bluuebunny/crossref_metadata_2025 huggingface dataset:
KCNH2A561V Heterozygous Mutation Inhibits KCNH2 Protein Expression via The Activation of UPR Mediated by ATF6
Authors: CHEN B , TAN L , CHEN D , WANG X , LIU J , HUANG X , WANG Y , HUANG S , MAO F , LIAN J
Published: November 2023

The potassium channel protein KCNH2 is encoded by KCNH2 gene, and there are more than 300 mutations of KCNH2. Unfolded protein response (UPR) is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER). The present study aimed to explore the UPR process and the role of activating transcription factor 6 (ATF6) in the abnormal expression of potassium voltage-gated channel subfamily H member 2 (KCNH2)A561V. The wild-type (wt) KCNH2 and A561V mutant KCNH2 was constructed with his-tag. The 293 cells were used and divided into KCNH2wt+KCNH2A561V, KCNH2wt and KCNH2A561V groups. The expression levels of ATF6 and KCNH2 in different groups were detected by Western blotting, reverse transcription-quantitative PCR, immunofluo-rescence and immuno-coprecipitation assays. The protein types and abundance of immuno-coprecipitation samples were analyzed by mass spectrometry. The proteomic analysis of the mass spectrometry results was carried out by using the reactome database and GO (Gene Ontology) tool. The mRNA expression levels of KCNH2 and ATF6 in the KCNH2wt+KCNH2A561V group were higher compared with the KCNH2A561V group. However, the full-length protein expression of ATF6 was inhibited, indicating that ATF6 was highly activated and a substantial number of ATF6 was sheared in KCNH2wt+KCNH2A561V group compared with control group. Furthermore, A561V-KCNH2 mutation leading to the accumulation of the immature form of KCNH2 (135 kDa bands) in ER, resulting in the reduction of the ratio of 155 kDa/135 kDa. In addition, the abundance of UPR-related proteins in the KCNH2A561V group was higher compared with the KCNH2wt+KCNH2A561V group. The ‘cysteine biosynthetic activity’ of GO:0019344 process and the ‘positive regulation of cytoplasmic translation activity’ of GO:2000767 process in the KCNH2A561V group were higher compared with the KCNH2wt+KCNH2A561V group. Hence, co-expression of wild-type and A561V mutant KCNH2 in 293 cells activated the UPR process, which led to the inhibition of protein translation and synthesis, in turn inhibiting the expression of KCNH2. These results provided a theoretical basis for clinical treatment of Long QT syndrome.
MicroRNA-206 Contributes to the Progression of Preeclampsia by Suppressing the Viability and Mobility of Trophocytes via the Inhibition of AGTR1
Authors: MO W , JIN J , WANG X , LUAN W , YAN J , LONG X
Published: November 2023

The development of preeclampsia (PE) is associated with the impaired trophoblast motility. MicroRNAs (miRs) contribute to the modulation of trophoblast invasion. In the current study, the role of miR-206/AGTR1 in the TNF-α-induced invasion defect of trophoblasts was explored. The levels of miR-206 and ATGR1 in clinical placenta tissues were investigated. Trophoblasts were treated with TNF-α, and the levels of miR-206 and ATGR1 were modulated. Changes in cell viability, invasion, and inflammation in trophoblasts were detected. The level of miR-206 was induced, while the level of AGTR1 was suppressed in placenta tissues. In in vitro assays, TNF-α suppressed viability, induced inflammatory response, inhibited invasion, upregulated miR-206, and down-regulated AGTR1. The inhibited expression of miR-206 or the overexpression of AGTR1 counteracted the effects of TNF-α, indicating the key role of the miR-206/AGTR1 in progression of PE. Collectively, miR-206 suppressed viability, induced inflammatory response, and decreased invasion of trophoblasts by inhibiting AGTR1.
Cumhuriyet Tarihinin Anlatımında Bir Kaynak Olarak “Mücellâ” Adlı Roman
Authors: ÇELİKER İlhan , AYBAY Ümit
Published: November 2023

Nazan Bekiroğlu, Mücellâ isimli romanında Trabzon özeli üzerinden sosyal yaşamın ayrıntılı bir tasvirini yaparken, bazen roman kahramanlarının kimi yerde de yazarın dilinden Türkiye siyasi tarihine de ana hatlarıyla değinmektedir. Her bir vatandaşın algılayabildiği, konuşabildiği ve günlük yaşantısında yansımalarına maruz kaldığı siyasal gelişmeler romanın kurgusu içerisinde dile getirilmektedir. 1930’ların başında tek parti döneminin kimi uygulamaları, İkinci Dünya Savaşı yıllarında Türkiye’nin izlediği politika ve savaş ortamının siyasi, ekonomik, sosyal yansımaları Trabzon özeli üzerinden işlenmektedir. Türkiye’de çok partili hayata geçiş, Demokrat Parti’nin iktidara gelişi, Türkiye’nin Kore Savaşı’na katılması, NATO’ya girişi ve bu dönemde Amerika ile yakın ilişkileri, Demokrat Parti’nin ekonomik, siyasi icraatları ve iktidar-muhalefet ilişkileri üzerinde durulan konulardır. Yaşanan siyasi krizlerden sonra 27 Mayıs ve 12 Mart müdahaleleri, Türkiye’nin 1960 ve 1970’lerde içerisine girdiği siyasi kriz ve anarşi ortamı kitapta değinilen diğer siyasal meselelerdir. Bu çalışmada, Bekiroğlu’nun gerek roman kahramanlarının dilinden gerekse yazar olarak dile getirdiği siyasal konular, ileri sürdüğü fikirler tespit edilmeye çalışılacak ve bu konular üzerinde değerlendirmeler yapılacaktır.
Çaresizlik mi, Meslek mi? Neoliberal Çağ’da Dilencilik: Samsun Kenti Örneği
Authors: EREN Selim , SUCU İlyas , KAYA Barışcan , KAYAALP Pelin , KAZAN Burakcan
Published: November 2023

Bu çalışmada, dilencilik olgusu neoliberal ekonomi-politiğin getirisi olan “yeni yoksulluk”, “göç”, “kentleşme” ve “çalışmanın reddi” gibi kavramlarla kesişimsel olarak düşünülmüş ve dilenciliğin eskisinden farklı olarak aldığı yeni görünümler ile kültürel edime dönüşme süreci sosyolojik bir perspektifle anlaşılmaya çalışılmıştır. Dilenciler tarafından dilenciliğin bir meslek olarak görülüp görülmemesi, dilencilerin örgütlü bir şekilde çalışıp çalışmadıkları, dilenme motivasyonları ile iç ve dış göçle birlikte dilencilik olgusunda meydana gelen değişimler tartışılmak istenilen temel sorulardır. Araştırmada niteliksel araştırma yöntemi kullanılmış, veriler derinlemesine görüşme tekniğiyle elde edilmiş, verilerin analizinde ise MAXQDA nitel veri analizi programı kullanılmıştır. Araştırmada; dilencilerin “yeni yoksulluk, göç ve mekânsal ayrışma bağlamında dilenciliği mecburiyetle özdeşleştirenler” ve “güvencesiz, eğreti çalışma koşullarından kaçarken, örgütlü bir şeklide dilenciliği meslekleştirerek bir kültür haline dönüştürenler” şeklinde iki temel tipoloji sergilediği; bu durumun hem neoliberal piyasa ekonomisinin bir sonucu olduğu hem de burayı yeniden ürettiği ve bu heterojenliğin farklı sosyal politikalar üretmeyi gerekli kıldığı sonucuna varılmıştır.
International Organization Sovereignty: Constructing Institutional and Structural Changes in the International System
Authors: Ifediora Obinna
Published: November 2023

International relations scholars explore the significance of modern states’ transfer of authority to international organizations (IOs) within the broader debate on changes and continuities in the “institutions” (sovereignty) and “structures” (forms of organizing politics) of the international system. This paper contributes to this dialogue by developing a theory of change to construct the claim of continental sovereignty by the African Union (AU). The theory explains that the transfer/internationalization of authority is transforming IOs into state-like structures possessing sovereignty as transferred authority and creating the international state system. Dominant IOs (e.g., UN) are legitimated by minor IOs, or constituent state structures (e.g., AU). Legitimation crises may occur when minor IOs oppose dominant IOs’ legitimacy claims. So, the rules of IO legitimation must comprise inclusive representations of constituent structures in decision-making organs and the alignment of norms, priorities, or goals with minor IOs. Noncompliance with these rules may cause fundamental changes.
Development of a contacting transwell co-culture system for the in vitro propagation of primary central nervous system lymphoma
Authors: Nishi Mayuko , Tateishi Kensuke , Sundararaj Jeremiah Stanleyraj , Ino Yoko , Nakai Yusuke , Hatayama Yasuyoshi , Yamaoka Yutaro , Mihana Yusaku , Miyakawa Kei , Kimura Hirokazu , Kimura Yayoi , Yamamoto Tetsuya , Ryo Akihide
Published: November 2023

Primary central nervous system lymphoma (PCNSL) is a malignant neoplasm of the central nervous system that is refractory to treatment and has extremely poor prognosis. One factor hindering the development of therapeutic options for PCNSL is its molecular heterogeneity and the extreme difficulty in establishing in vitro cell lines that permit intensive research on this disease. In the present study, we developed a method to propagate PCNSL cells in vitro using a contacting transwell cell culture system involving brain vascular pericytes. The co-culture system was found to recapitulate the tumor microenvironment that is influenced by the biological activity of adjacent pericytes, and to sustain the survival and proliferation of PCNSL cells in vitro. We further delineated the underlying molecular mechanisms and found that the HGF–c-Met axis may be involved in the long-term in vitro culture of PCNSL cells. Moreover, the peptidylprolyl isomerase Pin1 was found to play a key role in PCNSL cell survival and it sustained proliferation through interactions with key transcription factors related to B-cell lymphomagenesis. These results suggest that our in vitro co-culture system is well suited to analyzing the biological and molecular characteristics of PCNSL, and may contribute to the discovery of new therapeutic interventions.
Novel sandwich immunoassay detects a shrimp AHPND-causing binary PirABVp toxin produced by Vibrio parahaemolyticus
Authors: Jeon Min-Young , Han Jee Eun , Lee Dong Gwang , Cho Young-Lai , Jang Ju-Hong , Lee Jangwook , Park Jong-Gil , Kwon Do Hyung , Park Seon Young , Kim Wantae , Lee Kyunglee , Kim Ji Hyung , Lee Nam-Kyung
Published: November 2023

Introduction

The binary PirA/PirB toxin expressed by Vibrio parahaemolyticus (PirABVp) is a virulent complex that causes acute hepatopancreatic necrosis disease (AHPND) in shrimps, affecting the global shrimp farming industry. AHPND is currently diagnosed by detecting pirA and pirB genes by PCR; however, several V. parahaemolyticus strains do not produce the two toxins as proteins. Thus, an immunoassay using antibodies may be the most effective tool for detecting toxin molecules. In this study, we report a sandwich ELISA-based immunoassay for the detection of PirABVp.

Methods

We utilized a single-chain variable fragment (scFv) antibody library to select scFvs against the PirA or PirB subunits. Phage display panning rounds were conducted to screen and identify scFv antibodies directed against each recombinant toxin subunit. Selected scFvs were converted into IgGs to develop a sandwich immunoassay to detect recombinant and bacterial PirABVp.

Results

Antibodies produced as IgG forms showed sub-nanomolar to nanomolar affinities (KD), and a pair of anti-PirA antibody as a capture and anti-PirB antibody as a detector showed a limit of detection of 201.7 ng/mL for recombinant PirABVp. The developed immunoassay detected PirABVp in the protein lysates of AHPND-causing V. parahaemolyticus (VpAHPND) and showed a significant detectability in moribund or dead shrimp infected with a VpAHPND virulent strain compared to that in non-infected shrimp.

Discussion

These results indicate that the developed immunoassay is a reliable method for diagnosing AHPND by detecting PirABVp at the protein level and could be further utilized to accurately determine the virulence of extant or newly identified VpAHPND in the global shrimp culture industry.
HyBryte™ use in early-stage cutaneous T-cell lymphoma
Authors: Poligone Brian , Alexander-Savino Carolina V. , Kim Ellen J. , Mangold Aaron R. , Desimone Jennifer , Wong Henry K. , Rumage Adam T. , Donini Oreola , Haulenbeek Andrea , Schaber Christopher J. , Straube Richard , Pullion Christopher , Rook Alain H.
Published: November 2023

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL.
Serum branched chain amino acids: an effective indicator of diabetic kidney disease
Authors: Liu Min , Yang Yanhui , Liu Yajin , Peng Xiaoyue , Hou Yi , Zhang Xuejiao , Sun Haipeng , Shan Chunyan
Published: November 2023

Introduction

In recent years, there has been a growing association between elevated circulating levels of branched-chain amino acids (BCAA) and diabetes mellitus. However, the relationship between serum BCAA levels and diabetic kidney disease (DKD) remains ambiguous. This study aims to investigate serum BCAA levels in DKD patients at various stages and assess the correlation between BCAA and clinical characteristics.

Materials and methods

We enrolled patients with type 2 diabetes mellitus (T2DM) who were admitted to our hospital and categorized them into three groups based on different DKD stages: normal proteinuria, microproteinuria, and macroalbuminuria groups. Forty healthy volunteers were included as the control group, and we measured serum BCAA concentrations using liquid chromatography-mass spectrometry (LC-MS). Subsequently, we conducted correlation and regression analyses to assess the associations between BCAA and clinical indicators.

Results

Serum BCAA levels were significantly elevated in T2DM patients compared to healthy controls. However, these levels exhibited a gradual decline with the progression of DKD. Furthermore, after adjusting for age, gender, and disease duration, we observed an independent association between serum albumin, urinary transferrin, and urinary microalbumin with BCAA.

Discussion

Our findings suggest a noteworthy decline in serum BCAA levels alongside the advancement of DKD. Additionally, serum BCAA exhibits an independent correlation with renal function indicators. These observations point to the possibility that serum BCAA concentrations in individuals with T2DM hold promise as a crucial predictor for both the initiation and progression of DKD.
Sleep and circadian rhythm disturbance in kidney stone disease: a narrative review
Authors: He Si-Ke , Wang Jia-Hao , Li Tao , Yin Shan , Cui Jian-Wei , Xiao Yun-Fei , Tang Yin , Wang Jia , Bai Yun-Jin
Published: November 2023

The circadian rhythm generated by circadian clock genes functions as an internal timing system. Since the circadian rhythm controls abundant physiological processes, the circadian rhythm evolved in organisms is salient for adaptation to environmental change. A disturbed circadian rhythm is a trigger for numerous pathological events. Recently, accumulated data have indicated that kidney stone disease (KSD) is related to circadian rhythm disturbance. However, the mechanism between them has not been fully elucidated. In this narrative review, we summarized existing evidence to illustrate the possible association between circadian rhythm disturbance and KSD based on the epidemiological studies and risk factors that are linked to circadian rhythm disturbance and discuss some chronotherapies for KSD. In summary, KSD is associated with systemic disorders. Metabolic syndrome, inflammatory bowel disease, and microbiome dysbiosis are the major risk factors supported by sufficient data to cause KSD in patients with circadian rhythm disturbance, while others including hypertension, vitamin D deficiency, parathyroid gland dysfunction, and renal tubular damage/dysfunction need further investigation. Then, some chronotherapies for KSD were confirmed to be effective, but the molecular mechanism is still unclear.
Energy-carbon emission nexus in a residential building using BIM under different climate conditions: an application of multi-objective optimization
Authors: Alhamami Ali Hussain , Dodo Yakubu Aminu , Naibi Ahmad Usman , Alviz-Meza Aníbal , Mokhtarname Alireza
Published: November 2023

This study was carried out to investigate the impact of building insulation, a method of reducing energy consumption, on the amount of energy consumed in a building, as well as its impact on cooling and heating loads and carbon emission. A residential structure was designed in Revit, and DesignBuilder determined the cooling and heating loads, as well as the energy consumption. Under three distinct climate conditions, the impact of the environment on the energy-carbon emission nexus of residential buildings was assessed. The cold mountain climate of Koick, Slovakia; the arid desert climate of Ha’il, Saudi Arabia; and the tropical monsoon climate of Borneo, Indonesia were chosen. During the design stage, the Particle Swarm Optimization (PSO) method was used to minimize the energy consumption cost (ECC) and CO2 emissions. Over the course of 24 h, the cooling and heating loads decreased by 2.51 kW and 1.9 kW, respectively. When the two modes in Ha’il were combined, the heating load was reduced to 850 kWh and the cooling load was reduced to 650 kWh, according to the results. In Borneo, the heating load was reduced by 200 kWh, while in Koick, it was reduced by 2,000 kWh. The cooling load was reduced by 550 and 50 kWh in Borneo and Koick, respectively. This system appears to perform better in arid and hot climates in terms of both heating and cooling loads. However, energy losses in the arid and hot climate (Ha’il) are greater than in other climates. This could be due to temperature and humidity differences between the inside and outside. According to the findings of the PSO evolutionary algorithm optimization, the building can be constructed to reduce ECC by 19% by taking into account input characteristics such as Wind-to-Wall Ratio (WWR), wall, glazes, and weather conditions. This research provides useful insights into the practical application of optimization methods for reducing CO2 emissions, paving the way for more sustainable and eco-conscious architectural practices.
Diagnostic validity of premenstrual dysphoric disorder: revisited
Authors: Naik Shalini S. , Nidhi Yadav , Kumar Krishan , Grover Sandeep
Published: November 2023

The World Health Organization (WHO) and American Psychiatric Association (APA) have recognised premenstrual dysphoric disorder (PMDD) as an independent diagnostic entity, legitimising the distress and socio-occupational impairment experienced by affected women. However, the biological validity of this diagnosis remains inexplicit. This illness has also been criticised for a feminist-led, sympathetic reaction to the modern cultural challenges of urban, literate, employed, high-functioning women. This article systematically reviews existing literature on PMDD using the criteria established by Robins and Guze for the validity of a psychiatric diagnosis (clinical description, laboratory study, exclusion of other disorders, follow-up study, and family study). Despite the early recognition of premenstrual syndrome (PMS) in the 1950s, the research has encountered challenges due to two groups of proponents viewing it with psychologising bias and medicalising bias. PMDD is currently understood as the most severe form of PMS, characterised by the presence of psychological features. Recent evidence suggests that PMDD perhaps has neurodevelopmental underpinnings (attention deficit hyperactive disorder, adverse childhood experiences) affecting the fronto-limbic circuit that regulates the emotions. In addition, the affected individuals exhibit an increased sensitivity to gonadal hormonal fluctuations as observed during premenstrual, pregnancy, and perimenopausal phases of life. The prevalence is comparable between high-income countries and low- and middle-income countries (LAMIC), refuting the notion that it mostly affects modern women. Instead, a greater prevalence is observed in LAMIC. Despite the fact that educated women possess knowledge regarding the importance of getting help, there is a prevalent issue of inadequate help-seeking behaviour. This can be attributed to the perception of seeking help as an isolating experience, which is influenced by profound internalised stigma and discrimination in the workplace. Future studies must aim to develop culturally validated assessment tools and more research to understand the life course of the illness, in addition to systematically examining for more biological validators (animal models, genetics, imaging, neurotransmitters).
Accurate diagnosis of bullous pemphigoid requires multiple health care visits
Authors: Leisti Päivi , Pankakoski Anna , Jokelainen Jari , Varpuluoma Outi , Huilaja Laura , Panelius Jaana , Tasanen Kaisa
Published: November 2023

Introduction

Accurate use of diagnostic codes is crucial for epidemiological and genetic research based on electronic health record (EHR) data.

Methods

This retrospective study validated the International Classification of Diseases (ICD)-10 diagnostic code L12.0 for bullous pemphigoid (BP) using EHR data from two Finnish university hospitals. We found 1225 subjects with at least one EHR entry of L12.0 between 2009 and 2019. BP diagnosis was based on clinical findings characteristic of BP and positive findings on direct immunofluorescence (DIF), BP180-NC16A enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence (IIF) assay.

Results

True BP was found in 901 patients; the positive predictive value (PPV) for L12.0 was 73.6% (95% CI 71.0-76.0). L12.0 was more accurately registered in dermatology units than any specialized health care units (p<0.001). Including patients with multiple L12.0 registrations (≥3), increased the accuracy of the L12.0 code in both dermatology units and other settings.

Discussion

One diagnostic code of L12.0 is not enough to recognize BP in a large epidemiological data set; including only L12.0 registered in dermatology units and excluding cases with <3 L12.0 record entries markedly increases the PPV of BP diagnosis.
γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids
Authors: Dong Junxue , Holthaus David , Peters Christian , Koster Stefanie , Ehsani Marzieh , Quevedo-Olmos Alvaro , Berger Hilmar , Zarobkiewicz Michal , Mangler Mandy , Gurumurthy Rajendra Kumar , Hedemann Nina , Chumduri Cindrilla , Kabelitz Dieter , Meyer Thomas F.
Published: November 2023

Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer.
Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design
Authors: Clemente Bruna , Denis Maxime , Silveira Camila Pedroso , Schiavetti Francesca , Brazzoli Michela , Stranges Daniela
Published: November 2023

With the deepening of our understanding of adaptive immunity at the cellular and molecular level, targeting antigens directly to immune cells has proven to be a successful strategy to develop innovative and potent vaccines. Indeed, it offers the potential to increase vaccine potency and/or modulate immune response quality while reducing off-target effects. With mRNA-vaccines establishing themselves as a versatile technology for future applications, in the last years several approaches have been explored to target nanoparticles-enabled mRNA-delivery systems to immune cells, with a focus on dendritic cells. Dendritic cells (DCs) are the most potent antigen presenting cells and key mediators of B- and T-cell immunity, and therefore considered as an ideal target for cell-specific antigen delivery. Indeed, improved potency of DC-targeted vaccines has been proved in vitro and in vivo. This review discusses the potential specific targets for immune system-directed mRNA delivery, as well as the different targeting ligand classes and delivery systems used for this purpose.
Prognostic value of lymphocyte-to-monocyte ratio in gastric cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis
Authors: Mei Pingping , Feng Wenzhe , Zhan Yanrong , Guo Xiutian
Published: November 2023

Background

Emerging evidence suggests a correlation between the lymphocyte-monocyte ratio (LMR) and the prognosis in patients with gastric cancer (GC) undergoing immune checkpoint inhibitor (ICI) therapy. Nevertheless, the existing findings remain contentious.

Methods

A comprehensive search of literature was conducted in databases including PubMed, Embase, Web of Science, and the Cochrane Library, spanning from the inception of each database to August 30, 2023 to collect studies exploring the interplay between LMR and clinical outcomes. Eligible studies were selected following predefined inclusion and exclusion criteria. Primary outcomes encompassed progression-free survival (PFS) and overall survival (OS), which were estimated using hazard ratios (HR) and corresponding 95% confidence intervals (CI).

Results

Our analysis incorporated eight cohort studies, involving 815 patients. Aggregate data revealed associations between an elevated LMR at baseline and prolonged PFS (HR=0.58; 95% CI: 0.47–0.71, p<0.00001) and improved OS (HR=0.51, 95% CI: 0.33–0.79; p=0.003). Furthermore, LMR exhibited a favorable association with PFS after treatment (HR=0.48; 95% CI: 0.29–0.79; p= 0.004), while such a correlation was not evident in the OS analysis. Importantly, a high level of LMR was associated with prolonged PFS across varying sample sizes, follow-up duration, treatment combinations, line of therapy, and cut-off values.

Conclusion

A high pre-treatment LMR is associated with improved OS and PFS in GC patients treated with ICIs. LMR emerges as a potent biomarker for prognostic assessment in these patients, offering valuable insights for informed treatment decisions within the domain of GC immunotherapy.

Systematic review registration

PROSPERO, identifier CRD42021228512
ANCA-negative EGPA: only eosinophils without vasculitis? Insights from anti-T2 biologics
Authors: Piga Mario Andrea , Fraticelli Paolo , Antonicelli Leonardo , Garritani Maria Stella , Ghirelli Giulia , Martini Matteo , Di Vincenzo Angelica , Danieli Maria Giovanna , Moroncini Gianluca , Bilò Maria Beatrice
Published: November 2023

The pathogenic role of p-ANCA in eosinophilic granulomatosis with polyangiitis (EGPA) is a long-standing matter of debate. In this work, we report our real-life experience with EGPA patients, treated with biologics targeting type 2 (T2)-eosinophilic inflammation (Mepolizumab, Benralizumab, Dupilumab). Interestingly, we observed EGPA extrarespiratory relapses only in p-ANCA-positive patients (2/5 cutaneous vasculitis, 3/5 constitutional symptoms), with new rise of p-ANCA and normal eosinophil blood count. Notably, revising our cohort with the new ACR 2022 criteria, these five patients were the only ones to satisfy the entry criterion of vasculitis’ defined diagnosis at disease onset. These observations may suggest that biologics, selectively turning off T2 inflammation, may have unmasked p-ANCA exclusive role in the pathogenesis of vasculitis in EGPA. Therefore, we raise the question whether EGPA vasculitis exists only in p-ANCA-positive patients, and whether p-ANCA-negative disease is “only eosinophils without vasculitis”.
Local earthquake seismic tomography of the Southernmost Mariana subduction zone
Authors: Li Dong , Chen Chuanxu , Wu Shiguo
Published: November 2023

We employed seismic tomography to examine the velocity structure of the upper mantle in the Southernmost Mariana subduction zone. Our study focuses on data collected during a six-month experiment from 15 December 2016 to 12 June 2017, using 11 ocean bottom seismometers. By examining over 3700 local arrival times, we are able to determine the three-dimensional Vp and Vs structure. The subducting slab in this region displays a P- and S-wave velocity 2~6% higher than normal mantle and a lower Vp/Vs, with an average dip of 45° at depths ranging from 50 to 100 km. Additionally, our velocity images also shed new lights to the velocity anomalies of the mantle wedge region on top of the subducting slab, from the trench to the remnant arc. We observed slower velocity anomalies in the mantle wedge beneath the Southwest Mariana Rift, the West Mariana Ridge, and the forearc. In the outer forearc, a low-velocity anomaly is observed at depths shallower than 50 km, indicating mantle serpentinization and the presence of water. Additionally, a melt production region is observed beneath the central part of the forearc block at a depth of 40–60 km suggesting the possibility of melting processes in this region.
Frailty index in the Colonias of the Rio Grande Valley: health related quality of life and resilience
Authors: Manusov Eron G. , Diego Vincent P. , Williams-Blangero Sarah
Published: November 2023

Background

Frailty is characterized by an accumulation of deficits that lead to vulnerability to adverse health outcomes. The Frailty Index (FI) quantifies frailty by measuring deficits that increase susceptibility to stressors. This study focused on a population of Mexican Americans living in vulnerable communities in the Rio Grande Valley of south Texas. We used a Frailty Index developed based on common health-related data--the Patient Health Questionnaire (PHQ-9) and a Health-related Quality of Life survey (Duke Health Profile). Quality of life, resilience, and frailty are interrelated and influenced by chronic illness, mental illness, poverty, cognitive impairment, and community support.

Methods

We used Logistic regression analysis, factor component analysis, receiver operating characteristic curves, and odds ratios to identify potential associations between clinical variables and candidate predictor variables and seven physiological health variables, and two survey instruments. We analyzed data obtained from participants (894) that live in two Colonias located on the Texas-Mexico border. We calculated the FI with seven physiological variables, PHQ-9 score, and the 11 domain-specific Duke Profile scores, for a total of 19 health deficits. We then dichotomized FI (>0.25) and determined ROC curves through model selection to determine best predictors of frailty.

Results

Females (n = 622) had a higher starting frailty, and males (n = 272) had a significantly greater change rate with age. Women score higher in anxiety, depression, anxiety/depression, and pain. The frailty index and quality of life markers are strongly inversely related; poorer quality of life leads to greater frailty independent physiological health variables, the PHQ 9, sex, and age.

Conclusion

The study highlights the importance of addressing modifiable mental health and social stressors to reduce frailty. Furthermore, it suggests that factors supporting resilience and well-being, such as physical and mental health, social support, and perceived health, play a crucial role in frailty development. The findings have implications for interventions targeting vulnerable populations and emphasize the need for further research on the relationship between health-related quality of life and frailty.
Screening of Saccharomyces cerevisiae metabolite transporters by 13C isotope substrate labeling
Authors: Stanchev Lyubomir Dimitrov , Møller-Hansen Iben , Lojko Pawel , Rocha Catarina , Borodina Irina
Published: November 2023

The transportome of Saccharomyces cerevisiae comprises approximately 340 membrane-bound proteins, of which very few are well-characterized. Elucidating transporter proteins’ function is essential not only for understanding central cellular processes in metabolite exchange with the external milieu but also for optimizing the production of value-added compounds in microbial cell factories. Here, we describe the application of 13C-labeled stable isotopes and detection by targeted LC–MS/MS as a screening tool for identifying Saccharomyces cerevisiae metabolite transporters. We compare the transport assay’s sensitivity, reproducibility, and accuracy in yeast transporter mutant cell lines and Xenopus oocytes. As proof of principle, we analyzed the transport profiles of five yeast amino acid transporters. We first cultured yeast transporter deletion or overexpression mutants on uniformly labeled 13C-glucose and then screened their ability to facilitate the uptake or export of an unlabeled pool of amino acids. Individual transporters were further studied by heterologous expression in Xenopus oocytes, followed by an uptake assay with 13C labeled yeast extract. Uptake assays in Xenopus oocytes showed higher reproducibility and accuracy. Although having lower accuracy, the results from S. cerevisiae indicated the system’s potential for initial high-throughput screening for native metabolite transporters. We partially confirmed previously reported substrates for all five amino acid transporters. In addition, we propose broader substrate specificity for two of the transporter proteins. The method presented here demonstrates the application of a comprehensive screening platform for the knowledge expansion of the transporter-substrate relationship for native metabolites in S. cerevisiae.
Association of plasma MMP-2 levels and prognosis of patients with intracerebral hemorrhage: a prospective cohort study
Authors: Yu Wenmin , Peng Jin , Chen Zhiying , Li Huimin , Yang Jianyuan , Wu Yun , Zhang Manqing , Wu Moxin
Published: November 2023

Objective

The role of MMP-2 in patients with ICH is controversial and the impact of plasma MMP-2 level on clinical outcome is still unclear.

Materials and methods

In this study, the peripheral venous blood was acquired from 93 patients with ICH and 88 healthy controls within 24 h of hospitalization and at enrollment. We retrospectively investigated plasma MMP-2 levels of patients and healthy controls. The edema volume, the NIHSS score, the GCS score, and mRS were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma MMP-2 levels with clinical outcomes. In addition, the plasma MMP-14 levels and complement C4 level were tested to explore the relationship with plasma MMP-2 level.

Results

There was a significant reduction of plasma MMP-2 levels in ICH patients than that in healthy controls (38.02 ± 1.71 vs. 54.03 ± 2.15, p < 0.0001), and MMP-2 is negatively correlated with the edema volume (r = −0.2187, p < 0.05), NIHSS score (r = −0.2194, p < 0.05), blood leucocyte count (r = −0.2549, p = 0.012), and complement C4 level (r = −0.2723, p = 0.005). There is positive correlation between MMP-2 level and GCS score (r = 0.2451, p = 0.01) and MMP-14 level (r = 0.7013, p = 0.005). The multivariate analysis revealed that reduced plasma MMP-2 level is associated with elevated edema volume (OR = 0.2604, 95% CI [0.07 to 0.84], p = 0.02).

Conclusion

The plasma MMP-2 level in patients with ICH is significantly lower than that of healthy controls, and plasma MMP-2 level may be a prognostic factor. Plasma MMP-2 levels are correlated with the clinical outcomes of patients and negatively correlated with blood leucocyte count and complement C4 level in patients with ICH.
Tri-axial rubidium and helium optically pumped magnetometers for on-scalp magnetoencephalography recording of interictal epileptiform discharges: a case study
Authors: Feys Odile , Corvilain Pierre , Labyt Etienne , Mahmoudzadeh Mahdi , Routier Laura , Sculier Claudine , Holmes Niall , Brookes Matthew , Goldman Serge , Romain Rudy , Mitryukovskiy Sergey , Palacios-Laloy Agustin , Schwartz Denis , Betrouni Nacim , Derambure Philippe , Wallois Fabrice , Wens Vincent , De Tiège Xavier
Published: November 2023

Cryogenic magnetoencephalography (MEG) enhances the presurgical assessment of refractory focal epilepsy (RFE). Optically pumped magnetometers (OPMs) are cryogen-free sensors that enable on-scalp MEG recordings. Here, we investigate the application of tri-axial OPMs [87Rb (Rb-OPM) and 4He gas (He-OPM)] for the detection of interictal epileptiform discharges (IEDs). IEDs were recorded simultaneously with 4 tri-axial Rb- and 4 tri-axial He-OPMs in a child with RFE. IEDs were identified visually, isolated from magnetic background noise using independent component analysis (ICA) and were studied following their optimal magnetic field orientation thanks to virtual sensors. Most IEDs (>1,000) were detectable by both He- and Rb-OPM recordings. IEDs were isolated by ICA and the resulting magnetic field oriented mostly tangential to the scalp in Rb-OPMs and radial in He-OPMs. Likely due to differences in sensor locations, the IED amplitude was higher with Rb-OPMs. This case study shows comparable ability of Rb-OPMs and He-OPMs to detect IEDs and the substantial benefits of triaxial OPMs to detect IEDs from different sensor locations. Tri-axial OPMs allow to maximize spatial brain sampling for IEDs detection with a limited number of sensors.
Hematologic secondary malignancies among 102 Chinese patients with Waldenstrom’s macroglobulinemia: a single-center case experience and literature review
Authors: Wang Lingling , Xi Conglin , Huang Yongfen , Xu Hao , Miao Yuqing , Cheng Yuexin
Published: November 2023

Waldenstrom’s macroglobulinemia (WM) is a rare and indolent B-cell lymphoma. To investigate the type and survival of hematologic secondary malignancies (SMs) in Chinese patients with WM, we retrospectively reviewed the characteristics of 102 patients with WM from February 2002 to May 2023 in our center. Four men and two women were diagnosed with hematologic SMs. Of the six patients with hematologic SMs, one was diagnosed with acute myeloid leukemia (AML), one with multiple myeloma (MM), one with myelodysplastic syndrome (MDS), one with B-cell acute lymphoblastic leukemia (B-ALL), and two with diffuse large B-cell lymphoma (DLBCL). The median age was 65.5 years (56–74 years). The median interval time between diagnosis of WM and hematologic SMs was 39.5 months (10–117 months). Among those with WM with hematologic SMs, five died and one survived. Overall survival (OS) was just 33 months (12–119 months) on median. A total of 32 patients died and 64 survived in the group of WM without hematologic SMs, and the median OS was 82 months (3–250 months). This is the first study in the Chinese population on hematologic SMs in WM. The purpose of this study was to investigate the prognosis of hematologic SMs in WM in the Chinese population, as well as to compare the population’s characteristics to those of other centers. We investigated the underlying causes further and presented a research strategy for our forthcoming investigation. We intend to investigate risk factors for SMs as well as more accessible screening methods.
The Impact of Immunotherapy on Sleep and Circadian Rhythms in Patients with Cancer
Authors: Balachandran Diwakar D. , Bashoura Lara , Sheshadri Ajay , Manzullo Ellen , Faiz Saadia A.
Published: November 2023

Immunotherapy has revolutionized treatments for both early and advanced cancers, and as their role evolves, their impact on sleep and circadian rhythms continues to unfold. The recognition, evaluation, and treatment of sleep and circadian rhythm disturbance leads to improved symptom management, quality of life and treatment outcomes. An intricate complex relationship exists in the microenvironment with immunity, sleep and the tumor, and these may further vary based on the cancer, addition of standard chemotherapy, and pre-existing patient factors. Sleep and circadian rhythms may offer tools to better utilize immunotherapy in the care of cancer patients, leading to better treatment outcome, reduced symptom burden, and increased quality of life.
Integrated metabolomics and proteomics reveal biomarkers associated with hemodialysis in end-stage kidney disease
Authors: Lin Weiwei , Mousavi Fatemeh , Blum Benjamin C. , Heckendorf Christian F. , Moore Jarrod , Lampl Noah , McComb Mark , Kotelnikov Sergei , Yin Wenqing , Rabhi Nabil , Layne Matthew D. , Kozakov Dima , Chitalia Vipul C. , Emili Andrew
Published: November 2023

Background: We hypothesize that the poor survival outcomes of end-stage kidney disease (ESKD) patients undergoing hemodialysis are associated with a low filtering efficiency and selectivity. The current gold standard criteria using single or several markers show an inability to predict or disclose the treatment effect and disease progression accurately.

Methods: We performed an integrated mass spectrometry-based metabolomic and proteomic workflow capable of detecting and quantifying circulating small molecules and proteins in the serum of ESKD patients. Markers linked to cardiovascular disease (CVD) were validated on human induced pluripotent stem cell (iPSC)-derived cardiomyocytes.

Results: We identified dozens of elevated molecules in the serum of patients compared with healthy controls. Surprisingly, many metabolites, including lipids, remained at an elevated blood concentration despite dialysis. These molecules and their associated physical interaction networks are correlated with clinical complications in chronic kidney disease. This study confirmed two uremic toxins associated with CVD, a major risk for patients with ESKD.

Conclusion: The retained molecules and metabolite–protein interaction network address a knowledge gap of candidate uremic toxins associated with clinical complications in patients undergoing dialysis, providing mechanistic insights and potential drug discovery strategies for ESKD.
Research progress on the mechanism of angiogenesis in wound repair and regeneration
Authors: Shi Zhuojun , Yao Chong , Shui Yujie , Li Site , Yan Hong
Published: November 2023

Poor wound healing and pathological healing have been pressing issues in recent years, as they impact human quality of life and pose risks of long-term complications. The study of neovascularization has emerged as a prominent research focus to address these problems. During the process of repair and regeneration, the establishment of a new vascular system is an indispensable stage for complete healing. It provides favorable conditions for nutrient delivery, oxygen supply, and creates an inflammatory environment. Moreover, it is a key manifestation of the proliferative phase of wound healing, bridging the inflammatory and remodeling phases. These three stages are closely interconnected and inseparable. This paper comprehensively integrates the regulatory mechanisms of new blood vessel formation in wound healing, focusing on the proliferation and migration of endothelial cells and the release of angiogenesis-related factors under different healing outcomes. Additionally, the hidden link between the inflammatory environment and angiogenesis in wound healing is explored.
Seasonal variation in C:N:P stoichiometry, nonstructural carbohydrates, and carbon isotopes of two coniferous pioneer tree species in subtropical China
Authors: Liu Yuanxi , Xiao Jiandong , Sun Jianli , Zhao Zhijuan , Deng Xin , Wu Junwen , Zhang Deguo , Bao Yun
Published: November 2023

The characteristics of C:N:P stoichiometry, nonstructural carbohydrate (NSC) content, and C stable isotopes and their relationships affect plant responses to environmental changes and are critical to understanding the ecosystem carbon and water cycles. We investigated the water use strategies and physiological changes of two pioneer tree species (Pinus armandii and Pinus yunnanensis) in response to seasonal drought in subtropical China. The seasonal variation in needle δ13C values, C:N:P stoichiometry, and NSC contents of the two tree species were studied in 25-year-old plantation in central Yunnan Province. The needle δ13C values of both species were highest in summer. Soluble sugars, starch and NSC content of the two tree species decreased from spring to winter, while there was no significant difference in the seasonal variation of soluble sugars/starch in P. armandii needles, the maximum soluble sugars/starch in P. yunnanensis needles was in autumn. In addition, the C, N, and P contents of the needles and the C:N and C:P ratios of the two species showed different seasonal fluctuations, whereas the N:P ratio decreased with the season. The C:N:P stoichiometry and NSC content of the needles showed significant correlations, whereas the needle δ13C was weakly correlated with C:N:P stoichiometry and NSC content. Phenotypic plasticity analysis and principal component analysis revealed that the needle nutrient characteristics (NSC and P contents and N:P ratio) and needle δ13C values were critical indicators of physiological adaptation strategies of P. armandii and P. yunnanensis for coping with seasonal variation. These results increase our understanding of the water-use characteristics of the two pioneer tree species and the dynamic balance between the NSC, C, N, and P contents of the needles.