bluuebunny/crossref_metadata_2025 huggingface dataset:
An immunoregulator nanomedicine approach for the treatment of tuberculosis
Authors: Yang Luona , Chaves Lee , Kutscher Hilliard L. , Karki Shanta , Tamblin Maria , Kenney Patrick , Reynolds Jessica L.
Published: May 2023

Introduction: A nanoparticle composed of a poly (lactic-co-glycolic acid) (PLGA) core and a chitosan (CS) shell with surface-adsorbed 1,3 β-glucan (β-glucan) was synthesized. The exposure response of CS-PLGA nanoparticles (0.1 mg/mL) with surface-bound β-glucan at 0, 5, 10, 15, 20, or 25 ng or free β-glucan at 5, 10, 15, 20, or 25 ng/mL in macrophage in vitro and in vivo was investigated.

Results:In vitro studies demonstrate that gene expression for IL-1β, IL-6, and TNFα increased at 10 and 15 ng surface-bound β-glucan on CS-PLGA nanoparticles (0.1 mg/mL) and at 20 and 25 ng/mL of free β-glucan both at 24 h and 48 h. Secretion of TNFα protein and ROS production increased at 5, 10, 15, and 20 ng surface-bound β-glucan on CS-PLGA nanoparticles and at 20 and 25 ng/mL of free β-glucan at 24 h. Laminarin, a Dectin-1 antagonist, prevented the increase in cytokine gene expression induced by CS-PLGA nanoparticles with surface-bound β-glucan at 10 and 15 ng, indicating a Dectin-1 receptor mechanism. Efficacy studies showed a significant reduction in intracellular accumulation of mycobacterium tuberculosis (Mtb) in monocyte-derived macrophages (MDM) incubated with on CS-PLGA (0.1 mg/ml) nanoparticles with 5, 10, and 15 ng surface-bound β-glucan or with 10 and 15 ng/mL of free β-glucan. β-glucan-CS-PLGA nanoparticles inhibited intracellular Mtb growth more than free β-glucan alone supporting the role of β-glucan-CS-PLGA nanoparticles as stronger adjuvants than free β-glucan. In vivo studies demonstrate that oropharyngeal aspiration (OPA) of CS-PLGA nanoparticles with nanogram concentrations of surface-bound β-glucan or free β-glucan increased TNFα gene expression in alveolar macrophages and TNFα protein secretion in bronchoalveolar lavage supernatants.

Discussion: Data also demonstrate no damage to the alveolar epithelium or changes in the murine sepsis score following exposure to β-glucan-CS-PLGA nanoparticles only, indicating safety and feasibility of this nanoparticle adjuvant platform to mice by OPA.
Lung inflammation perturbation by engineered nanoparticles
Authors: Zhou Xiaofei , Jin Weitao , Ma Jingjun
Published: May 2023

In recent years, the unique and diverse physicochemical properties of nanoparticles have brought about their wide use in many fields; however, it is necessary to better understand the possible human health risks caused by their release in the environment. Although the adverse health effects of nanoparticles have been proposed and are still being clarified, their effects on lung health have not been fully studied. In this review, we focus on the latest research progress on the pulmonary toxic effects of nanoparticles, and we summarized their disturbance of the pulmonary inflammatory response. First, the activation of lung inflammation by nanoparticles was reviewed. Second, we discussed how further exposure to nanoparticles aggravated the ongoing lung inflammation. Third, we summarized the inhibition of the ongoing lung inflammation by nanoparticles loaded with anti-inflammatory drugs. Forth, we introduced how the physicochemical properties of nanoparticles affect the related pulmonary inflammatory disturbance. Finally, we discussed the main gaps in current research and the challenges and countermeasures in future research.
Profiling and targeting cancer stem cell signaling pathways for cancer therapeutics
Authors: Borlongan Mia C. , Wang Hongbin
Published: May 2023

Tumorigenic cancer stem cells (CSCs) represent a subpopulation of cells within the tumor that express genetic and phenotypic profiles and signaling pathways distinct from the other tumor cells. CSCs have eluded many conventional anti-oncogenic treatments, resulting in metastases and relapses of cancers. Effectively targeting CSCs’ unique self-renewal and differentiation properties would be a breakthrough in cancer therapy. A better characterization of the CSCs’ unique signaling mechanisms will improve our understanding of the pathology and treatment of cancer. In this paper, we will discuss CSC origin, followed by an in-depth review of CSC-associated signaling pathways. Particular emphasis is given on CSC signaling pathways’ ligand-receptor engagement, upstream and downstream mechanisms, and associated genes, and molecules. Signaling pathways associated with regulation of CSC development stand as potential targets of CSC therapy, which include Wnt, TGFβ (transforming growth factor-β)/SMAD, Notch, JAK-STAT (Janus kinase-signal transducers and activators of transcription), Hedgehog (Hh), and vascular endothelial growth factor (VEGF). Lastly, we will also discuss milestone discoveries in CSC-based therapies, including pre-clinical and clinical studies featuring novel CSC signaling pathway cancer therapeutics. This review aims at generating innovative views on CSCs toward a better understanding of cancer pathology and treatment.
Is the reversed congruency effect unique to the eye-gaze? Investigating the effects of finger pointing, eye-gaze and arrows stimuli on spatial interference
Authors: Bonventre Sofia , Marotta Andrea
Published: May 2023

Introduction

Spatial interference tasks have been recently used to investigate the supposed uniqueness of gaze processing and attention. For instance, it has been observed that gaze stimuli elicited faster responses when their direction was incongruent with their position (“reversed spatial congruency effect”, RCE), whereas arrows produced faster reaction times (RT) when it was congruent (“standard spatial congruency effect”, SCE). In the present study, we tested whether the RCE is unique to eye-gaze stimuli or can be observed in response to other important social stimuli such as pointing fingers.

Method

To this aim, congruency effects elicited by eye gaze, arrows, and pointing fingers were compared in a spatial interference task.

Results

The RCE was only observed in response to eye-gaze stimuli while pointing fingers and arrows elicited the SCE.

Discussion

This suggests that the RCE reversed congruency effect is specific to gaze stimuli and cannot be generalized to finger-pointing stimuli.
Digitalization of prevention and treatment and the combination of western and Chinese medicine in management of acute heart failure
Authors: Wang Yingxin , Cui Herong , Li Liwen , Cao Yajing , Qu Hanyun , Ailina Halisi , Dou Zhili , Tang Chuwei , Qin Wanli , Wang Chenlu , Yang Xue , Feng Shixing , Liu Yixing , Han Dongran
Published: May 2023

Digitalization has emerged as a new trend in healthcare, with great potential and creating many unique opportunities, as well as many challenges. Cardiovascular disease is one of the major causes of disease-related morbidity and mortality worldwide, and the threat to life posed by acute heart failure is evident. In addition to traditional collegiate therapies, this article reviews the current status and subdisciplinary impact of digital healthcare at the level of combined Chinese and Western medical therapies. It also further discusses the prospects for the development of this approach, with the objective of developing an active role for digitalization in the combination of Western and Chinese medicine for the management of acute heart failure in order to support maintenance of cardiovascular health in the population.
Outpatient intravenous diuresis in a rural setting: safety, efficacy, and outcomes
Authors: Pathangey Girish , D’Anna Susan P , Moudgal Rohitha A. , Min David B. , Manning Katharine A. , Taub Cynthia C. , Gilstrap Lauren G.
Published: May 2023

Purpose

To evaluate the safety, efficacy, and outcomes of outpatient intravenous diuresis in a rural setting and compare it to urban outcomes.

Methods

A single-center study was conducted on 60 patients (131 visits) at the Dartmouth-Hitchcock Medical Center (DHMC) from 1/2021–12/2022. Demographics, visit data, and outcomes were collected and compared to urban outpatient IV centers, and inpatient HF hospitalizations from DHMC FY21 and national means. Descriptive statistics, T-tests and chi-squares were used.

Results

The mean age was 70 ± 13 years, 58% were male, and 83% were NYHA III-IV. Post-diuresis, 5% had mild-moderate hypokalemia, 16% had mild worsening of renal function, and 3% had severe worsening of renal function. No hospitalizations occurred due to adverse events. The mean infusion-visit urine output was 761 ± 521 ml, and post-visit weight loss was −3.9 ± 5.0 kg. No significant differences were observed between HFpEF and HFrEF groups. 30-day readmissions were similar to urban outpatient IV centers, DHMC FY21, and the national mean (23.3% vs. 23.5% vs. 22.2% vs. 22.6%, respectively; p = 0.949). 30-day mortality was similar to urban outpatient IV centers but lower than DHMC FY21 and the national means (1.7% vs. 2.5% vs. 12.3% vs. 10.7%, respectively; p < 0.001). At 60 days, 42% of patients had ≥1 clinic revisit, 41% had ≥1 infusion revisit, 33% were readmitted to the hospital, and two deaths occurred. The clinic avoided 21 hospitalizations, resulting in estimated cost savings of $426,111.

Conclusion

OP IV diuresis appears safe and effective for rural HF patients, potentially decreasing mortality rates and healthcare expenses while mitigating rural-urban disparities.
Epigenetic modifications as therapeutic targets in atherosclerosis: a focus on DNA methylation and non-coding RNAs
Authors: Sum Hashum , Brewer Alison C.
Published: May 2023

Significant progress in the diagnosis and treatment of cardiovascular disease (CVD) has been made in the past decade, yet it remains a leading cause of morbidity and mortality globally, claiming an estimated 17.9 million deaths per year. Although encompassing any condition that affects the circulatory system, including thrombotic blockage, stenosis, aneurysms, blood clots and arteriosclerosis (general hardening of the arteries), the most prevalent underlying hallmark of CVD is atherosclerosis; the plaque-associated arterial thickening. Further, distinct CVD conditions have overlapping dysregulated molecular and cellular characteristics which underlie their development and progression, suggesting some common aetiology. The identification of heritable genetic mutations associated with the development of atherosclerotic vascular disease (AVD), in particular resulting from Genome Wide Association Studies (GWAS) studies has significantly improved the ability to identify individuals at risk. However, it is increasingly recognised that environmentally-acquired, epigenetic changes are key factors associated with atherosclerosis development. Increasing evidence suggests that these epigenetic changes, most notably DNA methylation and the misexpression of non-coding, microRNAs (miRNAs) are potentially both predictive and causal in AVD development. This, together with their reversible nature, makes them both useful biomarkers for disease and attractive therapeutic targets potentially to reverse AVD progression. We consider here the association of aberrant DNA methylation and dysregulated miRNA expression with the aetiology and progression of atherosclerosis, and the potential development of novel cell-based strategies to target these epigenetic changes therapeutically.
On the evolution of artificially maturated hydrocarbon source rocks
Authors: de Lacerda D. L. P. , Morschbacher M. J. , Justen J. C. R. , Vasquez G. F. , Spigolon A. L. D. , Menezes T. R. , Skinner R.
Published: May 2023

The elastic moduli are a function of properties that could vary between samples and change during maturation. Consequently, the effects of organic matter maturation on the elastic wave velocities of organic-rich rocks are challenging to describe. This work analyzes the isolated maturation effects on the organic content, pore volume, microstructure, and propagation velocities of elastic waves. To avoid any initial rock heterogeneity, we prepared a series of homogeneous samples from a unique outcrop block collected on the Eagle Ford formation with mineral composition initially determined using X-ray diffraction. From the initial set, four samples were held in their original condition and four were artificially maturated by hydropyrolysis until transformation rates were up to 95%. Then, the evolution of the sample properties was examined using an association of LECO TOC, Rock-Eval pyrolysis, vitrinite reflectance, mercury intrusion porosimetry (MIP), and ultrasonic pulse propagation. In addition, scanning electron microscopy images registered the microstructure evolution. To evaluate the effects of maturation on pore geometry and the organic matter elastic moduli, we analyze the relationship between the measured quantities using a rock physics inclusion model with the unmeasured properties taken as fitting parameters. The hydropyrolysis maturation increases the vitrinite reflectance from the initial 0.55% to 1.34% on the most matured sample. A total organic carbon reduction from 4.2% to 2.1% and a porosity increase from 9.2% to 21% are associated with observed maturation. The geochemical characterization on cleaned samples reveals an initial increment of soluble organic matter followed by a monotonical reduction related to oil migration out of bulk volume. The measurement of wave propagation velocities as a function of confining pressure displays an increasing pressure sensitivity with a downward trend in both velocity moduli. The petrophysical analysis indicates that the porosity increases through organic matter consumption and pore creation. The rock physics diagnoses indicate a decrease in the pore aspect ratio with an increase in the elastic modulus of the organic matter with maturation.
Extracellular vesicle-mediated intercellular and interorgan crosstalk of pancreatic islet in health and diabetes
Authors: Wei Junlun , Wang Zhenghao , Han Tingrui , Chen Jiaoting , Ou Yiran , Wei Lan , Zhu Xinyue , Wang Ke , Yan Zhe , Han Yuan-Ping , Zheng Xiaofeng
Published: May 2023

Diabetes mellitus (DM) is a systemic metabolic disease with high mortality and morbidity. Extracellular vesicles (EVs) have emerged as a novel class of signaling molecules, biomarkers and therapeutic agents. EVs-mediated intercellular and interorgan crosstalk of pancreatic islets plays a crucial role in the regulation of insulin secretion of β-cells and insulin action in peripheral insulin target tissues, maintaining glucose homeostasis under physiological conditions, and it’s also involved in pathological changes including autoimmune response, insulin resistance and β-cell failure associated with DM. In addition, EVs may serve as biomarkers and therapeutic agents that respectively reflect the status and improve function and viability of pancreatic islets. In this review, we provide an overview of EVs, discuss EVs-mediated intercellular and interorgan crosstalk of pancreatic islet under physiological and diabetic conditions, and summarize the emerging applications of EVs in the diagnosis and treatment of DM. A better understanding of EVs-mediated intercellular and interorgan communication of pancreatic islets will broaden and enrich our knowledge of physiological homeostasis maintenance as well as the development, diagnosis and treatment of DM.
Utilization of commercial collagens for preparing well-differentiated human beta cells for confocal microscopy
Authors: Brennecke Brianna R. , Yang USeong , Liu Siming , Ilerisoy Fatma S. , Ilerisoy Beyza N. , Joglekar Aditya , Kim Lucy B. , Peachee Spencer J. , Richtsmeier Syreine L. , Stephens Samuel B. , Sander Edward A. , Strack Stefan , Moninger Thomas O. , Ankrum James A. , Imai Yumi
Published: May 2023

Introduction

With technical advances, confocal and super-resolution microscopy have become powerful tools to dissect cellular pathophysiology. Cell attachment to glass surfaces compatible with advanced imaging is critical prerequisite but remains a considerable challenge for human beta cells. Recently, Phelps et al. reported that human beta cells plated on type IV collagen (Col IV) and cultured in neuronal medium preserve beta cell characteristics.

Methods

We examined human islet cells plated on two commercial sources of Col IV (C6745 and C5533) and type V collagen (Col V) for differences in cell morphology by confocal microscopy and secretory function by glucose-stimulated insulin secretion (GSIS). Collagens were authenticated by mass spectrometry and fluorescent collagen-binding adhesion protein CNA35.

Results

All three preparations allowed attachment of beta cells with high nuclear localization of NKX6.1, indicating a well-differentiated status. All collagen preparations supported robust GSIS. However, the morphology of islet cells differed between the 3 preparations. C5533 showed preferable features as an imaging platform with the greatest cell spread and limited stacking of cells followed by Col V and C6745. A significant difference in attachment behavior of C6745 was attributed to the low collagen contents of this preparation indicating importance of authentication of coating material. Human islet cells plated on C5533 showed dynamic changes in mitochondria and lipid droplets (LDs) in response to an uncoupling agent 2-[2-[4-(trifluoromethoxy)phenyl]hydrazinylidene]-propanedinitrile (FCCP) or high glucose + oleic acid.

Discussion

An authenticated preparation of Col IV provides a simple platform to apply advanced imaging for studies of human islet cell function and morphology.
Setup of a cryobank for ovarian tissue in a university-based setting
Authors: Baston-Büst Dunja M. , Scheliga Iwona , Bielfeld Alexandra P.
Published: May 2023

Establishing and maintaining a newly set-up cryobank for ovarian tissue in a university setting requires at least 1 year’s notice to start financial, spatial, lab equipment, and employee acquisition planning. Right before and after the start of the cryobank, the newly founded team should introduce itself to the hospitals and local and national health systems via mail, print flyers, and symposia in order to share the possibilities and the knowledge. Potential referrers should be provided with standard operating procedures and advice on getting used to the new system. Especially in the first year after the establishment, all procedures should be internally audited in order to avoid possible difficulties.
Causal relationship between circulating immune cells and the risk of type 2 diabetes: a Mendelian randomization study
Authors: Li Jin , Niu Qingmin , Wu Aiwei , Zhang Yuchu , Hong Liquan , Wang Hu
Published: May 2023

Objectives

Though type 2 diabetes (T2D) has been known as a metabolic disease caused by multiple factors, the etiology remains insufficiently understood. Here, we aimed to figure out whether circulating immune cell profiles causally impact T2D liability.

Methods

We applied one genome-wide association study (GWAS) summary statistics of blood traits in 563,085 participants from the Blood Cell Consortium and another GWAS of flow cytometric profile of lymphocyte subsets comprising 3,757 Sardinians to identify genetically predicted blood immune cells. We also obtained GWAS summary statistics in 898,130 individuals from the DIAGRAM Consortium to evaluate genetically predicted T2D. We primarily used inverse variance weighted (IVW) and weighted median methods to perform Mendelian randomization analyses and sensitivity analyses to evaluate heterogeneity and pleiotropy.

Results

For circulating blood leukocyte and its subpopulations, the increase of genetically predicted circulating monocyte count was causally correlated with a higher risk of T2D [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02–1.10, p = 0.0048]. For lymphocyte subsets, CD8+ T cell and CD4+ CD8dim T cell count were identified with causal effect on T2D susceptibility (CD8+ T cell: OR = 1.09, 95% CI = 1.03–1.17, p = 0.0053; CD4+ CD8dim T cell: OR = 1.04, 95% CI = 1.01–1.08, p = 0.0070). No pleiotropy was determined.

Conclusions

These findings demonstrated that higher circulating monocyte and T-lymphocyte subpopulation predicted increased T2D susceptibility, which confirmed the immunity predisposition for T2D. Our results may have the potential to provide new therapeutic targets for the diagnosis and treatment of T2D.
The impact of planting scenarios on agricultural productivity and thermal comfort in urban agriculture land (case study: Tabriz, Iran)
Authors: Rahimi Akbar , Nobar Zahra
Published: May 2023

Population growth is a significant challenge in developing countries because it leads to the destruction of green infrastructure and urban agriculture lands around cities, resulting in dissatisfaction with the environment. This study aims to revitalize abandoned agricultural lands within city limits due to urban planning, which can be considered a kind of green infrastructure. In Tabriz, Iran, urban agriculture and urban texture coexist, and the effect of native plant-crop combinations on micrometeorological conditions and thermal comfort on agricultural land was examined. The ENVI-MET model simulated the research area, and the output parameters were validated by comparing their values to field data. The model identified seven proposed scenarios that demonstrated higher performance in improving outdoor thermal comfort. The results showed that edible functions of deciduous plants increased with canopy height and diameter, which improved thermal comfort in high-temperature conditions. Adopting this form of planting would rejuvenate abandoned agricultural fields. Consequently, outdoor thermal comfort may be improved [1.42 predicted mean value (PMV) reduction in the land without plants and a 1.37 PMV reduction in the agriculture land simulation], leading to the rehabilitation of urban agricultural lands that have lost their function in developing cities. These research findings can be utilized to help address the impacts of population growth on green infrastructure and urban agriculture lands.
Pairing status and stimulus type predict responses to audio playbacks in female titi monkeys
Authors: Lau Allison R. , Cunningham Ashley D. , Bales Karen L.
Published: May 2023

Some paired primates use complex, coordinated vocal signals to communicate within and between family groups. The information encoded within those signals is not well understood, nor is the intricacy of individuals’ behavioral and physiological responses to these signals. Considering the conspicuous nature of these vocal signals, it is a priority to better understand paired primates’ responses to conspecific calls. Pair-bonded titi monkeys (Plecturocebus cupreus) sing duets comprised of the male and female’s long call. Here, we use a playback study to assess female titi monkeys’ responses to different vocal stimuli based on the subject’s pairing status. Six adult female titi monkeys participated in the study at two timepoints—pre-pairing and post-pairing. At each timepoint, subjects underwent three distinct playbacks—control recording, male solo vocalization, and pair duet. Behaviors such as locomotion and vocalizations were scored during and after the playback, and cortisol and androgen values were assessed via a plasma blood sample. Female titi monkeys attended more to social signals compared to the control, regardless of pairing status. However, in the time immediately following any playback type, female titi monkeys trilled more and spent a greater proportion of time locomoting during pre-pairing timepoints (compared to post-pairing). Female titi monkeys’ behavioral responses to social audio stimuli, combined with subjects’ increases in cortisol and androgens as paired individuals, imply female titi monkeys attend and respond to social signals territorially.
Ontogeny and brooding strategy of the early Cambrian arthropod Isoxys minor from the Qingjiang biota
Authors: Ma Jiaxin , Pates Stephen , Wu Yu , Lin Weiliang , Liu Cong , Wu Yuheng , Zhang Mingjing , Fu Dongjing
Published: May 2023

†Isoxys is a worldwide distributed bivalved arthropod known almost exclusively from Cambrian Burgess Shale-type Lagerstätten. Outline analyses using 34 specimens of the iconic large bivalved arthropod †Isoxys minor from the Cambrian Stage 3 (~518 Ma) Qingjiang biota and the Cambrian Stage 4 Guanshan biota, interpret that they are the same species and there is a very slight difference in the shape of the outlines of the carapaces between the two biotas. This suggests that environment might be driving intraspecific variation. Quantitative analysis of shape changes during growth using 51 specimens of †I. minor from the Qingjiang biota, reveals that its valves gradually elongate and the ratio of cardinal spines and spherical eyes relative to the valve length significantly decreases during postembryonic development. †I. minor has proportionally large cardinal spines and eyes in the earliest stages, and this allometric growth is beneficial for self-protection and foraging, which may have improved the survival rate of individuals with these characters. In addition, two of the specimens document the evidence of brood care in †I. minor, and the egg cluster occupies almost the entire dorsal region under the carapace. Compared to other early Paleozoic egg-carrying arthropods, †I. minor broods have the highest number (~300 per clutch) of small (Ø, ~0.5 mm) eggs. Since the ovigerous individuals are almost half the size of the adults, †I. minor may have possessed reproductive ability during the early life stage. The results indicate that spines played an antipredatory role for †I. minor, and that it followed an r-strategy of reproducing with many individuals at an early stage. †I. minor also represents the earliest diverging arthropod from which brood care has been documented.
Molecular biomarkers of progression from Barrett’s esophagus to esophageal adenocarcinoma
Authors: Taylor Luke , Alastal Hani Naeem , Rasheed Ashraf
Published: May 2023

Introduction

Barrett’s esophagus (BO) is a pre-malignant condition for esophageal adenocarcinoma (OAC), the incidence rate of which has risen dramatically over the last four decades in the Western world. The 5-year survival rate of OAC is poor, and one of the ways to improve it would be by focusing on identifying high-risk Barrett’s patients through a surveillance program. Currently, histologic dysplasia is the only recognized marker of progression to OAC. Molecular biomarkers found in tissue samples that predict which patients have a higher risk of progression to OAC may act as a reliable tool for the stratification of patients with BO.

Aim

To determine whether molecular biomarkers have a potential use in predicting which patients with BO have a higher risk of progression to OAC.

Methods

Immunohistochemistry was performed on 25 tissue samples obtained from the endoscopic biopsies of 19 patients with confirmed BO. Hematoxylin and eosin (H&E) staining was used to confirm the presence of BO and dysplasia. Staining was performed in an external independent laboratory. Statistical analysis using the Mann–Whitney U test was performed using R Studio® statistical software.

Results

Of the 19 patients sampled, three had low-grade dysplasia (LGD), and all had confirmed metaplasia diagnostic of BO. Expression of cyclin D1 was noted to be elevated in patients with LGD compared with those with metaplasia only (p = 0.042). Expression of Sox2 was elevated in metaplastic BO cells compared with normal squamous cells within the same stain (p = 0.046). Of all eight biomarkers tested, β-catenin had the greatest overall expression (p < 0.004).

Conclusions

Isolating elevated cyclin D1 in patients with LGD highlights its potential use as a biomarker in identifying BO patients at risk of developing dysplasia, and, in turn, their possible progression to OAC. Elevated levels of both Sox2 and β-catenin may also serve as markers for disease progression when overexpressed in BO patients. Both conclusions, however, would need long-term follow-up to fully establish their prognostic usefulness, as at the time of writing no patients in this study had gone on to develop OAC. Although only a small sample size was present for this study, and follow-up was limited, it serves as a strong pilot for further research into the use of novel biomarkers in predicting which BO patients are at high risk of developing dysplasia and progressing to OAC.
Immune-related adverse events of immune checkpoint inhibitors: a review
Authors: Yin Qinan , Wu Liuyun , Han Lizhu , Zheng Xingyue , Tong Rongsheng , Li Lian , Bai Lan , Bian Yuan
Published: May 2023

Since the first Immune Checkpoint Inhibitor was developed, tumor immunotherapy has entered a new era, and the response rate and survival rate of many cancers have also been improved. Despite the success of immune checkpoint inhibitors, resistance limits the number of patients who can achieve a lasting response, and immune-related adverse events complicate treatment. The mechanism of immune-related adverse events (irAEs) is unclear. We summarize and discuss the mechanisms of action of immune checkpoint inhibitors, the different types of immune-related adverse events and their possible mechanisms, and describe possible strategies and targets for prevention and therapeutic interventions to mitigate them.
Crosstalk between the gut microbiota and innate lymphoid cells in intestinal mucosal immunity
Authors: Guo Yuling , Liu Yujia , Rui Binqi , Lei Zengjie , Ning Xixi , Liu Yinhui , Li Ming
Published: May 2023

The human gastrointestinal mucosa is colonized by thousands of microorganisms, which participate in a variety of physiological functions. Intestinal dysbiosis is closely associated with the pathogenesis of several human diseases. Innate lymphoid cells (ILCs), which include NK cells, ILC1s, ILC2s, ILC3s and LTi cells, are a type of innate immune cells. They are enriched in the mucosal tissues of the body, and have recently received extensive attention. The gut microbiota and its metabolites play important roles in various intestinal mucosal diseases, such as inflammatory bowel disease (IBD), allergic disease, and cancer. Therefore, studies on ILCs and their interaction with the gut microbiota have great clinical significance owing to their potential for identifying pharmacotherapy targets for multiple related diseases. This review expounds on the progress in research on ILCs differentiation and development, the biological functions of the intestinal microbiota, and its interaction with ILCs in disease conditions in order to provide novel ideas for disease treatment in the future.
On-treatment lung immune prognostic index is predictive for first-line PD-1 inhibitor combined with chemotherapy in patients with non-small cell lung cancer
Authors: Xiong Anning , Xu Jianlin , Wang Shuyuan , Zhong Runbo , Lu Jun , Chu Tianqing , Zhang Wei , Li Ying , Zheng Xiaoxuan , Han Baohui , Nie Wei , Zhong Hua , Zhang Xueyan
Published: May 2023

Background

Inflammation is a factor that promotes tumor progression and immunosuppression. Lung immune prognostic index (LIPI) is a non-invasive and easily calculated indicator of inflammation. This study aimed to investigate whether continuous assessment of LIPI has predictive value for chemoimmunotherapy in non-small cell lung cancer (NSCLC) patients receiving first-line programmed cell death 1 (PD-1) inhibitor plus chemotherapy. In addition, the predictive value of LIPI in patients with the negative or low programmed death-ligand (PD-L1) expression level was also explored.

Methods

Totally, 146 stage IIIB to IV or recurrent NSCLC patients who received first-line PD-1 inhibitor combined with chemotherapy were enrolled in this study. The LIPI scores were calculated at baseline (PRE-LIPI) and after two cycles of the combined administration (POST-LIPI). This study analyzed the relationship between good/intermediate/poor PRE (POST)-LIPI and objective response rate (ORR), as well as progression-free survival (PFS) using logistic and Cox regression models. In addition, the predictive value of LIPI in patients with the negative or low PD-L1 expression level was explored. To further assess the potential predictive value of continuous assessment of LIPI, the association of sum (LIPI) [sum(LIPI) = PRE-LIPI + POST-LIPI] and PFS was analyzed in the 146 patients.

Results

Compared with good POST-LIPI group, significantly lower ORRs were found in intermediate POST-LIPI (P = 0.005) and poor POST-LIPI (P = 0.018) groups. Moreover, intermediate POST-LIPI (P =0.003) and poor POST-LIPI (P < 0.001) were significantly associated with a shorter PFS than good POST-LIPI. Additionally, a higher POST-LIPI score was still significantly associated with poorer treatment efficacy in patients with the negative or low PD-L1 expression level. Moreover, a higher sum (LIPI) score was significantly correlated with a shorter PFS (P = 0.001).

Conclusion

Continuous assessment of LIPI might be an effective method for predicting the efficacy of PD-1 inhibitor plus chemotherapy in NSCLC patients. In addition, in patients with the negative or low PD-L1 expression level, it might also have a potential predictive value for therapeutic efficacy to continuously assess LIPI during the treatment.
The effectiveness of calcium electroporation combined with gene electrotransfer of a plasmid encoding IL-12 is tumor type-dependent
Authors: Lisec Barbara , Markelc Bostjan , Ursic Valentinuzzi Katja , Sersa Gregor , Cemazar Maja
Published: May 2023

Introduction

In calcium electroporation (CaEP), electroporation enables the cellular uptake of supraphysiological concentrations of Ca2+, causing the induction of cell death. The effectiveness of CaEP has already been evaluated in clinical trials; however, confirmatory preclinical studies are still needed to further elucidate its effectiveness and underlying mechanisms. Here, we tested and compared its efficiency on two different tumor models to electrochemotherapy (ECT) and in combination with gene electrotransfer (GET) of a plasmid encoding interleukin-12 (IL-12). We hypothesized that IL-12 potentiates the antitumor effect of local ablative therapies as CaEP and ECT.

Methods

The effect of CaEP was tested in vitro as well as in vivo in murine melanoma B16-F10 and murine mammary carcinoma 4T1 in comparison to ECT with bleomycin. Specifically, the treatment efficacy of CaEP with increasing calcium concentrations alone or in combination with IL-12 GET in different treatment protocols was investigated. We closely examined the tumor microenvironment by immunofluorescence staining of immune cells, as well as blood vessels and proliferating cells.

Results

In vitro, CaEP and ECT with bleomycin reduced cell viability in a dose-dependent manner. We observed no differences in sensitivity between the two cell lines. A dose-dependent response was also observed in vivo; however, the efficacy was better in 4T1 tumors than in B16-F10 tumors. In 4T1 tumors, CaEP with 250 mM Ca resulted in more than 30 days of growth delay, which was comparable to ECT with bleomycin. In contrast, adjuvant peritumoral application of IL-12 GET after CaEP prolonged the survival of B16-F10, but not 4T1-bearing mice. Moreover, CaEP with peritumoral IL-12 GET modified tumor immune cell populations and tumor vasculature.

Conclusions

Mice bearing 4T1 tumors responded better to CaEP in vivo than mice bearing B16-F10 tumors, even though a similar response was observed in vitro. Namely, one of the most important factors might be involvement of the immune system. This was confirmed by the combination of CaEP or ECT with IL-12 GET, which further enhanced antitumor effectiveness. However, the potentiation of CaEP effectiveness was also highly dependent on tumor type; it was more pronounced in poorly immunogenic B16-F10 tumors compared to moderately immunogenic 4T1 tumors.
Cytokine release syndrome and cancer immunotherapies – historical challenges and promising futures
Authors: Shah Deep , Soper Brian , Shopland Lindsay
Published: May 2023

Cancer is the leading cause of death worldwide. Cancer immunotherapy involves reinvigorating the patient’s own immune system to fight against cancer. While novel approaches like Chimeric Antigen Receptor (CAR) T cells, bispecific T cell engagers, and immune checkpoint inhibitors have shown promising efficacy, Cytokine Release Syndrome (CRS) is a serious adverse effect and remains a major concern. CRS is a phenomenon of immune hyperactivation that results in excessive cytokine secretion, and if left unchecked, it may lead to multi-organ failure and death. Here we review the pathophysiology of CRS, its occurrence and management in the context of cancer immunotherapy, and the screening approaches that can be used to assess CRS and de-risk drug discovery earlier in the clinical setting with more predictive pre-clinical data. Furthermore, the review also sheds light on the potential immunotherapeutic approaches that can be used to overcome CRS associated with T cell activation.
Short chain fatty acids prime colorectal cancer cells to activate antitumor immunity
Authors: Mowat Courtney , Dhatt Jasmine , Bhatti Ilsa , Hamie Angela , Baker Kristi
Published: May 2023

Introduction

Colorectal cancer (CRC) is a leading cause of death worldwide and its growth can either be promoted or inhibited by the metabolic activities of intestinal microbiota. Short chain fatty acids (SCFAs) are microbial metabolites with potent immunoregulatory properties yet there is a poor understanding of how they directly regulate immune modulating pathways within the CRC cells.

Methods

We used engineered CRC cell lines, primary organoid cultures, orthotopic in vivo models, and patient CRC samples to investigate how SCFA treatment of CRC cells regulates their ability to activate CD8+ T cells.

Results

CRC cells treated with SCFAs induced much greater activation of CD8+ T cells than untreated CRC cells. CRCs exhibiting microsatellite instability (MSI) due to inactivation of DNA mismatch repair were much more sensitive to SCFAs and induced much greater CD8+ T cell activation than chromosomally instable (CIN) CRCs with intact DNA repair, indicating a subtype-dependent response to SCFAs. This was due to SCFA-induced DNA damage that triggered upregulation of chemokine, MHCI, and antigen processing or presenting genes. This response was further potentiated by a positive feedback loop between the stimulated CRC cells and activated CD8+ T cells in the tumor microenvironment. The initiating mechanism in the CRCs was inhibition of histone deacetylation by the SCFAs that triggered genetic instability and led to an overall upregulation of genes associated with SCFA signaling and chromatin regulation. Similar gene expression patterns were found in human MSI CRC samples and in orthotopically grown MSI CRCs independent of the amount of SCFA producing bacteria in the intestine.

Discussion

MSI CRCs are widely known to be more immunogenic than CIN CRCs and have a much better prognosis. Our findings indicate that a greater sensitivity to microbially produced SCFAs contributes to the successful activation of CD8+ T cells by MSI CRCs, thereby identifying a mechanism that could be therapeutically targeted to improve antitumor immunity in CIN CRCs.
The Aspect Hypothesis and L2 Russian
Authors: Whitehead Martelle Wendy , Shirai Yasuhiro
Published: May 2023

Introduction

Numerous studies have been conducted regarding the second language acquisition of tense-aspect morphology. A prevailing principle in this area is the Aspect Hypothesis, which predicts that learners are influenced by lexical aspect when applying tense- aspect markers (specifically, that learners will associate perfective/past markers with telic verbs and imperfective/past markers with atelic verbs). The Aspect Hypothesis has been widely tested in the acquisition of English, several Romance languages, Japanese, and Chinese. However, few studies have explored the second language acquisition of aspect in Slavic languages, which tend to have morphologically rich and complex tense-aspect systems. Additionally, few studies address the potential impact of task modality (for example, written vs. oral tasks) on the production of aspect.

Methods

The present study addresses these gaps by investigating how second language learners of Russian at varying proficiency levels use aspectual markers in the past tense when producing oral and written narratives. Data from written narratives (N= 42) and oral narratives (N= 42) were analyzed for lexical aspect and tense-aspect marking.

Results

The results indicate that the Aspect Hypothesis is supported to varying degrees depending on the task: the activity involving lower planning levels (oral narratives) was more supportive of the Aspect Hypothesis, compared to the written narrative task, which involves a higher level of planning. However, the results also show that the aspectual production of beginning-level Russian learners is not consistent with certain predictions of the Aspect Hypothesis.

Discussion

The study concludes by discussing the role of instruction and the L1 as possible explanations for this inconsistency.
Off-label use of rituximab in patients with systemic lupus erythematosus with extrarenal disease activity: a retrospective study and literature review
Authors: Sans-Pola Carla , Danés Immaculada , Bosch Josep Àngel , Marrero-Álvarez Patricia , Cortés Josefina , Agustí Antònia
Published: May 2023

Introduction

Off-label rituximab is commonly used for patients with systemic lupus erythematosus (SLE) with extrarenal disease activity.

Methods

The outcomes and tolerability of rituximab in adult patients with non-renal SLE treated at our hospital from 2013 to 2020 were described. Patients were followed-up until December 2021. Data were retrieved from electronic medical records. Response was classified into complete, partial or no response according to the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2 K)-based definitions.

Results

A total of 44 cycles were administered to 33 patients. Median age was 45 years and 97% were female. Median follow-up was 5.9 years (IQR 3.7–7.2). The most frequent symptoms that motivated rituximab use were thrombocytopenia (30.3%), arthritis (30.3%), neurological manifestations (24.2%) and cutaneous lupus (15.2%). After most treatment cycles a partial remission was achieved. The median SLEDAI-2 K score declined from 9 (IQR 5–13) to 1.5 (IQR 0–4) (p < 0.00001). The median number of flares significantly declined after receiving rituximab. Platelet counts significantly improved in patients with thrombocytopenia and patients with skin disorders or neurological manifestations also had a partial or complete response. Only 50% of patients with a predominant joint involvement had either a complete or a partial response. The median time to relapse after the first cycle was 1.6 years (95% CI, 0.6–3.1). Anti-dsDNA levels decreased significantly after rituximab from a median of 64.3 (IQR 12–373.9) to 32.7 (IQR 10–173), p = 0.00338. The most frequent adverse events were infusion-related reactions (18.2%) and infections (57.6%). All patients needed further treatment to maintain remission or to treat new flares.

Conclusion

A partial or complete response was documented after most rituximab cycles in patients with non-renal SLE. Patients with thrombocytopenia, neurolupus, and cutaneous lupus had better response than those with a predominant joint involvement.
Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study
Authors: Riggio Oliviero , Celsa Ciro , Calvaruso Vincenza , Merli Manuela , Caraceni Paolo , Montagnese Sara , Mora Vincenzina , Milana Martina , Saracco Giorgio Maria , Raimondo Giovanni , Benedetti Antonio , Burra Patrizia , Sacco Rodolfo , Persico Marcello , Schepis Filippo , Villa Erica , Colecchia Antonio , Fagiuoli Stefano , Pirisi Mario , Barone Michele , Azzaroli Francesco , Soardo Giorgio , Russello Maurizio , Morisco Filomena , Labanca Sara , Fracanzani Anna Ludovica , Pietrangelo Antonello , Di Maria Gabriele , Nardelli Silvia , Ridola Lorenzo , Gasbarrini Antonio , Cammà Calogero
Published: May 2023

Introduction

Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE.

Methods

We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT).

Results

During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission.

Conclusion

In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.
Case report: Successful immunomodulators combined with electromagnetic field therapy in a patient with methazolamide-induced Steven Johnson syndrome/toxic epidermal necrolysis overlap
Authors: Zhang Naiju , Su Tianjiao , Yan Jingwen , Zhang Mei , Zhao Shousong , Liu Chuanmiao , Chen Tianping
Published: May 2023

Methazolamide is used to treat patients with glaucoma. However, as a sulfonamide derivative, methazolamide shares the same adverse reaction profile as other sulfa-based medications. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare delayed-type hypersensitivity cutaneous reactions with high morbidity and mortality. Here, we report a severe SJS/TEN overlap syndrome in an 85-year-old Chinese male patient who received methazolamide 25 mg twice daily for his left eye glaucoma. The causal relationship between SJS/TEN and methazolamide was categorized as “highly likely” on the algorithm for assessing drug causality for epidermal necrolysis. In addition to the treatments with methylprednisolone and immunoglobulin, we used a special electromagnetic spectrum therapeutic apparatus to provide skin wound care. The patient had a thoroughly satisfying recovery. This is the first case report to use electromagnetic field therapy in a patient with SJS/TEN. We share our experience here and suggest that electromagnetic field therapy can provide advanced skin wound care and facilitate the recovery of SJS/TEN.
A novel lncRNA DFRV plays a dual function in influenza A virus infection
Authors: Wang Keyu , Gong Meiliang , Zhao Sumin , Lai Chengcai , Zhao Lingna , Cheng Sijie , Xia Min , Li Yuru , Wang Kun , Sun Heqiang , Zhu Pingjun , Zhou Yu , Ao Qiangguo , Deng Xinli
Published: May 2023

Long noncoding RNAs (lncRNAs) have been associated with a variety of biological activities, including immune responses. However, the function of lncRNAs in antiviral innate immune responses are not fully understood. Here, we identified a novel lncRNA, termed dual function regulating influenza virus (DFRV), elevating in a dose- and time-dependent manner during influenza A virus (IAV) infection, which was dependent on the NFκB signaling pathway. Meanwhile, DFRV was spliced into two transcripts post IAV infection, in which DFRV long suppress the viral replication while DFRV short plays the opposite role. Moreover, DFRV regulates IL-1β and TNF-α via activating several pro-inflammatory signaling cascades, including NFκB, STAT3, PI3K, AKT, ERK1/2 and p38. Besides, DFRV short can inhibit DFRV long expression in a dose-dependent manner. Collectively, our studies reveal that DFRV may act as a potential dual-regulator to preserve innate immune homeostasis in IAV infection.