bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unique features of
Entamoeba histolytica
glycerophospholipid metabolism; has the
E
.
histolytica
lipid metabolism network evolved through gene loss and gain to enable parasitic life cycle adaptation?
Authors: Mi-ichi Fumika , Tsugawa Hiroshi , Yoshida Hiroki , Arita Makoto 
Published: August 2023

ABSTRACT

Entamoeba histolytica
, a protozoan parasite, causes amoebiasis, which is a global public health problem. During the life cycle of this parasite, the properties of the cell membrane are changed markedly. To clarify the mechanism of membrane lipid changes, we exploited state-of-the-art untargeted lipidomic analysis, and atypical features of glycerophospholipids, lysoglycerophospholipids, and sphingolipids were observed compared with human equivalents. Here, we overview an entire
E. histolytica
glycerophospholipid metabolic pathway based on re-evaluated whole lipidome and genome along with the results of metabolic labeling experiments. We also discuss whether the
E. histolytica
lipid metabolism network, including the glycerophospholipid metabolic pathway, has unique features necessary for parasitic life cycle adaptation through gene loss and/or gain, and raise important questions involving biochemistry, molecular cell biology, and physiology underlying this network. Answering these questions will advance the understanding of
Entamoeba
physiology and will provide potential targets to develop new anti-amoebiasis drugs.
Investigating
in vivo Mycobacterium avium
subsp.
paratuberculosis
microevolution and mixed strain infections
Authors: Byrne Alexander , Bissonnette Nathalie , Ollier Séverine , Tahlan Kapil 
Published: August 2023

ABSTRACT

Mycobacterium avium
subsp.
paratuberculosis
(MAP) causes Johne’s Disease (JD) in ruminants, which is responsible for significant economic loss to the global dairy industry. Mixed strain infection (MSI) refers to the concurrent infection of a susceptible host with genetically distinct strains of a pathogen, whereas within-host changes in an infecting strain leading to genetically distinguishable progeny is called microevolution. The two processes can influence host-pathogen dynamics, disease progression and outcomes, but not much is known about their prevalence and impact on JD. Therefore, we obtained up to 10 MAP isolates each from 14 high-shedding animals and subjected them to whole-genome sequencing. Twelve of the 14 animals examined showed evidence for the presence of MSIs and microevolution, while the genotypes of MAP isolates from the remaining two animals could be attributed solely to microevolution. All MAP isolates that were otherwise isogenic had differences in short sequence repeats (SSRs), of which SSR1 and SSR2 were the most diverse and homoplastic. Variations in SSR1 and SSR2, which are located in
ORF1
and
ORF2
, respectively, affect the genetic reading frame, leading to protein products with altered sequences and computed structures. The ORF1 gene product is predicted to be a MAP surface protein with possible roles in host immune modulation, but nothing could be inferred regarding the function of ORF2. Both genes are conserved in
Mycobacterium avium
complex members, but SSR1-based modulation of
ORF1
reading frames seems to only occur in MAP, which could have potential implications on the infectivity of this pathogen.

IMPORTANCE

Johne’s disease (JD) is a major problem in dairy animals, and concerns have been raised regarding the association of
Mycobacterium avium
subsp.
paratuberculosis
(MAP) with Crohn’s disease in humans. MAP is an extremely slow-growing bacterium with low genome evolutionary rates. Certain short sequence repeats (SSR1 and SSR2) in the MAP chromosome are highly variable and evolve at a faster rate than the rest of the chromosome. In the current study, multiple MAP isolates with genetic variations such as single-nucleotide polymorphisms, and more noticeably, diverse SSRs, could simultaneously infect animals. Variations in SSR1 and SSR2 affect the products of the respective genes containing them. Since multiple MAP isolates can infect the same animal and the possibility that the pathogen undergoes further changes within the host due to unstable SSRs, this could provide a compensative mechanism for an otherwise slow-evolving pathogen to increase phenotypic diversity for overcoming host responses.
Immune checkpoint inhibitor-associated myocarditis and fulminant type I diabetes in a patient with metastatic non-small cell lung cancer
Authors: Davis Brandon Matthew , Fordjour Isaac , Chahin Michael , Guha Avirup 
Published: August 2023

A woman in her mid-60s presented to the hospital due to a history of nausea, vomiting, shortness of breath, dyspnoea on exertion and polyuria. She was receiving medical therapy for advanced non-small cell lung cancer and recently initiated immune checkpoint inhibitor (ICI) immunotherapy. Investigations revealed lab results consistent with diabetic ketoacidosis (DKA), elevated cardiac biomarkers, multiple cardiac arrhythmias and reduced ejection fraction on transthoracic echocardiogram. Cardiac catheterisation showed non-obstructive coronary arteries.The patient was diagnosed with an ICI-associated myocarditis and type I diabetes due to recent initiation of the ICI durvalumab. She was treated with the institutional DKA protocol and received corticosteroid therapy for drug toxicity according to guidelines. She was discharged with marked improvement in symptoms. The patient had good recovery after discharge with further investigations showing improvement in her cardiac ejection fraction on cardiac MRI. She remains on medical therapy with an insulin regimen for diabetes management.
Unravelling the determinants of medical practice variation in referrals among primary care physicians: insights from a retrospective cohort study in Southern Israel
Authors: Shashar Sagi , Ellen Moriah , Codish Shlomi , Davidson Ehud , Novack Victor 
Published: August 2023

ObjectivesReducing medical practice variation (MPV) is a central theme of system improvement because it is associated with poor health outcomes, increased costs and disparities in care. This study aimed to estimate the extent to which each determinant (patient, physician, clinic) explains MPV among primary care physicians and to identify the characteristics of health services with a greater explained variance.MethodsA retrospective cohort study of primary care physicians practising in non-private clinics of Clalit Health Services in Southern Israel, for longer than a year between 2011 and 2017 and with more than 100 adult patients per practice. We assessed the variation in referral rates among 17 health services and the proportion explained by each domain (patient, physician and clinic). We used generalised linear negative binomial mixed models and the Nakagawa’s R2, computing the marginal r2.ResultsThe study included 243 physicians working in 295 practices and 139 clinics. The mean-explained variance was 28.5%±10.0%, where physician characteristics explained 4.5% of the variation. The intrapractice variation (within a single physician between the years) was explained better than the interphysician (between physicians). Health services with high explained variation were blood tests characterised by both low intrapractice variation (Rs=−0.65, p value=0.005) and high referral rates (Rs=0.46, p value=0.06).ConclusionOver 70% of MPV is not explained by the patient, clinic and physician demographic and professional characteristics. Future research should focus on the fraction of MPV that is explained by the physicians’ psychological characteristics, and thus potentially identify psychological targets for behavioural modifications aimed at reducing MPV.
Cepharanthine and Oral Lichen Planus Efficacy (COLE) study: protocol for a multicentre randomised controlled study assessing the efficacy and safety of cepharanthine with topical corticosteroids in oral lichen planus
Authors: Yagyuu Takahiro , Isogawa Masahiro , Yamamoto Kazuhiko , Sugiura Tsutomu , Matsusue Yumiko , Kasahara Masato , Kirita Tadaaki 
Published: August 2023

IntroductionOral lichen planus (OLP) is a chronic, inflammatory oral condition leading to a range of symptoms from mild discomfort to severe pain, affecting patients’ quality of life. Standard therapy involves the use of topical corticosteroids, although some patients respond insufficiently or develop resistance to therapy. We aim to explore if adding cepharanthine, an herbal extract fromStephania cepharanthaHayata, can enhance the efficacy of corticosteroid therapy in symptomatic OLP.Methods and analysisThis open-label, parallel-group, multi-centre, randomised controlled study will be conducted at three Japanese hospitals. It will compare safety and efficacy of integrated oral cepharanthine and corticosteroid therapy versus standard corticosteroid therapy. 50 symptomatic OLP patients will be randomised 1:1 to receive cepharanthine (30 mg/day) plus topical dexamethasone, or topical dexamethasone alone for 8 weeks. The primary outcome will be changed in pain intensity while drinking room-temperature water, measured on a visual analogue scale. The primary outcome is the change in pain intensity from baseline when drinking room-temperature water, evaluated using a visual analogue scale. Secondary outcomes are changes in the longest diameter of the target lesion from baseline to weeks 4 and 8, improvement and deterioration rates according to appearance and severity criteria at weeks 4 and 8, change in pain intensity when drinking room-temperature water from baseline to week 4, changes in pain intensity at rest from baseline to weeks 4 and 8, and the rates of adverse events.Ethics and disseminationThis protocol was approved by the Certified Review Board of Nara Medical University (CRB5200002). Participants will provide informed consent. Results will be disseminated in peer-reviewed journals and conferences.Trial registration numberJapan Registry of Clinical Trials (jRCTs051220130).
Randomised controlled trial of perinatal vitamin D supplementation to prevent early-onset acute respiratory infections among Australian First Nations children: the ‘D-Kids’ study protocol
Authors: Binks Michael J , Bleakley Amy S , Pizzutto Susan J , Lamberth Michelle , Powell Verity , Nelson Jane , Kirby Adrienne , Morris Peter S , Simon David , Mulholland E Kim , Rathnayake Geetha , Leach Amanda J , D'Antoine Heather , Licciardi Paul V , Snelling Tom , Chang Anne B 
Published: August 2023

IntroductionGlobally, acute respiratory infections (ARIs) are a leading cause of childhood morbidity and mortality. While ARI-related mortality is low in Australia, First Nations infants are hospitalised with ARIs up to nine times more often than their non-First Nations counterparts. The gap is widest in the Northern Territory (NT) where rates of both acute and chronic respiratory infection are among the highest reported in the world. Vitamin D deficiency is common among NT First Nations neonates and associated with an increased risk of ARI hospitalisation. We hypothesise that perinatal vitamin D supplementation will reduce the risk of ARI in the first year of life.Methods and analysis‘D-Kids’ is a parallel (1:1), double-blind (allocation concealed), randomised placebo-controlled trial conducted among NT First Nations mother–infant pairs. Pregnant women and their babies (n=314) receive either vitamin D or placebo. Women receive 14 000 IU/week or placebo from 28 to 34 weeks gestation until birth and babies receive 4200 IU/week or placebo from birth until age 4 months. The primary outcome is the incidence of ARI episodes receiving medical attention in the first year of life. Secondary outcomes include circulating vitamin D level and nasal pathogen prevalence. Tertiary outcomes include infant immune cell phenotypes and challenge responses. Blood, nasal swabs, breast milk and saliva are collected longitudinally across four study visits: enrolment, birth, infant age 4 and 12 months. The sample size provides 90% power to detect a 27.5% relative reduction in new ARI episodes between groups.Ethics and disseminationThis trial is approved by the NT Human Research Ethics Committee (2018-3160). Study outcomes will be disseminated to participant families, communities, local policy-makers, the broader research and clinical community via written and oral reports, education workshops, peer-reviewed journals, national and international conferences.Trial registration numberACTRN12618001174279.
Finding Voices: a survey of young people’s experiences of the ED
Authors: Keating Liza , Wilson Sarah , Dainty Jack , Jones Dominic , Hill Jonathan 
Published: August 2023

BackgroundMental health presentations in young people are increasing. Recurrence of self-harm (SH) presentations is common and of great concern since self-harm is known to be a risk factor for suicide. Previous reports suggest that the ED experience for this group is poor. A study was carried out at the Royal Berkshire NHS Foundation Trust. The objective was to pilot new and existing measures to capture the perceived needs and expectations of young people attending ED following SH compared with those attending with suspected fractures (SFs).MethodsYoung people were approached to complete a questionnaire as they arrived in ED and again before they left. Questionnaires were a combination of pre-existing tools as well as piloting novel questions specific to the ED where no suitable tool previously existed. Satisfaction with the ED treatment was measured along with reattendance up to one year later.ResultsThe survey was started in 2019 and suspended in March 2020 at the outset of the COVID-19 pandemic and subsequently closed, having screened 917 and recruited 104 adolescents. All the measures showed satisfactory psychometric properties with internal consistencies (alpha) of over 0.75. The two patient groups differed at baseline: it was found that the SH group had lower mood on the Short Mood and Feelings Questionnaire (p<0.001) and scored more highly on the Borderline Personality Features Scale for Children than the SF group (p<0.001) but the expectations of care across both groups was similar. Using the experience measures, the SH group was less satisfied with treatment than the SF group (p=0.0263).ConclusionOur findings underline the similarities between the two groups in terms of their expectations of care. Terminating the study early at the outset of the COVID-19 pandemic has precluded any further firm conclusions to be drawn. Further research is needed.
Impact of leaflet thrombosis on valve haemodynamic status after transcatheter aortic valve replacement
Authors: Jang Mi Hee , Ahn Jung-Min , Kang Do-Yoon , Kim Kyung Won , Koo Hyun Jung , Yang Dong Hyun , Jung Seung Chai , Kim Byungjun , Wong Yiu Tung Anthony , Lam Cheung Chi Simon , Yin Wei-Hsian , Wei Jeng , Lee Yung-Tsai , Kao Hsien-Li , Lin Mao-Shin , Ko Tsung-Yu , Kim Won-Jang , Kang Se Hun , Ko Euihong , Lee Seung-Ah , Kim Dae-Hee , Kim Hoyun , Choi Yeonwoo , Lee Jinho , Park Seung-Jung , Park Duk-Woo 
Published: August 2023

ObjectivesThe effect of subclinical leaflet thrombosis, characterised by hypoattenuated leaflet thickening (HALT), on the valve haemodynamic function and durability of the bioprosthetic valve, is not yet determined. We determined the impact of HALT on valve haemodynamics after transcatheter aortic valve replacement (TAVR) and the predictors of haemodynamic structural valve deterioration (SVD).MethodsThe Anticoagulation vs Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization after Transcatheter Aortic Valve Replacement(ADAPT-TAVR) trial is a multicenter, randomised trial that compared edoxaban and dual antiplatelet therapy in patients who had undergone successful TAVR. The presence of HALT was evaluated by four-dimensional CT at 6 months and serial echocardiography performed at baseline, immediately post-TAVR and after 6 months. SVD was defined as at least one of the following: (1) mean transprosthetic gradient ≥20 mm Hg, (2) change in the mean gradient ≥10 mm Hg from baseline, or (3) new or increase in intraprosthetic aortic regurgitation of at least ≥1 grade, resulting in moderate or greater regurgitation.ResultsAt 6 months, HALT was found in 30 of 211 (14.2%) patients. The presence of HALT did not significantly affect aortic valve mean gradients (with vs without HALT; 14.0±4.8 mm Hg vs 13.7±5.5 mm Hg; p=0.74) at 6 months. SVD was reported in 30 of 206 patients (14.6%) at 6-month follow-up echocardiography. Older age (OR: 1.138; 95% CI: 1.019 to 1.293; p=0.033), use of aortic valve size ≤23 mm (OR: 6.254; 95% CI: 2.230 to 20.569; p=0.001) and mean post-TAVR pressure gradient (OR: 1.233; 95% CI: 1.123 to 1.371; p<0.001) were independent predictors of haemodynamic SVD; however, the presence of HALT was not identified as a predictor of SVD.ConclusionsIn patients who had undergone successful TAVR, aortic valve haemodynamic status was not influenced by the presence of HALT. Although HALT was not a predictor of haemodynamic SVD at 6 months, it warrants further longer-term follow-up to evaluate the effect on long-term valve durability.Trial registration numberNCT03284827(https://www.clinicaltrials.gov).
Nuclear staining for pan-Trk by immunohistochemistry is highly specific for secretory carcinoma of breast: pan-Trk in various subtypes of breast carcinoma
Authors: Ye Qiqi , Chen Hui , Han Cody , Peng Yan , Huang Xiao , Sun Hongxia , Wu Yun , Albarracin Constance T , Middleton Lavinia P , Sahin Aysegul A , Huo Lei , Ding Qingqing 
Published: August 2023

AimsSecretory carcinoma of breast (SCB) typically harboursETV6-NTRK3gene fusion. Pan-Trk immunohistochemistry analysis (IHC) has been shown to be sensitive for SCB diagnosis. However, weak focal pan-Trk nuclear staining was previously found in 10% of non-secretory breast carcinomas. To further examine pan-Trk IHC specificity, we evaluated pan-Trk staining in various breast carcinoma subtypes.MethodsThe study cohort consisted of 346 invasive breast carcinomas (IBCs), including 8 SCBs and 48 triple-negative histological mimickers (36 metaplastic carcinomas, including 12 matrix-producing carcinomas; 5 adenoid cystic carcinomas; 5 apocrine carcinomas; 2 acinic cell carcinomas), 101 triple-negative IBCs of no special type, 101 estrogen receptor (ER)-positive/HER2-negative IBCs and 88 HER2-positive IBCs. Six salivary gland secretory carcinomas were also included. Pan-Trk IHC was performed on tumours using a rabbit monoclonal pan-Trk antibody. Any nuclear staining in the invasive carcinoma cells was considered positive.ResultsAll 14 secretory carcinomas from breast and salivary gland exhibited moderate to strong pan-Trk nuclear staining. In contrast, no pan-Trk nuclear staining was identified in any of the 338 non-secretory IBCs. Focal cytoplasmic pan-Trk staining was observed in nine non-secretory IBCs (2.7%), and was considered nonspecific and negative.ConclusionsOur results indicate that pan-Trk nuclear staining is highly specific for SCB. In low-grade to intermediate-grade IBCs that share histological features with SCB, adding pan-Trk to a routing panel of estrogen receptor/progesterone receptor/HER2 is highly diagnostic. Our results also support using pan-Trk IHC to differentiate SCB from its triple-negative histological mimickers, such as adenoid cystic carcinoma, matrix-producing carcinoma, apocrine carcinoma and acinic cell carcinoma.
Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin
Authors: Zhang Zhijie , Liu Chang , Wang Muhan , Sun Rongcheng , Yang Zhe , Hua Zhen , Wu Yushuang , Wu Mengting , Wang Hang , Qiu Wen , Yin Hongping , Yang Meijia 
Published: August 2023

BackgroundThe suppression of chimeric antigen receptor (CAR) T cells by the tumor microenvironment (TME) is a crucial obstacle in the T-cell-based treatment of solid tumors. Extra domain B (EDB)-fibronectin is an oncofetal antigen expressed on the endothelium layer of the neovasculature and cancer cells. Though recognized as a T cell therapy target, engineered CAR T cells thus far have failed to demonstrate satisfactory in vivo efficacy. In this study, we report that targeting EDB-fibronectin by redirected TCR-CAR T cells (rTCR-CAR) bypasses the suppressive TME for solid tumor treatment and sufficiently suppressed tumor growth.We generated EDB-targeting CAR by fusing single-chain variable fragment to CD3ε, resulting in rTCR-CAR. Human primary T cells and Jurkat cells were used to study the EDB-targeting T cells. Differences to the traditional second-generation CAR T cell in signaling, immune synapse formation, and T cell exhaustion were characterized. Cytotoxicity of the rTCR-CAR T cells was tested in vitro, and therapeutic efficacies were demonstrated using xenograft models.MethodsResultsIn the xenograft models, the rTCR-CAR T cells demonstrated in vivo efficacies superior to that based on traditional CAR design. A significant reduction in tumor vessel density was observed alongside tumor growth inhibition, extending even to tumor models established with EDB-negative cancer cells. The rTCR-CAR bound to immobilized EDB, and the binding led to immune synapse structures superior to that formed by second-generation CARs. By a mechanism similar to that for the conventional TCR complex, EDB-fibronectin activated the rTCR-CAR, resulting in rTCR-CAR T cells with low basal activation levels and increased in vivo expansion.ConclusionOur study has demonstrated the potential of rTCR-CAR T cells targeting the EDB-fibronectin as an anticancer therapeutic. Engineered to possess antiangiogenic and cytotoxic activities, the rTCR-CAR T cells showed therapeutic efficacies not impacted by the suppressive TMEs. These combined characteristics of a single therapeutic agent point to its potential to achieve sustained control of solid tumors.
CLN-978, a novel half-life extended CD19/CD3/HSA-specific T cell-engaging antibody construct with potent activity against B-cell malignancies with low CD19 expression
Authors: Meetze Kristan , Mehta Naveen K , Li Bochong , Findlay Hannah M , London Timothy B , Patakas Agapitos , Michaelson Jennifer S , Baeuerle Patrick A 
Published: August 2023

BackgroundDespite significant progress in the development of T cell-engaging therapies for various B-cell malignancies, a high medical need remains for the refractory disease setting, often characterized by suboptimal target levels.MethodsTo address this issue, we have developed a 65-kDa multispecific antibody construct, CLN-978, with affinities tuned to optimize the killing of low-CD19 expressing tumor cells. CLN-978 bound to CD19 on B cells with picomolar affinity, and to CD3ε on T cells with nanomolar affinity. A serum albumin binding domain was incorporated to extend serum half-life. In this setting, we biophysically characterize and report the activities of CLN-978 in cell co-culture assays, multiple mouse models and non-human primates.ResultsHuman T cells redirected by CLN-978 could eliminate target cells expressing less than 300 copies of CD19 on their surface. The half-life extension and high affinity for CD19 led to significant antitumor activity in murine lymphoma models at very low doses of CLN-978. In primates, we observed a long serum half-life, deep and sustained depletion of normal B cells, and remarkable tolerability, in particular, reduced cytokine release when CLN-978 was administered subcutaneously.ConclusionsCLN-978 warrants further exploration. An ongoing clinical phase 1 trial is investigating safety, pharmacokinetics, pharmacodynamics, and the initial therapeutic potential of subcutaneously administered CLN-978 in patients with non-Hodgkin’s lymphoma.