Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic characterisation of breast fibroepithelial lesions in an international cohort

Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16‐gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non‐Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild‐type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Phenotypic variations of gastric neoplasms in familial adenomatous polyposis are associated with endoscopic status of atrophic gastritis

Gastric neoplasms (GN), including gastric adenoma and carcinoma, are well known as extracolonic manifestations of familial adenomatous polyposis (FAP). We aimed to investigate the clinicopathological features of GN in FAP patients and to clarify their relationship with the endoscopic status of the background mucosa.
Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential

ABSTRACT Metastasis accounts for the majority of all cancer deaths, yet the process remains poorly understood. A pivotal step in the metastasis process is the exiting of tumor cells from the circulation, a process known as extravasation. However, it is unclear how tumor cells extravasate and whether multicellular clusters of tumor cells possess the ability to exit as a whole or must first disassociate. In this study, we use in vivo zebrafish and mouse models to elucidate the mechanism tumor cells use to extravasate. We found that circulating tumor cells exit the circulation using the recently identified extravasation mechanism, angiopellosis, and do so as both clusters and individual cells. We further show that when melanoma and cervical cancer cells utilize this extravasation method to exit as clusters, they exhibit an increased ability to form tumors at distant sites through the expression of unique genetic profiles. Collectively, we present a new model for tumor cell extravasation of both individual and multicellular circulating tumor cells. This article has an associated First Person interview with the first author of the paper. Highlighted Article: Circulating tumor cell clusters spread throughout the body by using a unique method to exit blood vessels, which grants the tumor cells an increased ability to form secondary tumors.
Deep Lipidomics and Molecular Imaging of Unsaturated Lipid Isomers: A Universal Strategy Initiated by mCPBA Epoxidation.

Cellular lipidome is highly regulated through lipogenesis, rendering diverse double-bond positional isomers (C=C isomer) of a given unsaturated lipid species. In recent years, there are increasing reports indicating the physiological roles of C=C isomer compositions associated with diseases, while the biochemistry has not been broadly investigated due to the challenge in characterizing lipid isomers inherent to conventional mass spectrometry-based lipidomics. To address this challenge, we reported a universal, user-friendly, derivatization-based strategy, MELDI (mCPBA Epoxidation for Lipid Double-bond Identification), which enables both large-scale identification and spatial mapping of biological C=C isomers using commercial mass spectrometers without any instrument modification. With the developed liquid-chromatography mass spectrometry (LC-MS) lipidomics workflow, we elucidated more than 100 isomers among monounsaturated and polyunsaturated fatty acids and glycerophospholipids in both human serum, where uncommon isomers of low abundance were quantified for the first time. The capability of MELDI-LC-MS in lipidome analysis was further demonstrated using the differentiated 3T3-L1 adipocytes, providing an insight into the cellular lipid reprogramming upon stearoyl-coenzyme A desaturase 1 (SCD1) inhibition. Finally, we highlighted the versatility of MELDI coupled with ambient mass spectrometry imaging to spatially resolve cancer-associated alteration of lipid isomers in a metastatic mouse tissue section. Our results suggested that MELDI will contribute to current lipidomics pipelines with a deeper level of structural information, allowing us to investigate underlying lipid biochemistry.
Barriers and facilitators to the implementation of a stepped care intervention for personality disorder in mental health services.

BACKGROUND Individuals with personality disorders-particularly borderline personality disorder-are high users of mental health treatment services. Emergency service responses often focus on crisis management, and there are limited opportunities to provide appropriate longer term evidence-based treatment. Many individuals with personality disorders find themselves in a revolving cycle between emergency departments and waiting for community treatment. A stepped care approach may help to triage clients and allow access to interventions with minimal client, clinician and system burden. This study aims to understand the facilitators and barriers to real-world implementation of a stepped care approach to treating personality disorders. METHODS Managers and clinicians of health services engaged in implementation were interviewed to obtain accounts of experiences. Interviews were transcribed and thematically analysed to generate themes describing barriers and facilitators. RESULTS Participants identified personal attitudes, knowledge and skills as important for successful implementation. Existing positive attitudes and beliefs about treating people with a personality disorder contributed to the emergence of clinical champions. Training facilitated positive attitudes by justifying the psychological approach. Management support was found to bi-directionally effect implementation. CONCLUSIONS This study suggests specific organizational and individual factors may increase timely and efficient implementation of interventions for people with personality disorders. © 2019 John Wiley & Sons, Ltd.
Dermatofibrosarcoma Protuberans Re-excision and Recurrence Rates in the Netherlands Between 1989 and 2016.

Dermatofibrosarcoma protuberans is a rare soft tissue tumour with a very low (< 0.5%) rate of metastasis. Rates of re-excision and recurrence were determined using data from the Netherlands Cancer Registry between 1989 and 2016. Of the 1,890 instances of dermatofibrosarcoma protuberans included, 87% were treated with excision, 4% with Mohs micrographic surgery, and 9% otherwise or unknown. Linked pathology data were retrieved for 1,677 patients. Half of all excisions (847/1,644) were incomplete and 29% (192/622) of all re-excisions were incomplete. The cumulative incidence of a recurrence was 7% (95% confidence interval (95% CI) 6-8) during a median follow-up of 11 years (interquartile range (IQR) 6-17). After Mohs micrographic surgery (n = 34), there were no recurrences during a median follow-up of 4 years (IQR 3-6). Due to the high rate of incomplete excisions and recurrences after excision, this study supports the European guideline, which recommends treating dermatofibrosarcoma protuberans with Mohs micrographic surgery in order to decrease the rate of recurrence.
Genetic benefits of extreme sequential polyandry in a terrestrial‐breeding frog

Sequential polyandry may evolve as an insurance mechanism to reduce the risk of females choosing mates who are genetically inferior (intrinsic male quality hypothesis) or genetically incompatible (genetic incompatibility hypothesis). The prevalence of such indirect benefits remains controversial, however, because studies estimating the contributions of additive and nonadditive sources of genetic variation to offspring fitness have been limited to a small number of taxonomic groups. Here, we used artificial fertilization techniques combined with a crossclassified breeding design (North Carolina Type II) to simultaneously test the “good genes hypothesis” and the “genetic incompatibility hypothesis” in the brown toadlet (Pseudophryne bibronii); a terrestrial‐breeding species with extreme sequential polyandry. Our results revealed no significant additive or nonadditive genetic effects on fertilization success. Moreover, they revealed no significant additive genetic effects, but highly significant nonadditive genetic effects (sire by dam interaction effects), on hatching success and larval survival to initial and complete metamorphosis. Taken together, these results indicate that offspring viability is significantly influenced by the combination of parental genotypes, and that negative interactions between parental genetic elements manifest during embryonic and larval development. More broadly, our findings provide quantitative genetic evidence that insurance against genetic incompatibility favors the evolution and maintenance of sequential polyandry.
Inorganic arsenic in rice and rice products in New Zealand and Australia

ABSTRACT A total of 200 rice and rice products from New Zealand and Australia were purchased from retail outlets during 2017 for inorganic arsenic analysis by ICP-MS. The survey of foods placed a particular emphasis on products marketed specifically for infants and young. A total of 159 samples (80%) gave positive results for inorganic arsenic, with a mean concentration of 0.06 mg/kg and a range of <0.01–0.14 mg/kg. Two products marketed for infants and young children age-cohort had the highest concentrations of inorganic arsenic. Both exceeded the EU maximum level for rice destined for the production of food for infants and young children of 0.1 mg/kg. The mean concentration of inorganic arsenic for only raw rice samples was 0.07 mg/kg, with a range of <0.02–0.12 mg/kg. In general, the concentration of inorganic arsenic in rice and rice products from New Zealand and Australia was low compared to concentrations reported from comparable studies overseas.
Effects of gestational age at delivery and type of labor on neonatal outcomes among infants with gastroschisis†

Abstract Objective To investigate the effect of preterm gestational age (GA) on neonatal outcomes of gastroschisis and to compare the neonatal outcomes after spontaneous labor versus iatrogenic delivery both in the preterm and early term gestational periods. Study design A retrospective study of prenatally diagnosed gastroschisis cases born at Loma Linda University Medical Center and Lucile Packard Children’s Hospital (Loma Linda, CA) between January 2009 and October 2016. A total of 194 prenatally diagnosed gastroschisis cases were identified and included in the analysis. We compared infants delivered <37 0/7 to those ≥37 0/7 weeks’ gestation. Adverse neonatal outcome was defined as any of: sepsis, short bowel syndrome, prolonged ventilation, or death. Prolonged length of stay (LOS) was defined as ≥75th percentile value. Outcomes following spontaneous versus iatrogenic delivery were compared. Analyses were performed using chi-squared test or Fisher’s exact test for categorical variables, and Student’s t-test or Wilcoxon’s rank-sum test for continuous variables. Results One hundred and six neonates were born <37 weeks and 88 at ≥37 weeks. Adverse outcome was statistically similar among those born <37 weeks compared to ≥37 weeks (48 versus 34%, p = .07). Prolonged LOS was more frequent among neonates delivered <37 weeks (p = .03). Among neonates born <37 weeks, bowel atresia was more frequent in those with spontaneous versus iatrogenic delivery (p = .04). There was no significant difference in the adverse neonatal composite outcome between those with spontaneous preterm labor versus planned iatrogenic delivery at <37 weeks (n = 30 (58%) versus n = 21 (39%), p = . 08). Conclusions Neonates with gastroschisis delivered <37 weeks had prolonged LOS whereas the rate of adverse neonatal outcomes was similar between those delivered preterm versus term. Neonates born after spontaneous preterm labor had a higher rate of bowel atresia compared to those born after planned iatrogenic preterm delivery.
Do you feel like being proactive today? Trait-proactivity moderates affective causes and consequences of proactive behavior

Proactive people take initiative when others do not and persist in improving their environment or themselves. Although scholars assume that how we feel influences how proactive we are, there is no experimental research yet to support this. This experiment therefore tests whether positive and negative affect influence proactive behavior and additionally investigates whether engaging in proactivity also has affective consequences. While current theory proposes that positive affect enhances proactive behavior by stimulating broad-flexible thinking, we argue that negative affect should make people proactive through stimulating systematic-persistent thinking. Furthermore, we propose that proactive behavior increases subsequent positive affect rather than positive affect increasing proactive behavior. Last, we hypothesize that affective causes and consequences of proactive behavior are different for people who are rarely proactive (trait-passive-reactive individuals) and people who are often proactive (trait-proactive individuals). We pre-tested 180 participants on trait-proactivity. In the lab, we manipulated affect (negative/positive/neutral), measured proactive behavior in a team interaction task, and repeatedly measured participants’ affective experiences and physiological activation. Results showed that the link between affect and proactive behavior differed depending on participants’ trait-proactivity. First, positive affect made trait-proactive individuals less proactive, whereas negative affect made passive-reactive individuals more proactive. Second, passive-reactive individuals reported decreased negative affect after engaging in proactivity, whereas proactive individuals reported increased positive affect. These results suggest that proactive behavior can serve an affect regulation purpose, which is different for trait proactive individuals (up regulating positive affect) than for trait passive-reactive individuals (down regulating negative affect). These results are limited to core affect (feeling pleasant or unpleasant) and do not apply to specific emotions (feeling proud or anxious), and they are limited to short term and successful proactive behavior and do not apply to more long term, or unsuccessful proactive behavior.
Differentiation syndrome in acute promyelocytic leukaemia

Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all‐trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion. Immediate treatment with steroids at the first clinical suspicion is recommended and ATRA/ATO should be stopped in severe cases or if there is no response to treatment. The utility of steroid prophylaxis in order to prevent APL DS is less certain. Here we provide a detailed review of the pathogenesis, clinical signs and symptoms as well as management and prophylaxis strategies of APL DS.
The Role of Ozone Vibrational Resonances in the Isotope Exchange Reaction 16O16O + 18O → 18O16O + 16O: The Time-Dependent Picture.

We consider the time-dependent dynamics of the isotope exchange reaction in collisions between an oxygen molecule and an oxygen atom: 16O16O + 18O → 18O16O + 16O. A theoretical approach using the Multiconfiguration Time-Dependent Hartree method was employed to model the time evolution of the reaction. Two potential surfaces available in the literature were used in the calculations and the results obtained with the two surfaces are compared with each other as well as with results of a previous theoretical time-independent approach. The good agreement for the reaction probabilities with the previous theoretical results is found. Comparing the results obtained using two potential energy surfaces allows us to understand the role of the reef/shoulder-like feature in the minimum energy path of the reaction in the isotope exchange process. Also, it was found that the distribution of final products of the reaction is highly anisotropic, which agrees with experimental observations and, at the same time, suggests that the family of approximated statistical approaches, assuming a randomized distribution over final exit channels, is not applicable to this case.
In vivo photoacoustic imaging of major blood vessels in the pancreas and liver during surgery

Abstract. Abdominal surgeries carry considerable risk of gastrointestinal and intra-abdominal hemorrhage, which could possibly cause patient death. Photoacoustic imaging is one solution to overcome this challenge by providing visualization of major blood vessels during surgery. We investigate the feasibility of in vivo blood vessel visualization for photoacoustic-guided liver and pancreas surgeries. In vivo photoacoustic imaging of major blood vessels in these two abdominal organs was successfully achieved after a laparotomy was performed on two swine. Three-dimensional photoacoustic imaging with a robot-controlled ultrasound (US) probe and color Doppler imaging were used to confirm vessel locations. Blood vessels in the in vivo liver were visualized with energies of 20 to 40 mJ, resulting in 10 to 15 dB vessel contrast. Similarly, an energy of 36 mJ was sufficient to visualize vessels in the pancreas with up to 17.3 dB contrast. We observed that photoacoustic signals were more focused when the light source encountered a major vessel in the liver. This observation can be used to distinguish major blood vessels in the image plane from the more diffuse signals associated with smaller blood vessels in the surrounding tissue. A postsurgery histopathological analysis was performed on resected pancreatic and liver tissues to explore possible laser-related damage. Results are generally promising for photoacoustic-guided abdominal surgery when the US probe is fixed and the light source is used to interrogate the surgical workspace. These findings are additionally applicable to other procedures that may benefit from photoacoustic-guided interventional imaging of the liver and pancreas (e.g., biopsy and guidance of radiofrequency ablation lesions in the liver).
Morphogenetic and constructional differences of the carapace of aquatic and terrestrial turtles and their evolutionary significance

The postembryonic development of the turtle carapace was studied in the aquatic Еmys orbicularis and the terrestrial Тestudo graeca. Differences in the structure of the bony shell in aquatic and terrestrial turtles were shown to be associated with varying degrees of development of epidermal derivatives, namely, the thickness of the scutes and the depth of horny furrows. Sinking of the horny furrows into the dermis causes local changes in the structure of the collagen matrix, which might precondition the acceleration of the ossification. Aquatic turtles possess a relatively thin horny cover, whose derivatives are either weakly developed or altogether absent and thus make no noticeable impact on the growth dynamics of bony plates. Carapace plates of these turtles outgrow more or less evenly around the periphery, which results in uniform costals, relatively narrow and partly reduced neurals, and broad peripherals extending beyond the marginal scutes. In terrestrial turtles (Testudinidae), horny structures are much more developed and exert a considerable impact on the growth of bony elements. As a result, bony plates outgrow unevenly in the dermis, expanding fast in the zones under the horny furrows and slowly outside these zones. This determines the basic features of the testudinid carapace: alternately cuneate shape of costals, an alternation of broad octagonal and narrow tetragonal neurals, and the limitation of the growth of peripherals by pleuro‐marginal furrows. The evolutionary significance of morphogenetic and constructional differences in the turtle carapace, and the association of these differences with the turtle habitats are discussed.
The oncoprotein DEK affects the outcome of PARP1/2 inhibition during mild replication stress

DNA replication stress is a major source of genomic instability and is closely linked to tumor formation and progression. Poly(ADP-ribose)polymerases1/2 (PARP1/2) enzymes are activated in response to replication stress resulting in poly(ADP-ribose) (PAR) synthesis. PARylation plays an important role in the remodelling and repair of impaired replication forks, providing a rationale for targeting highly replicative cancer cells with PARP1/2 inhibitors. The human oncoprotein DEK is a unique, non-histone chromatin architectural protein whose deregulated expression is associated with the development of a wide variety of human cancers. Recently, we showed that DEK is a high-affinity target of PARylation and that it promotes the progression of impaired replication forks. Here, we investigated a potential functional link between PAR and DEK in the context of replication stress. Under conditions of mild replication stress induced either by topoisomerase1 inhibition with camptothecin or nucleotide depletion by hydroxyurea, we found that the effect of acute PARP1/2 inhibition on replication fork progression is dependent on DEK expression. Reducing DEK protein levels also overcomes the restart impairment of stalled forks provoked by blocking PARylation. Non-covalent DEK-PAR interaction via the central PAR-binding domain of DEK is crucial for counteracting PARP1/2 inhibition as shown for the formation of RPA positive foci in hydroxyurea treated cells. Finally, we show by iPOND and super resolved microscopy that DEK is not directly associated with the replisome since it binds to DNA at the stage of chromatin formation. Our report sheds new light on the still enigmatic molecular functions of DEK and suggests that DEK expression levels may influence the sensitivity of cancer cells to PARP1/2 inhibitors.