bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of talent development on business performance in Islamic rural banks
Authors: Nurfadilah Dety , Samidi Sudarmawan , Daryanto Wiwiek Mardawiyah
Published: December 2022

The objective of this study is to investigate talent development as a driver for strategic flexibility, digital readiness, and innovativeness and how these affect the business performance. This study used a quantitative approach using surveys from 391 managers and directors of Islamic rural banks in Indonesia, then the data were analyzed using structural equation modelling - partial least square (SEM-PLS). The results show that talent development has positive effects on innovativeness, strategic flexibility, and digital readiness. Moreover, strategic flexibility has positive mediating variables between digital readiness and innovativeness which also lead to business performance. This study provides contribution to the literature by integrating the digital readiness, strategic flexibility and innovativeness toward financial and non-financial performance. It also offers managerial implication that talent development drives those correlations.
Factors associated with critical care requirements in diabetic patients treated with dexamethasone for COVID-19 infection in the first wave of the pandemia
Authors: Batule Sol , Soldevila Berta , Figueredo Carme , Julián María Teresa , Egea-Cortés Laia , Reyes-Ureña Juliana , Casabona Jordi , Mateu Lourdes , Paredes Roger , Clotet Bonaventura , López Rosa , Puig-Domingo Manel , Alonso Núria
Published: December 2022

Introduction

Diabetes mellitus (DM) and hyperglycemia are important risk factors for poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). The aim of the present study was to analyze the factors associated with the composite outcome of the necessity of invasive mechanical ventilation (IMV) or admission to the intensive care unit (ICU) in subjects with severe COVID-19 infection treated with dexamethasone comparing patients with DM vs. patients without DM.

Research design and methods

An observational retrospective cohort study was performed, including hospitalized subjects with a diagnosis of SARS-CoV-2 pneumonia. Inclusion criteria were: age ≥18 years old with severe COVID-19 disease requiring daily intravenous 6 mg dexamethasone treatment for 10 days. Exclusion criteria were: <18 years old, non-severe illness and/or patients in charge of ICU. Variables related to clinical and analytical parameters, glycemic control, acquired-hospital superinfections, mortality, IMV requirement, ICU admission and length of stay were included.

Results

Two hundred and nine individuals with COVID-19 disease treated with dexamethasone were included. One hundred twenty-five out of these subjects (59.8%) were patients with DM. Overall, from the 209 subjects, 66 (31.6%) required IMV or were admitted to the ICU, with significant differences between patients with DM (n=50) vs. patients without DM (n=16) (76% vs. 24%, p=0.002). Among the group of subjects with DM (n=125), those who required IMV or were admitted to the ICU showed higher serum concentrations of C-reactive protein, interleukin-6, D-dimer, ferritin and pro-calcitonin and significantly lower serum concentrations of albumin compared to those who did not require IMV or were not admitted to the ICU. Besides, between these two groups of patients with DM, we observed no differences in glycemic parameters, including median capillary blood glucose values, glycosylated hemoglobin, coefficient of variability and hypoglycemic episodes. In the multinomial analysis, factors independently associated with the composite outcome of IMV or admission to the ICU in the insulin-treated group were the National Early Warning Score (NEWS) 2 score (OR 1.55 [1.17-2.17], p=0.005) and the presence of hospital-acquired superinfections (OR 35.21 [5.11-386.99], p=0.001).

Conclusions

In our study, parameters related to glycemic control were not associated with IMV requirement nor admission to the ICU in patients with DM and severe COVID-19 disease receiving daily 6 mg of dexamethasone for 10 days. However, hospital-acquired superinfections and disease severity at admission were independent factors associated with this composite outcome.
Predictive value of novel inflammatory markers platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio in arterial stiffness in patients with diabetes: A propensity score–matched analysis
Authors: Ning Peng , Yang Fan , Kang Jun , Yang Jing , Zhang Jiaxing , Tang Yi , Ou Yanghong , Wan Haiyan , Cao Hongyi
Published: December 2022

Background

Increased arterial stiffness is common in patients with diabetes, and inflammation is one of the main causes of increased arterial stiffness. Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR) are novel inflammatory markers that are reproducible, widely available, and easy to measure, and are associated with low costs. This study sought to investigate the predictive value of these novel inflammatory markers in patients with diabetes having arterial stiffness.

Methods

We retrospectively included inpatients with diabetes mellitus from the Endocrinology Department of the Chengdu Fifth People’s Hospital from June 2021 to May 2022 and collected data on their general information, biochemical indicators, and brachial-ankle pulse wave velocity (baPWV). After propensity matching, the risk relationship between PLR, NLR, and MLR and arterial stiffness was assessed in the recruited patients.

Results

A total of 882 hospitalized patients with diabetes were included in this study and categorized into the low baPWV (507 cases) or high baPWV group (375 cases) based on the baPWV. After propensity matching, there were 180 patients in all in the high and low baPWV groups. Univariate and multivariate logistic regression analyses revealed that high PLR, NLR, and MLR were independently associated with an increased risk of arterial stiffness in patients with diabetes. In the receiver operating characteristic curve analysis, the NLR area under the curve (AUC) was 0.7194 (sensitivity = 84.4%, specificity = 51.1%) when distinguishing low baPWV and high baPWV in patients with diabetes, which was higher than that for PLR AUC (0.6477) and MLR AUC (0.6479), and the combined diagnosis for AUC.

Conclusions

NLR was superior to PLR, and MLR and combined diagnosis have certain predictive values that indicate the increase in arterial stiffness in patients with diabetes. These predictive values can help with the early identification of increased arterial stiffness in patients with diabetes.
Serum metabolomic analysis in patients with Hashimoto’s thyroiditis
Authors: Jiang Xiao , Zhao Xinyu , Gu Xiaotong , Luo Tao , Li Pengqian , Wan Chuchu , Liu Haixia
Published: December 2022

Background

Hashimoto’s thyroiditis, an autoimmune thyroid disease, shows high morbidity worldwide, particularly in female. Patients with Hashimoto’s thyroiditis have an increasing risk of hypothyroidism during the occurrence and progression of Hashimoto’s thyroiditis. In recent years, metabolomics has been widely applied in autoimmune diseases, especially thyroid disorders. However, metabolites analysis in Hashimoto’s thyroiditis is still absent.

Methods

A total of 92 samples were collected, including 35 cases in the control group, 30 cases in the Hashimoto’s thyroiditis with euthyroidism group, and 27 cases in the Hashimoto’s thyroiditis with subclinical hypothyroidism group. SPSS 25.0 for statistical analysis and ROC curve, SIMCA 14.0, Metaboanalysis for multifactor analysis, and Origin 2021 for correlation analysis.

Results

21 metabolites were identified. 10 metabolites were obtained from control group versus HTE group, 8 serum metabolites were abnormal between control group and HTS group, 3 metabolites were derived from HTE group versus HTS. Kyoto Encyclopedia of Genes and Genomes Enrichment analysis showed that fatty acid degradation, Arginine, and proline metabolism have a significant impact on HTE, while lysine degradation, tyrosine metabolism play an important role HTS group, compared to control group. In the comparison between the HTE and HTS group, Valine, leucine, and isoleucine degradation and Valine, leucine, and isoleucine biosynthesis exists a key role. Correlation analysis shows clinical are not related to metabolites. ROC curve indicates SM, LPC, PC can efficiency in identification patients with HT in different clinical stage from healthy individuals.

Conclusion

Serum metabolites were changed in HT. Phospholipids such as SM, LPC, PC influence the pathogenesis of Hashimoto’s thyroiditis. Fatty acid degradation and lysine degradation pathways have an impact on different clinical stage of HT.
Association of the serum uric acid to creatinine ratio with metabolic syndrome in the middle age and older population in China
Authors: Zhong Danrong , Liu Dongchen , Guo Yongtian , Huang Haoyin , Li Lu , Wu Fangqin , Huang Suli
Published: December 2022

Background

Metabolic syndrome (MetS) has attracted great interest, with an increasing prevalence. Recent studies have shown that the serum uric acid-to-creatinine ratio (SUACr) might be an excellent biomarker for MetS risk prediction in diabetic patients and postmenopausal women. However, the relationship between SUACr and MetS in a middle-aged and older population remains unclear.

Methods

A total of 1277 participants were included in this cross-sectional study. Logistic regression modelling was performed to assess the association between SUACr and MetS in the total population. The dose–response relationship of SUACr and MetS was further assessed by a restricted cubic spline model (RCS). Furthermore, to explore the relationships between the levels of SUACr and the number of metabolic components, analysis of covariance (ANCOVA) was applied.

Results

The levels of SUACr were lower in the non-MetS participants (OR 1.60, 95% CI 1.36 to 1.89; P<0.001),. Positive and dose–response relationships were further confirmed by the RCS model. We also found that, with increased number of components, the SUACr tended to increase. Moreover, values of SUACr were strongly related to levels of triglycerides (TGs), body mass index (BMI), blood glucose levels, systolic blood pressure/diastolic blood pressure (SBP/DBP), and hypertension. In addition, the positive association between SUACr and MetS also occurred in those patients with normal uric acid levels.

Conclusion

Elevated values of SUACr were strongly associated with an increased risk of MetS; this positive relationship remained in those individuals with normal uric acid levels.
Mechanisms mediating the impact of maternal obesity on offspring hypothalamic development and later function
Authors: Furigo Isadora C. , Dearden Laura
Published: December 2022

As obesity rates have risen around the world, so to have pregnancies complicated by maternal obesity. Obesity during pregnancy is not only associated with negative health outcomes for the mother and the baby during pregnancy and birth, there is also strong evidence that exposure to maternal obesity causes an increased risk to develop obesity, diabetes and cardiovascular disease later in life. Animal models have demonstrated that increased weight gain in offspring exposed to maternal obesity is usually preceded by increased food intake, implicating altered neuronal control of food intake as a likely area of change. The hypothalamus is the primary site in the brain for maintaining energy homeostasis, which it coordinates by sensing whole body nutrient status and appropriately adjusting parameters including food intake. The development of the hypothalamus is plastic and regulated by metabolic hormones such as leptin, ghrelin and insulin, making it vulnerable to disruption in an obese in utero environment. This review will summarise how the hypothalamus develops, how maternal obesity impacts on structure and function of the hypothalamus in the offspring, and the factors that are altered in an obese in utero environment that may mediate the permanent changes to hypothalamic function in exposed individuals.
Interleukin-6 is dispensable in pituitary normal development and homeostasis but needed for pituitary stem cell activation following local injury
Authors: Laporte Emma , De Vriendt Silke , Hoekx Julie , Vankelecom Hugo
Published: December 2022

Recently, we discovered that the cytokine interleukin-6 (IL-6) acts as a pituitary stem cell-activating factor, both when administered in vivo and when added to stem cell organoid cultures in vitro. Moreover, its expression, predominantly localized in the gland’s stem and mesenchymal cells, promptly increases following damage in the adult pituitary, leading to stem-cell proliferative activation. Given these findings that IL-6 is involved in pituitary stem cell regulation, we addressed the question whether the cytokine has an impact on the pituitary phenotype during active phases of the gland’s remodeling, in particular embryonic development and neonatal maturation, as well as during homeostasis at adulthood and aging, all unknown today. Using the IL-6 knock-out (KO) mouse model, we show that IL-6 is dispensable for pituitary embryonic and neonatal endocrine cell development, as well as for hormonal cell homeostasis in adult and aging glands. The findings match the absence of effects on the stem cell compartment at these stages. However, using this IL-6 KO model, we found that IL-6 is needed for the acute stem-cell proliferative activation reaction upon pituitary injury. Intriguingly, regeneration still occurs which may be due to compensatory behavior by other cytokines which are upregulated in the damaged IL-6 KO pituitary, although at lower but prolonged levels, which might lead to a delayed (and less forceful) stem cell response. Taken together, our study revealed that IL-6 is dispensable for normal pituitary development and homeostasis but plays a key role in the prompt stem cell activation upon local damage, although its presence is not essentially needed for the final regenerative realization.
Taisho-Sanshoku koi have hardly faded skin and show attenuated melanophore sensitivity to adrenaline and melanin-concentrating hormone
Authors: Shinohara Yukari , Kasagi Satoshi , Amiya Noriko , Hoshino Yukihiro , Ishii Ryo , Hyodo Noriyuki , Yamaguchi Hiroaki , Sato Shoh , Amano Masafumi , Takahashi Akiyoshi , Mizusawa Kanta
Published: December 2022

Introduction

Koi carp, an ornamental fish derived from the common carp Cyprinus carpio (CC), is characterized by beautiful skin color patterns. However, the mechanism that gives rise to the characteristic vivid skin coloration of koi carp has not been clarified. The skin coloration of many teleosts changes in response to differences in the background color. This change in skin coloration is caused by diffusion or aggregation of pigment granules in chromatophores and is regulated mainly by sympathetic nerves and hormones. We hypothesized that there would be some abnormality in the mechanism of skin color regulation in koi carp, which impairs skin color fading in response to background color.

Methods

We compared the function of melanin-concentrating hormone (MCH), noradrenaline, and adrenaline in CC and Taisho-Sanshoku (TS), a variety of tri-colored koi.

Results and Discussion

In CC acclimated to a white background, the skin color became paler and pigment granules aggregated in melanophores in the scales compared to that in black-acclimated CC. There were no clear differences in skin color or pigment granule aggregation in white- or black-acclimated TS. The expression of mch1 mRNA in the brain was higher in the white-acclimated CC than that in the black-acclimated CC. However, the expression of mch1 mRNA in the brain in the TS did not change in response to the background color. Additionally, plasma MCH levels did not differ between white- and black-acclimated fish in either CC or TS. In vitro experiments showed that noradrenaline induced pigment aggregation in scale melanophores in both CC and TS, whereas adrenaline induced pigment aggregation in the CC but not in the TS. In vitro administration of MCH induced pigment granule aggregation in the CC but not in the TS. However, intraperitoneal injection of MCH resulted in pigment granule aggregation in both CC and TS. Collectively, these results suggest that the weak sensitivity of scale melanophores to MCH and adrenaline might be responsible for the lack of skin color change in response to background color in the TS.
Application of iron–carbon microbial galvanic activated sludge combined with MBR process in the treatment of wastewater from comprehensive railway station
Authors: Zhang Qi , Liang Zheng , Guan Xiaotao , Liang Jingwen , Gao Pan
Published: December 2022

The application of iron–carbon microbial cell activated sludge (ICMC-AS) was carried out in a membrane bioreactor (MBR) processor to treat wastewater from an integrated railway station. Results showed that the chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) removal efficiencies of the original MBR processor increased from 80%, 30%, and 10% to 92%, 93.5%, and 92%, respectively. Further research showed that the combined sewage treatment system also had a strong impact resistance ability. The combined sewage treatment system ran stably when the COD, TN, and TP concentrations changed greatly. The in-depth analysis of the reaction process and reaction rate of the combined sewage treatment system revealed that the combined system is dominated by COD removal with high nitrogen removal efficiency. The removal rate constants of various pollutants were in the order: KCOD (0.647 ± 0.017) > KNO3−−N (0.416 ± 0.044) > KNH4+−N (0.275 ± 0.014) > KTN (0.258 ± 0.083). Calculations of the energy saving and carbon emission reduction of the combined system showed that the system’s annual carbon emission reduction could reach more than 388,203.55 kg CO2e, which remarkably improves the carbon emission reduction effect and obtains a good green effect. The results indicate that adding ICMC-AS to the MBR processor for combined wastewater treatment can substantially improve the efficiency of wastewater treatment and obtain better energy-saving and emission-reducing effects. This combined application provides an effective way for the transformation and upgrading of small- and medium-scale water treatment systems.
Health condition and mycobiome diversity in Mediterranean tree species
Authors: Diez-Hermano Sergio , Ahmad Farooq , Niño-Sanchez Jonatan , Benito Alvaro , Hidalgo Elena , Escudero Laura Morejón , Morel Wilson Acosta , Diez Julio Javier
Published: December 2022

Introduction

Mediterranean forests are currently facing a surge in abiotic stressors such as droughts and massive fires as a result of climate crisis and human pressure. Susceptibility to biotic stressors has also increased, including a variety of pests and pathogens capable of weakening and potentially killing forest flora. Biodiversity of microbiome protects forests against declines as it increases trees’ resilience and adaptability.

Objectives

With the objective of analyzing the relationship between health status and fungal diversity, in the present work the mycobiota of declined and healthy specimens of keystone Mediterranean tree species is described and compared.

Methods

To this end, bark and wood from declining Spanish forests of Castanea sativa (chestnut), Quercus ilex (holm oak), Quercus suber (cork oak), and Quercus pyrenaica (pyrenean oak) were sampled and the Internal Transcribed Spacer (ITS1) genomic region was sequenced.

Results

Results showed a predominance of Ascomycota, Basidiomycota, and Mucoromycota in all samples. Alpha diversity at genus level was not affected by health status and was characterized by uneven, poorly distributed fungal communities dominated by a few genera. Differentially abundant (DA) genera between healthy and declined samples were found in chestnut (15), holm oak (6), and pyrenean oak (4) trees, but not in cork oak. Some genera known for their plant protection potential, such as Trichoderma, were found exclusively in healthy trees. Functional profiles revealed a predominance of phytopathogens and saprobes in all tree species, irrespective of their health status.

Discussion

This study emphasizes the importance of Mediterranean forests as biodiversity refuges and highlights the value of above-ground tissues as a valid approach to assess shifts in forests’ microbiome diversity in response to biotic and abiotic stressors.
Differences by transplant type in stool multiplex PCR testing for acute diarrhea in post-solid organ transplantation
Authors: Verma Abhishek , Hine Ashley M. , Joelson Andrew , Mei Rena , Lebwohl Benjamin , Axelrad Jordan E.
Published: December 2022

Background

Diarrhea in solid organ transplant (SOT) recipients is common, morbid, and increasingly evaluated using multiplex gastrointestinal PCR panel (GI panel) testing. We aimed to characterize differences between transplant organ types in GI panel evaluation of acute diarrhea in SOT recipients.

Methods

We performed a dual-center retrospective cross-sectional study of adult SOT recipients with acute diarrhea who underwent GI panel testing. Demographic, transplant, testing context, and GI panel data were collected. Patients were stratified by transplant type. The primary outcome was a positive GI panel.

Results

Of 300 transplant recipients (58 heart, 65 liver, 68 lung, and 109 renal), 118 had a positive GI panel. Renal transplant status correlated with more frequently positive GI panel and less frequent hospitalization. In a multivariate analysis adjusting for demographic factors, hospitalization, immunosuppression, and transplant age, renal transplantation was independently associated with a positive GI panel compared to lung transplantation (aOR 2.98, 95% CI 1.27-7.16). Older transplant age and outpatient testing were also independently associated with a positive GI panel. The GI panel result was associated with changes to antibiotic management.

Conclusions

In the evaluation of SOT recipients with acute diarrhea, GI panel result varies by transplant type, transplant age, and testing location and may affect subsequent antimicrobial therapy.
Heat stress increases immune cell function in Hexacorallia
Authors: Eliachar Shir , Snyder Grace Ann , Barkan Shany Klara , Talice Shani , Otolenghi Aner , Jaimes-Becerra Adrian , Sharoni Ton , Sultan Eliya , Hadad Uzi , Levy Oren , Moran Yehu , Gershoni-Yahalom Orly , Traylor-Knowles Nikki , Rosental Benyamin
Published: December 2022

Climate change induced heat stress has increased coral bleaching events worldwide. Differentially regulated immune genes are one of the primary responses to heat stress suggesting that immune activation is critical. However, the cellular immune mechanisms of coral bleaching is currently unknown, and it is still not known if the immune response documented during heat stress is a consequence of bleaching or is directly caused by the heat stress itself. To address this question, we have used two model system sea anemones (Order: Actiniaria): Exaiptasia diaphana and Nematostella vectensis. E. diaphana is an established sea anemone model for algal symbiont interaction, while N. vectensis is an established sea anemone model that lacks the algal symbiont. Here, we examined the effect of increased temperature on phagocytic activity, as an indication of immune function. Our data shows that immune cell activity increases during heat stress, while small molecule pinocytosis remains unaffected. We observed an increase in cellular production of reactive oxygen species with increasing temperatures. We also found that the cellular immune activity was not affected by the presence of the Symbiodiniaceae. Our results suggest that the immune activity observed in heat-stress induced bleaching in corals is a fundamental and basic response independent of the bleaching effect. These results establish a foundation for improving our understanding of hexacorallian immune cell biology, and its potential role in coral bleaching.
IκBNS-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses
Authors: Frentzel Sarah , Jeron Andreas , Pausder Alexander , Kershaw Olivia , Volckmar Julia , Schmitz Ingo , Bruder Dunja
Published: December 2022

IκB proteins regulate the inhibition and activation of NF-κB transcription factor complexes. While classical IκB proteins keep NF-κB complexes inactive in the cytoplasm, atypical IκB proteins act on activated NF-κB complexes located in the nucleus. Most of the knowledge regarding the function of IκB proteins has been collectedin vitro, while far less is known regarding their impact on activation and regulation of immune responses duringin vivoinfections. Combiningin vivo Listeria monocytogenes(Lm) infection with comparativeex vivotranscriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IκBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IκBNS-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally highNfkbidpromoter activity uncovered in Ly6Chighinflammatory monocytes prompted us to further characterize the specific contribution of IκBNSin the inflammatory response of monocytes to the infectious agent. Indeed, Ly6Chighmonocytes primed during Lm infection in the absence of IκBNSdisplayed a blunted response compared to wild type-derived Ly6Chighmonocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such asIl6,Nos2andIl1β. Strikingly, altered monocyte activation in IκBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IκBNSexclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IκBNS-/-mice for most of the analyzed mediators, IL-10 was virtually undetectable in IκBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IκBNSduring Lm infection with IκBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6Chighmonocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified IκBNSas molecular driver of inflammation in listeriosis.
A pan-cancer and single-cell sequencing analysis of CD161, a promising onco-immunological biomarker in tumor microenvironment and immunotherapy
Authors: Li He , Zhou Ke , Wang Kaiyue , Cao Hui , Wu Wantao , Wang Zeyu , Dai Ziyu , Chen Shi , Peng Yun , Xiao Gelei , Luo Peng , Zhang Jian , Liu Zaoqu , Cheng Quan , Zhang Hao
Published: December 2022

Background

CD161 has been linked to the appearance and development of various cancers.

Methods

The mutation map and the variation of CNVs and SNVs of CD161 were displayed according to cBioportal and GSCALite. We also evaluated the pathway enrichment and drug sensitivity of CD161 according to GSCALite. We performed a single-cell sequencing analysis of cancer cells and T cells in melanoma. The cell communication patterns related to CD161 were further explored. Multiplex immunofluorescence staining of tissue microarrays was used to detect the association between CD161 expression and macrophages and T cells.

Results

A high CD161 level was related to neoantigens expression, pathway enrichment, and drug sensitivity. In addition, single-cell sequencing analysis showed that CD161 was mainly expressed in T cells, M1 and M2 Macrophages, neoplastic, microglial cells, neurons, and cancer cells in many tumor types. Further study on pseudotime trajectories and functional annotation of CD161 proved the critical role of CD161 in tumor progression and T cell immunity in melanoma. Multiplex immunofluorescence revealed that CD161 is closely correlated with the immune infiltration of T cells and macrophages in multiple cancers. In addition, high CD161 expression predicted a favorable immunotherapy response.

Conclusion

CD161 is involved in the immune infiltration of T cells and macrophages and might be a promising target for tumor immunotherapy.
Chimeric antigen receptor T-cell therapy for multiple myeloma
Authors: Wang Zehua , Chen Chen , Wang Lei , Jia Yongxu , Qin Yanru
Published: December 2022

Multiple myeloma (MM) is a malignant plasma cell disorder that remains incurable for most patients, as persistent clonal evolution drives new mutations which confer MM high-risk signatures and resistance to standard care. The past two decades have significantly refashioned the therapeutic options for MM, especially adoptive T cell therapy contributing to impressive response rate and clinical efficacy. Despite great promises achieved from chimeric antigen receptor T-cell (CAR-T) therapy, the poor durability and severe toxicity (cytokine release syndrome and neurotoxicity) are still huge challenges. Therefore, relapsed/refractory multiple myeloma (RRMM), characterized by the nature of clinicopathologic and molecular heterogeneity, is frequently associated with poor prognosis. B Cell Maturation Antigen (BCMA) is the most successful target for CAR-T therapy, and other potential targets either for single-target or dual-target CAR-T are actively being studied in numerous clinical trials. Moreover, mechanisms driving resistance or relapse after CAR-T therapy remain uncharacterized, which might refer to T-cell clearance, antigen escape, and immunosuppressive tumor microenvironment. Engineering CAR T-cell to improve both efficacy and safety continues to be a promising area for investigation. In this review, we aim to describe novel tumor-associated neoantigens for MM, summarize the data from current MM CAR-T clinical trials, introduce the mechanism of disease resistance/relapse after CAR-T infusion, highlight innovations capable of enhanced efficacy and reduced toxicity, and provide potential directions to optimize manufacturing processes.
Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM)
Authors: Bai Kun-Hao , Zhu Ming-Jiao , Zhang Yi-Yang , Li Xue-Ping , Chen Si-Liang , Wang Da-Wei , Dai Yu-Jun
Published: December 2022

Immune checkpoint inhibitors represented by PD-1 have greatly changed the way cancer is treated. In addition to PD-1, new immune checkpoints are constantly excavated to better treat cancer. Recently, protein tyrosine phosphatase 1B (PTP1B) was identified as a new immune checkpoint and played a critical role in the treatment of tumors by inhibiting the proliferation and cytotoxicity of T cells induced by tumor antigen. To explore the targeting role of PTP1B in precision tumor therapy, we deeply analyzed the expression and prognosis of PTP1B in all tumors. Survival analysis results indicated that PTP1B was highly expressed in most tumor tissues and indicated poor prognosis in acute-myeloid-leukemia (LAML), brain-lower-grade-glioma (LGG), kidney-renal clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). The methylation status of PTP1B in these four tumors exhibited hypomethylation and mutation landscape showed that PTP1B had its specific characteristics in genomic instability and heterogeneity. The homologous recombination deficiency (HRD) and loss of heterozygosity (LOH) were positive related to PTP1B expression in liver-hepatocellular-carcinoma (LIHC) and kidney-chromophobe (KICH), while the immunescore and immune infiltration displayed a significant positive correlation with PTP1B expression in LGG and UVM. Drug sensitivity tests showed that the PTP1B inhibitor MSI-1436 had a sensitivity effect suppressing tumor cell viability and suggested it enhanced the efficacy of PD-1 inhibitors in cancers.
Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system
Authors: Houser Madelyn C. , Uriarte Huarte Oihane , Wallings Rebecca L. , Keating Cody E. , MacPherson Kathryn P. , Herrick Mary K. , Kannarkat George T. , Kelly Sean D. , Chang Jianjun , Varvel Nicholas H. , Rexach Jessica E. , Tansey Malú Gámez
Published: December 2022

Introduction

Progranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations.

Methods

First, we used gene co-expression network analysis of published data to test the hypothesis that Grn has a critical role in regulating the activation status of immune cell populations in both central and peripheral compartments. To investigate the extent to which PGRN-deficiency resulted in immune dysregulation, we performed deep immunophenotyping by flow cytometry of 19-24-month old male and female Grn-deficient mice (PGRN KO) and littermate Grn-sufficient controls (WT).

Results

Male PGRN KO mice exhibited a lower abundance of microglial cells with higher MHC-II expression, increased CD44 expression on monocytes in the brain, and more CNS-associated CD8+ T cells compared to WT mice. Furthermore, we observed an increase in CD44 on CD8+ T cells in the peripheral blood. Female PGRN KO mice also had fewer microglia compared to WT mice, and we also observed reduced expression of MHC-II on brain monocytes. Additionally, we found an increase in Ly-6Chigh monocyte frequency and decreased CD44 expression on CD8+ and CD4+ T cells in PGRN KO female blood. Given that Gpnmb, which encodes for the lysosomal protein Glycoprotein non-metastatic melanoma protein B, has been reported to be upregulated in PGRN KO mice, we investigated changes in GPNMB protein expression associated with PGRN deficits and found that GPNMB is modulated in myeloid cells in a sex-specific manner.

Discussion

Our data suggest that PGRN and GPNMB jointly regulate the peripheral and the central immune system in a sex-specific manner; thus, understanding their associated mechanisms could pave the way for developing new neuroprotective strategies to modulate central and peripheral inflammation to lower risk for neurodegenerative diseases and possibly delay or halt progression.
CARMA3: A potential therapeutic target in non-cancer diseases
Authors: Gui Zhen , Zhang Yan , Zhang Aihua , Xia Weiwei , Jia Zhanjun
Published: December 2022

Caspase recruitment domain and membrane-associated guanylate kinase-like protein 3 (CARMA3) is a scaffold protein widely expressed in non-hematopoietic cells. It is encoded by the caspase recruitment domain protein 10 (CARD10) gene. CARMA3 can form a CARMA3-BCL10-MALT1 complex by recruiting B cell lymphoma 10 (BCL10) and mucosa-​associated lymphoid tissue lymphoma translocation protein 1 (MALT1), thereby activating nuclear factor-​κB (NF-κB), a key transcription factor that involves in various biological responses. CARMA3 mediates different receptors-dependent signaling pathways, including G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Inappropriate expression and activation of GPCRs and/or RTKs/CARMA3 signaling lead to the pathogenesis of human diseases. Emerging studies have reported that CARMA3 mediates the development of various types of cancers. Moreover, CARMA3 and its partners participate in human non-cancer diseases, including atherogenesis, abdominal aortic aneurysm, asthma, pulmonary fibrosis, liver fibrosis, insulin resistance, inflammatory bowel disease, and psoriasis. Here we provide a review on its structure, regulation, and molecular function, and further highlight recent findings in human non-cancerous diseases, which will provide a novel therapeutic target.
Predictive model for BNT162b2 vaccine response in cancer patients based on blood cytokines and growth factors
Authors: Konnova Angelina , De Winter Fien H. R. , Gupta Akshita , Verbruggen Lise , Hotterbeekx An , Berkell Matilda , Teuwen Laure-Anne , Vanhoutte Greetje , Peeters Bart , Raats Silke , Massen Isolde Van der , De Keersmaecker Sven , Debie Yana , Huizing Manon , Pannus Pieter , Neven Kristof Y. , Ariën Kevin K. , Martens Geert A. , Bulcke Marc Van Den , Roelant Ella , Desombere Isabelle , Anguille Sébastien , Berneman Zwi , Goossens Maria E. , Goossens Herman , Malhotra-Kumar Surbhi , Tacconelli Evelina , Vandamme Timon , Peeters Marc , van Dam Peter , Kumar-Singh Samir
Published: December 2022

Background

Patients with cancer, especially hematological cancer, are at increased risk for breakthrough COVID-19 infection. So far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed.

Methods

We employed machine learning approaches to identify a biomarker signature based on blood cytokines, chemokines, and immune- and non-immune-related growth factors linked to vaccine immunogenicity in 199 cancer patients receiving the BNT162b2 vaccine.

Results

C-reactive protein (general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) correctly classified patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments.

Conclusion

We propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at persistent high risk of COVID-19 despite vaccination with BNT162b2. Our data also suggest that such a signature may reflect the inherent immunological constitution of some cancer patients who are refractive to immunotherapy.
Long-term sialidase-specific immune responses after natural infection with cholera: Findings from a longitudinal cohort study in Bangladesh
Authors: Chowdhury Fahima , Akter Afroza , Bhuiyan Taufiqur Rahman , Biswas Rajib , Firoj Md. Golam , Tauheed Imam , Harris Jason B. , Larocque Regina C. , Ross Allen G. , McMillan Nigel A. J. , Charles Richelle C. , Ryan Edward T. , Calderwood Stephen B. , Qadri Firdausi
Published: December 2022

Background

Immune responses that target sialidase occur following natural cholera and have been associated with protection against cholera. Sialidase is a neuraminidase that facilitates the binding of cholera toxin (CT) to intestinal epithelial cells. Despite this, little is known about age-related sialidase-specific immune responses and the impact of nutritional status and co-infection on sialidase-specific immunity.

Methods

We enrolled 50 culture-confirmed Vibrio cholerae O1 cholera cases presenting to the icddr,b Dhaka hospital with moderate to severe dehydration. We evaluated antibody responses out to 18 months (day 540) following cholera. We assessed immune responses targeting sialidase, lipopolysaccharide (LPS), cholera toxin B subunit (CtxB), and vibriocidal responses. We also explored the association of sialidase-specific immune responses to nutritional parameters and parasitic co-infection of cases.

Results

This longitudinal cohort study showed age-dependent differences in anti-sialidase immune response after natural cholera infection. Adult patients developed plasma anti-sialidase IgA and IgG responses after acute infection (P<0.05), which gradually decreased from day 30 on. In children, no significant anti-sialidase IgA, IgM, and IgG response was seen with the exception of a late IgG response at study day 540 (p=0.05 compared to adults). There was a correlation between anti-sialidase IgA with vibriocidal titers, as well as anti-sialidase IgA and IgG with anti-LPS and anti-CtxB antibody responses in adult patients, whereas in children, a significant positive correlation was seen only between anti-sialidase IgA and CtxB IgA responses. Stunted children showed significantly lower anti-sialidase IgA, IgG, and IgM antibody responses and higher LPS IgG and IgM antibody responses than healthy children. The anti-sialidase IgA and IgG responses were significantly higher in cases with concomitant parasitic infection.

Conclusion

Our data suggest that cholera patients develop age-distinct systemic and mucosal immune responses against sialidase. The stunted children have a lower anti-sialidase antibody response which may be associated with gut enteropathy and the neuraminidase plays an important role in augmented immune response in cholera patients infected with parasites.
Nomogram for predicting prognosis of patients with metastatic melanoma after immunotherapy: A Chinese population–based analysis
Authors: Zhao Jingjing , Li Dandan , Xie Songzuo , Deng Xinpei , Wen Xizhi , Li Jingjing , Wu Zhengrong , Yang Xinyi , Li Minxing , Tang Yan , Zhang Xiaoshi , Ding Ya
Published: December 2022

Background

Previous studies indicated the evidence that baseline levels of thyroid antibodies, thyroid status, and serum lactate dehydrogenase (LDH) and M stage may influence the prognosis of patients with advanced or metastatic melanoma treated with immune checkpoint inhibitors that targets programmed cell death-1 (PD-1) or programmed death ligand 1, which reported that dramatic improvements in survival rates were observed; however, the presence of controversy has prevented consensus from being reached. Study objectives were to develop a nomogram to identify several prognostic factors in Chinese patients with metastatic melanoma receiving immunotherapy.

Methods

This retrospective study included 231 patients from Sun Yat-sen University Cancer Center, and patients were split into internal cohort (n = 165) and external validation cohort (n = 66). We developed a nomogram for the prediction of response and prognosis on the basis of the levels of serum thyroid peroxidase antibody (A-TPO), free T3 (FT3), and LDH and M stage that were measured at the baseline of anti–PD-1 infusion. In addition, the follow-up lasted at least until 5 years after the treatment or mortality. RECIST v1.1 was used to classify treatment responses.

Results

Chi-square test showed that PD-1 antibody was more effective in patients with melanoma with high level baseline FT4 or earlier M stage. A multivariate Cox analysis showed that baseline FT3 (P = 0.009), baseline A-TPO (P = 0.016), and LDH (P = 0.013) levels and M stage (P < 0.001) independently predicted overall survival (OS) in patients with melanoma. The above factors are integrated, and a prediction model is established, i.e., nomogram. Survival probability area-under-the-curve values of 1, 2, and 3 years in the training, internal validation, and external validation cohorts showed the prognostic accuracy and clinical applicability of nomogram (training: 0.714, 0.757, and 0.764; internal validation: 0.7171963, 0.756549, and 0.7651486; external validation: 0.748, 0.710, and 0.856). In addition, the OS of low-risk (total score ≤ 142.65) versus high-risk (total score > 142.65) patients varied significantly in both training group (P < 0.0001) and external validation cohort (P = 0.0012).

Conclusions

According to this study, baseline biomarkers are associated with response to immunotherapy and prognosis among patients with metastatic melanoma. Treatment regimens can be tailor-made on the basis of these biomarkers.
Arm race between Rift Valley fever virus and host
Authors: Wang Xiao , Yuan Yupei , Liu Yihan , Zhang Leiliang
Published: December 2022

Rift Valley fever (RVF) is a zoonotic disease caused by Rift Valley fever virus (RVFV), an emerging arbovirus within the Phenuiviridae family of Bunyavirales that has potential to cause severe diseases in both humans and livestock. It increases the incidence of abortion or foetal malformation in ruminants and leads to clinical manifestations like encephalitis or haemorrhagic fever in humans. Upon virus invasion, the innate immune system from the cell or the organism is activated to produce interferon (IFN) and prevent virus proliferation. Meanwhile, RVFV initiates countermeasures to limit antiviral responses at transcriptional and protein levels. RVFV nonstructural proteins (NSs) are the key virulent factors that not only perform immune evasion but also impact the cell replication cycle and has cytopathic effects. In this review, we summarize the innate immunity host cells employ depending on IFN signal transduction pathways, as well as the immune evasion mechanisms developed by RVFV primarily with the inhibitory activity of NSs protein. Clarifying the arms race between host innate immunity and RVFV immune evasion provides new avenues for drug target screening and offers possible solutions to current and future epidemics.
Integrated analysis of necroptosis-related genes for evaluating immune infiltration and colon cancer prognosis
Authors: Yang Wei , Lu Shuaibing , Peng Liangqun , Zhang Zhandong , Zhang Yonglei , Guo Dandan , Ma Fei , Hua Yawei , Chen Xiaobing
Published: December 2022

Background

Colon cancer (CC) is the second most common gastrointestinal malignancy. About one in five patients have already developed distant metastases at the time of initial diagnosis, and up to half of patients develop distant metastases from initial local disease, which leads to a poor prognosis for CC patients. Necroptosis plays a key role in promoting tumor growth in different tumors. The purpose of this study was to construct a prognostic model composed of necroptosis-related genes (NRGs) in CC.

Methods

The Cancer Genome Atlas was used to obtain information on clinical features and gene expression. Gene expression differential analysis, weighted gene co-expression network analysis, univariate Cox regression analysis and the least absolute shrinkage and selection operator regression algorithm were utilized to identify prognostic NRGs. Thereafter, a risk scoring model was established based on the NRGs. Biological processes and pathways were identified by gene ontology and gene set enrichment analysis (GSEA). Further, protein-protein interaction and ceRNA networks were constructed based on mRNA-miRNA-lncRNA. Finally, the effect of necroptosis related risk score on different degrees of immune cell infiltration was evaluated.

Results

CALB1, CHST13, and SLC4A4 were identified as NRGs of prognostic significance and were used to establish a risk scoring model. The time-dependent receiver operating characteristic curve analysis revealed that the model could well predict the 1-, 3-, and 5-year overall survival (OS). Further, GSEA suggested that the NRGs may participate in biological processes, such as the WNT pathway and JAK-Stat pathway. Eight key hub genes were identified, and a ceRNA regulatory network, which comprised 1 lncRNA, 5 miRNAs and 3 mRNAs, was constructed. Immune infiltration analysis revealed that the low-risk group had significantly higher immune-related scores than the high-risk group. A nomogram of the model was constructed based on the risk score, necroptosis, and the clinicopathological features (age and TNM stage). The calibration curves implied that the model was effective at predicting the 1-, 3-, and 5-year OS of CC.

Conclusion

Our NRG-based prognostic model can assist in the evaluation of CC prognosis and the identification of therapeutic targets for CC.