bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo vaccination with cell line-derived whole tumor lysates: neoantigen quality, not quantity matters
Authors: Salewski Inken , Gladbach Yvonne Saara , Kuntoff Steffen , Irmscher Nina , Hahn Olga , Junghanss Christian , Maletzki Claudia 
Published: October 2020

Abstract
Background
Cancer vaccines provide a complex source of neoantigens. Still, increasing evidence reveals that the neoantigen quality rather than the quantity is predictive for treatment outcome.

Methods
Using the preclinical Mlh1−/− tumor model, we performed a side-by side comparison of two autologous cell-line derived tumor lysates (namely 328 and A7450 T1 M1) harboring different tumor mutational burden (TMB; i.e. ultra-high: 328; moderate-high: A7450 T1 M1). Mice received repetitive prophylactic or therapeutic applications of the vaccine. Tumor incidence, immune responses and tumor microenvironment was examined.

Results
Both tumor cell lysates delayed tumor formation in the prophylactic setting, with the A7450 T1 M1 lysate being more effective in decelerating tumor growth than the 328 lysate (median overall survival: 37 vs. 25 weeks). Comparable results were achieved in therapeutic setting and could be traced back to antigen-driven immune stimulation. Reactive T cells isolated from A7450 T1 M1-treated mice recognized autologous Mlh1−/− tumor cells in IFNγ ELISpot, but likewise YAC-1 cells, indicative for stimulation of both arms of the immune system. By deciphering local effects, vaccines shaped the tumor microenvironment differently. While A7450 T1 M1 prophylactically vaccinated tumors harbored low numbers of myeloid-derived suppressor cells (MDSC) and elevated CD8-T cell infiltrates, vaccination with the 328 lysate evoked MDSC infiltration. Similar effects were seen in the therapeutic setting with stable disease induction only upon A7450 T1 M1 vaccination. Untangling individual response profiles revealed strong infiltration with LAG3+ and PD-L1+ immune cells when treatments failed, but almost complete exclusion of checkpoint-expressing lymphocytes in long-term survivors.

Conclusions
By applying two tumor cell lysates we demonstrate that neoantigen quality outranks quantity. This should be considered prior to designing cancer vaccine-based combination approaches.
Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model
Authors: Wang Yaping , Shi Yu , Huang Yongquan , Liu Wei , Cai Guiyuan , Huang Shimin , Zeng Yanyan , Ren Siqiang , Zhan Hongrui , Wu Wen 
Published: October 2020

Abstract
Background
Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms.

Methods
A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence.

Results
The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia.

Conclusions
Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.
These legs were made for propulsion: advancing the diagnosis and treatment of post-stroke propulsion deficits
Authors: Awad Louis N. , Lewek Michael D. , Kesar Trisha M. , Franz Jason R. , Bowden Mark G. 
Published: October 2020

AbstractAdvances in medical diagnosis and treatment have facilitated the emergence of precision medicine. In contrast, locomotor rehabilitation for individuals with acquired neuromotor injuries remains limited by the dearth of (i) diagnostic approaches that can identify the specific neuromuscular, biomechanical, and clinical deficits underlying impaired locomotion and (ii) evidence-based, targeted treatments. In particular, impaired propulsion by the paretic limb is a major contributor to walking-related disability after stroke; however, few interventions have been able to target deficits in propulsion effectively and in a manner that reduces walking disability. Indeed, the weakness and impaired control that is characteristic of post-stroke hemiparesis leads to heterogeneous deficits that impair paretic propulsion and contribute to a slow, metabolically-expensive, and unstable gait. Current rehabilitation paradigms emphasize the rapid attainment of walking independence, not the restoration of normal propulsion function. Although walking independence is an important goal for stroke survivors, independence achieved via compensatory strategies may prevent the recovery of propulsion needed for the fast, economical, and stable gait that is characteristic of healthy bipedal locomotion. We posit that post-stroke rehabilitation should aim to promote independent walking, in part, through the acquisition of enhanced propulsion. In this expert review, we present the biomechanical and functional consequences of post-stroke propulsion deficits, review advances in our understanding of the nature of post-stroke propulsion impairment, and discuss emerging diagnostic and treatment approaches that have the potential to facilitate new rehabilitation paradigms targeting propulsion restoration.
A neglected problem in the utilization of free anterolateral thigh flap toward reconstructing complicated wounds of extremities: the obliteration of deep dead space
Authors: Ren Gao-hong , Xiang Da-yong , Wu Xiao-hu , Chen Yun-biao , Li Runguang 
Published: October 2020

Abstract
Background
Deep dead space may be thought as an independent risk factor of the poor infection control after flap reconstruction in complex limb wounds. But it can be easily neglected. The conventional skin flap and musculocutaneous flap are difficult to obliterate the deep dead space in irregular shape effectively. It was investigated that the clinical application of chimeric anterolateral thigh perforator flap in the treatment of complex wounds complicated with deep dead space of the extremities in the paper.

Methods
Fifty-six cases complicated with deep dead space wounds were registered in group. Following thorough debridement and treatment with VSD, the granulation tissues grew with well-controlled infection. And then the chimeric anterolateral thigh perforator flap was used to obliterate the deep dead space and repair the wounds. The postoperative flap survival and infection conditions were evaluated.

Results
Overall, the infection was effectively controlled, without persistent exudation or sinus tract formation after wound healing. While 5 cases lost to follow-up, the remaining 51 cases were followed up until 15 months on average. Generally, the affected extremities recovered satisfactorily with normal appearances and texture of the flaps, along with normal functions. Importantly, no recurrence of infection was observed.

Conclusion
During the grafting of chimeric perforator flap pedicled with lateral thigh muscle flap, the muscle flap is recommended to obliterate the deep dead space while the skin flap is being used to cover the wound. The combination of these two technologies performed well in the repair and reconstruction of the complex wounds of the extremities, possessing potential for broader clinical application.
Correlation of the anatomical sacral slope with pelvic incidence in female patients with developmental hip dysplasia: a retrospective cross-sectional study
Authors: Imai Norio , Suzuki Hayato , Sakagami Atsushi , Hirano Yuki , Endo Naoto 
Published: October 2020

Abstract
Background
The anatomical sacral slope is considered as an anatomical pelvic parameter independent of femoral head centers for measurement of anatomical sacral slope and was previously described to strongly correlate with pelvic incidence on a two-dimensional examination of healthy subjects. However, the correlation between anatomical sacral slope and pelvic incidence was unclear in patients with developmental dysplasia of the hip. This study aimed to examine the correlation between anatomical sacral slope and other spinopelvic parameters by analyzing plain radiographs of female patients with developmental dysplasia of the hip.

Methods
Eighty-four women with developmental dysplasia of the hip were examined. Lumbar lordosis, thoracic kyphosis, pelvic incidence, sacral slope, and anatomical sacral slope (the angle formed by the straight line of the S1 superior endplate and a line at a right angle to the anterior pelvic plane) were determined by analyzing plain radiographs. The correlations were examined by Pearson’s correlation coefficients, and intra- and inter-rater intraclass correlation coefficients were evaluated for reliability.

Results
A strong correlation was observed between pelvic incidence and anatomical sacral slope (r = 0.725, p < 0.001). In addition, the correlation between anatomical sacral slope and lumbar lordosis was similar to that between pelvic incidence and lumbar lordosis (r = 0.661, p < 0.001, and r = 0.554, p < 0.001, respectively). The intra-rater intraclass correlation coefficient values were 0.869 and 0.824 for anatomical sacral slope and pelvic incidence, respectively. Furthermore, the inter-rater intraclass correlation coefficient values were 0.83 and 0.685 for anatomical sacral slope and pelvic incidence, respectively.

Conclusions
We observed that the strong correlation between anatomical sacral slope and pelvic incidence in patients with developmental dysplasia of the hip was equal to that in normal healthy subjects. The correlation between anatomical sacral slope and lumbar lordosis was equal to that between pelvic incidence and lumbar lordosis. Additionally, the intraclass correlation coefficient values for the anatomical sacral slope were slightly higher than those for pelvic incidence. Thus, we conclude that anatomical sacral slope can be considered as a helpful anatomical pelvic parameter that is a substitute for pelvic incidence not only in normal healthy subjects, but also in patients with developmental dysplasia of the hip.
UBE2T-regulated H2AX monoubiquitination induces hepatocellular carcinoma radioresistance by facilitating CHK1 activation
Authors: Sun Jingyuan , Zhu Zhenru , Li Wenwen , Shen Mengying , Cao Chuanhui , Sun Qingcan , Guo Zeqin , Liu Li , Wu Dehua 
Published: October 2020

Abstract
Background
Radioresistance is the major obstacle in radiation therapy (RT) for hepatocellular carcinoma (HCC). Dysregulation of DNA damage response (DDR), which includes DNA repair and cell cycle checkpoints activation, leads to radioresistance and limits radiotherapy efficacy in HCC patients. However, the underlying mechanism have not been clearly understood.

Methods
We obtained 7 pairs of HCC tissues and corresponding non-tumor tissues, and UBE2T was identified as one of the most upregulated genes. The radioresistant role of UBE2T was examined by colony formation assays in vitro and xenograft tumor models in vivo. Comet assay, cell cycle flow cytometry and γH2AX foci measurement were used to investigate the mechanism by which UBE2T mediating DDR. Chromatin fractionation and immunofluorescence staining were used to assess cell cycle checkpoint kinase 1(CHK1) activation. Finally, we analyzed clinical data from HCC patients to verify the function of UBE2T.

Results
Here, we found that ubiquitin-conjugating enzyme E2T (UBE2T) was upregulated in HCC tissues, and the HCC patients with higher UBE2T levels exhibited poorer outcomes. Functional studies indicated that UBE2T increased HCC radioresistance in vitro and in vivo. Mechanistically, UBE2T-RNF8, was identified as the E2-E3 pair, physically bonded with and monoubiquitinated histone variant H2AX/γH2AX upon radiation exposure. UBE2T-regulated H2AX/γH2AX monoubiquitination facilitated phosphorylation of CHK1 for activation and CHK1 release from the chromatin to cytosol for degradation. The interruption of UBE2T-mediated monoubiquitination on H2AX/γH2AX, including E2-enzyme-deficient mutation (C86A) of UBE2T and monoubiquitination-site-deficient mutation (K119/120R) of H2AX, cannot effectively activate CHK1. Moreover, genetical and pharmacological inhibition of CHK1 impaired the radioresistant role of UBE2T in HCC. Furthermore, clinical data suggested that the HCC patients with higher UBE2T levels exhibited worse response to radiotherapy.

Conclusion
Our results revealed a novel role of UBE2T-mediated H2AX/γH2AX monoubiquitination on facilitating cell cycle arrest activation to provide sufficient time for radiation-induced DNA repair, thus conferring HCC radioresistance. This study indicated that disrupting UBE2T-H2AX-CHK1 pathway maybe a promising potential strategy to overcome HCC radioresistance.
Prognostic value of kallikrein-related peptidase 7 (KLK7) mRNA expression in advanced high-grade serous ovarian cancer
Authors: Gong Weiwei , Liu Yueyang , Diamandis Eleftherios P. , Kiechle Marion , Bronger Holger , Dorn Julia , Dreyer Tobias , Magdolen Viktor 
Published: October 2020

Abstract
Background
High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. A growing body of evidence suggests tumor-supporting roles of several members of the kallikrein-related peptidase (KLK) family, including KLK5 and KLK7, in this cancer subtype. In normal physiology, KLK5 and KLK7 are the major proteases involved in skin desquamation. Moreover, in several cancer types KLK5 and KLK7 co-expression has been observed. Recently, we have shown that elevated KLK5 mRNA levels are associated with an unfavorable prognosis in HGSOC. Therefore, the aim of this study was to investigate the clinical significance of KLK7 mRNA expression and to explore its relation to KLK5 levels in HGSOC.

Methods
mRNA expression levels of KLK7 were quantified by qPCR in a well-characterized patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO III/IV, n = 139). Previously determined KLK5 mRNA as well as KLK5 and KLK7 antigen concentrations were used to evaluate the relationship between the expression patterns of both factors on the mRNA as well as protein level in tumor tissue of HGSOC patients.

Results
There were strong, significant positive correlations between KLK5 and KLK7 both at the mRNA and the protein level, suggesting coordinate expression of these proteases in HGSOC. In univariate analyses, elevated KLK7 levels as well as the combination of KLK5 + KLK7 (high and/or high versus low/low) were significantly associated with worse progression-free survival (PFS). High mRNA expression levels of KLK7 and the combination of KLK5 and KLK7 showed a trend towards significance for overall survival (OS). In multivariate analyses, KLK7 mRNA expression represented an unfavorable, statistically significant independent predictor for PFS and OS.

Conclusions
The findings imply that both increased KLK5 and KLK7 mRNA expression levels represent unfavorable prognostic biomarkers in advanced high-grade serous ovarian cancer, whereby multivariate analyses indicate that KLK7 mRNA exhibits a stronger predictive value as compared to KLK5 mRNA and the combination of KLK5 and KLK7.
Resilience in a prehospital setting - a new focus for future research?
Authors: Jeppesen Elisabeth , Wiig Siri 
Published: October 2020

Abstract
Background
Handling and initiating of treatment in a prehospital setting are complex processes that involve many treatment options and include several parts of the chain of survival. Capacity to adapt to unexpected changes in the patients’ conditions or in the surroundings is a prerequisite for patient safety. Outside the healthcare sector, safety science is moving from an approach focused on the analysis and management of error (Safety I) to instead understanding the inherent properties of safety systems (Safety II). In healthcare the attention to why service providers are able to succeed under challenging conditions remains sparse. The aim of this commentary is to give a better understanding of how the concept and inclusion of resilience can inspire a new approach for future research in prehospital settings. So far, most resilience studies have been conducted in emergency departments while the role of contextual factors and adaptations in a prehospital setting has remained unexplored.

Main body
In contrast to traditional research on healthcare quality and safety, which tends to focus on failures, resilience research is interested in examining the overwhelming majority of healthcare processes with successful outcomes, to determine how high-quality patient care is generated. Resilience is conceptualized as a proactive ability to adjust to potentially harmful influences and challenges rather than to resist them. To better understand and promote resilience, there is a need to explore the underlying mechanisms of adaptation, trade-offs and improvisation that occur in the emergency chain. Attention to how people respond to disruptions, challenges and opportunities is vital. There are factors, recognized and unidentified, influencing adaptation, trade-offs and improvisation. Influencing factors at different levels could be of particular value to increase knowledge to better understand resilience in a practical perspective. As prehospital work conditions are highly unpredictable and diverse, learning through everyday work could be of great value if the experiences are transferred and integrated in training and simulation.

Conclusions
Empirical research is of crucial importance to build and support resilient systems and processes in a prehospital setting. We need a new framework and a new approach to how research on this topic is conducted and to support resilient performance. This should involve identifying factors that promote resilience, both on individual-, team- and system- levels.
Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia
Authors: Tuazon Anna Marie De Asis , Lott Paul , Bohórquez Mabel , Benavides Jennyfer , Ramirez Carolina , Criollo Angel , Estrada-Florez Ana , Mateus Gilbert , Velez Alejandro , Carmona Jenny , Olaya Justo , Garcia Elisha , Polanco-Echeverry Guadalupe , Stultz Jacob , Alvarez Carolina , Tapia Teresa , Ashton-Prolla Patricia ,   Brazilian Familial Cancer Network, Alemar Barbara , Netto Cristina Brinckmann Oliveira , Carraro Dirce Maria , Vargas Fernando Regla , da Silva Gustavo Stumpf , Nascimento Ivana Lúcia Oliveira , de Souza Kelly Rose Lobo , Achatz Maria Isabel , Moreira Miguel Angelo Martins , Torrales Maria Betânia , Pimenta Maristela , Machado-Lopes Taisa Manuela Bonfim , Vega Ana , Lazaro Conxi , Tornero Eva , Martinez-Bouzas Cristina , Infante Mar , De La Hoya Miguel , Diez Orland , Browning Brian L. ,   COLUMBUS Consortium, Bolaños Fernando , Murillo Raúl , Sánchez Yesid , Sanabria Carolina , Serrano Martha Lucia , Suarez John Jairo , Rannala Bruce , Teixeira Manuel R. , Carvallo Pilar , Echeverry Magdalena , Carvajal-Carmona Luis G. 
Published: October 2020

Abstract
Background
The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry.

Methods
BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia.

Results
The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period.

Conclusions
Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.
Suicide Reduction in Schizophrenia via Exercise (SUnRISE): study protocol for a multi-site, single-blind, randomized clinical trial of aerobic exercise for suicide risk reduction in individuals with schizophrenia
Authors: Beck-Felts Katie , Goodman Marianne , Ospina Luz H. , Wall Melanie , McEvoy Joseph , Jarskog Lars F. , Ballon Jacob S. , Bartels Matthew N. , Buchsbaum Richard , Sloan Richard P. , Stroup T. Scott , Kimhy David 
Published: October 2020

AbstractBackgroundSuicide risk among individuals with schizophrenia (SZ) is intractably high, with over 40% of individuals attempting to take their own lives during their lifetime and an estimated 5–10% completing suicide. At present, available pharmacological and psychotherapeutic treatments offer limited risk reduction benefits, and thus, there remains an urgent need to explore novel interventions that will ameliorate this risk. Aerobic exercise (AE) has been shown to improve a number of predictors of suicide risk (e.g., depressed mood, sleeping difficulties). As individuals with SZ display a highly sedentary lifestyle, AE may reduce suicide risk.MethodsEmploying a multi-site, single-blind, randomized clinical trial design, we will examine the impact of AE on risk for suicide and related variables in individuals with SZ. Participants will be randomized to one of two 12-week exercise interventions: AE or a stretching and toning (ST) control intervention. Primary outcome measures will include suicide risk (Columbia Suicide Severity Rating Scale, C-SSRS) and aerobic fitness (VO2max), along with additional measures of suicide risk, mood, emotion regulation, sleep, cognition, and physical activity, with assessments completed at baseline and after 6 and 12 weeks of interventions.DiscussionIt is hypothesized that AE will reduce suicide risk among individuals with SZ. This study may offer support for a more efficacious treatment method for this population in addition to the pre-existing pharmacological and psychotherapeutic treatment regimens.Trial registrationClinicaltrials.gov,NCT03270098. Registered on September 1, 2017.