bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surgical Treatment of Ischial Ulcers Associated with Deposition of β2-Microglobulin in Two Cases of Dialysis-related Amyloidosis
Authors: Fujita Tamaki , Hasegawa Yuuki , Osa Nagisa , Niimi Yosuke , Sakurai Hiroyuki 
Published: June 2023

Summary:
The accumulation of β2-microglobulin due to long-term hemodialysis is known as dialysis-related amyloidosis, a rare phenomenon that manifests as a subcutaneous mass. Subcutaneous β2-microglobulin amyloidomas are predominantly located on the buttocks. Owing to the load-bearing properties of this location and proximity to the anus, amyloidomas on the buttocks may be prone to pressure ulcers and infection. This report presents two cases of long-term hemodialysis patients who required surgical treatment for infected ulcers caused by buttock amyloidomas. In the first case, treatment failed after the amyloidoma was excised and covered with a single-stage skin flap. In the second case, successful treatment was accomplished by reducing the volume of the amyloidoma, followed by a pause to allow for granulation growth and a two-stage skin graft. Amyloids of this nature are known to be cytotoxic; thus, a robust wound preparation technique should be used until the excision site is fully covered with granulation tissue before wound closure is initiated at the time of surgery. In addition, buttock amyloidomas often extend subcutaneously through the hip joint, and repeated infections may lead to more severe outcomes, such as hip joint infections. The number of dialysis-related amyloidosis patients has been increasing in recent years; thus, we report these case studies to improve patient outcomes in similar cases.
Prediction of long-term survival among patients with cirrhosis using time-varying models
Authors: Goldberg David , Zarnegarnia Yalda 
Published: June 2023

Background:
Risk prediction among patients with cirrhosis has historically focused on short-term (ie, 90 days) mortality among patients waitlisted for a transplant. Although several models have been developed to predict intermediate and longer term survivals, they have important limitations, namely, including only baseline laboratory and clinical variables to predict survival over a time horizon of years.

Methods:
We developed prediction models using time-varying laboratory and clinical data among patients with cirrhosis in the OneFlorida Clinical Research Consortium. We fit extended Cox models and assessed model discrimination and calibration in complete-case analysis and imputation of missing laboratory data.

Results:
Among 15,277 patients, 9922 (64.9%) were included in the complete-case analysis. Final models included demographic (age and sex), time-updating laboratory (albumin, alanine transaminase, alkaline phosphatase, bilirubin, platelet, and sodium), and time-updating clinical (ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and bleeding esophageal varices) variables. Model discrimination was excellent in the complete-case analysis [AUC and concordance-index (C-index) > 0.85] at 1-, 2-, 3-, 4-, and 5-year time points. Model performance was unchanged with the exclusion of race and ethnicity as model predictors. Model discrimination was excellent (C-index >0.8) when imputation was used for patients with 1 or 2 missing laboratory variables.

Discussion:
Using data from a statewide sample of patients with cirrhosis, we developed and internally validated a time-updating model to predict survival with excellent discrimination. Based on its measures of discrimination (AUC and c-index), this model matched or exceeded the performance of other published risk models depending on the time horizon. If externally validated, this risk score could improve the care of patients with cirrhosis by improving counseling on intermediate and longer term outcomes to guide clinical decision-making and advanced care planning.
Exosome-associated lysophosphatidic acid signaling contributes to cancer pain
Authors: Khasabova Iryna A. , Khasabov Sergey G. , Johns Malcolm , Juliette Joe , Zheng Aunika , Morgan Hannah , Flippen Alyssa , Allen Kaje , Golovko Mikhail Y. , Golovko Svetlana A. , Zhang Wei , Marti James , Cain David , Seybold Virginia S. , Simone Donald A. 
Published: June 2023

Abstract
Pain associated with bone cancer remains poorly managed, and chemotherapeutic drugs used to treat cancer usually increase pain. The discovery of dual-acting drugs that reduce cancer and produce analgesia is an optimal approach. The mechanisms underlying bone cancer pain involve interactions between cancer cells and nociceptive neurons. We demonstrated that fibrosarcoma cells express high levels of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA). Lysophosphatidic acid increased proliferation of fibrosarcoma cells in vitro. Lysophosphatidic acid is also a pain-signaling molecule, which activates LPA receptors (LPARs) located on nociceptive neurons and satellite cells in dorsal root ganglia. We therefore investigated the contribution of the ATX–LPA–LPAR signaling to pain in a mouse model of bone cancer pain in which fibrosarcoma cells are implanted into and around the calcaneus bone, resulting in tumor growth and hypersensitivity. LPA was elevated in serum of tumor-bearing mice, and blockade of ATX or LPAR reduced tumor-evoked hypersensitivity. Because cancer cell–secreted exosomes contribute to hypersensitivity and ATX is bound to exosomes, we determined the role of exosome-associated ATX–LPA–LPAR signaling in hypersensitivity produced by cancer exosomes. Intraplantar injection of cancer exosomes into naive mice produced hypersensitivity by sensitizing C-fiber nociceptors. Inhibition of ATX or blockade of LPAR attenuated cancer exosome-evoked hypersensitivity in an ATX–LPA–LPAR-dependent manner. Parallel in vitro studies revealed the involvement of ATX–LPA–LPAR signaling in direct sensitization of dorsal root ganglion neurons by cancer exosomes. Thus, our study identified a cancer exosome-mediated pathway, which may represent a therapeutic target for treating tumor growth and pain in patients with bone cancer.
Clinical Characteristics Associated With Posttransplant Survival Among Adults 70 Years Old or Older Undergoing Liver Transplantation
Authors: Wang Melinda , Ge Jin , Ha Nghiem , Shui Amy M. , Huang Chiung-Yu , Cullaro Giuseppe , Lai Jennifer C. 
Published: June 2023

Goals:
We sought to identify pre-liver transplantation (LT) characteristics among older adults associated with post-LT survival.

Background:
The proportion of older patients undergoing deceased-donor liver transplantation (DDLT) has increased over time.

Study:
We analyzed adult DDLT recipients in the United Network for Organ Sharing registry from 2016 through 2020, excluding patients listed as status 1 or with a model of end-stage liver disease exceptions for hepatocellular carcinoma. Kaplan-Meier methods were used to estimate post-LT survival probabilities among older recipients (age ≥70 y). Associations between clinical covariates and post-LT mortality were assessed using Cox regressions.

Results:
Of 22,862 DDLT recipients, 897 (4%) were 70 years old or older. Compared with younger recipients, older recipients had worse overall survival (P < 0.01) (1 y: 88% vs 92%, 3 y: 77% vs 86%, and 5 y: 67% vs 78%). Among older adults, in univariate Cox regressions, dialysis [hazards ratio (HR): 1.96, 95% CI: 1.38-2.77] and poor functional status [defined as Karnofsky Performance Score (KPS) <40] (HR: 1.82, 95% CI: 1.31-2.53) were each associated with mortality, remaining significant on multivariable Cox regressions. The effect of dialysis and KPS <40 at LT on post-LT survival (HR: 2.67, 95% CI: 1.77-4.01) was worse than the effects of either KPS <40 (HR: 1.52, 95% CI: 1.03-2.23) or dialysis alone (HR: 1.44, 95% CI: 0.62-3.36). Older recipients with KPS >40 without dialysis had comparable survival rates compared with younger recipients (P = 0.30).

Conclusions:
While older DDLT recipients had worse overall post-LT survival compared with younger recipients, favorable survival rates were observed among older adults who did not require dialysis and had poor functional status. Poor functional status and dialysis at LT may be useful to stratify older adults at higher risk for poor post-LT outcomes.
Endoscopic Balloon Dilatation-Based Membrane Resection for Membranous Duodenal Stenosis: A Feasibility and Safety Study (With Video)
Authors: Wang Xing , Lin Kai , Liu Haifeng , Hu Zhihong , Ye Guogang , Sheng Qingfeng , Lv Zhibao 
Published: June 2023

Objectives:
Surgery is generally considered as the first-line therapy for membranous duodenal stenosis (MDS) in children. However, abdominal surgery leaves permanent scars and may even cause intestinal adhesion. Therefore, an effective, safe, and minimally invasive method is urgently needed. This study aimed to evaluate the safety, efficacy, and feasibility of endoscopic balloon dilatation-based membrane resection (EBD-MR) to treat MDS in children.

Methods:
We retrospectively reviewed patients with MDS treated with EBD-MR in Shanghai Children’s Hospital from May 2016 to August 2021. Primary study outcome was clinical success, defined as weight gain and complete remission of vomiting, without the need for repeat endoscopic or surgical intervention during follow-up. Secondary outcomes included technical success, diameter changes of the membrane opening, and adverse events.

Results:
Nineteen children (9 females, mean age 14.5 ± 11.2 months) received endoscopic treatment for MDS, and clinical success was achieved in 18 of 19 patients (94.7%). No bleeding, perforation, and jaundice occurred. Diameters of the membrane opening increased from 2.97 ± 2.87 mm to 9.78 ± 1.27 mm after the treatment, symptoms of vomiting did not reappear during 10–73 months of follow-up, and body mass index of the children increased from 14.9 ± 2.2 kg/m2 (pre-operation) to 16.2 ± 3.7 kg/m2 (6 months after operation). One patient required surgical revision because of existence of a second web; three patients received 2–3 sessions of endoscopic treatment to obtain the final remission.

Conclusions:
The EBD-MR technique is safe, effective, and feasible for MDS, which provided an excellent alternative to surgical management for the disease in pediatric patients.
Ultrasound-Guided Injections for Treatment of Facial Paralysis Sequelae: A Randomized Study on Body Donors
Authors: Vejbrink Kildal Villiam , Rodriguez-Lorenzo Andrés , Pruidze Paata , Reissig Lukas , Weninger Wolfgang J. , Tzou Chieh-Han John , Jonsson Lars , Meng Stefan 
Published: June 2023

Background:
Botulinum toxin injection is the gold standard treatment of synkinesis and gustatory hyperlacrimation in facial paralysis patients. However, poor injection accuracy may lead to suboptimal treatment results and complications. Diplopia, ptosis, and lagophthalmos are common after lacrimal gland injections. Intra-ocular injections have been reported in the treatment of both synkinesis and excessive tearing. Ultrasound guidance should increase injection accuracy in the facial region, but this has not been proven.

Methods:
Twenty-six hemifaces of non-embalmed cadavers were studied in a randomized split-face manner. Ink was injected with ultrasound or landmark guidance into the lacrimal gland and three common synkinetic muscles: the orbicularis oculi, depressor anguli oris, and mentalis. Injection accuracy was evaluated through several measures.

Results:
Using ultrasound guidance, most ink (>50%) was found inside the correct target in 88% of cases, compared with 50% using landmark guidance (p<0.001). This was most pronounced in the lacrimal gland (62% vs. 8%), depressor anguli oris (100% vs. 46%), and mentalis (100% vs. 54%) (p<0.05). All ink was found inside the correct target (no ink outside) in 65% using ultrasound guidance vs. 29% without (p<0.001). Injection accuracy (any ink in target) was 100% when using ultrasound guidance vs. 83% without (p<0.01). Twenty-three percent of landmark-guided depressor anguli oris injections stained the facial artery (p=0.22).

Conclusions:
Ultrasound guidance significantly increased injection accuracy and reduced the amount of ink lost in surrounding tissue when compared with landmark guidance. Clinical trials are needed to explore the effects of ultrasound guidance on treatment outcome, duration, and complications in facial paralysis patients.
Capture Efficiency Of Long-Adapter Single-Strand Oligonucleotide Probe Libraries
Authors: Chkaiban Lamia , Tosi Lorenzo , Parekkadan Biju 
Published: June 2023

AbstractHigh throughput techniques that can massively produce in parallel, longer DNA sequences of interest can accelerate the decoding of gene functions. LASSO probes are a molecular biology tool that can enrich for DNA targets in a genomic sample via a multiplexed, single-pot reaction for downstream sequencing and/or cloning. Here we have explored aspects of process development and the design of the probes that relate to binding thermodynamics to determine impact on cloned library sequences. Control of ligase concentration, polymerase type, and melting temperature of probe are critical when translating the use of LASSO probes for homogeneous and high fidelity DNA capture.
Micro-circulating hyperdynamic blood flow as a key pathogenic factor in early sepsis
Authors: Feng X.H. , Liu Wei , Sun Y.B. , Zeng Y. , Yu Bu-Wei 
Published: June 2023

AbstractObjectiveThe pathogenesis of sepsis is still unknown. Sepsis 3.0 points out that “how to define sepsis and septic shock itself is still a challenge”. This study confirmed the inevitability and universality of Hyperdynamic microcirculation in sepsis, and put forward the detoxification mechanism of Hyperdynamic blood flow and the “Feng-Bernoulli warm shock” mechanism, that is, the pathogenic mechanism of sepsis.MethodsSepsis models of pigs, rabbits and sheep were established by intravenous injection of lipopolysaccharide (LPS) and cecal ligation and perforation (CLP), and the changes of sublingual microcirculation velocity in the same branch before and after modeling were detected. SD rat model of mild sepsis was established to verify that the acceleration of blood flow is the manifestation of immune detoxification mechanism.ResultsThe blood flow in the same branch was accelerated after the animal sepsis model was established, which was more than doubled on average. The microcirculation blood flow accelerated before the change of cardiac output CO. Rats entered a toxic state after the rapid blood flow occurred, but they could heal themselves.ConclusionThe acceleration of microcirculation blood flow in sepsis is inevitable and universal, which is the cause of high output and low resistance of sepsis, and has the functions of accelerating detoxification and immunity. However, due to Bernoulli effect, it will cause oxygen exchange disorder, which is named “Feng-Bernoulli warm shock”, ultimately leading to hypoxia. This is the primary pathogenic mechanism of early sepsis.
Re-annotation of SARS-CoV-2 proteins using an HHpred-based approach opens new opportunities for a better understanding of this virus
Authors: Brézellec Pierre 
Published: June 2023

AbstractSince the publication of the genome of SARS-CoV-2 – the causative agent of COVID-19 – in January 2020, many bioinformatic tools have been applied to annotate its proteins. Although effcient methods have been used, such as the identification of protein domains stored in Pfam, most of the proteins of this virus have no detectable homologous protein domains outside the viral taxa. As it is now well established that some viral proteins share similarities with proteins of their hosts, we decided to explore the hypothesis that this lack of homologies could be, at least in part, the result of the documented loss of sensitivity of Pfam Hidden Markov Models (HMMs) when searching for domains in “divergent organisms”. In order to improve the annotation of SARS-CoV-2 proteins, we used the HHpred protein annotation tool. To avoid “false positive predictions” as much as possible, we designed a robustness procedure to evaluate the HHpred results. In total, 6 robust similarities involving 6 distinct SARS-CoV-2 proteins were detected. Of these 6 similarities, 3 are already known and well documented, and one is in agreement with recent crystallographic results. We then examined carefully the two similarities that have not yet been reported in the literature. We first show that the C-terminal part of Spike S (the protein that binds the virion to the cell membrane by interacting with the host receptor, triggering infection) has similarities with the human prominin-1/CD133; after reviewing what is known about prominin-1/CD133, we suggest that the C-terminal part of Spike S could both improve the docking of Spike S to ACE2 (the main cell entry receptor for SARS-CoV-2) and be involved in the delivery of virions to regions where ACE2 is located in cells. Secondly, we show that the SARS-CoV-2 ORF3a protein shares similarities with human G protein-coupled receptors (GPCRs), such as Lutropin-choriogonadotropic hormone receptor, primarily belonging to the “Rhodopsin family”. To further investigate these similarities, we compared Prominin 1 and Lutropin-choriogonadotropic hormone receptor to a set of viral proteins using HHPRED. Interestingly, Prominin 1 showed similarities with 6 viral Spike glycoproteins, primarily from coronaviruses. Equally interestingly, Lutropin-choriogonadotropic hormone receptor showed similarities with 23 viral G-protein coupled receptors, particularly from Herpesvirales. We conclude that the approach described here (or similar approaches) opens up new avenues of research to better understand SARS-CoV-2 and could be used to complement virus annotations, particularly for less-studied viruses.
Defining Microbial Community Functions in Chronic Human Infection with Metatranscriptomics
Authors: Adekoya Aanuoluwa E. , Kargbo Hoody A. , Ibberson Carolyn B. 
Published: June 2023

AbstractChronic polymicrobial infections (cPMIs) harbor complex bacterial communities with diverse metabolic capacities, leading to competitive and cooperative interactions. Although the microbes present in cPMIs have been established through culture-dependent and -independent methods, the key functions that drive different cPMIs and the metabolic activities of these complex communities remain unknown. To address this knowledge gap, we analyzed 102 published metatranscriptomes collected from cystic fibrosis sputum (CF) and chronic wound infections (CW) to identify key bacterial members and functions in cPMIs. Community composition analysis identified a high prevalence of pathogens, particularlyStaphylococcusandPseudomonas, and anaerobic members of the microbiota, includingPorphyromonas, Anaerococcus, and Prevotella. Functional profiling with HUMANn3 and SAMSA2 revealed that while functions involved in bacterial competition, oxidative stress response, and virulence were conserved across both chronic infection types, ≥40% of the functions were differentially expressed (padj < 0.05, fold-change >2). Higher expression of antibiotic resistance and biofilm functions were observed in CF, while tissue destructive enzymes and oxidative stress response functions were highly expressed in CW samples. Of note, strict anaerobes had negative correlations with traditional pathogens in both CW (P= -0.43) and CF (P= -0.27) samples and they significantly contributed to the expression of these functions. Additionally, we show microbial communities have unique expression patterns and distinct organisms fulfill the expression of key functions in each site, indicating the infection environment strongly influences bacterial physiology and that community structure influences function. Collectively, our findings indicate that community composition and function should guide treatment strategies for cPMIs.ImportanceThe microbial diversity in polymicrobial infections (PMIs) allows for community members to establish interactions with one another which can result in enhanced disease outcomes such as increased antibiotic tolerance and chronicity. Chronic PMIs result in large burdens on health systems, as they affect a significant proportion of the population and are expensive and difficult to treat. However, investigations into physiology of microbial communities in actual human infection sites is lacking. Here, we highlight that the predominant functions in chronic PMIs differ, and anaerobes, often described as contaminants, may be significant in the progression of chronic infections. Determining the community structure and functions in PMIs is a critical step towards understanding the molecular mechanisms that drive microbe-microbe interactions in these environments.
Structural Basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB
Authors: Kot Erik F. , Goncharuk Sergey A. , Franco María Luisa , Arseniev Alexander S. , Benito-Martínez Andrea , Costa Mario , Cattaneo Antonino , Vilar Marçal , Mineev Konstantin S. 
Published: June 2023

ABSTRACTNeurotrophin receptors of the Trk family are involved in the regulation of brain development and neuroplasticity, and therefore can serve as targets for anti-cancer and stroke-recovery drugs, antidepressants, and many others. The structures of Trk protein domains in various states upon activation need to be elucidated to allow rational drug design. However, little is known about the conformations of the transmembrane and juxtamembrane domains of Trk receptors. In the present study, we employed NMR spectroscopy to solve the structure of the TrkB dimeric transmembrane domain in the lipid environment. We verified the structure using mutagenesis and confirmed that the conformation corresponds to the active state of the receptor. Subsequent study of TrkB interaction with the antidepressant drug fluoxetine, and the antipsychotic drug chlorpromazine, provided a clear self-consistent model, describing the mechanism by which fluoxetine activates the receptor by binding to its transmembrane domain.
Structural Organization of the Retriever-CCC Endosomal Recycling Complex
Authors: Boesch Daniel J. , Singla Amika , Han Yan , Kramer Daniel A. , Liu Qi , Suzuki Kohei , Juneja Puneet , Zhao Xuefeng , Long Xin , Medlyn Michael J. , Billadeau Daniel D. , Chen Zhe , Chen Baoyu , Burstein Ezra 
Published: June 2023

AbstractThe recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.