dataesr/scientific-paragraphs-categorization huggingface dataset:
ACKNOWLEDGMENTS The authors thank  Prof. Hiroshi Nishino  for providing the feces extract as well as a general advice along the way;  Iain Couzin  for his valuable feedback on the manuscript;  Antoine Hoffmann  for helpful comments on data analysis;  Margarete Ehrenfried  for rearing P. americana. We also thank  Alina Hebling ,  Hannah Honner  and  Jahn Nitschke  for help with experiments and analysis. The authors thank the 4 anonymous reviewers for their insightful suggestions. This work was completed with the support of the  Deutsche Forschungsgemeinschaft (DFG, German Research Foundation ) under Germany's Excellence Strategy -EXC  2117-422037984.
The signature was validated to strongly predict BCR (HR, 2. 44; 95% CI, 1. 53-3. 87; p = 1. 62e-4) after adjusting for clinico-pathological factors such as GS, surgical margin status, age, and stage. 47 These TAAs, although previously investigated in other cancer types, are relatively novel PC-associated TAAs. Despite this, the signature has not been independently validated on other large databases. [50] [51] [52]  Finally, although checkpoint inhibition has not yet proven of meaningful benefit in metastatic prostate cancer, there is some recent limited evidence that increased programmed death-ligan 1 (PD-L1) expression is associated with biochemical recurrence. 53, 54 quid biopsy technology has further enhanced the detection possibilities related to PC recurrence, using more sophisticated techniques compared to measurements of PSA levels, upon which the conventional notion of BCR is based.
61 similar phase trial, ELAAT (Clinicaltrial. gov identifier: NCT00439751), was designed by the Canadian Urological Oncology Group to assess the optimal timing of ADT in men with PSA rise post-RT, but failed to reach its accrual goal. In an attempt to improve significance by increasing the cohort size, a pooled analysis of the TOAD and ELAAT data was performed (n = 261 + 78 = 339). The reasons to start ADT in the two trials were development of symptoms, metastases on conventional imaging, or PSA-DT of ⩽6 months. The combined analysis showed no difference in all-cause mortality (HR 0. 75, p = 0. 37) or PC-specific mortality, whereas time to local progression, distant progression, and prostate cancer complications differed significantly in favor of immediate ADT. Several explanations may account for the loss of significance for OS in the combined analysis: ELAAT accrued older patients with a higher all-cause mortality risk and a lower relative risk of PC-specific mortality (relative to the overall mortality risk) and had a smaller difference in PSA between the immediate and deferred arms (3.
57; 95% CI, 1. 09-15. 97; p = 0. 05). In contrast, in patients with PSA > 1. 5 ng/ml, there was a 25% 12-year absolute benefit (HR: 0. 45, 95%CI: 0. 25-0. 81). 72 e ongoing British RADICALS-HT trial addresses not only the question of addition of GnRH analogues or bicalutamide to post-operative RT (immediate or salvage), but also of the optimal duration of treatment, using a 3-arm randomization (RT alone versus RT plus 6 months of hormonal treatment versus RT plus 24 months of hormonal treatment) (Clinicaltrials. gov identifier: NCT00541047). With the implementation of next generation imaging techniques in the clinical workflow, 73 a considerable proportion of relapsing prostate cancer patients are diagnosed with an oligometastatic disease, an intermediate state between a localized relapse, and a widespread metastatic status.
In the last years, MDT modalities like stereotactic body radiotherapy (SBRT) or salvage lymph node dissection have emerged as valid treatment options to treat these patients, to postpone systemic therapies, and in some cases to improve outcome. 74, 75 Although two major prospective studies published so far proposed MDT as alternative to systemic ADT,  34, 31  emerging evidence suggest a potential synergistic effect of this combined strategy to improve outcome of these patients. A third phase III trial is currently ongoing (Clinicaltrials. gov identifier: NGR-GU002) assessing docetaxel in patients with persistently elevated PSA ⩾ 0. 2 ng/ml (Clinicaltrials. gov identifier: NCT03070886). [87]  It ought to be highlighted that the STAMPEDE trial allowed for previously treated relapsing nonmetastatic patients with PSA progression only, although the reported numbers for previously treated M0 (which would include the pure BCR patients) were small both for the control (3%), docetaxel (2%), docetaxel/zoledronic acid (4%), and abiraterone acetate (3%) arms.
gov identifier: NCT02972060). The hypothesis of this study is that AR antagonists may have a similar efficacy in reducing PSA compared to ADT, with a better tolerability due to the maintenance of normal systemic testosterone levels. The primary endpoint is PSA response at 24 weeks. The phase II STREAM trial assessed the combination of prostate bed RT (66 Gy), 6 months of ADT and enzalutamide in patients with a GP ⩾ 7, and a PSA recurrence within 4 years of RP, with PSA levels of 0. 2-4. 0 ng/ml. In a cohort of 38 men, the combination had a good safety profile, without any grade 4/5 or unexpected toxicities. The primary endpoint of 2-year PFS was 65% (95% CI: 47, 78) versus 51% (95% CI: 33, 67) for historic controls. PSA remained at undetectable levels in 69% at 2 years, and the 3-year PFS was 53% (95% CI 37, 68).
2% of the total cohort. 95 e ongoing randomised phase II FORMULA-509 trial assesses the addition of the same combination (abiraterone and apalutamide) to salvage RT and ADT for high-risk BCR patients such as PSA ⩾ 0. 7 ng/ml, pathologic N+ disease, or numerous adverse risk factors (e. g. , pT3b-T4, primary pattern 5 disease) (Clinicaltrials. gov identifier: NCT03141671). The phase II BALANCE (Clinicaltrials. gov identifier: NRG GU-006) trial assesses in a placebocontrolled fashion the addition of 6 months apalutamide to salvage RT in high-risk BCR patients, including patients that never negativized their PSA post-RP. As the trial does not allow for ADT, patients with PSA > 1 ng/ml are excluded, aiming to use PSA as a biomarker for the use of NHA (Clinicaltrial. gov identifier: NCT03371719).
99-105 Furthermore, the adenovirus/PSA vaccine APP21 is currently assessed as a monotherapy versus combination with ADT in a randomised phase II trial (Clinicaltrials. gov identifier: NCT00583752). Checkpoint inhibition Some steps have also been made in the direction of using checkpoint inhibition in BCR. The anti-CTLA4 tremelimumab was assessed in combination with short-term (6 months) bicalutamide treatment in a phase I trial, reporting G3 diarrhoea and rash as dose-limiting toxicities. In 3 out of 11 patients (27%) delayed prolongation of PSA-DT was observed several months after completing treatment. 106 Nivolumab monotherapy for up to 2 years is currently assessed in high-risk BCR patients with PSA-DT < 10 months (Clinicaltrials. gov identifier: NCT03637543). An ongoing trial assesses the use of nivolumab monotherapy in patients with MMR-deficient/ MSI-high and PC with rising PSA (Clinicaltrials.
Immunotherapy combination trials A currently ongoing phase II trial (Clinicaltrials. gov identifier: NCT03315871) involves the use of the Prostvac recombinant vaccine in biochemically recurrent PC, in combination with bintrafusp alpha, a bifunctional anti-PD-L1/ anti-TGFbetaRII fusion protein in biochemically recurrent PC patients, as well as CV301, a poxviral based TAA vaccine targeting MUC1 and CEA. A combination of the pTVG-HP vaccine with pembrolizumab is also currently ongoing (Clinicaltrials. gov identifier: NCT03600350). Recently, a phase I/II trial of a combination synthetic DNA therapy of plasmids encoding for PSA and PSMA (INO-5150) and interleukin-12 (INO-9012) in 62 patients with rising PSA reported a good safety profile, with immunogenicity observed in 76% and 85% of patients remaining progression-free at 72 weeks.
108 e phase II ROAR trial (Clinicaltrials. gov identifier: NCT03533946) evaluates rucaparib in the same setting, requiring a BRCAness signature tested on liquid or soft tissue biopsy, with a primary endpoint of PSA50 response. A combination of olaparib with the anti-PDL1 agent durvalumab is also evaluated in a phase II trial on BCR patients with alterations in the DNA repair pathway genes (Clinicaltrials. gov identifier: NCT03810105).
84 For inclusion in the trial, patients had to present with one or more of the following: node-positive ade- nocarcinoma, positive surgical margins, GS ⩾ 8, PSA velocity >0. 75 ng/ml per year, PSA- 76,77 Ongoing trials are prospectively test- ing the use of SBRT with or without 6 months of concomitant ADT (Clinicaltrials. gov identifier: NCT04302454), the impact of intermittent ADT with or without elective nodal pelvic irradiation (Clinicaltrials. gov identifier: NCT03630666), or elective nodal irradiation versus SBRT, both com- bined with 6 months of ADT, 78 in patients with an exclusive oligometastatic nodal relapse. Androgen receptor targeted agents are also tested with SBRT in other ongoing clinical trials. 79 Chemotherapy Unsurprisingly, docetaxel trials have focused on high-risk BCR patients, given their higher risk for distant metastasis.
3% versus 71. 3%, p = 0. 04), metastatic PC (14. 5% versus 23%, p = 0. 005) and PC-specific mortality (5. 5% versus 13. 4%, p < 0. 0001). 71 Lack of benefit for PSA levels <0. 6 ng/ml (HR: 1. 16). 72 RADICALS: RT versus RT + 6 months of ADT versus RT + 24 months of ADT; ongoing (Clinicaltrials. gov identifier: NCT00541047). NRG Oncology/RTOG 0534 SPPORT: prostate bed RT versus prostate bed RT + 6 months ADT versus prostate bed RT with WPRT +6 mo ADT. Better freedom from failure and MFS with WPRT (HR 0. 52, p < 0. 014) 70 PROTECT: sipuleucel-T versus control; no difference in median to biochemical failure (18 months versus 15. 4 months, HR: 0. 936, p = 0. 737) (Beer CCR 2011) 98 NCIC Clinical Trials Group: intermittent versus continuous ADT; intermittent non-inferior to continuous (OS 8. 8 versus 9.
1 years, HR for death: 1. 02; 7-year PC- specific death 18% versus 15%, HR: 1. 18, p = 0. 24) 66 TOAD: immediate versus delayed ADT (>2 years); immediate ADT borderline improved 5-year OS (HR: 0. 54, p = 0. 047) but not in the PSA-relapse subgroup (86. 4% versus 91. 2%, HR: 0. 59, p = 0. 19) 61 ELAAT: intermittent versus deferred ADT; failed to reach accrual goal (Clinicaltrials. gov identifier: NCT00439751) TOAD + ELAAT pooled analysis: no difference in all- cause or PC-specific mortality (HR 0. 75; p = 0. 37) 65 TAX 3503: 18 months ADT + bicalutamide +/-docetaxel × 10 cycles; terminated early, trend towards improving median PFS (26. 2 versus 24. 7 months, HR: 0. 80, p = 0. 09) and OS (NR versus NR, HR: 0. 51, p = 0. 08) 83 RisingPSA: hormonal therapy +/-docetaxel × 6 cycles; no significant difference in PSA-PFS (20.
8 ng/ml post-RP or > 2 ng/ ml post RP), PSA- DT 5-15 mo BCR, PSA- DT > 3 mo BCR, PSA- DT < 12 mo HLA-A*0201- restricted BCR patients HLA-A2 (+) BCR pts Design Phase II Phase II Phase II Phase II Phase II Phase I/II Phase II FIH Phase I Phase I Trial NCT00734851 STAND (NCT01431391) ECOG 9802 NCT02649439 NCT01341652 NCT02362451 NCT00694551 Type of treatment Chemotherapy Docetaxel + rapid androgen cycling Docetaxel + sunitinib Vaccines Sipuleucel-T Prostvac (pox-viral vaccine) Prostvac DOM-PSMA 27 pTVG-HP (MVI-816, encoding PAP) TARP (T-cell receptor alternate reading frame protein) PSMA/TARP peptide vaccine Anti-angiogenics.
The incidence of serious AEs and drug discontinuation due to AEs trended higher with XVd (Additional file 1: Table  S4 ). There was no clear trend regarding AEs leading to a fatal outcome, although the slight excess number of deaths with XVd in the PI-treated subgroup were Trial registration: ClinicalTrials. gov (NCT03110562). Registered 12 April 2017. https:// clini caltr ials. gov/ ct2/ show/ NCT03 110562. restricted to India prior to the institution of increased monitoring, after which there were no additional deaths.
Acknowledgements JetPub Scientific Communications, LLC supported by funding from  Karyopharm , provided drafts and editorial assistance to the authors during preparation of this manuscript. Janssen Cilag and Specialized therapeutics. SJ reports consulting services for  AbbVie, Bristol-Myers Squibb, Janssen Pharmaceuticals ,  Merck & Co. PM reports personal fees from  Celgene ,  Amgen ,  Takeda ,  Janssen and Abbvie. ML reports receiving consulting fees and lecture fees from  Takeda ,  Celgene ,  Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals , and  Janssen. NJB reports grants and personal fees from  Celgene ; personal fees from  Janssen ,  Amgen ,  Takeda ,  Abbvie ,  GSK  and  Karyopharm. YC , JJ, MA, JS and MGK are employees of and stockholders of Karyopharm.
The same integration site is used to create all repeat-carrying strains in this study (Table  2 ). FIGURE LEGENDS (B) Mutation of two constructs can be assayed simultaneously in one cross. (C) Analyzed perfect repeats R1-R6 have the same overall length and the same linker sequence (green). Repeats differ with respect to GC content and relative orientation (Table  1 ). (D) Mutation of R1-R6 by DIM-2-dependent RIP was analyzed in five crosses (Table  3 ). Cross and repeat IDs are indicated. 50 ascospore clones (per repeat construct, per cross) were analyzed for RIP in the linker region. A 681-bp segment of the 729-bp linker was sequenced. The level of RIP is expressed as the number of mutations per site ("mutation frequency", red) and as "partitioned RIP propensity" (PRP) profile (black). Data in panels D and E are plotted at the same scale (both x-axis and y-axis).
(E) DIM-2-dependent RIP in the lpl-proximal flank was analyzed for the two GC-rich repeats R5 and R6 (crosses X4 and X5, respectively). (B) Repeats were always provided by male parents (Table  3 ). 50 random ascospore clones were analyzed (per repeat per cross). The magnitude of RIP is expressed as in Fig. 1D. Data are plotted at the same scale as in Fig. 1D  (both x-axis and y-axis). Recombination-independent pairing of direct (A) versus inverted (B) repeats is expected to create the same amount of DNA supercoiling. The way by which this supercoiling is utilized can be strongly influenced by the relative orientation of the closely-positioned repeat units.
ACKNOWLEDGMENTS This work was supported by  ANR  " Laboratoires  d'excellence" grants  11-LABX-0011  (A. K. M) and  10-LABX-0062  (E. G. ),  ANR JCJC  grant  ANR-19-CE12-0002  (E. G),  FRM  grant  AJE20180539525  (E. G. ),  CNRS  (A. K. M), and  Institut Pasteur (E. G. ).
The cerebellum was not evaluated for LC3B, p62 and NeuN immunohistochemistry since no immunostaining was found in this area. Spongiosis and PrP Sc deposition were semiquantitatively scored on a scale of 0 (lack of spongiosis/ PrP Sc deposit) to 5 (very intense spongiosis/PrP Sc deposit) since semiquantitative evaluation is the standard method to assess these features  [42]. Semiquantitative evaluation for spongiosis and PrPSc was performed twice for each mouse and brain area. Caspase-3 staining was quantitatively evaluated by counting all the stained cells present in the whole sagittal section of each mouse brain at a 20 × magnification. LC3B, p62 and NeuN immunostaining was assessed using the Image J software. The Image J assessed markers staining was evaluated by the colour deconvolution method as previously described  [43] , which measures both the number of stained cells and the intensity at once.
After detection of the interest protein, β-actin immunodetection was also performed in both membranes to normalize band intensity quantification. Membranes were washed with PBST for 1 h at room temperature and then incubated with mouse monoclonal anti β-actin antibody (1:2000, Bio-Rad, VMA00048) for 2 h at room temperature and developed as described above. The image J software was also used to quantify band intensity in Western blots. For this purpose, each band was individually selected and circumscribed with the rectangular ROI (region of interest) selection and then "Gels" function was used, obtaining the corresponding histograms for each band. This was followed by quantification of the peak area of intensity of the histograms. Obtained values were normalized through the measure of the intensity of β-actin bands.
Complementary DNA (cDNA) was obtained from 200 ng of total RNA using qScript™ cDNA Supermix (Quanta Biosciences™, Beverly, MA, USA). Resulting cDNA was diluted 1:5 in water for further analyses. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed with TaqMan probes (Thermo Fisher Scientific) used for the amplification of the selected genes. PCR reactions were performed using TaqMan Universal PCR Master Mix (Thermo Fisher Scientific), and PCR was carried out in a StepOne Real-Time PCR System (Thermo Fisher Scientific) using universal conditions. All reactions were run in triplicate in a total volume of 5 μL, using 2. 25 μL of diluted cDNA. The expression of two housekeeping genes (H6pd, Sdha) was used to normalize results. Relative gene expression quantification was subsequently determined using normalized data and relative quantification was performed using the 2 -ddCt method.
Fig. 5  LC3B determination in Tg338 and C57BL6 prion infected mice after TTC intramuscular injection. A Different staining levels of LC3B immunostaining found in mice cerebral cortex, showing a cytoplasmic staining in neurons. B Comparison of the evaluation through Image J software of the LC3B immunostaining in TTCinjected and control groups of Tg338 and C57BL6 lines in medulla oblongata (Mobl), mesencephalon (Mes), hypothalamus (Ht), thalamus (Th), hippocampus (Hc), septal area/striatum (Sa), parietal cortex (Pc) and frontal cortex (Fc). Treated mice of both lines show higher LC3B accumulation. Significant differences were studied using the Mann-Whitney U test (*p < 0. 05 and **p < 0. 01) and found in Mes, Ht, Th and Pc in C57BL6 mice and in Mobl, Mes, Ht, Th, Pc, Sa and Fc in Tg338 mice.
The fact that neuronal survival was higher in the TTC-treated group even though spongiosis was similar in TTC-treated and control mice could be related to the reduction of the apoptosis observed in treated mice. The finding that TTC affected apoptosis and autophagy and that this was linked to an increase on neuronal survival in TTC-treated mice suggests that TTC is able to reduce apoptosis and to regulate autophagy. Moreover, the differences in p62, LC3 and NeuN expression between control and Fig. 6  Assessment of p62 expression in Tg338 and C57BL6 prion infected mice after TTC intramuscular injection. A Representative images of p62 immunostaining in cerebral cortex of mice, where a cytoplasmic labeling can be observed. B Evaluation of p62 staining in brains of control and treated C57BL6 and Tg338 mice using the Image J software in the aforementioned brain areas.
Identification and localization of the male-specific locus of arapaima. To identify the sex locus of arapaima, we sequenced a pool of male and a pool of female genomic DNAs. These pool-sequencing (Pool-Seq) datasets were aligned to the male (heterogametic sex, XY) and female (homogametic sex, XX) assemblies to search for sex-biased signatures. When the Pool-Seq reads were aligned to the female assembly, two prominent peaks of male-specific single nucleotide variants (SNVs) were detected (heterozygous variations in males but homozygous for the same allele in all females) on chromosomes (Chr) 26 and 5, and a minor peak on Chr 10 (Fig. 1A ). No signal of sex-linkage appeared using the male reference assembly, however (Fig. 1B ). The sequence containing the peak of male-specific SNVs in the female assembly Chr05 (Fig.
1D ). The DNA sequence of kidins220bΔ is highly diverged (5. 7% amino acid and 6. 1% cDNA identity) from to the homologous kidins220b (15,043 bp DNA and 3477 bp CDS) on Chr05 suggesting that this gene fragment is corrupted. All RNA-seq datasets examined (see "Methods") lacked transcripts from the Chr26, supporting the view that it is non-functional. In contrast, the id2bbY copy is highly conserved, with 93. 2% cDNA identity and 86. 9% amino acid identity. Due to the third round (3R) of whole-genome duplication (WGD) of teleosts, many genes known from other vertebrates exist as in two versions, so-called ohnologs. Our analyses of the arapaima genomes identified two copies of id2 in females according to the 3R expectation. However, three copies were observed in males. To reconstruct the evolution of the id2 gene family in vertebrates, were retrieved all genes with annotation "id2" from the fully sequenced high-quality reference genomes of 9 teleost species, spotted gar (basal actinopterygian), human, mouse, chicken, turtle, gecko, African clawed frog, coelacanth, and elephant shark to build a gene tree (Fig.
Genome annotation. Repeats in the assembly were identified and masked by RepeatModeler and Repeat-Masker (http:// www. repea tmask er. org). The assembly was first scanned by RepeatModeler for de novo identification of repeats. The results, together with FishTEDB 59 , were then transferred to RepeatMasker for similarity scan and final repeat masking. Protein coding genes were annotated by collecting and synergizing gene evidence from homolog alignment, expression data mapping and ab inito prediction  60. Briefly, for homolog alignment, 611,738 protein sequences from Swiss-Prot (www. unipr ot. org) and from related fish species were used as query. These species include Paramormyrops kingsleyae, Erpetoichthys calabaricus, Scleropages formosus, Lepisosteus oculatus, Salmo salar, Danio rerio and Callorhinchus milii (www.
ensem bl. org). GeneWise  61  and Exonerate (https:// www. ebi. ac. uk/ about/ verte brate-genom ics/ softw are/ exone rate) were used independently to align protein queries to the assembly and to determine the gene structure. GenBlastA  62  were also used as support to GeneWise to roughly locate each protein sequence on the assembly. For expression data mapping, RNA-seq reads used in our previous study  13  were mapped on the assembly using HISAT  63  and parsed using StringTie 64 for gene structure. In parallel, transcripts were first assembled using Trinity  65  and then mapped to the assembly using PASA  66. For ab initio prediction, SNAP (https:// github. com/ KorfL ab/ SNAP), GeneMark-ES  67  and AUGUSTUS  68  were used. Finally, gene structures that were consistently predicted in each of the above parallel approaches were selected as high-quality gene models to train AUGUSTUS, and all collected gene evidences were transferred to the trained AUGUSTUS for final annotation.
The final gene models were mapped to Pfam (https:// pfam. xfam. org/), Swiss-Prot and NCBI nr database (fish only) using BLAST  69  , and genes with no hit and not supported by RNA-seq reads were removed. Identification of the male sex-specific marker by PoolSex. Pool-sequencing libraries were prepared from male and female gDNA pools of the same individuals analyzed in Du et al. 13  , using the Illumina TruSeq Nano DNA HT Library Prep Kit (Illumina, San Diego, CA, USA) according to the manufacturer's protocol. After fragmentation of each gDNA pool (200 ng/pool) by sonication using an M220 Focused-ultrasonicator (COVA-RIS), the size selection was performed using SPB beads retaining fragments of 550 bp. Following the blunt 3′ end fragments mono-adenylation and ligation to specific paired-end adaptors, the amplification of the construction was performed using Illumina-specific primers.