dataesr/scientific-paragraphs-categorization huggingface dataset:
FUNDING This work was supported by a number of entities including grants from the  Breakthrough Project of the Strategic Priority Program of the Chinese Academy of Sciences (CAS)  ( XDB13000000  to G-DW); the  National Natural Science Foundation of China  ( 91731304 ,  31621062 ); the  Intramural Program of the National Human Genome Research Institute of the National Institutes of Health, USA  (to EAO); a  CAS  international collaborating grant proposal ( 152453KYSB20150002  to G-DW); the  Morris Animal Foundation  (to RKW); the  Swedish Research Council  (to KLT); the  European Research Council  ( ERC-2013-StG-337574-UNDEAD  to GL and LF); the  Natural Environmental Research Council  ( NE/K005243/1  and  NE/K003259/1  to GL and LF); grant ' Cani-DNA CRB'  ( ANR-11-INBS-0003 ) for the  French Tissue Bank  (to CA and CH); and a  Young Innovation Promotion Association Award  (to G-DW).
METHODS Study Design and Participants This prospective observational explorative study is part of the ongoing ProHand-study; ClinicalTrials. gov Identifier: NCT02878304. Patients were recruited consecutively from a subacute inpatient rehabilitation unit in Stockholm, Sweden, admitting patients aged 18-67 years from March 2013 until September 2016. In Sweden, patients aged above 67 years are normally referred to geriatric rehabilitation clinics. The study comprised assessments at admission to a subacute in-patient rehabilitation at 2-6 weeks (T1), (on average 3), at 3 (T2) and 6 months (T3) after stroke (Figure  1 ). Inclusion required: 2-6 weeks after first-ever computed tomography or MRI-verified stroke with upper limb weakness. The admitting team physician verified central paresis of the upper limb at admission by clinical examination.
Further, an ischemic nerve block reduced the stretch reflex and the NC, supporting that NC measures the neural component of the total resisting forces  (8). NeuroFlexor measurements have good reliability (inter-rater intraclass correlation coefficient: 0. 90-0. 94; test-retest: 0. 90-0. 96) and sensitivity to change  (32, 34). The resting tension before the initiation of passive extension is also quantified to ensure that movements were passive. A standardized procedure was followed (see Figure  2A )  (32). The less affected hand was examined first followed by the more affected hand (contralateral to the lesion). To distinguish between normal and abnormal force values (see Figures  2B, C ), we used normative data established in n = 107 healthy subjects based on the mean + 3SD (cut-offs: NC > 3.
Lesion Maps Before delineating lesion maps, the T1-weighted images were normalized to MNI template using SPM12 (http://www. fil. ion. ucl. ac. uk/spm/software/spm12/). Cost function masking was used to avoid distortion of lesion by normalization procedure  (35). To rule out poor normalization, images were inspected visually. Lesion maps were manually drawn on all axial slices of normalized anatomical images (from T1) using MRIcron  (36)  by researcher (PL) blinded to all clinical data except the side of the stroke. Lesion location was verified on FLAIR and diffusion images and lesion maps were binarized. A neuroradiologist (EL) and an experienced neurologist (J-CB) verified lesion maps (test of interrater reliability in a subset of 17 lesion maps showed an intraclass correlation = 0. 94). Left-sided lesions were flipped to the right to enable group analysis  (37).
Weighted Corticospinal Tract Lesion Load The weighted corticospinal tract lesion load (wCST-LL) was calculated by computing the overlap between patient's lesion and the CST template  (38) , a measure related to motor outcome  (39). We used the same method and constructed CST as detailed previously Birchenall et al. (40). In brief, first we constructed this CST template from diffusion weighted imaging (74 directions with b-value of 3,000 s/mm2) in 18 healthy subjects (mean age 31. 7 years). Probabilistic tracking was performed using the FMRIB Software Library (FSL 5. 06, www. fmrib. ox. ac. uk/ fsl) with regions of interest including precentral gyri, posterior limb of internal capsule, cerebral peduncles and anteromedial pons. Resulting CST tracts were normalized into MNI space [see  Birchenall et al.
Statistical Analysis We used Statistica 13. 2 (http://statistica. io/latest-version) and IBM Statistica SPSS 23 (https://www. ibm. com/analytics/us/en/ technology/spss/) software for the statistical analysis. To explore the clinical significance of spasticity occurrence and severity, spasticity sub-groups were defined according to NC amplitude and temporal pattern. Generalized Expectation Maximization analysis was performed to verify sub-group clusters at T1. Linear Mixed Model for Longitudinal Data was applied to explore longitudinal changes in outcome variables. Results from the best fitting model (with the smallest Akaike Information Criterion) are presented. Post hoc tests were adjusted according to Bonferroni. Residuals were plotted to verify that assumptions of the models were met. No imputation of missing data was performed.
To control for other stroke-related impairments and demographic data each model was repeated adding the following covariates, one at a time; age, sex, stroke type and side, neglect, National Institutes of Health Stroke Scale, sensation and pain (Table  1  and Table e-1). Correlation between NC, outcome measures and lesion size and location were explored using Pearson or Spearman's tests. Multiple regression analysis was applied to investigate partial correlation statistics. Occurrence of pain was analyzed with Fisher's exact test and logistic regression. For voxel-based lesion symptom mapping we used permutation methods, shown to be useful in controlling for false positives  (41). We only studied voxels lesioned in minimum six patients. The significance level, alpha, was set at p < 0. 05.
The blockade of PD-L1 promoted infiltration of CD8 + T cells into the tumor site and induced local immune activation. Furthermore, the combination of gemcitabine with anti-PD-L1 mAb exhibited significant synergistic effect, eliciting a complete response without overt toxicity in treated mice  [86]. A clinical study (NCT01313416) on the combination of gemcitabine and pidilizumab (CT-011), a humanized mAb against PD-1 has been closed to enrolment. CT-011 is designed to specifically bind to PD-1, thus inhibiting PD-1 activity and attenuating apoptotic processes of effector or memory T lymphocytes, ultimately resulting in the activation of a CTL antitumor immune response  [69]. CT-011 has been studied in murine models of other cancers, including leukemia, melanoma, lung cancer and colorectal carcinoma.
To prove this concept, multiple clinical trials of PD-1/PD-L1 blockade in combination with GVAX vaccine therapy are ongoing (NCT02243371; NCT02648282; NCT02451982). For example, a randomized phase I/II clinical trial (NCT02451982) is ongoing to evaluate the efficacy of GVAX with or without anti-PD-1 mAb (nivolumab) as neoadjuvant or adjuvant treatment in resectable pancreatic cancer patients at Johns Hopkins University. However, there are some limitations and several challenges have been associated with cancer immunotherapy targeting neoantigens. Antigens used in cancer vaccines should preferably be molecules that are different from normal cells, to ensure that antitumor immune response generated by vaccination only targeted on antigen bearingtumor cells but not normal cells. Most tumor antigens are derived from mutated or modified self-proteins, leading to a risk of immune tolerance.
Accumulating evidence suggests that tumor neoantigens are one of the important targets for an antitumor immune response. Indeed, a higher neoantigen load and increased level of TILs are associated with improved survival in patients with colorectal  [100]  and endometrial cancer  [101]. Therefore, the development of neoantigen cancer vaccines is highly dependent on the correct prediction and identification of neoantigens. Neoantigen prediction involves a series of computational steps, starting with the identification of mutations at the DNA level by comparing the whole exome sequences with those matched normal cells, followed by identifying targeted neoepitopes with the help of tumor RNA expression profiling, and finally determining the binding affinity of predicted epitopes to the MHC molecules with the use of software programs such as NetMHC or SYFPEITHI  [98, 102].
Currently, a phase Ib clinical trial (NCT02304393) is assessing the safety, pharmacokinetics, pharmacodynamics and activity of a combination treatment of a CD40 mAb (RO7009789)) in conjunction with atezolizumab (anti-PD-L1) in patients with metastatic or locally advanced solid tumors. Another ongoing phase Ib/II study (NCT03214250) aims to investigate the safety and efficacy of a CD40 mAb (APX005M) administered with gemcitabine and nab-paclitaxel with or withoutanti-PD-1 mAb (nivolumab) in metastatic pancreatic cancer patients.
2  Frequency of mesothelin protein expression in various common solid malignancies  [121] , although its aberrant or overexpression in preclinical and clinical studies showed that it plays an active role in both tumor malignancy and aggressiveness by promoting tumor proliferation, leading to invasion, metastasis, and conferring resistance towards cytotoxic agents  [119]. In one of the completed phase I clinical trials (NCT01897415), T cells were engineered to express anti-mesothelin CAR and administered into patients with chemotherapy refractory metastatic pancreatic cancer. Of the six patients treated, two patients achieved stable disease in that study. Currently, an ongoing non-randomized phase I/II clinical trial (NCT01583686) is being conducted to determine the safety and efficacy of administering the engineered tumor fighting cells (anti-mesothelin cells) in metastatic cancer patients (ovarian, lung, cervical, mesothelioma and pancreatic cancer), followed by the administration of a preparative regimen (fludarabine, cyclophosphamide and aldeslekin).
Furthermore, an ongoing non-randomized phase I study (NCT03323944) is evaluating the safety and feasibility of transducing meso-cells in unresectable or metastatic pancreatic cancer patients, either given as a single agent or in combination with cyclophosphamide. Several clinical trials (Table  1 ) and ongoing clinical trials (Table  2 ) Targeting of other tumor antigens such as CEA (carcinoembryonic antigen), FAP, and mucin (MUC)-1 also has marked activity in murine models of pancreatic cancer. CEA is a glycoprotein that is highly expressed on the surface of the majority of pancreatic cancer cells. Targeting CEA by CAR T cells has been shown to induce tumor regression and produce long-term tumor eradication in 67% of pancreatic tumor-bearing mice without autoimmune effects. Interestingly, engineered T cells with a dual-receptor CAR (dCAR-T) exert high cytotoxicity against pancreatic tumor cells expressing tumor antigens, CEA and mesothelin, resulting in 80% apoptosis of tumor cell  [96].
Pancreatic tumor-bearing mice receiving dCAR-T cells released higher levels of cytokines, including IL-2, IL-6, IFN-λ and TNF-α, and showed a marked reduction in tumor growth compared to controls receiving CAR-T cells alone  [96]. However, a CEA-targeted CAR T cell clinical study was halted early, after several treated patients suffered from shortness of breath, highlighting the risks and caution needed when pursuing these studies  [122]. Several clinical trials are ongoing to better understand the safety, adverse events and potential effectiveness of CEA-targeted CAR T cells in liver metastases (NCT02850536), colorectal cancer (NCT02959151), and CEA positive cancer, including gastric cancer, lung cancer, pancreatic cancer, breast cancer and colorectal cancer (NCT02349724). MUC-1 has recently become an interesting target in cancer immunotherapy and it is overexpressed in nearly 90% of pancreatic cancers  [123].
This study showed increased levels of CD4 + and CD8 + T cells and significant tumor necrosis in treated patients, suggesting that CAR-T cell therapy could be a promising treatment strategy for patients with solid tumors  [126]. Clinical trials are ongoing to assess the efficacy and safety of MUC-1-targeted CAR-T cell therapy in patients with relapsed or refractory solid tumors, including pancreatic adenocarcinoma (NCT02587689 & NCT02617134). New generations of CAR are under investigation to further enhance their activities and specificities, while also decreasing off-target toxicity. It should be noted that the immunosuppressive environment, as well as the effect of upregulation of immune checkpoint inhibitors on CAR T cells, can significantly restrict the full potential of CAR T cell therapy  [127, 128].
The expression of PD-1 was significantly reduced in anti-PD-1-secreting CAR T cells compared with CAR T cells. Compared with both CAR T cell monotherapy alone and combination therapy, mice treated with anti-PD-1-secreting CAR T cells had a significantly higher ratio of CD8 + versus CD4 + T cells at the tumor site  [133]. Similar results were observed in a renal cell carcinoma mouse model, where CAR T cells secreting anti-PD-L1 antibodies were shown to greatly diminish the exhaustion of T cells and further enhance tumor regression compared with CAR T cells alone  [134]. Altogether, these data indicated that this combinatorial strategy could enhance effector function of T cells in the presence of immune checkpoint inhibitors, resulting in tumor regression and improved survival  [128]. Ongoing novel clinical studies (NCT03182803 and NCT03030001) are designed to evaluate the efficacy and safety of CAR T cells engineered to express immune checkpoint antibodies in advanced recurrent or refractory malignant solid tumors.
Zhu and coworkers  [136]  demonstrated that the efficacy of anti-PD-1 or anti-CTLA4-based immunotherapy was enhanced via CSF1R/CSF1 blockade. It is important to highlight that the tumor growth reduced more than 90% when CSF1R blockade was combined with either anti-CTLA-4 or anti-PD-1 compared to the mice treated only with anti-CTLA-4 or anti-PD-1 alone. Building on these results, a phase I clinical trial (NCT03153410) using the combination of IMC-CS4 (CSF1R mAb) with GVAX and anti-PD-1 is ongoing for patients with borderline resectable pancreatic cancer. Another anti-CSF1R agent, PLX-3397 (pexidartinib) in combination with anti-PD-L1 Ab (durvalumab) is currently in phase I clinical trial (NCT02777710) for patients with advanced pancreatic and colorectal cancers. (2) Janus Kinase (JAK) inhibitors The JAK/STAT signaling pathways are essential for a wide range of cytokines and growth factors, leading to critical cellular events such as hematopoiesis and the development of the immune system  [143].
In a randomized double-blind, phase II study, ruxolitinib plus capecitabine improved survival in patients with metastatic pancreatic cancer who failed to respond to gemcitabine chemotherapy  [149]. Unfortunately, subsequent phase III studies (NCT02117479 & NCT02119663) have closed to enrolment as there was no significant improvement in patient survival. The efficacy of ruxolitinib therapy could be enhanced by using it as an adjunct agent to suppress chronic inflammation and facilitate infiltration of CD8 + T cells, rather than as a monotherapeutic agent for overcoming anti-PD-L1 immunotherapy resistance in pancreatic cancer patients  [144]. (3) Bruton's Tyrosine Kinase (BTK) inhibitors BTK is a member of Tec tyrosine kinase family which is important for B cell development, differentiation and signaling.
Another phase II clinical trial (NCT02940301) is recruiting patients with Hodgkin lymphoma to determine the efficacy of ibrutinib in combination with an anti-PD-1 antibody (nivolumab). (4) Immune checkpoint therapy with radiotherapy (RT) RT can convert the TME from a 'cold' state that lacks infiltration of antitumor immune cells and is resistant to immunotherapy to a 'hot' state, which can activate the immune system in triggering an antitumor response, leading to cytotoxicity and the release of stimulatory agents that could enhance the recruitment of T cells to the tumor site. For instance, antitumor T cells that are generated spontaneously or via vaccination may be prevented from entry into the tumor site due to the presence of the desmoplastic stroma of cancer  [155]. In contrast, by inducing tumor cell death coupled with the release of danger signals, radiation can stimulate activation and migration of DCs to the tumor-draining lymph nodes where the activation of antitumor T cells will be stimulated.
Although the molecular mechanisms have yet to be fully elucidated, the central message generated by Azad and coworkers  [158]  clearly provides an important insight on the potential of immune checkpoint inhibitors to radio-sensitize a large group of RT-resistant tumors, including pancreatic cancer that traditionally has been classified as non-immunogenic. Clinical research on combination strategies is rapidly progressing. There are numerous clinical studies that examine concurrent treatment, in combination with RT, with either PD-L1 blockade or anti-PD-L1 mAbs in various types of solid tumors. Interestingly, unresectable, non-metastatic pancreatic cancer is also being investigated in a phase Ib clinical study (NCT02868632) to evaluate the efficacy of RT plus either anti-CTLA-4 mAb alone, anti-PD-L1 mAb alone, or the combination of both immune checkpoint inhibitors.
Recently, a randomized phase II study (NCT02866383) in metastatic pancreatic cancer patients who are intolerant to chemotherapeutic agents is ongoing to determine the efficacy and safety profile of nivolumab or nivolumab plus ipilimumab administered simultaneously with high dose RT; this is estimated to end in 2019. Another similar pilot study (NCT02311361) is also investigating the efficacy of immune checkpoint inhibition (tremelimumab and/or MEDI4736) with RT in unresectable metastatic pancreatic cancer patients.
Additionally, increased infiltration of CD8 + T cells, reduced tumor burden and improved overall survival were observed in tumor-bearing mice treated with combination therapy comprising FAK inhibition and PD-1 blockade, compared to PD-1 blockade alone; this suggests that the efficacy of anti-PD-1 can be enhanced by inhibiting the expression of FAK  [165]. More conclusive evidence will be available when the phase I/II clinical trial (NCT02758587) is completed. This trial involves patients with advanced solid tumors, including pancreatic cancers, who receive a FAK inhibitor (defactinib) in combination with an anti-PD-1 mAb (pembrolizumab). Another potential therapeutic target within the stroma of pancreatic cancer is hyaluronan (HA). Accumulation of HA or HA combined with its binding proteins (HABPs) forms a size selective barrier to antitumor immune cells and the efficient delivery of therapeutic drugs; this creates an immunosuppressive environment which prevents infiltration of T cells, as well as preventing chemotherapeutic agents and mAbs from entering the tumor and reaching their site of action.
However, the actual mechanism of HA depletion induced by PEGPH20 is still under investigation  [171]. To date, there are no clinical studies investigating PEGPH20 as monotherapy or combinatory treatment in cancers  [172]. Numerous clinical trials are currently enrolling patients; these trials will evaluate the efficacy of PEGPH20 in combination with other therapeutic agents (Table  4 ). A non-randomized pilot study (NCT02921022) investigating the effects of PEGPH20 plus a combination regimen (gemcitabine, nab-paclitaxel and rivaroxaban) in patients with/without prior thromboembolic events is currently ongoing. A Phase I clinical trial (NCT03481920) is currently underway to evaluate the pharmacodynamics and efficacy of PEGPH20 plus avelumab (anti-PD-L1 mAb) in chemotherapy-resistant pancreatic cancer patients  [173].
Another clinical trial (NCT03267940) is ongoing to evaluate the safety, tolerability and antitumor activity of PEGPH20 with anti-PD-L1 in patients with cholangiocarcinoma/gallbladder cancer. The safety and tolerability of a combination of PEGPH20 and anti-PD-1 is also under investigation in HA-high patients with lung cancer and gastric cancer (NCT02563548). Targeting the tumor stroma could modulate its immunosuppressive conditions by facilitating the normalization of blood vessels and weakening the immunosuppressive effects of cancer-associated fibroblasts; this will effectively enhance the transportation of oxygen and therapeutic agents as well as the infiltration of effector T cells to the tumor tissues, thereby, enhancing the efficacy of the immune checkpoint therapies  [174].
Combinations of mismatch repair deficiency and PD-1 blockade in tumors Surprisingly, the effectiveness of immunotherapy can be predicted based on the presence of mismatch repair deficiency. Mismatch repair deficient (dMMR) cancers are hypothesized to have large numbers of mutationassociated neoantigens (MANAs) which can be recognized by the host antitumor immune cells  [175, 176]. dMMR is associated with frameshift mutations that take place within the coding sequences, resulting in the production of functionally inactive proteins that can be presented via MHC molecules to CD8 + T cells as tumor neoantigens, consequently eliciting an antitumor immune response as well as the infiltration of T cells into the TME  [177]. An early clinical trial (NCT02060188) showed that colorectal cancer with mismatch repair deficiency was associated with an increased tumor neoantigen load and infiltration of immune effector cells, consequently enhancing tumor sensitivity to immune checkpoint blockade, particularly anti-PD-1  [178].
A phase II clinical trial (NCT01876511) is ongoing to evaluate the clinical activity of pembrolizumab (anti-PD-1) in patients with dMMR tumors. The objective response rate (ORR) and progrssion-free survival were significantly higher (40 and 78% respectively) in dMMR cancer patients compared with MMR-proficient colorectal cancer patients ((0 and 11%, respectively)  [179] , supporting the hypothesis that dMMR tumors are more responsive to immune checkpoint blockade than MMR-proficient tumors.
Future efforts can be anticipated to harness neoantigen-specific antitumor immunity to treat patients with immune checkpoint inhibitor-resistant cancers such as pancreatic cancer and to identify immunogenic hotspots for directed neoantigen targeting  [192]. Personalized immunotherapy based on individual genetic information, molecular biology and immune profiling is hypothesized to result in the greatest clinical outcomes for cancer patients  [193] , leading either to the conversion of untreatable cancer into a controllable chronic disease or long term tumor eradication  [194]. In addition, more efforts should be made in the development of databases and bioinformatics platforms, as an enormous amount of genomics and biomarkers data have been generated; at the same time, this could empower the practice of precision immune-oncology.
The Red Blood Cell (RBC) is a metabolically-driven cell vital for processes such a gas transport and homeostasis. RBC possesses at its surface exposing antigens proteins that are critical in blood transfusion. Due to their importance, numerous studies address the cell function as a whole but more and more details of RBC structure and protein content are now studied using massive state-of-the art characterisation techniques. Yet, the resulting information is frequently scattered in many scientific articles, in many databases and specialized web servers. To provide a more compendious view of erythrocytes and of their protein content, we developed a dedicated database called RESPIRE that aims at gathering a comprehensive and coherent ensemble of information and data about proteins in RBC. This celldriven database lists proteins found in erythrocytes.