented by specifically targeting the vagal-driven cholinergic anti-inflammatory pathway (CAP). The CAP is a concept that involves an anti-inflammatory effect of vagal efferents by the release of acetylcholine (ACh). Nicotinic acetylcholine receptor alpha7 subunit (α7nAChRs) is required for ACh inhibition of macrophage-TNF release and cytokine modulation. Hence, targeting the α7nAChRs through vagus nerve stimulation (VNS) could be of interest in the management of patients with SARS-CoV-2 infection. Indeed, through the wide innervation of the organism by the vagus nerve, especially the lungs and gastrointestinal tract, VNS appears as a serious candidate for a few side effect treatment that could dampen or prevent the cytokine storm observed in COVID-19 patients with severe symptoms. Finally, a continuous vagal tone monitoring in patients with COVID-19 could be used as a predictive marker of COVID-19 illness course but also as a predictive marker of response to COVID-19 treatment such as VNS or others.
Government-mandated warnings on cannabis legally sold for recreational use
Authors: Malouff John M. , Schutte-Malouff Ben P.
Published: July 2020

Background

Frequent cannabis use can pose risks to health and safety. Multiple governments have legalized the sale of cannabis for recreational use and mandated health and safety warnings for recreational cannabis packages or signs at sales locations. The purposes of this study were to identify common themes across warnings and to compare the actual warnings with those previously recommended by cannabis experts and cannabis users.

Methods

We searched Google and Google Scholar for online lists of governments that allow or will soon allow the sale of cannabis for recreational use. Using the online lists we found, we searched for laws mandating the warnings, using the search terms “mandated warnings for recreational use marijuana” in addition to the name of the jurisdiction under review. We evaluated the content of the warnings and compared them with warnings recommended by cannabis experts and by users of recreational cannabis.

Results

Each search led to millions of results. Within the top results of each of the searches there were website links to official legislative websites, databases and documents of the jurisdiction under review. We used these official documents. The search revealed that 11 U.S. states and two countries allow the recreational use of cannabis and that 10 U.S. states and Canada mandate warnings on legally sold recreational cannabis. The mandated warnings can be categorized as focusing on one of nine risks: (1) negative health effects on the user, (2) harm to children or fetuses, (3) risks related to driving or operating machinery, (4) risks of habit formation leading to over-use, (5) risks relating to over-use on a single occasion, especially with regard to edible cannabis, (6) developmental risks for young people, (7) harm caused by secondary smoke, (8) risks of effects lasting several hours, and (9) risks specific to using cannabis topicals. The warnings include no graphic images and no phone number to call for help quitting.

Conclusions

The warnings, as a group, parallel most warnings recommended by cannabis experts and a sample of recreational users of cannabis. The effects of the warnings are unknown, but prior research findings on warnings for cannabis and for other substances suggest potential for positive effects in raising awareness of risks and decreasing the risks. The warnings could be used in public health campaigns. Public health professionals may find it possible through research to help improve the warnings, either in presentation or in content. Cannabis researchers can use the list to identify additional risks suitable for inclusion in mandated warnings.
Transient carriage and low-level colonization of orally administrated lytic and temperate phages in the gut of mice
Authors: Bao Hongduo , Zhang Hui , Zhou Yan , Zhu Shujiao , Pang Maoda , Shahin Khashayar , Olaniran Ademola , Schmidt Stefan , Wang Ran
Published: July 2020

Many studies have shown the efficacy of phage therapy in reducing gastrointestinal pathogens. However, it is unclear whether phages can successfully colonize the gut when administered in an adequate amount for a long time. About 1 × 108 PFU/mL of purified lytic phage PA13076 or temperate phage BP96115 were fed daily to mice via drinking water over 31 days, to elucidate the distribution of phages in the gastrointestinal tract. At day 16 and 31, six different segments of the gastrointestinal tract with their contents, including stomach, duodenum, jejunum, ileum, cecum, colon, and fresh feces, were aseptically collected. The phage titers were determined using the double-layered plate method with S. Enteritidis ATCC 13076 or S. Pullorum SPu-109 used as host cells. The results indicated that a small portion of administered phages survived exposure to gastric acid and entered the intestinal tract. The prevalence of phages in the gastrointestinal tract was lower than 1% of the primary phage count. Highest phage titers were detected in the cecum with 104 ~ 105 PFU/g, and most of the phages were eliminated from the body via feces with 106 PFU/g. On day 16 and day 31, the same level of phage titers in different segments of the gastrointestinal tract indicated that the colonization of phages had reached saturation at day 16. These results demonstrate transient phage carriage and low-level colonization of orally administrated lytic and temperate gut phages in mice.

Graphical abstract
Biomechanical effects of stitches on the intra-articular mid-substance of quadruple hamstring-tendon grafts for anterior cruciate ligament reconstruction – a pilot comparative cadaveric study
Authors: Saur Maurise , Clavert Philippe , Bonnomet François , Favreau Henri , Ehlinger Matthieu
Published: July 2020

Background

There is little data in the literature regarding the preparation methods of the intra-articular portion of quadruple hamstring-tendon grafts for anterior cruciate ligament (ACL) reconstruction. The aim of this study was to compare the biomechanical properties of a sutured transplant to that of a non-sutured transplant. The hypothesis was that adding stitches to the intra-articular portion of the graft increased its resistance.

Method

A comparative cadaveric study was carried out on five pairs of knees. The average age of the cadavers was 68 years. The exclusion criterion was past knee surgery. In the Sutured Group (SG) two stitches were made on the grafts. No stitches were made on the grafts of the Non-sutured Group (NSG). A tensile failure test was carried out using an Instron® loading machine. The maximal load to failure and stiffness were recorded and we observed the mode of failure for each graft. Statistical analysis was performed using the Wilcoxon rank sum test. Level of significance was set at p < 0.05.

Results

The hypothesis proposed was not confirmed; adding stitches to the intra-articular portion of the four-strand hamstring-tendon graft does not increase its biomechanical properties. The maximal load to failure was 233.5 N ± 40.6 (186.7–274.5 N) for the NSG, 19.6% higher than for the SG which was 195.2 N ± 42.9 (139.0–238.2 N). Nevertheless, the difference observed was not statistically significant (p = 0.188). The stiffness of the grafts for the NSG was 23.5 N/mm ± 5.3 (17.8–29 N/mm) and 19.7 N/mm ± 5.5 (13.2–24.7 N/mm) for the SG grafts. Overall stiffness values for the NSG were 19% higher than those of the SG; however, the results were not statistically significant (p = 0.438). The failure mode was a rupture at the fixation point except for one sample from the SG which failed at an intra-articular stitch.

Conclusion

Whilst the initial hypothesis was not verified, nevertheless, the maximal loads to failure and stiffness were approximately 20% higher when there were no intra-articular stitches compared to the situation where stitches were added to the intra-articular portion of the graft. This was a cadaveric pilot study and, therefore, whilst we are not able to extend our results to clinical practice, the outcomes would indicate the need for further development of this and related protocols deriving from the question of whether there is weakening the graft when adding stitches to its mid-substance. These results remain to be confirmed by further research.
Whole body diffusion-weighted MRI in detection of metastasis and lymphoma: a prospective longitudinal clinical study
Authors: Goda Heba H. , AbdAllah Abd Elkareem H. , Ahmed Eman A. , Megally Hassan I. , Khalaf Marwa I. , Taha Ahmed M. , Mohamed Hosam Eldeen G.
Published: July 2020

Background

Whole-body diffusion-weighted magnetic resonance imaging (WB-DWI-MRI) is an emerging tool that has an increasing role in the diagnosis of metastasis and lymphoma. This is a longitudinal study in actual clinical settings designed to assess WB-DWI-MRI in detection of tumor spread. The study included all patients who were referred to Radiology Department, during the period from June 2016 till May 2018, with either a known primary tumor (either laboratory, radiologically, or histologically proven, of any type, affecting any organ) or with biopsy-proven lymphoma of any subtype, affecting any organ. All patients underwent WB coronal T1-weighted, STIR, axial T2-weighted, and DWI-MRI examinations before commencing any treatment with curative intent. The body was divided into lymph nodes (LNs), skeletal system, and organs (brain, lung, and liver). Patients were followed up till the nature of the lesion(s) was confirmed (clinically, radiologically, or histologically).

Results

The study included 46 patients; 27 patients had metastases and 19 had lymphomas. Sensitivities, specificities, and accuracies for LN detection were 77%, 85%, and 83%; for skeletal metastasis were 88%, 94%, and 92%; for brain lesions were 78%, 95%, and 91%; and for lung lesion were 64%, 88%, and 76%, respectively. As for the liver, all lesions were correctly identified and did not miss any lesion with accuracy of 100%. Overall, 1739 lesions were discovered in 1271 regions out of 3818 examined regions with overall sensitivity, specificity, and accuracy of 86%, 92%, and 90% respectively.

Conclusion

The diagnostic performance of WB-DWI-MRI is variable among different anatomical sites. It has good performance in diagnosis of some organs as liver, bone marrow, and some LNs regions as porta-hepatis. It has a less diagnostic performance in the lung, and LNs located in cervical, mediastinum, supraclavicular, and mesenteric regions.
Versatile mechanisms of 2-substituted benzimidazoles in targeted cancer therapy
Authors: Ibrahim Heba A. , Refaat Hanan M.
Published: July 2020

Background

The aim of this review is to provide an overview on diverse anticancer activities of 2-substituted benzimidazole derivatives.

Main body

This review provides a correlation between the various mechanisms of action of benzimidazoles as anticancer and the substitution pattern around the nucleus.

Conclusion

The linker group and substitution at N-1, C-2, C-5, and C-6 positions have been found to be the most contributory factors for anticancer activity. This will help in the further design to afford more selective, potent, and multi-target anticancer of 2-substituted benzimidazole-based compounds.
RP-HPLC method development and validation for bedaquiline fumarate to evaluate its forced degradation behaviour and stability in official dissolution media
Authors: Pardhi Vishwas , Pant Geetanjali , Flora S. J. S.
Published: July 2020

Background

A simple, rapid and accurate reverse phase RP-HPLC method for the validation of antitubercular drug bedaquiline fumarate (BQF) was developed. The stability and forced degradation behaviour of bedaquiline fumarate (BQF) in official dissolution media (0.01 N HCl) and methanol were assessed.

Results

The method provided linear responses within the concentration range which varies from 10 to 100 μg/mL with LOD values of 2.6 μg/mL and LOQ of 7.9 μg/mL. Mean percent recovery varied between 97.46 and 103.82% and precise mean RSD of 0.31% (repeatability) and 0.48% (intermediate precision). The method was validated for other parameters like specificity, system suitability and robustness. Potential degradation of the BQF when exposed to direct sunlight in official dissolution media was 90.75% and in methanolic stock solution was 91.98%. Acid-alkali degradation study showed 86.59% loss of BQF in 0.5 N NaOH, and in acidic environment (0.5 N HCl), there was 6.15% loss. Thermal degradation of BQF was 70.11% loss in official dissolution media at 80 °C. No significant change in drug concentrations was noted when exposed and protected from normal daylight at room temperature and at 2–8 °C temperature.

Conclusion

The developed method has significant applicability for the qualitative and quantitative determination of BQF in different pharmaceutical formulations in the official dissolution media in routine quality control analysis.
ASCO Quality Training Program: A Five-Year Review
Authors: Keng Michael , Quinn Doris , Cunningham Gene , Bingham John , Chiang Anne , Eisinger Michael , Gilligan Timothy , Gilmore Terry , Guerrier Vedner , Karri Sirisha , Kaufman Laurie , Mohamed Ashraf , Srivastava Piyush
Published: July 2020

PURPOSE:

ASCO introduced the Quality Training Program (QTP) in 2013 with the aim to train oncology professionals to design, implement, and lead successful quality improvement (QI) activities and assume leadership positions to champion culture change in their practices.

METHODS:

The QTP is a formal 6-month program taught by QI faculty and mentored by QI coaches over 5 days of in-person learning across 3 sessions and hands-on learning at the participants’ practices. Sessions include seminars, case examples, and small-group exercises. Participants attend in multidisciplinary teams and focus on a problem they wish to solve in their practice. Scheduled conference calls with QI coaches are held between sessions. Participants complete pre- and post-QTP surveys (10-point Likert scale, with 1 = no knowledge/competence and 10 = complete knowledge/competence) and provide direct written feedback.

RESULTS:

Since its inception, QTP has had 15 courses (10 domestic and 5 international) with 120 teams and 544 total participants. QTP is led by an 8-member steering group with 16 faculty and coaches. All postsurvey items showed an increase in knowledge and competence. Each item’s score was calculated as the mean difference between before and after scores. Participants stated an increase of 46%-84% (overall mean increase: knowledge, 38%; competence, 37%). The greatest increases were in methodology and practical tools to make changes in practice (writing an aim statement, implementing rapid improvement, using process analysis tools, flowcharting the process). The most common suggestion for improvement was allowing more time for the project. Participants are encouraged to write articles and present work in poster and plenary sessions. QTP courses have led to 7 manuscripts and 21 abstract presentations to national meetings. Six QTP alumni are now QI coaches and faculty.

CONCLUSION:

The QTP is a successful QI course for oncology professionals who need to measure performance, investigate quality and safety issues, and implement change. It is the only oncology-focused QI training, as all faculty and coaches are providers and QI specialists with oncology experience, which makes this a unique opportunity. The success will provide further momentum to offer QTP domestically and around the world.
Circadian Rhythms in Hormone-sensitive Lipase in Human Adipose Tissue: Relationship to Meal Timing and Fasting Duration
Authors: Arredondo-Amador María , Zambrano Carolina , Kulyté Agné , Luján Juán , Hu Kun , Sánchez de Medina Fermín , Scheer Frank A J L , Arner Peter , Ryden Mikael , Martínez-Augustin Olga , Garaulet Marta
Published: July 2020

Background

Fat mobilization in adipose tissue (AT) has a specific timing. However, circadian rhythms in the activity of the major enzyme responsible for fat mobilization, hormone-sensitive lipase (HSL), have not been demonstrated in humans.

Objective

To analyze in a cross-sectional study whether there is an endogenous circadian rhythm in HSL activity in human AT ex vivo and whether rhythm characteristics are related to food timing or fasting duration.

Methods

Abdominal AT biopsies were obtained from 18 severely obese participants (age: 46 ± 11 years; body mass index 42 ± 6 kg/m2) who underwent laparoscopic gastric bypass. Twenty-four-hour rhythms of HSL activity and LIPE (HSL transcript in humans) expression in subcutaneous AT were analyzed together with habitual food timing and night fasting duration.

Results

HSL activity exhibited a circadian rhythm (P = .023) and reached the maximum value at circadian time 16 (CT) that corresponded to around midnight (relative local clock time. Similarly, LIPE displayed a circadian rhythm with acrophase also at night (P = .0002). Participants with longer night fasting duration >11.20 hours displayed almost double the amplitude (1.91 times) in HSL activity rhythm than those with short duration (P = .013); while habitual early diners (before 21:52 hours) had 1.60 times higher amplitude than late diners (P = .035).

Conclusions

Our results demonstrate circadian rhythms in HSL activity and may lead to a better understanding of the intricate relationships between food timing, fasting duration and body fat regulation.