bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-invasive respiratory support in SARS-CoV-2 related acute respiratory distress syndrome: when is it most appropriate to start treatment?
Authors: Nevola Riccardo , Russo Antonio , Scuotto Samuel , Imbriani Simona , Aprea Concetta , Abitabile Marianna , Beccia Domenico , Brin Chiara , Carusone Caterina , Cinone Francesca , Cirigliano Giovanna , Colantuoni Sara , Cozzolino Domenico , Cuomo Giovanna , Del Core Micol , Gjeloshi Klodian , Marrone Aldo , Medicamento Giulia , Meo Luciana Agnese , Nappo Francesco , Padula Andrea , Pafundi Pia Clara , Ranieri Roberta , Ricozzi Carmen , Rinaldi Luca , Romano Ciro Pasquale , Ruocco Rachele , Ruosi Carolina , Salvati Annabella , Sasso Ferdinando Carlo , Sellitto Ausilia , Sommese Pino , Villani Angela , Coppola Nicola , Adinolfi Luigi Elio
Published: December 2022

Background

Acute respiratory distress syndrome (ARDS) is one of the most severe complications of SARS-CoV-2 infection. Non-Invasive Respiratory Support (NRS) as Continuous Positive Airway Pressure (CPAP) and/or Non-Invasive Ventilation (NIV) has been proven as effective in the management of SARS-CoV-2-related ARDS. However, the most appropriate timing for start NRS is unknown.

Methods

We conducted a prospective pilot study including all consecutive patients who developed moderate SARS-CoV-2-related ARDS during hospitalization. Patients were randomly divided into two intervention groups according to ARDS severity (assessed by PaO2/FiO2-P/F) at NRS beginning: group A started CPAP/NIV when P/F was ≤ 200 and group B started CPAP/NIV when P/F was ≤ 150. Eligible patients who did not give their consent to CPAP/NIV until the severe stage of ARDS and started non-invasive treatment when P/F ≤ 100 (group C) was added. The considered outcomes were in-hospital mortality, oro-tracheal intubation (OTI) and days of hospitalization.

Results

Among 146 eligible patients, 29 underwent CPAP/NIV when P/F was ≤ 200 (Group A), 68 when P/F was ≤ 150 (Group B) and 31 patients agreed to non-invasive treatment only when P/F was ≤ 100 (Group C). Starting NRS at P/F level between 151 and 200 did not results in significant differences in the outcomes as compared to treatment starting with P/F ranging 101–150. Conversely, patients undergone CPAP/NIV in a moderate stage (P/F 101–200) had a significantly lower in-hospital mortality rate (13.4 vs. 29.0%, p = 0.044) and hospitalization length (14 vs. 15 days, p = 0.038) than those in the severe stage (P/F ≤ 100). Age and need for continuous ventilation were independent predictors of CPAP/NIV failure.

Conclusions

Starting CPAP/NIV in patients with SARS-CoV-2-related ARDS in moderate stage (100 > P/F ≤ 200) is associated to a reduction of both in-hospital mortality and hospitalization length compared to the severe stage (P/F ≤ 100). Starting CPAP/NIV with a P/F > 150 does not appear to be of clinical utility.
Association of cumulative monocyte to high-density lipoprotein ratio with the risk of type 2 diabetes: a prospective cohort study
Authors: Wu Dan , Lan Yulong , Xu Yuancheng , Xu Songna , Huang Yuejun , Balmer Lois , Maharra Gehendra , Xu Wencan , Wang Wei , Wu Shouling
Published: December 2022

Background

Recent studies have established that monocyte-derived inflammation plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). It is unclear whether chronic metabolic inflammation, reflected by the cumulative monocyte to high-density lipoprotein ratio (CumMHR), predisposes the general population to T2DM.

Methods

This study included 40,813 participants without diabetes from a real-life, community-based cohort (the Kailuan Study) attending a 2-year cycle of health survey since 2006. Cumulative exposure was obtained from 2006/2007 to 2010/2011. Follow-up started at 2010/2011 and through 2020. Multivariable-adjusted Cox regression models were used to calculate the CumMHR-associated risk of incident T2DM.

Results

Over a median follow-up period of 7.98 (IQR: 5.74–8.87) years, 4,848 T2DM cases occurred. The CumMHR was positively associated with the risk of incident T2DM after adjusting for age, sex, smoking, drinking habits, physical activities, BMI, triglyceride-glycemia index, log(leukocyte count), log(hsCRP), blood pressure, renal function, and medication uses with adjusted HRs of 1.0 (ref.), 1.18 (1.05‒1.25), 1.17 (1.07‒1.27), 1.38 (1.26‒1.50), respectively, in CumMHR Quartiles 1, 2, 3 and 4. When follow-up ended at 2014/2015, the short-term (4‒year) adjusted T2DM risks in CumMHR Quartiles 2, 3, and 4 were 1.14 (1.01‒1.29), 1.17 (1.04‒1.32), 1.40 (1.25‒1.58), respectively, relative to Quartile 1. A significant interaction between CumMHR and cumulative high-sensitivity C-reactive protein (CumCRP) was observed (P-interaction: 0.0109). The diabetic risk in the highest quartile of CumMHR was higher (1.53 [1.28‒1.84]) when CumCRP < 1 mg/L, attenuated with increasing CumCRP levels (1 ~ 10 mg/L) and disappeared in CumCRP ≥ 10 mg/L. Hypertension, overweight, or smoking habits further modified the CumMHR-associated diabetic risk.

Conclusions

Cumulative MHR may be a promising supplement to hsCRP for more comprehensively assessing the influence of metabolic inflammation on T2DM susceptibility. For primary prevention, targeting high CumMHR, especially in cases at low risk of diabetes defined by traditional risk factors, may further help reduce the diabetic risk.
The clinical value of metabolic syndrome and its components with respect to sudden cardiac death using different definitions: Two decades of follow-up from the Tehran Lipid and Glucose Study
Authors: Masrouri Soroush , Moazzeni Seyyed Saeed , Cheraghloo Neda , Azizi Fereidoun , Hadaegh Farzad
Published: December 2022

Background

To evaluate the impact of different definitions of metabolic syndrome (MetS) and their components on the risk of sudden cardiac death (SCD) among the Iranian population according to the World Health Organization (WHO), International Diabetes Federation (IDF), Adult Treatment Panel III (ATP III), and Joint Interim Statement (JIS) criteria.

Methods

The study population included a total of 5,079 participants (2,785 women) aged ≥ 40 years, free of cardiovascular disease (CVD) at baseline. Participants were followed for incident SCD annually up to 20 March 2018. Multivariable Cox proportional hazards regression models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MetS and its components for incident SCD.

Results

The prevalence of MetS ranged from 27.16% to 50.81%, depending on the criteria used. Over a median of 17.9 years of follow-up, 182 SCD events occurred. The WHO, IDF, and JIS definitions were strong predictors of SCD with multivariable-adjusted HRs (95% CI) of 1.68 (1.20–2.35), 1.51 (1.12–2.03), and 1.47 (1.08–1.98), respectively; these associations significantly attenuated after further adjustment for MetS components. MetS by the ATP III definition was not associated with the risk of SCD after controlling for antihypertensive, glucose-lowering, and lipid-lowering medication use. Among the components of MetS, high blood pressure (WHO definition), high waist circumference (using the national cutoff of ≥ 95 cm), and high glucose component by the JIS/IDF definitions remained independent predictors of SCD with HRs of 1.79 (1.29–2.48), 1.46 (1.07–2.00), and 1.52 (1.12–2.05), respectively.

Conclusions

The constellation of MetS, except for when defined with ATP III definition, is a marker for identifying individuals at higher risk for SCD; however, not independent of its components. Among MetS components, abdominal obesity using the population-specific cutoff point, high glucose component (JIS/IDF definitions), and high blood pressure (WHO definition) were independent predictors of SCD.
Changes in Fasting plasma glucose status and risk of mortality events in individuals without diabetes over two decades of Follow-up: a pooled cohort analysis
Authors: Kohansal Karim , Masrouri Soroush , Khalili Davood , Ramezankhani Azra , Azizi Fereidoun , Blaha Michael J , Hadaegh Farzad
Published: December 2022

Background

We aimed to assess the gender-specific impact of 3-year changes in fasting plasma glucose (FPG) status on the risk of all-cause, cardiovascular (CV), and cancer mortality in individuals without type 2 diabetes (T2DM) during an 18-year follow-up.

Methods

The study population included 14,378 participants aged 30–60 years (8272 women) from three population-based cohort studies, including Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Tehran Lipid and Glucose Study. Subjects were classified into six categories based on the approximately three-year changes in FPG status: (1) normal FPG (NFG) to NFG (reference category); (2) NFG to impaired fasting glucose (IFG) (i.e., 126 > FPG ≥ 100 mg/dl); (3) NFG to T2DM; (4) IFG to NFG; (5) IFG to IFG; (6) IFG to T2DM. Multivariable stratified Cox regression, adjusting for age, body mass index (BMI), BMI-Change, smoking status, hypertension, and hypercholesterolemia was used to estimate hazard ratios (HRs (95% CI)) for all-cause and cause-specific mortality events. Women-to-men ratios of HRs (RHRs) for each category were also estimated.

Results

During follow-up, 2,362 all-cause mortality events were recorded. Among women, all categories of FPG change, excluding IFG-NFG (HR, 95%CI 1.24 (0.98–1.57), p = 0.07), were associated with a higher risk of all-cause mortality compared to the NFG-NFG category. Moreover, women in IFG-T2DM group were at increased risk for CV mortality (2.21 (1.42–3.44)). We also found that women in NFG-IFG (1.52 (1.20–1.91)), NFG-T2DM (2.90 (1.52–5.51)), and IFG-IFG (1.30 (1.02–1.66)) categories had a higher risk for cancer mortality. However, among men, a higher risk of all-cause mortality was found for only two groups of NFG-T2DM (1.78 (1.15–2.74)) and IFG-T2DM (1.34 (1.04–1.72)). Women with IFG-IFG had a 24% higher risk for all-cause mortality events than their men counterparts (RHR; 1.24 (1.01–1.54)). After further adjustment for physical activity, results were in line with the main findings, excluding T2DM up to six years after the measurement period and early mortality events.

Conclusion

In women, the IFG status, whether as incident, persistent, or converted to T2DM, had a higher risk for mortality events; however, among men, only conversion to T2DM conferred an excess risk of all-cause mortality.
Persistence of Plasmodium falciparum HRP-2 antigenaemia after artemisinin combination therapy is not associated with gametocytes
Authors: Oulton Tate , Mahamar Almahamoudou , Sanogo Koualy , Diallo Makonon , Youssouf Ahamadou , Niambele Sidi M. , Samaké Siaka , Keita Sekouba , Sinaba Youssouf , Sacko Adama , Traore Sekou F. , Lanke Kjerstin , Collins Katharine A. , Bradley John , Drakeley Chris , Stone Will J. R. , Dicko Alassane
Published: December 2022

Background

In some settings, sensitive field diagnostic tools may be needed to achieve elimination of falciparum malaria. To this end, rapid diagnostic tests (RDTs) based on the detection of the Plasmodium falciparum protein HRP-2 are being developed with increasingly lower limits of detection. However, it is currently unclear how parasite stages that are unaffected by standard drug treatments may contribute to HRP-2 detectability and potentially confound RDT results even after clearance of blood stage infection. This study assessed the detectability of HRP-2 in periods of post-treatment residual gametocytaemia.

Methods

A cohort of 100 P.falciparum infected, gametocyte positive individuals were treated with or without the gametocytocidal drug primaquine (PQ), alongside standard artemisinin-based combination therapy (ACT), in the context of a randomised clinical trial in Ouelessebougou, Mali. A quantitative ELISA was used to measure levels of HRP-2, and compared time to test negativity using a standard and ultra-sensitive RDT (uRDT) between residual gametocyte positive and negative groups.

Results

Time to test negativity was longest by uRDT, followed by ELISA and then standard RDT. No significant difference in time to negativity was found between the treatment groups with and without residual gametocytes: uRDT (HR 0.79 [95% CI 0.52–1.21], p = 0.28), RDT (HR 0.77 [95% CI 0.51–1.15], p = 0.20) or ELISA (HR 0.88 [95% CI 0.59–1.32], p = 0.53). Similarly, no difference was observed when adjusting for baseline asexual parasite density. Quantified levels of HRP-2 over time were similar between groups, with differences attributable to asexual parasite densities. Furthermore, no difference in levels of HRP-2 was found between individuals who were or were not infectious to mosquitoes (OR 1.19 [95% CI 0.98–1.46], p = 0.077).

Conclusions

Surviving sexual stage parasites after standard ACT treatment do not contribute to the persistence of HRP-2 antigenaemia, and appear to have little impact on RDT results.
‘HIV ended up in second place’ − prioritizing social integration in the shadow of social exclusion: an interview study with migrants living with HIV in Sweden
Authors: Nkulu-Kalengayi Faustine Kyungu , Ouma Anne Adhiambo , Hurtig Anna-Karin
Published: December 2022

Background

Migrants are overrepresented among people living with HIV in Sweden as they often face conditions that increased their risk and vulnerability for HIV/STI infections prior, during or after migration. Yet, there is limited research on their experiences and perceptions of living with HIV in the Swedish context. This study aims to explore migrants’ experiences of living with HIV in Sweden.

Methods

This is a qualitative study based on in-depth interviews with 13 migrants from 11 countries living with HIV in Sweden. Interviews were analysed with thematic analysis using an intersectional perspective to explore the interactions of multiple social identities such as ethnicity, socio-economic status, gender, age, and sexual orientation that shape an individual’s or group’s experiences.

Results

The analysis resulted in a main theme: ‘Prioritizing social integration-HIV ends up in second place’, which is based on four subthemes: ‘Better opportunities in the new country than what the home country could offer’, ‘Better conditions for LGBTQI people than in the home country’, ‘Navigating a new system: linguistic and bureaucratic challenges’ and ‘Feeling like a second-class resident: racism, xenophobia and multiple discrimination’. The results suggest that migrants living with HIV in Sweden experience social integration as a greater challenge than HIV infection. Although the new country offers opportunities for better living conditions, many participants described being challenged in their daily life by linguistic and structural barriers in their encounters with public services. They are facing multiple discrimination simultaneously as migrants due to their multiple and intersecting identities (e.g. being non-white, foreigners/foreign-born and non-Swedish speakers), which is compounded by HIV status and thus limit their opportunities in the new country and too often result in an existence of exclusion.

Conclusion

The study shows that most of the challenges that migrants living with HIV face are related to their status as migrants rather than HIV status, which is often not known by the public or authorities. These challenges are similar, but still differ depending on social position, previous experiences, time since arrival and since diagnosis. This emphasizes the importance of both intersectional, intersectoral and multisectoral approaches to address reported issues.
Help-seeking and challenges faced by transwomen following exposure to gender-based violence; a qualitative study in the Greater Kampala Metropolitan Area, Uganda
Authors: Ssekamatte Tonny , Nalugya Aisha , Isunju John Bosco , Naume Muyanga , Oputan Patience , Kiguli Juliet , Wafula Solomon Tsebeni , Kibira Simon Peter S. , Ssekamatte David , Orza Luisa , Mugambe Richard K. , Wanyenze Rhoda K.
Published: December 2022

Background

The high prevalence of gender-based violence (GBV) among transwomen is a human rights and public health challenge. Nonetheless, there is limited evidence of sources of GBV support services and the challenges faced by transwomen while help-seeking, especially in transphobic settings like Uganda. This study explored the sources of GBV support services and the challenges faced by transwomen in the Greater Kampala Metropolitan Area during help-seeking.

Methods

A qualitative study design involving 60 transwomen and 10 key informants was conducted. Respondents were recruited using snowball sampling. An in-depth interview (IDI), and a focus group discussion guide were used to collect data from 20 IDI respondents and six focus group discussants. Each focus group discussion averaged six participants. A key informant interview guide was used for key informant interviews. Data were transcribed verbatim and analysed following a thematic framework, informed by the socio-ecological model. Data were organised into themes and subthemes using NVivo 12.0.

Results

The sources of support following exposure to GBV included key population-friendly healthcare facilities and civil society organisations (CSOs), and friends and family. Friends and family provided emotional support while key population-friendly healthcare facilities offered medical services including HIV post-exposure prophylaxis. Key population CSOs provided shelter, nutritional support, and legal advice to GBV victims. Lack of recognition of transgender identity; long distances to healthcare facilities; discrimination by healthcare providers and CSO staff, inappropriate questioning of the trans-gender identity by police officers and healthcare providers, and the lack of trans-competent healthcare providers and legal personnel hindered help-seeking following exposure to GBV.

Conclusion

The immediate sources of GBV support services included key population-friendly healthcare facilities and CSOs, police, and friends and family. However, a significant number of transwomen did not report incidences of GBV. Transwomen were discriminated against at some key population healthcare facilities and CSOs, and police, which hindered help-seeking following exposure to GBV. This study highlights the need to tackle internalized stigma and discrimination against transwomen at the existing sources of GBV support. There is also a need to train law enforcers and legal personnel on the right to access healthcare among transwomen in Uganda.
Association between combined exposure to plasma heavy metals and dyslipidemia in a chinese population
Authors: Luo Tingyu , Chen Shiyi , Cai Jiansheng , Liu Qiumei , Gou Ruoyu , Mo Xiaoting , Tang Xu , He Kailian , Xiao Song , Wei Yanfei , Lin Yinxia , Huang Shenxiang , Li Tingjun , Chen Ziqi , Li Ruiying , Li You , Zhang Zhiyong
Published: December 2022

Background

Exposure to heavy metals in the environment is widespread, while the relationship between combined exposure to heavy metals and dyslipidemia is unclear.

Methods

A cross-sectional study was performed, and 3544 participants aged 30 years or older were included in the analyses. Heavy metal concentrations in plasma were based on inductively coupled plasma‒mass spectrometry. The relationship between heavy metals and dyslipidemia was estimated by logistic regression. BKMR was used to evaluate metal mixtures and their potential interactions.

Results

In logistic regression analysis, participants in the fourth quartile of Fe and Zn (Fe > 1352.38 µg/L; Zn > 4401.42 µg/L) had a relatively higher risk of dyslipidemia (Fe, OR = 1.13, 95% CI: 0.92,1.38; Zn, OR = 1.30, 95% CI: 1.03,1.64). After sex stratification, females in the third quartile of plasma Zn (1062.05-4401.42 µg/L) had a higher relative risk of dyslipidemia (OR = 1.75, 95% CI: 1.28, 2.38). In BKMR analysis, metal mixtures were negatively associated with dyslipidemia in females when all metal concentrations were above the 50th percentile. In the total population (estimated from 0.030 to 0.031), As was positively associated with dyslipidemia when other metals were controlled at the 25th, 50th, or 75th percentile, respectively, and As was below the 75th percentile. In females (estimated from − 0.037 to -0.031), Zn was negatively associated with dyslipidemia when it was above the 50th percentile.

Conclusion

This study indicated that As was positively associated with dyslipidemia and that Zn may be negatively associated with dyslipidemia in females. Combined metal exposure was negatively associated with dyslipidemia in females. Females with low plasma Zn levels are more likely to develop dyslipidemia and should receive more clinical attention in this population.
Reversing the immunosuppressive microenvironment with reduced redox level by microwave-chemo-immunostimulant Ce–Mn MOF for improved immunotherapy
Authors: Zeng Zhiheng , Fu Changhui , Sun Xiaohan , Niu Meng , Ren Xiangling , Tan Longfei , Wu Qiong , Huang Zhongbing , Meng Xianwei
Published: December 2022

Backgrounds

Reversing the immunosuppressive tumor microenvironment (TME) in the tumor is widely deemed to be an effective strategy to improve immune therapy. In particular, the redox balance in TME needs to be well controlled due to its critical role in mediating the functions of various cells, including cancer cells and immune-suppressive cells.

Results

Here, we propose an efficient strategy to reshape the redox homeostasis to reverse immunosuppressive TME. Specifically, we developed a microwave-chemo-immunostimulant CMMCP to promote the infiltration of the tumor-T cells by simultaneously reducing the reactive oxygen species (ROS) and glutathione (GSH) and improving the oxygen (O2) levels in TME. The CMMCP was designed by loading chemotherapy drugs cisplatin into the bimetallic Ce–Mn MOF nanoparticles coated with polydopamine. The Ce–Mn MOF nanoparticles can effectively improve the catalytic decomposition of ROS into O2 under microwave irradiation, resulting in overcoming hypoxia and limited ROS generation. Besides, the activity of intracellular GSH in TME was reduced by the redox reaction with Ce–Mn MOF nanoparticles. The reprogrammed TME not only boosts the immunogenic cell death (ICD) induced by cisplatin and microwave hyperthermia but also gives rise to the polarization of pro-tumor M2-type macrophages to the anti-tumor M1-type ones.

Conclusion

Our in vivo experimental results demonstrate that the microwave-chemo-immunostimulant CMMCP significantly enhances the T cell infiltration and thus improves the antitumor effect. This study presents an easy, safe, and effective strategy for a whole-body antitumor effect after local treatment.
A mitochondria-anchored supramolecular photosensitizer as a pyroptosis inducer for potent photodynamic therapy and enhanced antitumor immunity
Authors: Wang Hong , Jing Guoxin , Niu Jintong , Yang Li , Li Youyuan , Gao Yi , Wang Huichao , Xu Xiaorong , Qian Yechang , Wang Shilong
Published: December 2022

Background

The discovery of a potent photosensitizer with desirable immunogenic cell death (ICD) ability can prominently enhance antitumor immunity in photodynamic therapy (PDT). However, majority of commercially-available photosensitizers suffer from serious aggregation and fail to elicit sufficient ICD. Pyroptosis as a newly identified pattern for potent ICD generation is rarely disclosed in reported photosensitizers. In addition, the photosensitizer with excellent mitochondria-anchored ability evokes prominent mitochondria oxidative stress, and consequently induces ICD.

Results

Herein, a novel supramolecular photosensitizer LDH@ZnPc is reported, without complicated preparation, but reveals desirable pyroptosis-triggered ability with mitochondria anchoring feature. LDH@ZnPc is obtained through isolation of ZnPc using positive charged layered double hydroxides (LDH), and excellent mitochondria-anchored ability is achieved. More importantly, LDH@ZnPc-mediated PDT can effectively initiate gasdermin D (GSDMD)-dependent pyroptosis of tumor cells. In vitro and in vivo results verify robust ICD ability and potent tumor inhibition efficacy, and antitumor immunity towards distant tumor inhibition.

Conclusions

This study reveals that LDH@ZnPc can act as an excellent pyroptosis inducer with simultaneous mitochondria anchoring ability for enhancing photodynamic therapy and boosting antitumor immunity.

Graphical Abstract
Nanotopographical cues for regulation of macrophages and osteoclasts: emerging opportunities for osseointegration
Authors: He Yide , Gao Yuanxue , Ma Qianli , Zhang Xige , Zhang Yumei , Song Wen
Published: December 2022

Nanotopographical cues of bone implant surface has direct influences on various cell types during the establishment of osseointegration, a prerequisite of implant bear-loading. Given the important roles of monocyte/macrophage lineage cells in bone regeneration and remodeling, the regulation of nanotopographies on macrophages and osteoclasts has arisen considerable attentions recently. However, compared to osteoblastic cells, how nanotopographies regulate macrophages and osteoclasts has not been properly summarized. In this review, the roles and interactions of macrophages, osteoclasts and osteoblasts at different stages of bone healing is firstly presented. Then, the diversity and preparation methods of nanotopographies are summarized. Special attentions are paid to the regulation characterizations of nanotopographies on macrophages polarization and osteoclast differentiation, as well as the focal adhesion-cytoskeleton mediated mechanism. Finally, an outlook is indicated of coordinating nanotopographies, macrophages and osteoclasts to achieve better osseointegration. These comprehensive discussions may not only help to guide the optimization of bone implant surface nanostructures, but also provide an enlightenment to the osteoimmune response to external implant.
Splenic-targeting biomimetic nanovaccine for elevating protective immunity against virus infection
Authors: Huo Jian , Zhang Angke , Wang Shuqi , Cheng Hanghang , Fan Daopeng , Huang Ran , Wang Yanan , Wan Bo , Zhang Gaiping , He Hua
Published: December 2022

Background

The prevalence of viral infectious diseases has become a serious threat to public safety, economic and social development. Vaccines have been served as the most effective platform to prevent virus transmission via the activation of host immune responses, while the low immunogenicity or safety, the high cost of production, storage, transport limit their effective clinical application. Therefore, there is a need to develop a promising strategy to improve the immunogenicity and safety of vaccines.

Methods

We developed a splenic-targeting biomimetic nanovaccine (NV) that can boost protective humoral and cellular immunity against african swine fever virus (ASFV) infection. The universal PLGA nanoparticles (CMR-PLGA/p54 NPs) coated with mannose and CpG (TLR9 agonist) co-modified red blood cell (RBC) membrane were prepared, which comprised a viral antigen (p54) and can be served as a versatile nanovaccine for elevating protective immunity.

Results

CMR-PLGA/p54 NVs could be effectively uptaken by BMDC and promoted BMDC maturation in vitro. After subcutaneous immunization, antigen could be effectively delivered to the splenic dendritic cells (DCs) due to the splenic homing ability of RBC and DC targeting capacity of mannose, which promoted antigen presentation and DCs maturation, and further elicited higher levels of cytokines secretion and specific IgG titers, CD4+ and CD8+ T cells activation and B maturation. Moreover, NVs demonstrated notable safety during the immunization period.

Conclusions

This study demonstrates the high potential of CMR-PLGA NPs as vaccine delivery carriers to promote humoral and cellular immune responses, and it provides a promising strategy to develop safe and effective vaccines against viral infectious diseases.
Proteomic analysis of small extracellular vesicles from the plasma of patients with hepatocellular carcinoma
Authors: Dong Wei , Xia Zeyu , Chai Zehua , Qiu Zhidong , Wang Xuehong , Yang Zebin , Wang Junnan , Zhang Tingrui , Zhang Qinqin , Jin Junfei
Published: December 2022

Purpose

Liver cancer is one of the most common tumors with the seventh-highest incidence and the third-highest mortality. Many studies have shown that small extracellular vesicles (sEVs) play an important role in liver cancer. Here, we report comprehensive signatures for sEV proteins from plasma obtained from patients with hepatocellular carcinoma (HCC), which might be valuable for the evaluation and diagnosis of HCC.

Methods

We extracted sEVs from the plasma of controls and patients with HCC. Differentially expressed proteins in the sEVs were analyzed using label-free quantification and bioinformatic analyses. Western blotting (WB) was used to validate the abovementioned sEV proteins.

Results

Proteomic analysis was performed for plasma sEVs from 21 patients with HCC and 15 controls. Among the 335 identified proteins in our study, 27 were significantly dysregulated, including 13 upregulated proteins that were involved predominantly in the complement cascade (complement C1Q subcomponent subunit B (C1QB), complement C1Q subcomponent subunit C (C1QC), C4B-binding protein alpha chain (C4BPA), and C4B-binding protein beta chain (C4BPB)) and the coagulation cascade (F13B, fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG)). We verified increased levels of the C1QB, C1QC, C4BPA, and C4BPB proteins in the plasma sEVs from patients with HCC in both the discovery cohort and validation cohort.

Conclusions

The complement cascade in sEVs was significantly involved in HCC progression. C1QB, C1QC, C4BPA, and C4BPB were highly abundant in the plasma sEVs from patients with HCC and might represent molecular signatures.
Clinical application of noninvasive chromosomal screening for elective single-blastocyst transfer in frozen-thawed cycles
Authors: Chen Rui , Tang Ni , Du Hongzi , Yao Yaxin , Zou Yangyun , Wang Jing , Zhao Dunmei , Zhou Xueliang , Luo Yang , Li Lei , Mao Yuling
Published: December 2022

Background

The objective of this study was to explore the clinical application of noninvasive chromosomal screening (NICS) for elective single-blastocyst transfer (eSBT) in frozen-thawed cycles.

Methods

This study retrospectively analysed the data of 212 frozen-thawed single-blastocyst transfers performed in our centre from January 2019 to July 2019. The frozen embryos were selected based on morphological grades and placed in preincubation for 6 h after warming. Then spent microdroplet culture media of frozen-thawed blastocysts were harvested and subjected to NICS. The clinical outcomes were evaluated and further stratified analysis were performed, especially different fertilization approaches.

Results

The clinical pregnancy, ongoing pregnancy, and live birth rates in the euploidy group were significantly higher than those in the aneuploidy group (56.2% versus 29.4%) but were nonsignificantly different from those in the chaotic abnormal/NA embryos group (56.2% versus 60.4%). Compared with day6 (D6) blastocysts, D5 blastocysts had a nonsignificantly different euploidy rate (40.4% versus 48.1%, P = 0.320) but significantly increased clinical pregnancy (57.7% versus 22.2%, P < 0.001), ongoing pregnancy (48.1% versus 14.8%, P < 0.001), and live birth rates (48.1% versus 13.0%, P < 0.001). The percentage of chaotic abnormal/NA embryos group was significantly higher among D5 embryos than among D6 embryos (30.1% versus 11.1%, P = 0.006). The percentage of aneuploid embryos was higher among the embryos with lower morphological quality(21.5% among ‘good’ embryos versus 34.6% among ‘fair’ embryos versus 46.0% among ‘poor’ embryos, P = 0.013); correspondingly, the overall clinical pregnancy, ongoing pregnancy and live birth rate rates showed similar declines.

Conclusions

NICS combined with morphological assessment is an effective tool to guide frozen-thawed SBT. The optimal embryo for SBT is a ‘euploid embryo with good morphology’, followed sequentially by a ‘chaotic abnormal/NA embryo with good morphology’, ‘euploid embryo with fair morphology’, and ‘chaotic abnormal/NA embryo with fair morphology’.
Survival outcomes following treatment delays among patients with early-stage female cancers: a nationwide study
Authors: Min Yu , Liu Zheran , Huang Rendong , Li Ruidan , Jin Jing , Wei Zhigong , He Ling , Pei Yiyan , Li Ning , Su Yongllin , Hu Xiaolin , Peng Xingchen
Published: December 2022

Background

The coronavirus disease 2019 (COVID-19) severely hindered the timely receipt of health care for patients with cancer, especially female patients. Depression and anxiety were more pronounced in female patients than their male counterparts with cancer during treatment wait-time intervals. Herein, investigating the impact of treatment delays on the survival outcomes of female patients with early-stage cancers can enhance the rational and precise clinical decisions of physicians.

Methods

We analyzed five types of cancers in women from the Surveillance, Epidemiology, and End Results (SEER) program between Jan 2010 and Dec 2015. Univariate and multivariate Cox regression analyses were used to determine the impacts of treatment delays on the overall survival (OS) and cancer-specific survival (CSS) of the patients.

Results

A total of 241,661 females with early-stage cancer were analyzed (12,617 cases of non-small cell lung cancer (NSCLC), 166,051 cases of infiltrating breast cancer, 31,096 cases of differentiated thyroid cancer, 23,550 cases of colorectal cancer, and 8347 cases of cervical cancer). Worse OS rates were observed in patients with treatment delays ≥ 3 months in stage I NSCLC (adjustedHazard ratio (HR) = 1.11, 95% Confidence Interval (CI): 1.01–1.23, p = 0.044) and stage I infiltrating breast cancer (adjustedHR = 1.23, 95% CI 1.11–1.37, p < 0.001). When the treatment delay intervals were analyzed as continuous variables, similar results were observed in patients with stage I NSCLC (adjustedHR = 1.04, 95% CI 1.01–1.06, p = 0.010) and in those with stage I breast cancer (adjustedHR = 1.03, 95% CI 1.00–1.06, p = 0.029). However, treatment delays did not reduce the OS of patients with differentiated thyroid cancer, cervical cancer, or colorectal cancer in the early-stage. Only intermediate treatment delays impaired the CSS of patients with cervical cancer in stage I (adjustedHR = 1.31, 95% CI 1.02–1.68, p = 0.032).

Conclusion

After adjusting for confounders, the prolonged time from diagnosis to the initiation of treatment (< 6 months) showed limited negative effects on the survival of most of the patients with early-stage female cancers. Whether our findings serve as evidence supporting the treatment deferral decisions of clinicians for patients with different cancers in resource-limited situations needs further validation.
Noninvasive prediction of axillary lymph node status in breast cancer using promoter profiling of circulating cell-free DNA
Authors: Guo Zhi-Wei , Liu Qing , Yang Xu , Cai Geng-Xi , Han Bo-Wei , Huang Li-Min , Li Chun-Xi , Liang Zhi-Kun , Zhai Xiang-Ming , Lin Li , Li Kun , Zhang Min , Liu Tian-Cai , Pan Rui-lin , Wu Ying-Song , Yang Xue-Xi
Published: December 2022

Background

Lymph node metastasis (LNM) is one of the most important factors affecting the prognosis of breast cancer. The accurate evaluation of lymph node status is useful to predict the outcomes of patients and guide the choice of cancer treatment. However, there is still lack of a low-cost non-invasive method to assess the status of axillary lymph node (ALN). Gene expression signature has been used to assess lymph node metastasis status of breast cancer. In addition, nucleosome footprint of cell-free DNA (cfDNA) carries gene expression information of its original tissues, so it may be used to evaluate the axillary lymph node status in breast cancer.

Methods

In this study, we found that the cfDNA nucleosome footprints between the ALN-positive patients and ALN-negative patients showed different patterns by implementing whole-genome sequencing (WGS) to detect 15 ALN-positive and 15 ALN-negative patients. In order to further evaluate its potential for assessing ALN status, we developed a classifier with multiple machine learning models by using 330 WGS data of cfDNA from 162 ALN-positive and 168 ALN-negative samples to distinguish these two types of patients.

Results

We found that the promoter profiling between the ALN-positive patients and ALN-negative patients showed distinct patterns. In addition, we observed 1071 genes with differential promoter coverage and their functions were closely related to tumorigenesis. We found that the predictive classifier based on promoter profiling with a support vector machine model, named PPCNM, produced the largest area under the curve of 0.897 (95% confidence interval 0.86–0.93).

Conclusions

These results indicate that promoter profiling can be used to distinguish ALN-positive patients from ALN-negative patients, which may be helpful to guide the choice of cancer treatment.
A weighted non-negative matrix factorization approach to predict potential associations between drug and disease
Authors: Wang Mei-Neng , Xie Xue-Jun , You Zhu-Hong , Ding De-Wu , Wong Leon
Published: December 2022

Background

Associations of drugs with diseases provide important information for expediting drug development. Due to the number of known drug-disease associations is still insufficient, and considering that inferring associations between them through traditional in vitro experiments is time-consuming and costly. Therefore, more accurate and reliable computational methods urgent need to be developed to predict potential associations of drugs with diseases.

Methods

In this study, we present the model called weighted graph regularized collaborative non-negative matrix factorization for drug-disease association prediction (WNMFDDA). More specifically, we first calculated the drug similarity and disease similarity based on the chemical structures of drugs and medical description information of diseases, respectively. Then, to extend the model to work for new drugs and diseases, weighted $$K$$
K
nearest neighbor was used as a preprocessing step to reconstruct the interaction score profiles of drugs with diseases. Finally, a graph regularized non-negative matrix factorization model was used to identify potential associations between drug and disease.

Results

During the cross-validation process, WNMFDDA achieved the AUC values of 0.939 and 0.952 on Fdataset and Cdataset under ten-fold cross validation, respectively, which outperforms other competing prediction methods. Moreover, case studies for several drugs and diseases were carried out to further verify the predictive performance of WNMFDDA. As a result, 13(Doxorubicin), 13(Amiodarone), 12(Obesity) and 12(Asthma) of the top 15 corresponding candidate diseases or drugs were confirmed by existing databases.

Conclusions

The experimental results adequately demonstrated that WNMFDDA is a very effective method for drug-disease association prediction. We believe that WNMFDDA is helpful for relevant biomedical researchers in follow-up studies.
The intrarenal landscape of T cell receptor repertoire in clear cell renal cell cancer
Authors: Zhang Wei , Zhang Qian , Zhu Chao , Shi Zhiyuan , Shao Chen , Chen Yujie , Wang Nan , Jiang Yanxia , Liang Qing , Wang Kejia
Published: December 2022

Background

Clear cell renal cell cancer (ccRCC) is accompanied by T-cell infiltration. In this study, we sought to determine the difference in T-cell infiltration and the T-cell receptor (TCR) immune repertoire between ccRCC and peritumour tissue.

Methods

T-cell infiltration was examined using immunohistochemistry (IHC) and haematoxylin and eosin (HE) staining. The chi-squared test and Pearson correlation analysis were applied to evaluate the relationship between clinical traits and CD3, CD4, and CD8 expression. Immune repertoire sequencing (IR-Seq) was used to describe the profile of the TCR repertoire.

Results

The adjacent tissue showed increased expression of CD3, CD4 and CD8 compared with ccRCC tissue (PCD3 = 0.033; PCD4 = 0.014; PCD8 = 0.004). Indicated CD3+ T-cell density in ccRCC tissue was positively correlated with that in peritumour tissue (P = 0.010, r = 0.514), which implied the T cells in peritumour tissue directly infect the number of cells infiltrating in ccRCC tissue. Moreover, there was a positive correlation between Vimentin expression and indicated positive T-cell marker in ccRCC tissue (PCD3 = 0.035; PCD4 = 0.020; PCD8 = 0.027). Advanced stage revealed less CD4+ T-cell infiltration in ccRCC tissue (PCD4 = 0.023). The results from IR-Seq revealed an obvious increase in VJ and VDJ segment usage, as well as higher complementarity-determining region 3 (CDR3) amino acid (aa) clonotypes in ccRCC. The matched antigen recognized by the TCR of ccRCC may be potential targets.

Conclusions

The current study collectively demonstrates diminished T-cell infiltration and increased CDR3 aa diversity in ccRCC, which may be associated with immunotherapeutic targets for ccRCC patients.
Monocytes educated by cancer-associated fibroblasts secrete exosomal miR-181a to activate AKT signaling in breast cancer cells
Authors: Pakravan Katayoon , Mossahebi-Mohammadi Majid , Ghazimoradi Mohammad H. , Cho William C. , Sadeghizadeh Majid , Babashah Sadegh
Published: December 2022

Background

Cancer-associated fibroblasts (CAFs), one of the major components of the tumor stroma, contribute to an immunosuppressive tumor microenvironment (TME) through the induction and functional polarization of protumoral macrophages. We have herein investigated the contribution of CAFs to monocyte recruitment and macrophage polarization. We also sought to identify a possible paracrine mechanism by which CAF-educated monocytes affect breast cancer (BC) cell progression.

Methods

Monocytes were educated by primary CAFs and normal fibroblast (NF); the phenotypic alterations of CAF- or NF-educated monocytes were measured by flow cytometry. Exosomes isolated from the cultured conditioned media of the educated monocytes were characterized. An in vivo experiment using a subcutaneous transplantation tumor model in athymic nude mice was conducted to uncover the effect of exosomes derived from CAF- or NF-educated monocytes on breast tumor growth. Gain- and loss-of-function experiments were performed to explore the role of miR-181a in BC progression with the involvement of the AKT signaling pathway. Western blotting, enzyme-linked immunosorbent assay, RT-qPCR, flow cytometry staining, migration assay, immunohistochemical staining, and bioinformatics analysis were performed to reveal the underlying mechanisms.

Results

We illustrated that primary CAFs recruited monocytes and established pro-tumoral M2 macrophages. CAF may also differentiate human monocyte THP-1 cells into anti-inflammatory M2 macrophages. Besides, we revealed that CAFs increased reactive oxygen species (ROS) generation in THP-1 monocytes, as differentiating into M2 macrophages requires a level of ROS for proper polarization. Importantly, T-cell proliferation was suppressed by CAF-educated monocytes and their exosomes, resulting in an immunosuppressive TME. Interestingly, CAF-activated, polarized monocytes lost their tumoricidal abilities, and their derived exosomes promoted BC cell proliferation and migration. In turn, CAF-educated monocyte exosomes exhibited a significant promoting effect on BC tumorigenicity in vivo. Of clinical significance, we observed that up-regulation of circulating miR-181a in BC was positively correlated with tumor aggressiveness and found a high level of this miRNA in CAF-educated monocytes and their exosomes. We further clarified that the pro-oncogenic effect of CAF-educated monocytes may depend in part on the exosomal transfer of miR-181a through modulating the PTEN/Akt signaling axis in BC cells.

Conclusions

Our findings established a connection between tumor stromal communication and tumor progression and demonstrated an inductive function for CAF-educated monocytes in BC cell progression. We also proposed a supporting model in which exosomal transfer of miR-181a from CAF-educated monocytes activates AKT signaling by regulating PTEN in BC cells.
Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis
Authors: Zai Zhuoyan , Xu Yayun , Qian Xuewen , Li Zihan , Ou Ziyao , Zhang Tao , Wang Longfei , Ling Yian , Peng Xiaoqing , Zhang Yihao , Chen Feihu
Published: December 2022

Background

Destruction of articular cartilage and bone is the main cause of joint dysfunction in rheumatoid arthritis (RA). Acid-sensing ion channel 1a (ASIC1a) is a key molecule that mediates the destruction of RA articular cartilage. Estrogen has been proven to have a protective effect against articular cartilage damage, however, the underlying mechanisms remain unclear.

Methods

We treated rat articular chondrocytes with an acidic environment, analyzed the expression levels of mitochondrial stress protein HSP10, ClpP, LONP1 by q-PCR and immunofluorescence staining. Transmission electron microscopy was used to analyze the mitochondrial morphological changes. Laser confocal microscopy was used to analyze the Ca2+, mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) level. Moreover, ASIC1a specific inhibitor Psalmotoxin 1 (Pctx-1) and Ethylene Glycol Tetraacetic Acid (EGTA) were used to observe whether acid stimulation damage mitochondrial function through Ca2+ influx mediated by ASIC1a and whether pretreatment with estrogen could counteract these phenomena. Furthermore, the ovariectomized (OVX) adjuvant arthritis (AA) rat model was treated with estrogen to explore the effect of estrogen on disease progression.

Results

Our results indicated that HSP10, ClpP, LONP1 protein and mRNA expression and mitochondrial ROS level were elevated in acid-stimulated chondrocytes. Moreover, acid stimulation decreased mitochondrial membrane potential and damaged mitochondrial structure of chondrocytes. Furthermore, ASIC1a specific inhibitor PcTx-1 and EGTA inhibited acid-induced mitochondrial abnormalities. In addition, estrogen could protect acid-stimulated induced mitochondrial stress by regulating the activity of ASIC1a in rat chondrocytes and protects cartilage damage in OVX AA rat.

Conclusions

Extracellular acidification induces mitochondrial stress by activating ASIC1a, leading to the damage of rat articular chondrocytes. Estrogen antagonizes acidosis-induced joint damage by inhibiting ASIC1a activity. Our study provides new insights into the protective effect and mechanism of action of estrogen in RA.