bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical characteristics and prognosis of Chinese patients with hereditary transthyretin amyloid cardiomyopathy
Authors: He Shan , Tian Zhuang , Guan Hongzhi , Li Jian , Fang Quan , Zhang Shuyang 
Published: November 2019

Abstract

Background
Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized progressive cardiomyopathy with heterogenous clinical manifestations that lead to its misdiagnosis and poor prognosis. This study was performed to describe the clinical characteristics and natural history of Chinese patients to improve clinical awareness of this condition.

Methods
In this study, we retrospectively investigated 23 patients with a confirmed diagnosis of hereditary ATTR-CM in Peking Union Medical College hospital from From January 1, 2000 to December 31, 2018.

Results
In all, 16 patients (69.6%) were males, the median age at disease onset was 45 (33,55) years old. The median duration from symptom onset to diagnosis was 30 (18,46) months. Phenotypes were classified as exclusively cardiac (n = 1, 4.3%) and mixed type (n = 22, 95.6%). The common mutations were Gly47Arg (7 patients [30.4%]) and Val30Ala (3 patients [13%]). Ventricular hypertrophy was observed in 23 (100%) patients, the mean thickness of the ventricular septum was 16.1 ± 3.9 mm, the mean thickness of the left ventricular posterior wall was 15.1 ± 2.8 mm. The mean left ventricle ejection fraction (LVEF) was 57.3 ± 11.9% and only 5 patients (21.7%) had LVEF < 50%. 18 (78.3%) patients had abnormal electrocardiography and the most common feature was pseudoinfarct pattern (56.5%). Overall survival at 12, 24, 36, 48, and 60 months after diagnosis was 77.8, 55.6, 38.9, 27.8, and 11.1%, respectively. Survival was better in patients with EF ≥50% than in those with EF < 50% [log Rank (Mantel-Cox), χ2 = 4.03, P = 0.045].

Conclusions
The clinical characteristics of ATTR are heterogeneous: men are more likely to be affected and onset symptoms are not obvious in the heart and mainly include peripheral neuropathy and autonomic neuropathy; however, LV hypertrophy, especially a thick ventricular septum and posterior wall with preserved LVEF, are often detected on echocardiography. Abnormal ECG manifestations are common. The prognosis is poor, and patients with EF > 50% have better survival. Clinicians should be more aware of the complex clinical profile of ATTR amyloidosis to avoid misdiagnosis in practice.
Nonclonal chromosomal alterations and poor survival in cytopenic patients without hematological malignancies
Authors: Imataki Osamu , Kubo Hiroyuki , Takeuchi Akihiro , Uemura Makiko , Kadowaki Norimitsu 
Published: November 2019

Abstract

Background
Clonal chromosomal alterations (CCAs) reflect recurrent genetic changes derived from a single evolving clone, whereas nonclonal chromosomal alterations (NCCAs) comprise a single or nonrecurrent chromosomal abnormality. CCAs and NCCAs in hematopoietic cells have been partially investigated in cytopenic patients without hematological malignancies.

Methods
This single-center retrospective study included 253 consecutive patients who underwent bone marrow aspiration to determine the cause of cytopenia between 2012 and 2015. Patients with hematological malignancies were excluded. CCA was defined as a chromosomal aberration detected in more than two cells, and NCCA was defined as a chromosomal aberration detected in a single cell.

Results
The median age of the patients was 66 years. There were 135 patients without hematological malignancies (median age, 64 years; 69 females); of these, 27 patients (median age, 69 years; 8 females) harbored chromosomal abnormalities. CCAs were detected in 14 patients; the most common CCA was −Y in eight patients, followed by inv.(9) in three patients and mar1+, inv. (12), and t (19;21) in one patient each. NCCAs were detected in 13 patients; the most frequent NCCA was +Y in four patients, followed by del (20), + 8, inv. (2), − 8, and add (6) in one patient each. Moreover, nonclonal translocation abnormalities, including t (9;14), t (14;16), and t (13;21), were observed in three patients. One patient had a complex karyotype in a single cell. The remaining 106 patients with normal karyotypes comprised the control group (median age, 65 years; range, 1–92 years; 56 females). Further, follow-up analysis revealed that the overall survival of the NCCA group was worse than that of the CCA and the normal karyotype groups (P < 0.0001; log-rank test).
The survival of the NCCA-harboring cytopenic patients was worse than that of the CCA-harboring cytopenic patients without hematological malignancies, suggesting that follow-up should be considered for both CCA- and NCCA-harboring cytopenic patients.
Behavioral analysis in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain
Authors: Nishino Tasuku , Tamada Kota , Maeda Akane , Abe Takaya , Kiyonari Hiroshi , Funahashi Yasuhiro , Kaibuchi Kozo , Takumi Toru , Konishi Hiroaki 
Published: November 2019

Abstract
Grb2-associated regulator of Erk/MAPK (GAREM), is an adaptor protein related to the several cell growth factor receptor-signaling. The GAREM family has two subtypes, GAREM1 and GAREM2, both encoded in the human and mouse genome. Recent genome-wide research identified GAREM2 as a candidate of neurodegenerative diseases. Here, we use knockout (KO) mice to show the role of GAREM2, that is highly expressed in the brain. According to the comprehensive behavioral battery, they exhibited less anxiety both in elevated plus maze and open field tests, mildly increased social approaching behavior in the reciprocal social interaction test, and longer latency to immobility in the tail suspension test as compared to wild-type (WT). Additionally, the extension of neurites in the primary cultured neurons was suppressed in ones derived from GAREM2 KO mice. Furthermore, we also identified Intersectin, as a binding partner of GAREM2 in this study. Intersectin is also a multi-domain adaptor protein that regulates endocytosis and cell signaling, which can potentially alter the subcellular localization of GAREM2. The important molecules, such as the neurotrophin receptor and Erk family, that are involved in the signaling pathway of the neural cell growth in the mouse brain, have been reported to participate in emotional behavior. As GAREM plays a role in the cellular growth factor receptor signaling pathway, GAREM2 may have a common role related to the transduction of Erk signaling in the higher brain functions.
Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer
Authors: Kim Sehui , Jang Ji-Young , Koh Jaemoon , Kwon Dohee , Kim Young A. , Paeng Jin Chul , Ock Chan-Young , Keam Bhumsuk , Kim Miso , Kim Tae Min , Heo Dae Seog , Chung Doo Hyun , Jeon Yoon Kyung 
Published: November 2019

Abstract

Background
We investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC).

Methods
Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1low and PD-L1high NSCLC cells after transfection or knockdown of PD-L1, respectively. Jurkat T-cell activation was assessed after co-culture with NSCLC cells. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA).

Results
Transfecting PD-L1 in PD-L1low cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. By contrast, knocking-down PD-L1 in PD-L1high cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vector-transfected tumor cells. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC (p < 0.001). In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274high rather than CD274low group. Consistently, there were fewer CD8+ T-cells in PD-L1positive/HK2high tumors compared to PD-L1positive/HK2low tumors in squamous cell carcinoma.

Conclusions
PD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint.
PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer
Authors: Jin Xin , Fang Rui , Fan Ping , Zeng Lipeng , Zhang Bin , Lu Xiaoming , Liu Tao 
Published: November 2019

Abstracts

Background
Overexpressed PES1 promotes carcinogenesis in various types of malignant tumors. However, the biological role and clinical significance of PES1 in pancreatic cancer are still unexplored.

Methods
The expression level of PES1 in pancreatic cancer cell lines and pancreatic cancer patient samples was determined using Western Blotting analysis, RT-qPCR analysis, immunohistochemical (IHC) analysis of tissue microarray, and the GEPIA web tool. MTS assay, colony formation assay, and xenograft tumor assay were used to evaluate the tumor growth ability of pancreatic cancer cells.

Results
We established that the expression of PES1 was abnormally increased in pancreatic cancer tissues and led to poor prognosis of pancreatic cancer patients. We also found that PES1 was responsible for promoting cell growth and contributed to bromodomain and cancer cell resistance to extra-terminal (BET) inhibitors in pancreatic cancer. Furthermore, we showed that PES1 interacted with BRD4 to enhance c-Myc expression, which is the primary cause of cancer cell resistance to BET inhibitors in pancreatic cancer. Finally, CDK5 inhibitors were proven to destabilize PES1 and overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.

Conclusions
We have shown that PES1 could be one of the promoting factors of tumor growth and a prognosis-related protein of pancreatic cancer. Targeting PES1 with CDK5 inhibitors might help overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.
Prognostic ability of the sequential organ failure assessment score in accidental hypothermia: a multi-institutional retrospective cohort study
Authors: Kandori Kenji , Okada Yohei , Matsuyama Tasuku , Morita Sachiko , Ehara Naoki , Miyamae Nobuhiro , Jo Takaaki , Sumida Yasuyuki , Okada Nobunaga , Watanabe Makoto , Nozawa Masahiro , Tsuruoka Ayumu , Fujimoto Yoshihiro , Okumura Yoshiki , Kitamura Tetsuhisa , Iiduka Ryoji 
Published: November 2019

Abstract

Background
Severe accidental hypothermia (AH) is life threatening. Thus, prognostic prediction in AH is essential to rapidly initiate intensive care. Several studies on prognostic factors for AH are known, but none have been established. We clarified the prognostic ability of the Sequential Organ Failure Assessment (SOFA) score in comparison with previously reported prognostic factors among patients with AH.

Methods
The J-point registry database is a multi-institutional retrospective cohort study for AH in 12 Japanese emergency departments. From this registry, we enrolled patients who were treated at the intensive care unit (ICU) in various critical care medical centers. In-hospital mortality was the primary outcome. We investigated the discrimination ability of each candidate prognostic factor and the in-hospital mortality by applying the logistic regression models with areas under the receiver operating characteristic curve (AUROC) with 95% confidence interval (CI).

Results
Of the 572 patients with AH registered in the J-point registry, 220 were eligible for the analyses. The in-hospital mortality was 23.2%. The AUROC of the SOFA score (0.80; 95% CI: 0.72–0.86) was the highest among all factors. The other factors were serum potassium (0.65; 95% CI: 0.55–0.73), lactate (0.67; 95% CI: 0.57–0.75), quick SOFA (qSOFA) (0.55; 95% CI: 0.46–0.65), systemic inflammatory response syndrome (SIRS) (0.60; 95% CI: 0.50–0.69), and 5A severity scale (0.77; 95% CI: 0.68–0.84).

Discussion
Although serum potassium and lactate had relatively good discrimination ability as mortality predictors, the SOFA score had slightly better discrimination ability. The reason is that lactate and serum potassium were mainly reflected by the hemodynamic state; conversely, the SOFA score is a comprehensive score of organ failure, basing on six different scores from the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Meanwhile, the qSOFA and SIRS scores underestimated the severity, with low discrimination abilities for mortality.

Conclusions
The SOFA score demonstrated better discrimination ability as a mortality predictor among all known prognostic factors in patients with AH.
Microalbuminuria risks and glomerular filtration in children with sickle cell anaemia in Nigeria
Authors: Ocheke I. E. , Mohamed S. , Okpe E. S. , Bode-Thomas F. , McCullouch M. I. 
Published: November 2019

AbstractIntroductionEvidence of kidney damage is observed in children with sickle cell anaemia (SCA) and this continues through adulthood with progression to severe functional impairment in some. One of the earliest features of kidney damage associated with SCA is microalbuminuria. Our objective was to determine the risk factors of microalbuminuria in these children and its relationship with estimated glomerular filtration rate.MethodsThis was a cross-sectional and comparative study involving three hundred and twenty three children with SCA in steady state and equal numbers of apparently healthy age and sex matched haemoglobin AA (HbAA) control, aged 6 months to 18 years. They were consecutively recruited over a 6 month period.ResultMicroalbuminuria was present in 26% of the study subjects compared with 1.85% of controlP = 0.001). Anaemia and high estimated glomerular filtration rate (eGFR) showed strong positive correlation with microalbuminuria (OR = 3.19, CI 0.953–1.116,p = 0.003 and OR = 1.7, CI 1.042–1.066,p = 0.001 respectively). Similarly, eGFR was higher in subjects with SCA than in controls and as well as in those with microalbuminuria compared with those who do not (p = < 0.01).ConclusionsThe two most important risk factors for microalbuminuria were anaemia and high eGFR. Age category was associated more with microalbuminuria than just age as a variable. Glomerular filtration rate was higher in children with microalbuminuria than those who do not and it was also higher in children with SCA than in control.
Long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms
Authors: Sasannejad Cina , Ely E. Wesley , Lahiri Shouri 
Published: November 2019

AbstractAcute respiratory distress syndrome (ARDS) survivors experience a high prevalence of cognitive impairment with concomitantly impaired functional status and quality of life, often persisting months after hospital discharge. In this review, we explore the pathophysiological mechanisms underlying cognitive impairment following ARDS, the interrelations between mechanisms and risk factors, and interventions that may mitigate the risk of cognitive impairment. Risk factors for cognitive decline following ARDS include pre-existing cognitive impairment, neurological injury, delirium, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation, and environmental factors in the intensive care unit, which can co-occur synergistically in various combinations. Detection and characterization of pre-existing cognitive impairment imparts challenges in clinical management and longitudinal outcome study enrollment. Patients with brain injury who experience ARDS constitute a distinct population with a particular combination of risk factors and pathophysiological mechanisms: considerations raised by brain injury include neurogenic pulmonary edema, differences in sympathetic activation and cholinergic transmission, effects of positive end-expiratory pressure on cerebral microcirculation and intracranial pressure, and sensitivity to vasopressor use and volume status. The blood-brain barrier represents a physiological interface at which multiple mechanisms of cognitive impairment interact, as acute blood-brain barrier weakening from mechanical ventilation and systemic inflammation can compound existing chronic blood-brain barrier dysfunction from Alzheimer’s-type pathophysiology, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage. Although some contributory elements, such as the presenting brain injury or pre-existing cognitive impairment, may be irreversible, interventions such as minimizing mechanical ventilation tidal volume, minimizing duration of exposure to sedating medications, maintaining hemodynamic stability, optimizing fluid balance, and implementing bundles to enhance patient care help dramatically to reduce duration of delirium and may help prevent acquisition of long-term cognitive impairment.
Population-specific factors associated with fractional excretion of uric acid
Authors: Narang Ravi K. , Vincent Zoe , Phipps-Green Amanda , Stamp Lisa K. , Merriman Tony R. , Dalbeth Nicola 
Published: November 2019

Abstract

Background
Reduced renal clearance of uric acid is a major contributor to hyperuricemia. The aim of this study was to examine clinical and genetic variables associated with fractional excretion of uric acid (FEUA).

Methods
Participants (with and without gout) in the Genetics of Gout in Aotearoa study with available genotyping and FEUA data were included (n = 1713). Ten FEUA-associated loci detected within a genome-wide association study for serum urate in a European population were analysed. A polygenic score for FEUA was calculated in each ancestry group to model the cumulative effects of the genetic variants on FEUA. Associations between FEUA and both clinical variables and polygenic score were tested using linear regression models.

Results
The mean (SD) FEUA was 5.13 (2.70) % in Eastern Polynesian participants, 4.70 (5.89) % in Western Polynesian participants, and 5.89 (2.73) % in New Zealand European participants. Although association with FEUA was observed for SLC2A9 rs11942223 in New Zealand European participants (P = 2.39 × 10− 8), this association was not observed in Eastern or Western Polynesian participants. The polygenic score was positively associated with FEUA in all ancestry groups. In New Zealand European participants, body mass index, diuretic use, polygenic score, and male sex were associated with FEUA and explained 22% of FEUA variance in the regression model. In Eastern and Western Polynesian participants, the tested variables explained 10% and 4% of FEUA variance respectively.

Conclusions
Both clinical and genetic variables contribute to renal clearance of uric acid. SLC2A9 exerts effects on FEUA variance in people of European ancestry, but not in those of Polynesian ancestry. There is a large unexplained variance in FEUA, particularly in people of Polynesian ancestry.
Live and let die: epigenetic modifications of Survivin and Regucalcin in non-small cell lung cancer tissues contribute to malignancy
Authors: Nitschkowski Dörte , Marwitz Sebastian , Kotanidou Sousana A. , Reck Martin , Kugler Christian , Rabe Klaus F. , Ammerpohl Ole , Goldmann Torsten 
Published: November 2019

Abstract
Recently, it was shown that the epigenetic age of non-small cell lung cancer (NSCLC) tissues is different from the chronological age of patients. Here, we demonstrate that Regucalcin and Survivin, molecules which are known to be involved in the process of aging and overcoming aging, are epigenetically modified in NSCLC tissues compared to corresponding tumor-free tissues from the same donors by using methylome bead chip and corresponding transcriptome analyses. A high expression of Survivin on the RNA level was negatively correlated with patients’ survival in adenocarcinomas while a high Regucalcin expression was correlated positively. In stage 1 adenocarcinomas, this separation is even sharper for both genes. Within these, adenocarcinomas, smokers with low expression of Survivin show a better outcome, while the high expression of Regucalcin seems to be protective in never smokers. On the protein level, these molecules were detected by immunohistochemistry using tissue microarrays. Since Survivin can be secreted and we observed a high abundance of the protein also in the adjacent immune cells of the tumor microenvironment, an effect on benign cells can be assumed. These findings show that epigenetic re-programming of Survivin and Regucalcin in non-small cell lung cancer leads to enhanced expression of Survivin and reduced expression of Regucalcin, with a possible role of both molecules as predictive markers.
Review of the Manitoba cohort of patients with hereditary angioedema with normal C1 inhibitor
Authors: McKibbin Lundy , Barber Colin , Kalicinsky Chrystyna , Warrington Richard 
Published: November 2019

Abstract

Background
Hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) is a rare, underappreciated condition characterized by recurrent subcutaneous angioedema. The underlying pathophysiology and diagnostic criteria continues to evolve. There is a significant overlap between HAE-nC1 INH and idiopathic nonhistaminergic angioedema, ultimately this may be found to be the same condition. Characterization of cohorts suspected to have either of these conditions is warranted to help refine diagnosis, pathophysiology, and treatment response.

Methods
A retrospective chart review of 418 patients diagnosed with angioedema was conducted. The following inclusion criteria was used: lack of response to antihistamines, steroids, and epinephrine; normal C4, C1 inhibitor (C1 INH) level and function; lack of urticaria or pruritus; occurrence without offending drugs; and positive family history. Enzyme immunoassays for C1 INH function were performed at the Mayo Clinic. Charts meeting these criteria were reviewed for frequency and type of episodes as well as use and response to therapies.

Results
6 patients met the above criteria. 3 of these completed genetic testing, none were found to have factor XII abnormalities. None had angiopoietin 1 or plasminogen gene sequencing. 5 of 6 patients were successfully treated with C1 INH or tranexamic acid for acute treatment of attacks (4 with C1 INH and 1 with tranexamic acid). 4 patients have used Icatibant with good response (typically under 40 min for near full recovery); of these, 3 required Icatibant as acute treatment after other therapies (C1 inhibitor and tranexamic acid) were ineffective. There were 9 patients who otherwise met criteria, but due to a lack of family history were classified as having idiopathic non-histaminergic angioedema.

Conclusions
This retrospective chart review found 6 HAE-nC1 INH patients in Manitoba. 1 responded to tranexamic acid and not C1 INH, 4 typically responded to C1 INH, and 1 responded exclusively to Icatibant. All patients—4 total—who used Icatibant responded; of these 4 patients, 3 required Icatibant after other therapies had failed.