bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy
Authors: Mallardo Domenico , Fordellone Mario , White Andrew , Ottaviano Margaret , Sparano Francesca , Bailey Michael , Facchini Arianna Bianca , Ong Sufey , Maiolino Piera , Caracò Corrado , Church Sarah , Cavalcanti Ernesta , Warren Sarah , Budillon Alfredo , Cesano Alessandra , Simeone Ester , Chiodini Paolo , Ascierto Paolo Antonio 
Published: September 2023

Abstract
Background
Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma.

Methods
A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb–IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis.

Results
The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFβ2, a marker of the N2 neutrophils with immunosuppressive activity.

Conclusions
These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.
Clinical characteristics of abruptly increased paediatric patients with Omicron BF.7 or BA.5.2 in Beijing
Authors: Yu Lei , Wang Congying , Li Xiaoyun , Wang Xinning , Kang Yingying , Ma Xiaomei , Sun Rui , Sun Yu , Zhu Runan , Jia Liping , Yao Yao , Li Xiaohui , Zhang Daitao , Pan Yang , Lv Bing , Yuan Jing , Zhao Linqing , Gu Qinglong , Zhang Jian 
Published: September 2023

Abstract
Background
The coronavirus disease 2019 outbreak has hit Beijing since mid-Nov, 2022, with soaring growth of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children. Therefore, it is vital to determine the clinical manifestations of epidemic SARS-CoV-2 strains in paediatric patients.

Methods
In this study, nucleic acid tests (NATs) for SARS-CoV-2 were performed in paediatric outpatients with symptoms of acute respiratory tract infection during 18 Nov–6 Dec, 2022. Half of the outpatients positive for SARS-CoV-2 were randomly selected to screen for other respiratory pathogens, whereas those with low cycle threshold values in SARS-CoV-2 NATs were amplified and sequenced to determine the SARS-CoV-2 variants. Finally, children positive for SARS-CoV-2 with clinical information in detail were enrolled in a follow-up study to identify potential factors significantly associated with long recovery.

Results
Among 9625 paediatric outpatients tested for nucleic acid of SARS-CoV-2, 733 (7.62%, 733/9625) were identified as SARS-CoV-2 NAT positive, with only three (0.82%, 3/366) co-infected with other pathogens among 366 randomly selected patients, and 71 (62.83%) determined as Omicron subvariant BF.7 and 42 (37.22%) as BA.5.2 among 113 successfully sequenced. Among the 681 patients with complete clinical information, fever was the most common symptom (96.8%). In a follow-up study of 592 patients, 46.96% became asymptomatic on the third day and 65.71% on the fifth day. Only 1.7% of infected children experienced febrile seizures. Combined with abnormal C-reactive protein, a higher percentage of antibiotics administration was observed. More co-living members and longer duration of first symptoms served as independent risk factors for long-term recovery, especially in children vaccinated for SARS-CoV-2.

Conclusions
BF.7 and BA.5.2 were the dominate Omicron subvariants and caused milder infections during the SARS-CoV-2 outbreak in Beijing. The number of co-living members and duration of first symptoms were independent risk factors for long-term recovery.
Cognition of abdominal pain and abdominal discomfort in Chinese patients with irritable bowel syndrome with diarrhea
Authors: Lu Jia , Chen Yang , Shi Lili , Li Xiaoqing , Fei Guijun , Li Ji , Yang Aiming , Fang Xiucai 
Published: September 2023

Abstract
Background
In Asia, the proportion of patients with irritable bowel syndrome (IBS) with abdominal discomfort alone is significantly higher than that in western countries. The purposes of this study are to understand the cognition of abdominal pain and abdominal discomfort in Chinese patients with IBS and to compare the clinical characteristics of patients with abdominal pain alone and with abdominal discomfort alone.

Methods
Patients with IBS with diarrhea (IBS-D) who met the Rome III diagnostic criteria and had episodes of at least one day/week were consecutively enrolled. The cognition of abdominal pain and abdominal discomfort were investigated through face-to-face unstructured interview. Patients were divided into a pain group and a discomfort group according to the cognition interviews, then the characteristics and severity of symptoms (IBS symptom severity scale, IBS-SSS), IBS quality of life (IBS-QOL) and psychological state were compared between groups.

Results
A total of 88 patients with IBS-D were enrolled. Most of the patients with self-reported abdominal pain described their pain as spasm/cramping; patients with self-reported abdominal discomfort had as many as 24 different descriptions of discomfort. Most patients having abdominal pain and discomfort could accurately distinguish the two symptoms. The degree of abdominal pain in the pain group was higher than abdominal discomfort in the discomfort group (P = 0.002). There was no significant difference in IBS-SSS, extra-intestinal pain, IBS-QOL, and psychological state between the two groups.

Conclusions
For Chinese patients with IBS-D, abdominal pain and abdominal discomfort are two different symptoms, but they have similar clinical features.

Trial registration
ChiCTR, ChiCTR1900028082. Registered 11 December 2019 - Retrospectively registered, http://www.chictr.org.cn.
Electrolyte imbalance causes suppression of NK and T cell effector function in malignant ascites
Authors: Hrvat Antonio , Schmidt Mathias , Wagner Bernd , Zwanziger Denise , Kimmig Rainer , Volbracht Lothar , Brandau Sven , Mallmann-Gottschalk Nina 
Published: September 2023

Abstract
Background
Malignant ascites commonly occurs in advanced or recurrent stages of epithelial ovarian cancer during peritoneal carcinomatosis and is correlated with poor prognosis. Due to its complex composition of cellular and acellular components malignant ascites creates a unique tumor microenvironment, which mediates immunosuppression and promotes progression of disease. However, the immunosuppressive mechanisms remain poorly understood.

Methods
In the present study, we explored the antitumor activity of healthy donor NK and T cells directed against ovarian cancer cells in presence of malignant ascites derived from patients with advanced or recurrent peritoneal carcinomatosis. A wide range of methods was used to study the effect of ascites on NK and T cells (FACS, ELISA, EliSpot, qPCR, Live-cell and confocal microscopy, Western blot and electrolyte flux assays). The ascites components were assessed using quantitative analysis (nephelometry, potentiometry and clinical chemistry) and separation methods (dialysis, ultracentrifugal filtration and lipid depletion).

Results
Ascites rapidly inhibited NK cell degranulation, tumor lysis, cytokine secretion and calcium signaling. Similarly, target independent NK and T cell activation was impaired in ascites environment. We identified imbalanced electrolytes in ascites as crucial factors causing extensive immunosuppression of NK and T cells. Specifically, high sodium, low chloride and low potassium content significantly suppressed NK-mediated cytotoxicity. Electrolyte imbalance led to changes in transcription and protein expression of electrolyte channels and impaired NK and T cell activation. Selected inhibitors of sodium electrolyte channels restored intracellular calcium flux, conjugation, degranulation and transcript expression of signaling molecules. The levels of ascites-mediated immunosuppression and sodium/chloride/potassium imbalance correlated with poor patient outcome and selected molecular alterations were confirmed in immune cells from ovarian cancer patients.

Conclusion
Our data suggest a novel electrolyte-based mechanism of immunosuppression in malignant ascites of patients with peritoneal carcinomatosis. We show for the first time that the immunosuppression of NK cytotoxicity in coculture assays is correlated to patient poor survival. Therapeutic application of sodium channel inhibitors may provide new means for restoring immune cell activity in ascites or similar electrolyte imbalanced environments.
Amitriptyline overdose—an uncommon cause of acute transient exotropia presenting to the emergency setting: a case report
Authors: Rajaratnam Arun 
Published: September 2023

Abstract
Background
Acute presentations of acquired exotropia or divergent alignment of either or both eyes are commonly observed following intracranial vascular events, trauma, orbital, and endoscopic sinus surgeries.

Case presentation
The reported case is about a 16-year-old previously healthy Tamil female who presented to the emergency department with a few hours of reduced responsiveness. With the only clue in the history being about a family conflict the previous day, the examination revealed a noticeable exotropia along with a constellation of anticholinergic findings: a low Glasgow Coma Score, mydriasis, tachycardia, floppy limbs, exaggerated reflexes, and a palpable urinary bladder. Amitriptyline overdose leading to significant neurological involvement was suspected, and she was immediately offered urine alkalinization. Resources for urine and blood toxicological studies were not available. The patient gained consciousness 24 hours later and confirmed an overdose of ten amitriptyline tablets. Exotropia, a unique manifestation of this patient’s neurotoxicity, spontaneously resolved in 36 hours.

Discussion and conclusions
The reported case is about an uncommon clinical finding of exotropia seen in a common toxicological emergency: acute amitriptyline overdose. The importance of having a wide knowledge of various clinical presentations of drug toxicities is highlighted here, as any delay in diagnosis or initiation of life-saving measures could have resulted in fatal consequences.
Diplopia in a patient presenting with “blurred vision”: a case report
Authors: Harrison Anil , Mudhar Onkar , Yoo Jun , Rampal Mayank 
Published: September 2023

Abstract
Background
Myasthenia gravis is an autoimmune condition affecting the neuromuscular junction and causing muscle weakness along with fatigue (myasthenia). When the clinical manifestations of myasthenia gravis are isolated to the eye muscles, only causing weak eye movements, it is referred to as ocular myasthenia gravis, which can mimic a 1 and ½ syndrome.

Case presentation
An African-American female in her fifties with past medical history of hypertension presented to our outpatient clinic with complaints of blurred vision for two weeks. Her symptoms were associated with facial discomfort and a generalized headache. On physical examination upon her initial presentation, there was demonstratable swelling of the left upper eyelid with drooping. Her extraocular movements revealed defects with the abduction and adduction of the right eye, and the left eye would not adduct, although the outward movement was normal. The left eye failed to lift/elevate completely when looking upwards, a pseudo 1 and ½ syndrome. A positive Cogan lid twitch was also noticed. Imaging of the brain and orbit ruled out central causes. Diagnosis of ocular myasthenia gravis was made in accordance with positive anti-acetylcholine receptor antibodies. With 120 mg pyridostigmine oral dose, the patient experienced improvement subjectively and objectively, and the patient was discharged on oral pyridostigmine and prednisone. Six months later, with prednisone having been tapered off, the patient developed a myasthenic crisis and was treated with plasmapheresis and intravenous immunoglobulins. After recovering from the myasthenic crisis, efgartigimod infusions were instituted, which helped our patient restore normal life.

Conclusion
Our patient who presented with “blurred vision” was discovered to have binocular diplopia due to significant dysconjugate eye movements. After diligently ruling out central etiologies, we concluded that her presentation was due to a peripheral etiology. Her serologies and her presentation helped confirm a diagnosis of ocular myasthenia gravis. Also, as in most cases, our patient also progressed to develop generalized myasthenia gravis while on pyridostigmine. Efgartigimod infusions instituted after our patient recovered from a myasthenic crisis have helped her restore a normal life.
Challenges and opportunities of utilizing design thinking in the industry 4.0 era: based on the case study of industry wastewater treatment system development project process
Authors: Lee Hyejin , Zhang Yilei , Zhang Huihua , Liu Xuanchen 
Published: September 2023

AbstractThis paper reviews the research process conducted on developing a new system for industry wastewater treatment application to increase efficiency and sustainability by adopting industry 4.0 technology. The challenge of this project was to (a) utilize the design thinking methodology (human-centered design) entire process; (b) focus on heavy industry rather than the targeted user; and (c) adapt state of art technology. The objective was to revisit and invent new methods, such as metaphoric analysis, body thinking, and organization persona that would contribute to high-level innovative ideas: specifically, (a) the organization persona allowed to understand the dynamics of the complicated stakeholder structure; (b) the role of prototyping was mainly descriptive for communication; and (c) the case’s idea generation was used to affect the entire process of the project as well as benchmarking other industries. This paper attempts to address whether it is possible to create a new methodology that would address innovative business opportunities in complicated and high-tech adapting industries.
Gut microbes exacerbate systemic inflammation and behavior disorders in neurologic disease CADASIL
Authors: Liu Sheng , Men Xuejiao , Guo Yang , Cai Wei , Wu Ruizhen , Gao Rongsui , Zhong Weicong , Guo Huating , Ruan Hengfang , Chou Shuli , Mai Junrui , Ping Suning , Jiang Chao , Zhou Hongwei , Mou Xiangyu , Zhao Wenjing , Lu Zhengqi 
Published: September 2023

Abstract
Background
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3. The clinical manifestations are influenced by genetic and environmental factors that may include gut microbiome.

Results
We investigated the fecal metagenome, fecal metabolome, serum metabolome, neurotransmitters, and cytokines in a cohort of 24 CADASIL patients with 28 healthy household controls. The integrated-omics study showed CADASIL patients harbored an altered microbiota composition and functions. The abundance of bacterial coenzyme A, thiamin, and flavin-synthesizing pathways was depleted in patients. Neurotransmitter balance, represented by the glutamate/GABA (4-aminobutanoate) ratio, was disrupted in patients, which was consistent with the increased abundance of two major GABA-consuming bacteria, Megasphaera elsdenii and Eubacterium siraeum. Essential inflammatory cytokines were significantly elevated in patients, accompanied by an increased abundance of bacterial virulence gene homologs. The abundance of patient-enriched Fusobacterium varium positively correlated with the levels of IL-1β and IL-6. Random forest classification based on gut microbial species, serum cytokines, and neurotransmitters showed high predictivity for CADASIL with AUC = 0.89. Targeted culturomics and mechanisms study further showed that patient-derived F. varium infection caused systemic inflammation and behavior disorder in Notch3R170C/+ mice potentially via induction of caspase-8-dependent noncanonical inflammasome activation in macrophages.

Conclusion
These findings suggested the potential linkage among the brain-gut-microbe axis in CADASIL.
Pyrroloquinoline quinone drives ATP synthesis in vitro and in vivo and provides retinal ganglion cell neuroprotection
Authors: Canovai Alessio , Tribble James R. , Jöe Melissa , Westerlund Daniela Y. , Amato Rosario , Trounce Ian A. , Dal Monte Massimo , Williams Pete A. 
Published: September 2023

AbstractRetinal ganglion cells are highly metabolically active requiring strictly regulated metabolism and functional mitochondria to keep ATP levels in physiological range. Imbalances in metabolism and mitochondrial mechanisms can be sufficient to induce a depletion of ATP, thus altering retinal ganglion cell viability and increasing cell susceptibility to death under stress. Altered metabolism and mitochondrial abnormalities have been demonstrated early in many optic neuropathies, including glaucoma, autosomal dominant optic atrophy, and Leber hereditary optic neuropathy. Pyrroloquinoline quinone (PQQ) is a quinone cofactor and is reported to have numerous effects on cellular and mitochondrial metabolism. However, the reported effects are highly context-dependent, indicating the need to study the mechanism of PQQ in specific systems. We investigated whether PQQ had a neuroprotective effect under different retinal ganglion cell stresses and assessed the effect of PQQ on metabolic and mitochondrial processes in cortical neuron and retinal ganglion cell specific contexts. We demonstrated that PQQ is neuroprotective in two models of retinal ganglion cell degeneration. We identified an increased ATP content in healthy retinal ganglion cell-related contexts both in in vitro and in vivo models. Although PQQ administration resulted in a moderate effect on mitochondrial biogenesis and content, a metabolic variation in non-diseased retinal ganglion cell-related tissues was identified after PQQ treatment. These results suggest the potential of PQQ as a novel neuroprotectant against retinal ganglion cell death.
Establishment and characterization of a canine chondrosarcoma cell line: Mango
Authors: Wang Meilin , Wang Xiao , He Lixin , Gao Hongbo , Li Wenxuan , Feng Huili , Zhao Qingyuan , Zhang Wenwen , Li Chengzong , Zhang Bohan , Qiu Changwei 
Published: September 2023

AbstractIn the global progress of bone tumor research, established stable and long-lasting transgenic chondrosarcoma (CSA) cell lines are rare, mainly of murine and human origin, while the establishment of canine CSA cell lines has yet to be reported. This study established a canine CSA cell line to facilitate the basic clinical study of canine CSA. Fifty five cases of canine osteolytic disease were collected, and more than 10 bone tumor samples from dogs with typical clinical signs were used for primary cell culture. A cell line with stable passaging for more than 100 generations and mouse tumorigenic ability was successfully cultured. According to the clinical characteristics of the dog and the histopathological results of the primary tumor, CSA was diagnosed, and the CSA cell line was designated Mango. Immunohistochemical (IHC) results showed that the immunoreactivity of bone gamma-carboxyglutamate protein (BGLAP), secreted protein acidic and rich in cysteine (SPARC), alkaline phosphatase (ALPL), vimentin (VIM) and S100 were positive. However, the immunoreactivity of pan-cytokeratin (PCK), chromogranin A (CGA), and platelet endothelial cell adhesion molecule-1 (CD31) was negative. Immunofluorescence (IF) results showed that the protein expressions in the Mango cell line were consistent with the IHC identification of the primary tumor. The Mango cell line’s doubling time was 43.92 h, and the cell formation rate exceeded 20%. There were abnormal chromosome numbers, hetero staining with toluidine blue, and certain calcification abilities. It could be passaged stably and continuously without changing the cell morphology and characteristics. In vivo, the cells were successfully injected into the nude mice model with a tumorigenic rate of 100%. The immunophenotype of the xenograft tumor was consistent with that of the primary tumor. Therefore, we effectively established a canine CSA cell line. As a promising cell material, this cell line can be used to construct a tumor-bearing model conducive to the subsequent basic research of canine CSA. Moreover, because of its similarity to human CSA, the animal model of CSA is also indispensable for investigating human CSA.
Uric Acid Is Not Associated With Cardiovascular Health in Youth With Type 1 Diabetes: SEARCH for Diabetes in Youth Study
Authors: South Andrew M , Rigdon Joseph , Voruganti Saroja , Stafford Jeanette M , Dabelea Dana , Marcovina Santica , Mottl Amy K , Pihoker Cate , Urbina Elaine M , Jensen Elizabeth T 
Published: September 2023

Abstract

Context
Uric acid's role in cardiovascular health in youth with type 1 diabetes is unknown.

Objective
Investigate whether higher uric acid is associated with increased blood pressure (BP) and arterial stiffness over time in adolescents and young adults with type 1 diabetes and if overweight/obesity modifies this relationship.

Methods
Longitudinal analysis of data from adolescents and young adults with type 1 diabetes from 2 visits (mean follow up 4.6 years) in the SEARCH for Diabetes in Youth multicenter prospective cohort study from 2007 to 2018. Our exposure was uric acid at the first visit and our outcome measures were the change in BP, pulse wave velocity (PWV), and augmentation index between visits. We used multivariable linear mixed-effects models and assessed for effect modification by overweight/obesity.

Results
Of 1744 participants, mean age was 17.6 years, 49.4% were female, 75.9% non-Hispanic White, and 45.4% had a follow-up visit. Mean uric acid was 3.7 mg/dL (SD 1.0). Uric acid was not associated with increased BP, PWV-trunk, or augmentation index over time. Uric acid was marginally associated with PWV-upper extremity (β = .02 m/s/year, 95% CI 0.002 to 0.04). The magnitude of this association did not differ by overweight/obesity status.

Conclusion
Among adolescents and young adults with type 1 diabetes, uric acid was not consistently associated with increased BP or arterial stiffness over time. These results support findings from clinical trials in older adults with diabetes showing that lowering uric acid levels does not improve cardiovascular outcomes.