bluuebunny/crossref_metadata_2025 huggingface dataset:
In Support of Initial Parenteral Medical Management of Intrathecal Baclofen Withdrawal in Spasticity Patients
Authors: LaRowe Brian L. , Nussbaum Vicki M.
Published: August 2021

Background: Spasticity may present as a wide range of symptoms and conditions. With this protean presentation, a consensus regarding the best course of treatment does not exist. Those patients most severely affected may receive significant benefit from intrathecal baclofen delivery. However, this therapy may itself lead to patient injury in the event of withdrawal. Objective: Withdrawal from intrathecal baclofen may devolve rapidly into a situation in which the patient may incur significant morbidity and even death. A focused, prompt treatment plan would afford the patient the best possible outcome. Methods: The medical literature was reviewed for reports of plans of treatment of baclofen withdrawal and the results obtained. The nature of this problem does not lend itself to a typical study design, depending on case reports and basic pharmacological science application. The paucity of such reports severely limits categorical comparison of patient characteristics and clinical circumstances. Clinical situations, patient characteristics, and therapies were considered and compared. Outcomes of the varied treatments were evaluated for efficacy. Results: Inaccurate diagnoses, delayed correct diagnoses, and the absence of a consistent, treatment plan contributed to widely disparate outcomes. Prompt, correct diagnosis and intensive care unit–based continuous benzodiazepine infusion with titration led to a controlled clinical situation and maximized patient outcomes. Conclusions: Patients going through withdrawal from intrathecal baclofen achieved best outcomes when treated with a continuous infusion and titration of an intravenous benzodiazepine. A well-defined treatment protocol employing this management, reporting serial outcomes, would enable further refinement of the treatment of this clinical problem.
A comprehensive RNA editome reveals that edited Azin1 partners with DDX1 to enable hematopoietic stem cell differentiation
Authors: Wang Fengjiao , He Jiahuan , Liu Siqi , Gao Ai , Yang Liu , Sun Guohuan , Ding Wanqiu , Li Chuan-Yun , Gou Fanglin , He Manman , Wang Fang , Wang Xiaoshuang , Zhao Xiangnan , Zhu Ping , Hao Sha , Ma Yanni , Cheng Hui , Yu Jia , Cheng Tao
Published: August 2021

Adenosine-to-inosine RNA editing and the catalyzing enzyme adenosine deaminase are both essential for hematopoietic development and differentiation. However, the RNA editome during hematopoiesis and the underlying mechanisms are poorly defined. Here, we sorted 12 murine adult hematopoietic cell populations at different stages and identified 30 796 editing sites through RNA sequencing. The dynamic landscape of the RNA editome comprises stage- and group-specific and stable editing patterns, but undergoes significant changes during lineage commitment. Notably, we found that antizyme inhibitor 1 (Azin1) was highly edited in hematopoietic stem and progenitor cells (HSPCs). Azin1 editing results in an amino acid change to induce Azin1 protein (AZI) translocation to the nucleus, enhanced AZI binding affinity for DEAD box polypeptide 1 to alter the chromatin distribution of the latter, and altered expression of multiple hematopoietic regulators that ultimately promote HSPC differentiation. Our findings have delineated an essential role for Azin1 RNA editing in hematopoietic cells, and our data set is a valuable resource for studying RNA editing on a more general basis.
Interaction of smoking and being bullied on suicidal behaviors: a school-based cross-sectional survey in China
Authors: Hu Jie , Song Xianbing , Li Danlin , Zhao Shuai , Wan Yuhui , Fang Jun , Zhang Shichen
Published: August 2021

Background

Suicidal behaviors are seriously social issues among adolescents in the world. Exposed to smoking and being bullied are risk factors of suicidal behaviors. The present study was aimed to examine the interaction of smoking and being bullied on suicidal behaviors among Chinese adolescents.

Methods

A total of 18,900 students were involved in the questionnaire study, in four cities of China from November 2017 to January 2018. Suicidal behaviors, smoking, and being bullied were measured by self-reported validated instruments. Chi-square tests and logistic regression were used to analyze the associations of suicidal ideation (SI)/suicidal plan (SP)/suicidal attempt (SA), smoking, and being bullied.

Results

The prevalence of smoking, being bullied, SI/SP/SA, were 3.1%, 20.6%, 26.4%, 13.2%, and 5.2% respectively. Interaction analysis indicated that being bullied was associated with a greater increase in the likelihood of suicidal behaviors for adolescents with smoking than for those without smoking.

Conclusions

These finding suggest that smoking exacerbates the association between being bullied and suicidal behaviors. Future research should explore how and why smoking appears to more bully-victims than for those without smoking and how to mitigate it.
Insight into temporal–spatial variations of DOM fractions and tracing potential factors in a brackish-water lake using second derivative synchronous fluorescence spectroscopy and canonical correlation analysis
Authors: Lu Kuotian , Xu Weining , Yu Huibin , Gao Hongjie , Gao Xiaobo , Zhu Ningmei
Published: August 2021

Background

Insight into temporal–spatial variations of dissolved organic matter (DOM) fractions were undertaken to trace potential factors toward a further understanding aquatic environment in Lake Shahu, a brackish-water lake in northwest China, using synchronous fluorescence spectroscopy (SFS) combined with principal component analysis (PCA), second derivative and canonical correlation analysis (CCA).

Result

Five fluorescence peaks were extracted from SFS by PCA, including tyrosine-like fluorescence (TYLF), tryptophan-like fluorescence (TRLF), microbial humic-like fluorescence (MHLF), fulvic-like fluorescence (FLF), and humic-like fluorescence (HLF), whose relative contents were obtained by second derivative synchronous fluorescence spectroscopy. The increasing order of total fluorescence components contents was July (11,789.38 ± 12,752.61) < April (12,667.58 ± 15,246.91) < November (19,748.87 ± 17,192.13), which was attributed to tremendous enhancement in TYLF content from April (1615.56 ± 258.56) to November (5631.96 ± 634.82). The PLF (the sum of TYLF and TRLF) dominated the fluorescence components, whose proportion was 40.55, 37.09, or 46.91% in April, July, or November. DOM fractions in November were distinguished from April and July, which could be attributed to that water of the Yellow River was continuously loaded into the lake as water replenishment from April to September. From the replenishment period to non-replenishment, the contents of the five components gradually changed from low in the middle and high around the lake to high throughout entire lake. Based on the CCA results, the potential factors included TYLF, TRLF, MHLF, SD, and BOD5 in April, which were relative to organic matter pollution. The potential factors contained TYLF, TRLF, FLF, Chl-a, TP, CODCr, and DO in July, indicating the enrichment of TP lead algae and plants growth. The potential factors in November consisted of TYLF, TRLF, CODCr, SD, TN, and FLF, representing residue of the algae and plants have been deeply degraded.

Conclusion

The replenishment of water led to enrichment of TP, resulting in growth of algae and plants, and was the key factor of water quality fluctuations. This work provided a workflow from perspective of DOM to reveal causes of water quality fluctuations in a brackish-water lake and may be applied to other types of waterbodies.
The transmembrane domain and luminal C-terminal region independently support invariant chain trimerization and assembly with MHCII into nonamers
Authors: Cloutier Maryse , Fortin Jean-Simon , Thibodeau Jacques
Published: August 2021

Background

Invariant chain (CD74, Ii) is a multifunctional protein expressed in antigen presenting cells. It assists the ER exit of various cargos and serves as a receptor for the macrophage migration inhibitory factor. The newly translated Ii chains trimerize, a structural feature that is not readily understood in the context of its MHCII chaperoning function. Two segments of Ii, the luminal C-terminal region (TRIM) and the transmembrane domain (TM), have been shown to participate in the trimerization process but their relative importance and impact on the assembly with MHCII molecules remains debated. Here, we addressed the requirement of these domains in the trimerization of human Ii as well as in the oligomerization with MHCII molecules. We used site-directed mutagenesis to generate series of Ii and DR mutants. These were transiently transfected in HEK293T cells to test their cell surface expression and analyse their interactions by co-immunoprecipitations.

Results

Our results showed that the TRIM domain is not essential for Ii trimerization nor for intracellular trafficking with MHCII molecules. We also gathered evidence that in the absence of TM, TRIM allows the formation of multi-subunit complexes with HLA-DR. Similarly, in the absence of TRIM, Ii can assemble into high-order structures with MHCII molecules.

Conclusions

Altogether, our data show that trimerization of Ii through either TM or TRIM sustains nonameric complex formation with MHCII molecules.
A single amino acid residue substitution in BraA04g017190.3C, a histone methyltransferase, results in premature bolting in Chinese cabbage (Brassica rapa L. ssp. Pekinensis)
Authors: Tan Chong , Ren Jie , Wang Lin , Ye Xueling , Fu Wei , Zhang Jiamei , Qi Meng , Feng Hui , Liu Zhiyong
Published: August 2021

Background

Flowering is an important inflection point in the transformation from vegetative to reproductive growth, and premature bolting severely decreases crop yield and quality.

Results

In this study, a stable early-bolting mutant, ebm3, was identified in an ethyl methanesulfonate (EMS)-mutagenized population of a Chinese cabbage doubled haploid (DH) line ‘FT’. Compared with ‘FT’, ebm3 showed early bolting under natural cultivation in autumn, and curled leaves. Genetic analysis showed that the early-bolting phenotype was controlled by a single recessive nuclear gene. Modified MutMap sequencing, genotyping analyses and allelism test provide strong evidence that BrEBM3 (BraA04g017190.3 C), encoding the histone methyltransferase CURLY LEAF (CLF), was the strongly candidate gene of the emb3. A C to T base substitution in the 14th exon of BrEBM3 resulted in an amino acid change (S to F) and the early-bolting phenotype of emb3. The mutation occurred in the SET domain (Suppressor of protein-effect variegation 3–9, Enhancer-of-zeste, Trithorax), which catalyzes site- and state-specific lysine methylation in histones. Tissue-specific expression analysis showed that BrEBM3 was highly expressed in the flower and bud. Promoter activity assay confirmed that BrEBM3 promoter was active in inflorescences. Subcellular localization analysis revealed that BrEBM3 localized in the nucleus. Transcriptomic studies supported that BrEBM3 mutation might repress H3K27me3 deposition and activate expression of the AGAMOUS (AG) and AGAMOUS-like (AGL) loci, resulting in early flowering.

Conclusions

Our study revealed that an EMS-induced early-bolting mutant ebm3 in Chinese cabbage was caused by a nonsynonymous mutation in BraA04g017190.3 C, encoding the histone methyltransferase CLF. These results improve our knowledge of the genetic and genomic resources of bolting and flowering, and may be beneficial to the genetic improvement of Chinese cabbage.
Emergency medical staffs’ knowledge and attitude about organ donation after circulatory determined death (DCD) and its related factors
Authors: Kondori Jafar , Ghafouri Rouzbeh Rajaei , Zamanzadeh Vahid , Attari Ahmad Mirza Aghazadeh , Large Stephen R. , Sheikhalipour Zahra
Published: August 2021

Background

Adverse attitudes and insufficient knowledge about organ donation after Circulatory Determined Death (DCD) among emergency staff can have important consequences for the proper identification of potential DCD donors. This is aided by the constant application of donation after Circulatory Determined Death policies, and the relative strength of support for this type of donation. Therefore, this study was conducted to investigate the awareness and attitude of emergency personnel about organ donation after Circulatory Determined Death.

Methods

This descriptive study was carried out with the participation of 49 physicians and 145 nurses working in the emergency departments of educational and medical centers of Tabriz University of Medical Sciences. Nurses were selected by simple random sampling, and all physicians working in the emergency departments were included in the study. The questionnaire of Knowledge and Attitude regarding Organ Donation after Circulatory Determined Death designed by Rodrigue et al. was used. Data were analyzed using descriptive statistics and independent samples t-test, one-way ANOVA, and chi-square test.

Results

Most of the nurses (62.8%) and physicians (66.7%) had a high level of knowledge about organ donation after circulatory determined death. The mean attitude score was 101.84 (SD: 9.88) out of 170 for nurses and 106.53 (SD: 11.77) for physicians. Physicians who carried organ donation cards had a more positive attitude toward organ donation after circulatory determined death.

Conclusion

According to this study findings, knowledge and attitude of the emergency staff about organ donation was both high and positive. It is recommended to devise necessary guidelines for organ donation in Iranian emergency departments to assist in the training of colleagues in organ donation ensuring no necessary measures are missed. The results of this study would support the development of guidelines for the successful introduction of DCD in Iran.
Case report: aseptic meningitis secondary to varicella-zoster virus (VZV) without an exanthem post MMR vaccination
Authors: Sahra Syeda , Jahangir Abdullah , Glaser Allison , Mobarakai Neville , Jahangir Ahmad
Published: August 2021

Background

Varicella-zoster virus (VZV) is a known cause of aseptic meningitis, with a predisposition for an immunocompromised population. A dermatomal rash usually accompanies aseptic meningitis secondary to VZV.

Case presentation

We report the case of a 31-year-old male with a history of chickenpox in childhood and recent shingles who presented with severe frontal headaches secondary to VZV meningitis. The patient had also recently received the measles-mumps-rubella (MMR) vaccine. He recovered without any neurological sequala.

Conclusion

This case report describes an immunocompetent patient with recent MMR vaccination who developed aseptic meningitis secondary to VZV without any dermatomal involvement (Zoster Sine Herpete).
Impact of antibiotic pretreatment on cultures in children with osteomyelitis and septic arthritis: a retrospective review
Authors: Lansell Amanda , Vasili Yasasvi , Suchdev Parminder S. , Figueroa Janet , Kirpalani Anjali
Published: August 2021

Background

In the management of pediatric osteomyelitis or septic arthritis, delay in treatment may affect outcome, while receipt of antibiotics prior to culture may affect culture results. We aimed to determine if pathogen identification decreased in cultures that were pretreated with antibiotics.

Methods

We conducted a retrospective cohort study of 584 hospitalized children between 30 days and 18 years of age admitted to two tertiary children’s hospitals. Logistic regression assessed the effect of antibiotic duration on blood, bone, joint aspirate, and “other” culture positivity.

Results

Overall, 42% of blood cultures, 70% of bone cultures, 39% of joint cultures, and 70% of “other” cultures were positive. Compared with children who did not receive antibiotics prior to culture, there were no significant differences in odds of a positive culture in children whose cultures were pretreated with antibiotics for any of the culture types [OR (95% CI) 0.90 (0.56–1.44) for blood cultures, 0.77 (0.25–2.34) for bone cultures, 0.71 (0.39–1.28) for joint cultures, 1.18 (0.58–2.41) “for other” cultures; all p > 0.05]. Furthermore, the duration (hours) of antibiotics in the pretreated cultures was also not a significant predictor of culture positivity (OR ranged from 0.99–1.00 for all cultures, p > 0.05).

Conclusions

Culture positivity was not associated with antibiotic pretreatment in any of the samples, even for longer duration of antibiotics prior to culture, though the small sample size of subgroups is an important limitation. In pediatric patients hospitalized with osteomyelitis and/or septic arthritis, early initiation of antibiotics may not affect culture positivity.
Sub-national disparities in accessing anti-malarial drug treatment in eastern Indonesia
Authors: Ipa Mara , Laksono Agung Dwi , Astuti Endang Puji , Prasetyowati Heni , Pradani Firda Yanuar , Hendri Joni , Ruliansyah Andri , Surendra Henry , Elyazar Iqbal R. F.
Published: August 2021

Background

Poor access to health care providers was among the contributing factors to less prompt and ineffective malaria treatment. This limitation could cause severe diseases in remote areas. This study examined the sub-national disparities and predictors in accessing anti-malarial drug treatment among adults in Eastern Indonesia.

Methods

The study analyzed a subset of the 2018 National Basic Health Survey conducted in all 34 provinces in Indonesia. We extracted socio-demographic data of 4655 adult respondents diagnosed with malaria in the past 12 months in five provinces in Eastern Indonesia. The association between socio-demographic factors and the access to anti-malarial drug treatment was assessed using logistic regression.

Results

Over 20% of respondents diagnosed with malaria within last 12 months admitted that they did not receive anti-malarial drug treatment (range 12–29.9%). The proportion of untreated cases was 12.0% in East Nusa Tenggara, 29.9% in Maluku, 23.1% in North Maluku, 12.7% in West Papua, and 15.6% in Papua. The likelihood of receiving anti-malarial drug treatment was statistically lower in Maluku (adjusted OR = 0.258; 95% CI 0.161–0.143) and North Maluku (adjusted OR = 0.473; 95% CI 0.266–0.840) than those in Eastern Nusa Tenggara (reference). Urban respondents were less likely to receive malaria treatment than rural (adjusted OR = 0.545; 95% CI 0.431–0.689).

Conclusions

This study found that there were sub-national disparities in accessing anti-malarial drug treatment in Eastern Indonesia, with a high proportion of untreated malaria cases across the areas. Findings from this study could be used as baseline information to improve access to anti-malarial drug treatment and better target malaria intervention in Eastern Indonesia.
Local experience of using traditional medicine in northern Rwanda: a qualitative study
Authors: Tan Mengxin , Otake Yuko , Tamming Teisi , Akuredusenge Valerie , Uwinama Beatha , Hagenimana Fabien
Published: August 2021

Background

The popular use of traditional medicine in low-income settings has previously been attributed to poverty, lack of education, and insufficient accessibility to conventional health service. However, in many countries, including in Rwanda, the use of traditional medicine is still popular despite the good accessibility and availability of conventional health services. This study aims to explore why traditional medicine is popularly used in Rwanda where it has achieved universal health coverage.

Methods

The qualitative study, which included in-depth interviews and participant observations, investigated the experience of using traditional medicine as well as the perceived needs and reasons for its use in the Musanze district of northern Rwanda. We recruited 21 participants (15 community members and 6 traditional healers) for in-depth interviews. Thematic analysis was conducted to generate common themes and coding schemes.

Results

Our findings suggest that the characteristics of traditional medicine are responding to community members’ health, social and financial needs which are insufficiently met by the current conventional health services. Participants used traditional medicine particularly to deal with culture-specific illness –uburozi. To treatuburoziappropriately, referrals from hospitals to traditional healers took place spontaneously.

Conclusions

In Rwanda, conventional health services universally cover diseases that are diagnosed by the standard of conventional medicine. However, this universal health coverage may not sufficiently respond patients’ social and financial needs arising from the health needs. Given this, integrating traditional medicine into national health systems, with adequate regulatory framework for quality control, would be beneficial to meet patients’ needs.
Exploring healthcare students’ interprofessional teamwork in primary care simulation scenarios: collaboration to create a shared treatment plan
Authors: Lunde Lene , Moen Anne , Jakobsen Rune B. , Rosvold Elin O. , Brænd Anja M.
Published: August 2021

Background

Primary care providers assume responsibility for patients with increasingly complex problems requiring interprofessional collaboration. Introducing interprofessional education in healthcare curricula prepares healthcare students for this reality. Solving simulation scenarios as an educational strategy is promoted to support interprofessional education in health care, and is mostly used in acute clinical situations. This paper aims to explore how healthcare students’ actions influence interprofessional collaboration and treatment plan identification when they solve common, sub-acute patient scenarios in primary care situations.

Methods

Interaction analysis of video recordings from the simulation scenarios was performed with a focus on the students’ joint actions; specifically how these actions unfold and how productive the students were in terms of developing treatment plans.

Results

We found variation in the groups’ interactions, the paths they followed, and the quality of their knowledge output in their shared treatment plan. The groups with the capacity to collaborate and engage in sharing information, and explain and elaborate on concepts, were more successful in developing comprehensive treatment plans. Furthermore, these groups managed the duality of defining and solving the immediate problem and collaboratively preparing for future care.

Conclusions

Analysis of the activities in our scenarios showed the students’ potential to practice interprofessional collaboration. Our study illustrates that simulation of sub-acute scenarios in primary care is an underexplored but suitable arena to train communication and teamwork in complex situations. The simulation scenarios are also feasible for use on-site in an educational facility or in practice with minimal equipment and resources.
Plasma nesfatin-1 and DDP-4 levels in patients with coronary artery disease: Kozani study
Authors: Kadoglou Nikolaos P. E. , Korakas Emmanouil , Lampropoulos Stylianos , Maratou Eirini , Kassimis George , Patsourakos Nikolaos , Plotas Panagiotis , Moutsatsou Paraskevi , Lambadiari Vaia
Published: August 2021

Background

Nesfatin-1, a novel adipokine and dipeptidyl peptidase-4 (DPP4), a mam malian serine protease, are potent factors of atherosclerosis. In the present cross-sectional study, we investigated whether the plasma nesfatin-1 and DPP4 is associated with the prevalence and severity of coronary artery disease (CAD) with and without diabetes mellitus (DM).

Methods

We consecutively enrolled a total of 240 patients with significant CAD (previous revascularization or angiographically-proven coronary artery stenosis > 50%) presented with either unstable angina (UA, N = 76) or stable chronic CAD (SCAD, N = 165). 85 patients with at least 2 classical cardiovascular risk factors but without significant CAD served as controls. The severity of CAD was assessed using coronary angiography by the Gensini score. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), nesfatin-1 and DPP4 levels were assayed.

Results

No differences were found for age, sex, hypertension and diabetes distribution between groups. Low nesfatin-1 levels were found in both CAD groups (UA & SCAD) with respect to controls. The difference between UA and SCAD groups was marginally non-significant. There was a significant increase of DPP4 along UA to SCAD and control groups. Differences between groups remained unchanged in non-diabetic participants. Nesfatin-1 significantly correlated to hsCRP (r = − 0.287, p = 0.036), HOMA-IR (r = − 0.587, p = 0.007) and hyperlipidemia (r = − 0.331, p = 0.034). DPP4 was significantly associated with hs-CRP (r = 0.353 p < 0.001) and FPG (r = 0.202, p = 0.020) in univariate analysis, but those correlations were lost in multiple regression analysis. There was a negative correlation between nesfatin-1 and the severity of CAD, quantified by the Gensini score (r = − 0.511, p < 0.001), but no association was found for DPP4.

Conclusions

Serum DPP4 levels are increased in patients with CAD, while serum nesfatin-1 levels have a negative association with both the incidence and the severity of CAD. These results are independent of the presence of diabetes mellitus. In addition, both peptides have a strong association with hsCRP.

Trial registration ClinicalTrials.gov Identifier: NCT00306176
Vanillic acid and methoxyhydroquinone production from guaiacyl units and related aromatic compounds using Aspergillus niger cell factories
Authors: Lubbers Ronnie J. M. , Dilokpimol Adiphol , Nousiainen Paula A. , Cioc Răzvan C. , Visser Jaap , Bruijnincx Pieter C. A. , de Vries Ronald P.
Published: August 2021

Background

The aromatic compounds vanillin and vanillic acid are important fragrances used in the food, beverage, cosmetic and pharmaceutical industries. Currently, most aromatic compounds used in products are chemically synthesized, while only a small percentage is extracted from natural sources. The metabolism of vanillin and vanillic acid has been studied for decades in microorganisms and many studies have been conducted that showed that both can be produced from ferulic acid using bacteria. In contrast, the degradation of vanillin and vanillic acid by fungi is poorly studied and no genes involved in this metabolic pathway have been identified. In this study, we aimed to clarify this metabolic pathway in Aspergillus niger and identify the genes involved.

Results

Using whole-genome transcriptome data, four genes involved in vanillin and vanillic acid metabolism were identified. These include vanillin dehydrogenase (vdhA), vanillic acid hydroxylase (vhyA), and two genes encoding novel enzymes, which function as methoxyhydroquinone 1,2-dioxygenase (mhdA) and 4-oxo-monomethyl adipate esterase (omeA). Deletion of these genes in A. niger confirmed their role in aromatic metabolism and the enzymatic activities of these enzymes were verified. In addition, we demonstrated that mhdA and vhyA deletion mutants can be used as fungal cell factories for the accumulation of vanillic acid and methoxyhydroquinone from guaiacyl lignin units and related aromatic compounds.

Conclusions

This study provides new insights into the fungal aromatic metabolic pathways involved in the degradation of guaiacyl units and related aromatic compounds. The identification of the involved genes unlocks new potential for engineering aromatic compound-producing fungal cell factories.
Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages
Authors: Sun Jia-Lei , Zhang Ning-Ping , Xu Ru-Chen , Zhang Guang-Cong , Liu Zhi-Yong , Abuduwaili Weinire , Wang Fu , Yu Xiang-Nan , Shi Xuan , Song Guang-Qi , Wu Hao , Liu Tao-Tao , Shen Xi-Zhong , Deng Bin , Weng Shu-Qiang , Dong Ling , Zhu Ji-Min
Published: August 2021

Background

Tumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM.

Methods

TAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages.

Results

We revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages.

Conclusions

Collectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.
Hepatocyte growth factor pathway expression in breast cancer by race and subtype
Authors: Jones Gieira S. , Hoadley Katherine A. , Olsson Linnea T. , Hamilton Alina M. , Bhattacharya Arjun , Kirk Erin L. , Tipaldos Heather J. , Fleming Jodie M. , Love Michael I. , Nichols Hazel B. , Olshan Andrew F. , Troester Melissa A.
Published: August 2021

Background

African American women have the highest risk of breast cancer mortality compared to other racial groups. Differences in tumor characteristics have been implicated as a possible cause; however, the tumor microenvironment may also contribute to this disparity in mortality. Hepatocyte growth factor (HGF) is a stroma-derived marker of the tumor microenvironment that may affect tumor progression differentially by race.

Objective

To examine whether an HGF gene expression signature is differentially expressed by race and tumor characteristics.

Methods

Invasive breast tumors from 1957 patients were assessed for a 38-gene RNA-based HGF gene expression signature. Participants were black (n= 1033) and non-black (n= 924) women from the population-based Carolina Breast Cancer Study (1993–2013). Generalized linear models were used to estimate the relative frequency differences (RFD) in HGF status by race, clinical, and demographic factors.

Results

Thirty-two percent of tumors were positive for the HGF signature. Black women were more likely [42% vs. 21%; RFD = + 19.93% (95% CI 16.00, 23.87)] to have HGF-positive tumors compared to non-black women. Triple-negative patients had a higher frequency of HGF positivity [82% vs. 13% in non-triple-negative; RFD = + 65.85% (95% CI 61.71, 69.98)], and HGF positivity was a defining feature of basal-like subtype [92% vs. 8% in non-basal; RFD = + 81.84% (95% CI 78.84, 84.83)]. HGF positivity was associated with younger age, stage, higher grade, and high genomic risk of recurrence (ROR-PT) score.

Conclusion

HGF expression is a defining feature of basal-like tumors, and its association with black race and young women suggests it may be a candidate pathway for understanding breast cancer disparities.
Rapid spheroid assays in a 3-dimensional cell culture chip
Authors: Teh Jia Lin , Abdul Rahman Siti Fairus , Domnic Gregory , Satiyasilan Lengishwarra , Chear Nelson Jeng Yeou , Singh Darshan , Mohana-Kumaran Nethia
Published: August 2021

Objective

The spheroid model provides a physiological platform to study cancer cell biology and drug sensitivity. Usage of bovine collagen I for spheroid assays is costly especially when experiments are conducted in 24-well plates, as high volume of bovine collagen I is needed. The aim of the study was to downsize spheroid assays to a microfluidic 3D cell culture chip and compare the growth, invasion and response to drug/compound of spheroids embedded in the 3D chip to spheroids embedded in 24-well plates.

Results

Spheroids generated from nasopharyngeal carcinoma cell line HK-1 continuously grew and invaded into collagen matrix in a 24-well plate. Similar observations were noticed with spheroids embedded in the 3D chip. Large spheroids in both 24-well plate and the 3D chip disintegrated and invaded into the collagen matrix. Preliminary drug sensitivity assays showed that the growth and invasion of spheroids were inhibited when spheroids were treated with combination of cisplatin and paynantheine at high concentrations, in a 24-well plate. Comparable findings were obtained when spheroids were treated with the same drug combination in the 3D chip. Moving forward, spheroid assays could be performed in the 3D chip in a more high-throughput manner with minimal time and cost.
Tau-related grey matter network breakdown across the Alzheimer’s disease continuum
Authors: Pelkmans Wiesje , Ossenkoppele Rik , Dicks Ellen , Strandberg Olof , Barkhof Frederik , Tijms Betty M. , Pereira Joana B. , Hansson Oskar
Published: August 2021

Background

Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer’s disease (AD) and have been associated with amyloid-β (Aβ) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum.

Methods

We included 533 individuals (178 Aβ-negative cognitively unimpaired (CU) subjects, 105 Aβ-positive CU subjects, 122 Aβ-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions.

Results

Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (allp< 0.001), indicative of a less optimal network organisation. Already in CU Aβ-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology.

Conclusions

Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.
Dispersants as marine oil spill treating agents: a review on mesoscale tests and field trials
Authors: Merlin Francois , Zhu Zhiwen , Yang Min , Chen Bing , Lee Kenneth , Boufadel Michel C. , Isaacman Lisa , Zhang Baiyu
Published: August 2021

The increasing oil demand and busy waterways highlight the importance of oil spill preparedness and responses. Dispersants attract attention as an effective response tool to manage the impacts of major spill incidents. Despite in-depth laboratory evaluations on the effectiveness of chemical dispersants and their impacts on the transportation and fate of spilled oils, how dispersant works at sea remains a question and calls for the tests with greater realism to validate laboratory results, bring in energy impacts, and evaluate dispersant application equipment. Mesoscale studies and field trials have thus been widely conducted to assist better spill response operations. Such research attempts, however, lack a systematic summary. This study tried to fill the knowledge gaps by introducing the mesoscale facilities developed to advance the understanding of dispersant effectiveness on various sea conditions. An up-to-date overview of mesoscale studies and field trial assessments of dispersant effectiveness has also been conducted. We ended this review by highlighting the importance of public perception and future research needs to promote the approval and application of dispersants in spill incidents.
The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer
Authors: Giatromanolaki Alexandra , Harris Adrian L. , Koukourakis Michael I.
Published: August 2021

Background

Arginine (Arg) is essential for cancer cell growth and also for the activation of T cells. Thus, therapies aiming to reduce Arg utilization by cancer may prove detrimental for the immune response.

Methods

We examined the expression of two major enzymes involved in arginine depletion and replenishment, namely arginase ARG2 and argininosuccinate synthase ASS1, respectively, in a series of 98 NSCLCs. Their association with immune infiltrates and the postoperative outcome were also studied.

Results

ARG2 was expressed mainly by cancer-associated fibroblasts (CAFs) (58/98 cases; 59.2%), while ASS1 by cancer cells (75/98 cases; 76.5%). ASS1 and ARG2 expression patterns were not related to hypoxia markers. Auxotrophy, implied by the lack of expression of ASS1 in cancer cells, was associated with high angiogenesis (p < 0.02). ASS1 expression by cancer cells was associated with a high density of iNOS-expressing tumor-infiltrating lymphocytes (iNOS+TILs). ARG2 expression by CAFs was inversely related to the TIL-density and linked with poorer prognosis (p = 0.02). Patients with ASS1 expression by cancer cells had a better prognosis especially when CAFs did not express ARG2 (p = 0.004).

Conclusions

ARG2 and ASS1 enzymes are extensively expressed in NSCLC stroma and cancer cells, respectively. Auxotrophic tumors have a poor prognosis, potentially by utilizing Arg, thus reducing Arg-dependent TIL anti-tumor activity. ASS1 expression in cancer cells would allow Arg fueling of iNOS+TILs and enhance anti-tumor immunity. However, upregulation of ARG2 in CAFs may divert Arg from TILs, allowing immune escape. Identification of these three distinct phenotypes may be useful in the individualization of Arg-targeting therapies and immunotherapy.
The pathogenic role of c-Kit+ mast cells in the spinal motor neuron-vascular niche in ALS
Authors: Kovacs Mariángeles , Alamón Catalina , Maciel Cecilia , Varela Valentina , Ibarburu Sofía , Tarragó Lucas , King Peter H. , Si Ying , Kwon Yuri , Hermine Olivier , Barbeito Luis , Trias Emiliano
Published: August 2021

Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.
Experience of using home-based fortified diet in rehabilitation of malnourished children at Indus Hospital, Karachi, Pakistan: an institution based retrospective chart review study
Authors: Shahid Saba , Mahesar Marvi , Rahim Anum , Sadiq Yumna
Published: August 2021

Background

Globally, it is estimated that 50 million children under five are wasted. National nutrition survey-2018 has shown that 23.3 and 45.5% of children are wasted and stunted in Pakistan. Many studies have shown that hospital-based management of malnutrition is not practical due to high cost and iatrogenic infections and currently WHO recommends community-based management of malnutrition with provision of therapeutic food. There is limited evidence of community rehabilitation of malnourished children by using home fortified diet in Pakistan. This study explores use of energy dense, home fortified diet in achieving weight gain of malnourished children in Karachi.

Methods

A descriptive, retrospective chart review of pediatric patients (aged 6 month–5 years) seen in Indus Hospital between January 2017 to June 2018 was conducted. A pre-designed data abstraction form was used to record detailed information about demographic characteristics, feeding, anthropometric, micronutrient, and nutritional details at enrollment and on follow-up.

Results

A total of 361 patients were included in the final analysis. The median age (IQR) of children was 15 (14) months. Forty eight percent (n = 172) children had diarrhea and 54% (n = 195) children had respiratory tract infection. The median length of stay in the program was 28 days. The median (IQR) for average weight gain was 4.8 (0–10.3) g/Kg/day, 64.6% (n = 226) children defaulted, 29% (n = 102) were cured and 3% (n = 10) died.

Conclusion

This study showed adequate weight gain and recovery in malnourished children by using home fortified diet in real life situations without using therapeutic food or monetary support. Home fortified diets may serve as effective strategy in community-based rehabilitation of malnourished children.
Gut microbiome is affected by gut region but robust to host physiological changes in captive active-season ground squirrels
Authors: Grond Kirsten , Kurtz Courtney C. , Hatton Jasmine , Sonsalla Michelle M. , Duddleston Khrystyne N.
Published: August 2021

Background

Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) are obligate hibernators and are only active 4–5 months annually. During this period, squirrels rapidly acquire fat for use during hibernation. We investigated how the gut microbiome changed over the active season in the mucosa and lumen of two gut sections: the cecum and ileum. We sequenced the 16S rRNA gene to assess diversity and composition of the squirrel gut microbiome and used differential abundance and network analyses to identify relationships among gut sections.

Results

Microbial composition significantly differed between the cecum and ileum, and within the ileum between the mucosa and lumen. Cecum mucosa and lumen samples did not differ in alpha diversity and composition, and clustered by individual squirrel. Ileum mucosa and lumen samples differed in community composition, which can likely be attributed to the transient nature of food-associated bacteria in the lumen. We did not detect a shift in microbiome diversity and overall composition over the duration of the active season, indicating that the squirrel microbiome may be relatively robust to changes in physiology.

Conclusions

Overall, we found that the 13-lined ground squirrel microbiome is shaped by microenvironment during the active season. Our results provide baseline data for new avenues of research, such as investigating potential differences in microbial function among these physiologically unique gut environments.
Breast involvement in granulomatosis with polyangiitis: a case report
Authors: Basetti Bhavya , Periakaruppan Gokulakrishnan , Murali Arunan , Dev Bhawna , Radhakrishnan Prabhu Radhan , Sai P. M. Venkata
Published: August 2021

Background

Granulomatosis with polyangiitis (GPA) previously known as Wegener's granulomatosis is a rare complex immune-mediated disease and a multisystem disorder with varying presentations where many of the imaging features of GPA overlap with those of other diseases, and hence its diagnosis can be challenging.

Case presentation

Here we report a case of a 48-year-old female who presented with complaints of hemoptysis, difficulty in speech, bilateral progressive hearing loss and, a palpable lump in the right breast. The case was initially misdiagnosed as breast carcinoma but biopsy proved to be GPA. Here we present the multisystem manifestations of GPA involving the head and neck, breast, lungs, spleen with involvement of the breast being very rare. The breast lesion showed improvement with steroids on follow-up.

Conclusions

GPA is a multisystem disease and though breast lesions in GPA are rare, a thorough knowledge about this uncommon manifestation is required and clinical, radiological, and histopathological correlation is of utmost importance in the evaluation of a breast lesion in cases of multisystem involvement to avoid unnecessary surgeries. The differential diagnosis of breast tumors should include such rare conditions that can sometimes mimic breast cancer. Early diagnosis and initiation of the immunosuppressive treatment help in a better prognosis of the disease.