bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Short-Course Antibiotic Therapy Suitable for Pseudomonas Aeruginosa Bloodstream Infections in Onco-Hematology Patients with Febrile Neutropenia? Results of a Multi-Institutional Analysis
Authors: Feng Xiaomeng , Jiang Erlie , Feng Sizhou
Published: December 2023

Background. Several studies have suggested that short-course antibiotic therapy does not increase infection recurrence or mortality in immunocompetent patients. While similar studies in patients with hematological malignancies were rare.

Methods. This cohort included onco-hematology patients with Pseudomonas aeruginosa (PA) bloodstream infections (BSI). These patients had undergone chemotherapy or hematopoietic stem cell transplantation (HSCT) and experienced febrile neutropenia. Inverse probability of treatment weighting was used to balance the confounding factors.

Results. 434 patients met eligibility criteria (short-course, 7-11 days, n=229; prolonged therapy, 12-21 days, n=205). In the weighted cohort, after multivariate analysis, the recurrent PA infection at any site or mortality within 30 days of completing therapy occurred in 8 (3.9%) patients in the short-course group and in 10 (4.9%) in the prolonged-course group ( p = 0.926), the recurrent infection within 90 days occurred in 20 (9.8%) patients in the short-course group and in 13 (6.3%) patients in the prolonged-course group ( p =0.276), and the recurrent fever within 7 days occurred in 17 (8.3%) patients in the short-course group and in 15 (7.4%) in the prolonged-course group ( p = 0.980). While multidrug-resistant PA, relapsed/refractory hematological malignancies and perianal mucositis were the key determinants of infection recurrence/mortality other than the short course of antibiotic treatment (p<0.05 for all). On average, patients who received short-course antibiotic therapy spent 3.3 fewer days in the hospital ( p<0.001).

Conclusions. We found that onco-hematology patients with PA BSI who received approximately 8 days of antibiotics had similar clinical outcomes to those who received a prolonged-course therapy, with the potential added benefit of earlier hospital discharge.
Impact of Multiple Minor Histocompatibility Antigen Differences on Graft-Versus-Host Disease and Relapse Risk in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients
Authors: Mueller Christian , Alawi Malik , Loeffler Juergen , Bonin Michael , Schreiber Andreas , Kreyenberg Hermann , Wiegering Verena , Woelfl Matthias , Caruana Ignazio , Schlegel Paul G. , Eyrich Matthias
Published: December 2023

BACKGROUND Success of allogeneic hematopoietic cell transplantation (alloHCT) is sharped by alloreactivity, i.e. the ability of donor T-cells to recognize particular recipient motifs as non-self and get activated. Donor T-cells recognizing recipient tissue can cause harmful graft-versus-host disease (GvHD) while activity against leukemic blasts can protect against relapse (GvL). In HLA-matched alloHCT, alloreacticity is driven by subtle nonpathogenic variants in natural proteins, socalled minor histocompatibility antigens (miHAgs), however, not all variants are immunogenic. METHODS To analyze the impact of mHAgs-differences on alloHCT outcomes, we selected a purely pediatric cohort of 102 HLA-matched allo HCTs transplanted between 2003 and 2017. Panel sequencing of 46 validated miHAgs was performed using Ilumina MiSeq, only variants in the graft-versus-host direction were considered. RESULTS In a logistic regression model for the whole cohort acute GvHD incidence was significantly dependent on the proportion of miHAg mismatches (all genes) with an 95%-CI 1.0263-1.1998, p=.01 and an odds ratio of 1.1066. From all variants tested, only mismatches in TRIM42 were significant as a predictor with a FDR <.05. Furthermore, proportion of mismatches was a predictor of all-cause mortality. Risk of relapse was evaluated by regression analysis for competing risks: proportion of miHAg mismatches failed to be predictive for relapse ( p=.37). However, looking at patients with acute lymphobastic leukemia (ALL) only (n=36), mismatches in hematopoiesis-restricted genes protected from relapse (95%-CI 1.0016-1.0712, p=.04, hazard ratio 1.0358). CONCLUSION Thus, in children GvHD and mortality seem to be related to the overall number of miHAg-differences whereas variants in hematopoiesis-restriced genes protect from ALL relapse. These data implicate that selection of TCRs with a specificity for hematopoietic miHAgs could be a way to improve GvL effect without increasing the risk of GvhD.
Checkpoint Inhibitor PD-1H/VISTA Affects Myeloma Bone Disease By Osteoclast Cytoskeleton Remodeling
Authors: Fu Jing , Li Shirong , MA Huihui , Brown Lewis M , Mapara Markus , Lentzsch Suzanne
Published: December 2023

Introduction

We have recently described the critical role of checkpoint inhibitor PD-1H/VISTA in osteoclast activation and multiple myeloma bone disease. Highly expressed in osteoclast precursors and mature osteoclasts, PD-1H functions as the receptor for osteoclastogenic factor MMP-13 and mediates MMP-13 induced osteoclast activation and myeloma bone disease ( Nat Commun14, 4271 (2023)). Despite the extensive functional study of PD-1H in immune disease models, the PD-1H interacting cellular complex is yet to be defined. Here we report how PD-1H interacts with cytoskeleton proteins contributing to osteoclast remodeling in multiple myeloma bone disease.

Methods and Results

To identify interacting proteins of PD-1H, PD-1H-His 6 recombinant protein was overexpressed in mouse mononuclear BMCs, and PD-1H-His 6 binding protein complex was pulled down by Ni-NTA agarose beads followed by mass spectrum analysis (Figure A). LIM and SH3 domain protein 1 (LASP1) was one of the most abundant cytoskeleton proteins identified in the PD-1H complex. We therefore first confirmed its binding to PD-1H by two-way co-IP assays (Figure B and C). Co-localization of LASP1 and PD-1H were further confirmed by immunofluorescence assay when co-expressed in HEK293 cells (Figure D). LASP1 is an F-actin-binding protein that stabilizes F-actin bundles and is involved in podosome regulation in macrophages (PLoS ONE 7(4): e35340). It has four domains: LIM, two nebulin-like repeats (N1 and N2) and SH3 domains. While nebulin-like repeats mediate binding to F-actin, SH3 domain is the major protein-protein binding site (PLoS ONE 7(4): e35340). In co-IP assay using PD-1H and domain deleted LASP1, deletion of LIM (△LIM) or either one or both nebulin-like repeats (△N1, △N2 and △N1/2) did not affect the binding to PD-1H. Instead, deletion of SH3 (△SH3) in LASP1 lead to loss of PD-1H binding, demonstrating that PD-1H binds to LASP1 at the SH3 domain (Figure E). Next, the association of LASP1 and PD-1H in the osteoclast cytoskeleton was demonstrated by confocal immunofluorescence microscopy. LASP1 co-localized with F-actin (Figure F) and PD-1H (Figure G) at the sealing ring in mature osteoclasts. Interestingly, although MMP-13 stimulation increased the size of osteoclasts and the sealing ring, MMP-13 did not change the co-localization pattern of LASP1 with PD-1H or F-actin.

Conclusions

Taken together, this study reveals the novel mechanism of PD-1H regulation of osteoclasts cytoskeleton reorganization, which is critical for osteoclast bone resorption activity. PD-1H directly associates with LASP1 at its C-terminal SH3 domain. Although LASP1 was reported to regulates podosomes function in macrophages, its role in osteoclast cytoskeletons remain largely obscure. The future study will be focused on delineating the role of LASP1 in osteoclast function, and its role in MMP-13/PD-1H signaling regulated myeloma bone disease.
Correlation of TCR Repertoire Diversity with Myeloid Gene Mutations in Chronic and Advanced Phase Myeloproliferative Neoplasms
Authors: Piris-Villaespesa Miguel , Marquet Juan , Fernandez-Lanza Val , García Gutiérrez Valentín , Jimenez Carlos , del Castillo Francisco J , Muñoz Gloria , López Javier
Published: December 2023

Introduction: Myeloproliferative neoplasms (MPN) are characterized by a chronic phase (CP), with indolent clinical behavior and, in 10-30% of cases, progression to advanced phases (AP), with aggressive behavior and compromised prognosis. Numerous factors have been associated with progression to AP, including the acquisition of mutations in recurrently mutated myeloid genes (1,2). On the other hand, decreased diversity in the T-cell receptor (TCR) repertoire has been associated with worse prognosis in solid tumors. The purpose of this work is to study the correlation between the acquisition of mutations in myeloid genes and the diversity of the TCR repertoire in chronic and advanced myeloproliferative neoplasms.

Methods: Patients with chronic CP and AP myeloproliferative neoplasms were selected. The selected patients underwent an NGS panel of 48 myeloid genes. Only pathogenic (P) or likely pathogenic (LP) variants were considered. In parallel, the study of the TCR repertoire by NGS with the panel “AmpliSeq for Illumina Immune Repertoire Plus, TCR beta Panel” (Illumina™) was performed on the available samples. Finally, the obtained data were correlated. The study was approved by the local ethics committee.

Results: A total of 22 patients were selected, 10 in CP and 12 in AP. Regarding diagnosis, 8 were polycythemia vera (PV), 4 essential thrombocythemia (ET), 6 secondary myelofibrosis (MFS) (1 to PV and 5 to ET), 2 systemic mastocytosis (MS) and 1 primary myelofibrosis (MFP). Eighty percent were male and the mean age was 68 years. The AP patients were significantly older (74 vs. 62 years of age, p<0,001). Regarding the myeloid NGS panel result, 41 mutations were found in 19 patients. Fourteen percent of the patients had no mutation, 36% had an isolated driver mutation and 50% had additional mutations. Of these, 9% were in CP and 81% were in AP. The most recurrently mutated genes were JAK2 (45.4%), CALR (18.2%), ASXL1, IDH2, SRSF2, IDH2 (all 13.6%), MPL and KIT (both 9.1%). Regarding the results of the TCR repertoire, it was possible to perform the study in 11 patients, 4 in CP and 7 in AP. Only 6/11 had results of sufficient quality to allow analysis. Of these 6 patients, 3 were in CP and 3 in AP. As can be seen in Figure 1, the diversity of the TCR between CP patients and PC patients was different. Thus, while the pattern of diversity in the CP phase shows the expected distribution, the diversity in AP shows a characteristic pattern.

Conclusions: APs of MPNs show an abnormal TCR diversity pattern. This pattern may be related to the acquisition of myeloid gene mutations in AP. To our knowledge, this is the first study demonstrating an alteration in TCR diversity in AP and opens the door to future fields of research.
The KIR-HLA-CD16a Immunogenetic Profile Influences NK Cell-Mediated ADCC and Response to Rituximab Therapy in B-Cell Lymphomas
Authors: Khanolkar Rutvij A. , Akhter Ariz , Storek Jan , Khan Faisal
Published: December 2023

Rituximab-based chemoimmunotherapy (R-CHOP) is the standard of care in most B-cell lymphomas, however there is marked interpatient heterogeneity in treatment response. An important mechanism of Rituximab (anti-CD20) action is through natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), but the factors influencing this are poorly understood. Here, we present findings from a preclinical study investigating the role of NK cell receptor polymorphisms and HLA allelic variation on ADCC against aggressive B-cell lymphoma cell lines. Genotyping was conducted using Luminex-based SSO and Sanger sequencing. Multicolor flow cytometry was used to assess the response of activated NK cells from healthy donors against 8 lymphoma cell lines. Individuals carrying the GG or GT allele in CD16a were found to have a 3-8 fold greater NK cell response compared to individuals with a TT allele and rituximab-mediated ADCC was significantly greater in individuals with a KIR-3DL1 allele when tested against B-cell lymphomas lacking the HLA-Bw4 allele. An additive effect was observed when considering both CD16a and KIR-HLA together. As expected, CD20 expression was a strong correlate of NK cell response. In summary, NK cell-mediated ADCC in response to ADCC appears to be influenced by the KIR-HLA-CD16a genotype. These findings suggest a potential role for immunogenotyping in B-cell lymphomas treated with Rituximab. Additionally, the presence of the shared F c receptor domain opens the possibility of applying this framework towards predicting NK cell responses to antibody therapies in other diseases.
NAMPT Haploinsufficiency Is a Therapeutic Vulnerability in High-Risk Myeloid Malignancies
Authors: Senagolage Madhavi D. , Khan Saira , Skuli Sarah , Carroll Martin , McNerney Megan E.
Published: December 2023

Monosomy 7 (−7) and del7q are the most common high-risk cytogenetic abnormalities and occur across the spectrum of myeloid disorders. -7/del(7q) also co-occur with other high-risk factors such as mutations or deletion of TP53. Standard, non-specific chemotherapy drugs are less effective in these high-risk patients, resulting in a median survival rate of approximately one year. To identify novel, targeted agents for these neoplasms, we sought “collateral lethal” genes, i.e. essential, druggable genes encoded on chromosome 7 that are haploinsufficient upon their loss of heterozygosity.

To this end, we first identified essential genes located on chromosome 7. We mined genome-wide CRISPR/Cas9 screen data from 27 human acute myeloid leukemia (AML) cell lines within the DepMap database and identified 65 chromosome 7-encoded, candidate essential genes in AML. To determine those essential genes with known inhibitors, we intersected these 65 candidates with the Drug-Gene Interaction and canSAR.ai databases. We found that nicotinamide phosphoribosyltransferase ( NAMPT), the rate-limiting enzyme that catalyzes the first step of NAD + biosynthesis from nicotinamide, was one of four essential and druggable targets on chromosome 7. Notably, NAMPT was the only essential gene on chromosome 7 with a first-in-class orally bioavailable inhibitor, KPT 9274, currently in clinical trials (NCT04914845). Moreover, NAMPT DNA copy number, mRNA, and protein levels all negatively correlated with cell line sensitivity to NAMPT loss, implicating NAMPT as a collateral lethal candidate gene. We confirmed that isogenic human AML cell lines CRISPR-engineered to partially reduce NAMPT DNA copy led to reduced NAMPT protein levels, indicating NAMPT is a haploinsufficient gene. Cells with ~50% NAMPT levels were significantly more sensitive to the KPT 9274 treatment, and became less viable and more apoptotic, compared to control locus edited cells. To determine whether TP53 status could alter this vulnerability, we generated cell lines with both TP53 loss and 50% NAMPT loss. We found TP53 mutational status did not attenuate the observed effects of NAMPT inhibition on cell survival. Viability assays with primary patient AML samples confirmed that -7/del(7q) status imparts significantly elevated sensitivity to KPT 9274 treatment than samples with diploid chromosome 7 alleles.

In summary, our findings reveal NAMPT heterozygosity as a therapeutic vulnerability in high-risk myeloid neoplasms that warrants clinical follow-up. Further, we provide a framework centered on data-mining for uncovering collateral lethal genes in other cancers with recurrent chromosomal arm level deletions.
Model-based analysis of the incidence trends and transmission dynamics of COVID-19 associated with the Omicron variant in representative cities in China
Authors: Ma Yifei , Xu Shujun , Luo Yuxin , Li Jiantao , Lei Lijian , He Lu , Wang Tong , Yu Hongmei , Xie Jun
Published: December 2023

Background

In 2022, Omicron outbreaks occurred at multiple sites in China. It is of great importance to track the incidence trends and transmission dynamics of coronavirus disease 2019 (COVID-19) to guide further interventions.

Methods

Given the population size, economic level and transport level similarities, two groups of outbreaks (Shanghai vs. Chengdu and Sanya vs. Beihai) were selected for analysis. We developed the SEAIQRD, ARIMA, and LSTM models to seek optimal modeling techniques for waves associated with the Omicron variant regarding data predictive performance and mechanism transmission dynamics, respectively. In addition, we quantitatively modeled the impacts of different combinations of more stringent interventions on the course of the epidemic through scenario analyses.

Results

The best-performing LSTM model showed better prediction accuracy than the best-performing SEAIQRD and ARIMA models in most cases studied. The SEAIQRD model had an absolute advantage in exploring the transmission dynamics of the outbreaks. Regardless of the time to inflection point or the time to Rt curve below 1.0, Shanghai was later than Chengdu (day 46 vs. day 12/day 54 vs. day 14), and Sanya was later than Beihai (day 16 vs. day 12/day 20 vs. day 16). Regardless of the number of peak cases or the cumulative number of infections, Shanghai was higher than Chengdu (34,350 vs. 188/623,870 vs. 2,181), and Sanya was higher than Beihai (1,105 vs. 203/16,289 vs. 3,184). Scenario analyses suggested that upgrading control level in advance, while increasing the index decline rate and quarantine rate, were of great significance for shortening the time to peak and Rt below 1.0, as well as reducing the number of peak cases and final affected population.

Conclusions

The LSTM model has great potential for predicting the prevalence of Omicron outbreaks, whereas the SEAIQRD model is highly effective in revealing their internal transmission mechanisms. We recommended the use of joint interventions to contain the spread of the virus.
Comparative study of trimming and resection of diseased finger superficial flexor tendons in gouty carpal tunnel syndrome
Authors: Liu Jinquan , Gu Fengming , Liu Qianyuan , Chen Wenxuan , Ying Qiuwen , Xu Yi , Zhu Aiping , Tang Li , Jing Danfeng , Xu Zhonghua , Pan Xiaoyun , Mi Jingyi
Published: December 2023

Background

Hyperuricemia can lead to synovial hyperplasia in the wrist. In severe cases, it can lead to the deposition of gouty stone in the carpal tunnel, resulting in increased pressure in the carpal tunnel and compression of the median nerve to cause carpal tunnel syndrome (CTS), which is called gouty carpal tunnel syndrome (GCTS). As for the surgical treatment of gouty carpal tunnel syndrome, scholars have different opinions on whether it is necessary to remove the superficial flexor tendon. The purpose of this study was to compare the clinical efficacy of trimming and resection of the diseased superficial flexor tendon in the treatment of gouty carpal tunnel syndrome.

Methods

Clinical data were collected from May 2016 to July 2021 from 10 patients (13 affected wrists) diagnosed with gouty carpal tunnel syndrome and classified into two groups according to the surgical modality: the diseased portion of the gout-eroded superficial finger tendon was trimmed in 9 wrists, and the diseased superficial finger flexor tendon was excised in 4 wrists. Values related to flexion and extension functions, 2-PD, DASH, BCTQ, VAS and recurrence in the affected fingers were compared between the two groups as well as before and after surgery in each group.

Results

All affected limbs used were cleared of gouty stones, finger numbness improved, no skin necrosis occurred, and all incisions healed at stage I. At follow-up (13.58 ± 5.53 months), there was no significant difference between groups in flexion and extension function, 2-PD, DASH, BCTQ, and VAS with respect to the affected fingers, and patients in both groups improved significantly before and after surgery. Treatment of only one wrist involved trimming to remove lesion-affected portions of tendon, which reappeared 1 year after surgery, and there was one case of poor recovery from greater piriformis muscle atrophy in both procedures.

Conclusion

Regarding surgical treatment of patients with gouty carpal tunnel syndrome in which the gouty stone has invaded the superficial flexor tendons of the fingers, the diseased superficial flexor tendons can be selectively excised, and the postoperative mobility of the affected fingers may not be impaired.
Improving preoperative prediction of surgery duration
Authors: Riahi Vahid , Hassanzadeh Hamed , Khanna Sankalp , Boyle Justin , Syed Faraz , Biki Barbara , Borkwood Ellen , Sweeney Lianne
Published: December 2023

Background

Operating rooms (ORs) are one of the costliest units in a hospital, therefore the cumulative consequences of any kind of inefficiency in OR management lead to a significant loss of revenue for the hospital, staff dissatisfaction, and patient care disruption. One of the possible solutions to improving OR efficiency is knowing a reliable estimate of the duration of operations. The literature suggests that the current methods used in hospitals, e.g., a surgeon’s estimate for the given surgery or taking the average of only five previous records of the same procedure, have room for improvement.

Methods

We used over 4 years of elective surgery records (n = 52,171) from one of the major metropolitan hospitals in Australia. We developed robust Machine Learning (ML) approaches to provide a more accurate prediction of operation duration, especially in the absence of surgeon’s estimation. Individual patient characteristics and historic surgery information attributed to medical records were used to train predictive models. A wide range of algorithms such as Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were tested for predicting operation duration.

Results

The results show that the XGBoost model provided statistically significantly less error than other compared ML models. The XGBoost model also reduced the total absolute error by 6854 min (i.e., about 114 h) compared to the current hospital methods.

Conclusion

The results indicate the potential of using ML methods for reaching a more accurate estimation of operation duration compared to current methods used in the hospital. In addition, using a set of realistic features in the ML models that are available at the point of OR scheduling enabled the potential deployment of the proposed approach.
A pan-cancer analysis indicates long noncoding RNA HAND2-AS1 as a potential prognostic, immunomodulatory and therapeutic biomarker in various cancers including colorectal adenocarcinoma
Authors: Samadi Pouria , Shahnazari Mina , Shekari Abolfazl , Maghool Fatemeh , Jalali Akram
Published: December 2023

The HAND2-AS1 (HAND2 Antisense RNA 1) Long noncoding RNA (lncRNA) has emerged as a participant in the initiation of various cancer types, underscoring its pivotal involvement in both oncological processes and immune responses. To gain deeper insights into the functional nuances of HAND2-AS1 and identify novel avenues for cancer immunotherapy, a comprehensive evaluation of this gene was undertaken. Here, based on the co-expression network analysis and construction of interacting lncRNA–mRNA genes, we introduce the HAND2-AS1 lncRNA, emphasizing its key roles in tumorigenesis and immune regulation. Our study spans across 33 distinct cancer types, revealing the HAND2-AS1’s aberrant expression patterns, methylation variations, mutational signatures, and immune engagement. Across a majority of tumors, HAND2-AS1 exhibited a propensity for down-regulation, remarkably an association with poor survival outcomes. The outcomes of functional enrichment analyses strongly suggest HAND2-AS1’s engagement in tumor progression and its association with various immune pathways across diverse tumor classifications. Additionally, a positive correlation emerged between HAND2-AS1 expression and the infiltration levels of key immune cells, encompassing not only immunosuppressive entities such as tumor-associated macrophages, cancer-associated fibroblasts, and Tregs, but also immune effector cells like NK cells and CD8+ T cells, spanning a pan-cancer context. Furthermore, the differential expression of HAND2-AS1 appears to have downstream consequences on various pathways, thus implicating it as a potential regulator in diverse cancer types. Finally, we have employed CRC tumor and normal samples to carry out clinical validation of HAND2-AS1. Our study unveils HAND2-AS1’s potential as a pan-cancer tumor suppressor, and its essential role in the tumorigenesis and immune surveillance. The increased HAND2-AS1 expression emerges as a promising candidate for prognostic evaluation, therapeutic strategy, and a focal point for immunotherapeutic interventions.
Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aβ burden and restores memory functions in 5xFAD mice
Authors: Zeng Xiaoyan , Cheung Stanley K. K. , Shi Mengqi , Or Penelope M. Y. , Li Zhining , Liu Julia Y. H. , Ho Wayne L. H. , Liu Tian , Lu Kun , Rudd John A. , Wang Yubing , Chan Andrew M.
Published: December 2023

Glial cell-mediated neuroinflammation and neuronal attrition are highly correlated with cognitive impairment in Alzheimer’s disease. YKL-40 is a secreted astrocytic glycoprotein that serves as a diagnostic biomarker of Alzheimer’s disease. High levels of YKL-40 are associated with either advanced Alzheimer’s disease or the normal aging process. However, the functional role of YKL-40 in Alzheimer’s disease development has not been firmly established. In a 5xFAD mouse model of Alzheimer’s disease, we observed increased YKL-40 expression in the cerebrospinal fluid of 7-month-old mice and was correlated with activated astrocytes. In primary astrocytes, Aβ1-42 upregulated YKL-40 in a dose-dependent manner and was correlated with PI3-K signaling pathway activation. Furthermore, primary neurons treated with YKL-40 and/or Aβ1-42 resulted in significant synaptic degeneration, reduced dendritic complexity, and impaired electrical parameters. More importantly, astrocyte-specific knockout of YKL-40 over a period of 7 days in symptomatic 5xFAD mice could effectively reduce amyloid plaque deposition in multiple brain regions. This was also associated with attenuated glial activation, reduced neuronal attrition, and restored memory function. These biological phenotypes could be explained by enhanced uptake of Aβ1-42 peptides, increased rate of Aβ1-42 degradation and acidification of lysosomal compartment in YKL-40 knockout astrocytes. Our results provide new insights into the role of YKL-40 in Alzheimer’s disease pathogenesis and demonstrate the potential of targeting this soluble biomarker to alleviate cognitive defects in symptomatic Alzheimer’s disease patients.
Impact of NAD+ metabolism on ovarian aging
Authors: Liang Jinghui , Huang Feiling , Song Zhaoqi , Tang Ruiyi , Zhang Peng , Chen Rong
Published: December 2023

Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme in cellular redox reactions, is closely associated with age-related functional degeneration and metabolic diseases. NAD exerts direct and indirect influences on many crucial cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell functionality. These cellular processes and functions are essential for maintaining tissue and metabolic homeostasis, as well as healthy aging. Causality has been elucidated between a decline in NAD levels and multiple age-related diseases, which has been confirmed by various strategies aimed at increasing NAD levels in the preclinical setting. Ovarian aging is recognized as a natural process characterized by a decline in follicle number and function, resulting in decreased estrogen production and menopause. In this regard, it is necessary to address the many factors involved in this complicated procedure, which could improve fertility in women of advanced maternal age. Concerning the decrease in NAD+ levels as ovarian aging progresses, promising and exciting results are presented for strategies using NAD+ precursors to promote NAD+ biosynthesis, which could substantially improve oocyte quality and alleviate ovarian aging. Hence, to acquire further insights into NAD+ metabolism and biology, this review aims to probe the factors affecting ovarian aging, the characteristics of NAD+ precursors, and the current research status of NAD+ supplementation in ovarian aging. Specifically, by gaining a comprehensive understanding of these aspects, we are optimistic about the prominent progress that will be made in both research and therapy related to ovarian aging.
Ethnobotanical contributions to global fishing communities: a review
Authors: Mendoza Jimlea Nadezhda , Hanazaki Natalia , Prūse Baiba , Martini Agnese , Bittner Maria Viktoria , Kochalski Sophia , Macusi Edison , Ciriaco Aimee , Mattalia Giulia , Sõukand Renata
Published: December 2023

Background

Ethnobotanical knowledge about the role of plants in fisheries provides valuable ecological information vital for sustainable management of local resources; however, it is diluted and understudied globally. This literature review aims to map the knowledge of plant use within traditional fishing communities.

Methods

Through the PRISMA method, we identified and selected 34 articles reporting the use of plants in fisheries, and including 344 taxa of plants and algae. Uses of plants and algae were grouped into different categories.

Results

In the novel categorization of fishery-related uses we proposed, the most mentioned were for fishing and building/repair of fishing artifacts and habitat-related uses, while the records of plants related to fiber uses, providing aid in fishing management and species causing problems, were among the least mentioned. Semi-structured interview is most commonly used with local resource users, especially fishery experts, in exploring perceptions on plant use within traditional fishing communities. Diversity was high in all the recorded families, but most were reported locally.

Conclusion

Ethnobotanical studies with fishers are not common in the documented literature but they provide a large number of use reports. On the basis this review, in most of the world, the information is of a casual and sporadic nature. Fishers can provide information on aquatic plants and algae that create problems and aid in fishing management, which are crucial in understanding the ecosystem of a region experiencing environmental challenges. This knowledge is greatly understudied globally and undergoing a rapid decline, as highlighted in several of the reviewed articles. Thus, further systematic research on fishery-related uses of plants by fisherfolk is needed considering its potential contribution to the sustainable management of fishery resources.
An efficient screening system of disease-resistant genes from wild apple, Malus sieversii in response to Valsa mali pathogenic fungus
Authors: Wen Xuejing , Yuan Jiangxue , Bozorov Tohir A. , Waheed Abdul , Kahar Gulnaz , Haxim Yakupjan , Liu Xiaojie , Huang Lili , Zhang Daoyuan
Published: December 2023

For molecular breeding of future apples, wild apple (Malus sieversii), the primary progenitor of domesticated apples, provides abundant genetic diversity and disease-resistance traits. Valsa canker (caused by the fungal pathogen Valsa mali) poses a major threat to wild apple population as well as to cultivated apple production in China. In the present study, we developed an efficient system for screening disease-resistant genes of M. sieversii in response to V. mali. An optimal agrobacterium-mediated transient transformation of M. sieversii was first used to manipulate in situ the expression of candidate genes. After that, the pathogen V. mali was inoculated on transformed leaves and stems, and 3 additional methods for slower disease courses were developed for V. mali inoculation. To identify the resistant genes, a series of experiments were performed including morphological (incidence, lesion area/length, fungal biomass), physiological (H2O2 content, malondialdehyde content), and molecular (Real-time quantitative Polymerase Chain Reaction) approaches. Using the optimized system, we identified two transcription factors with high resistance to V. mali, MsbHLH41 and MsEIL3. Furthermore, 35 and 45 downstream genes of MsbHLH41 and MsEIL3 were identified by screening the V. mali response gene database in M. sieversii, respectively. Overall, these results indicate that the disease-resistant gene screening system has a wide range of applications for identifying resistant genes and exploring their immune regulatory networks.
Efficacy of acupuncture combined with active exercise training in improving pain and function of knee osteoarthritis individuals: a systematic review and meta-analysis
Authors: Chen Jia , Guo Hong , Pan Juanhong , Li Hongpeng , Wang Yongshen , Liu Zhixiang , Xie Yulong , Jin Song
Published: December 2023

Objective

To conduct a systematic review and meta-analysis to investigate the clinical efficacy of acupuncture combined with active exercise training in improving pain and function of knee osteoarthritis (KOA) individuals.

Data sources

PubMed, EMBASE, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan Fang Data, Technology Periodical Database and China Biology Medicine were searched from their inceptions to April 5, 2023.

Review methods

We analyzed trials of acupuncture combined with active exercise training for KOA. The included studies were of high quality (Jadad ≥ 4) and RCTs. Study selection, data extraction, risk of bias and quality assessment were independently performed by two reviewers. We performed systematic analyses based on different outcome measures, including total efficiency rate, visual analogue scale (VAS), the Western Ontario and Mcmaster Universities Osteoarthritis Index (WOMAC), the Lysholm Knee Scale (LKS) and range of motion (ROM). We used Review Manager 5.3 and Stata/MP 14.0 to analyze the data. And it was verified by trial sequence analysis (TSA). If I2 > 50% and p < 0.05, we performed sensitivity analysis and subgroup analysis to find the source of heterogeneity. Publication bias was studied by funnel plot and Egger’s test was used to verify it.

Results

Full 11 high-quality studies (Jadad ≥ 4) including 774 KOA individuals were included in this review for meta-analysis. The results showed that acupuncture combined with active exercise training (combined group) was superior to the acupuncture group in improving the total effective rate [RR = 1.13, 95%CI (1.05, 1.22), I2 = 0%, P = 0.70], reducing the pain level (VAS) [MD = − 0.74, 95%CI (− 1.04,  − 0.43), I2 = 68%, P < 0.05], improving knee joint function (WOMAC) [MD =  − 6.97, 95%CI (− 10.74, − 3.19), I2 = 76%, P < 0.05] and improving joint range of motion (ROM) [MD = 6.25, 95%CI (2.37, 10.04), I2 = 0%, P = 0.71]. Similarly, the combined group showed significant improvements in the total effective rate [RR = 1.31, 95% CI (1.18, 1.47), I2 = 48%, P = 0.10], pain (VAS) [MD = 1.42, 95% CI (− 1.85, − 1.00), I2 = 65%, P = 0.02] and knee function (WOMAC) [MD = 7.05, 95% CI (− 11.43, − 2.66), I2 = 86%, P < 0.05] compared with the non-acupuncture group.

Conclusion

The combined effect of all studies showed significant benefits of acupuncture combined with active exercise training in improving the total effective rate, reducing pain, promoting recovery of knee function and expanding range of motion. However, some evaluation indicators are highly subjective and need to be further confirmed by more objective and evidence-based high-quality RCTs in future.

Systematic Review Registration: [PROSPERO], identifier [No. CRD42023425823].
The effect of switch therapy to tenofovir versus entecavir maintenance on recurrence of hepatocellular carcinoma after surgery (SWITE): study protocol for a randomized controlled trial
Authors: Peng Wei , Yi Mengshi , Qi Xin , Qi Weili , Li Chuan , Wen Tianfu
Published: December 2023

Background

Antiviral therapy has been reported to be associated with lower recurrence rate of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV) infection. While entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were both recommended as first-line therapies for HBV patients, recent retrospective studies proposed a lower incidence rate of HCC occurrence or recurrence in those receiving TDF compared ETV. However, the survival benefits of switching to TDF therapy after prolonged ETV treatment before surgery remain uncertain. We delineate the rationale and design of SWITE, a randomized, open-label, phase III trial contrasting TDF switch therapy versus ETV maintenance in HBV-related HCC patients.

Methods and analysis

This is a prospective, randomized, controlled, single-center study with two parallel groups of patients with HBV-related HCC who have received long-term ETV therapy before surgery. West China Hospital will enroll 238 patients, randomized in a 1:1 ratio to TDF switch therapy or ETV maintenance after surgery. The primary endpoint of this study is 3-year recurrence free survival (RFS), with the secondary endpoint being 3-year overall survival (OS) after curative surgery of HCC. Safety events will be diligently recorded.

Ethics and dissemination

The study protocol aligns with the ethical guidelines of the 1975 Declaration of Helsinki. It was approved by ethics committee of West China Hospital (approval number: 2022-074) and was registered with chictr.org.cn (chiCTR2200057867). Informed consent will be obtained from all participants. The results of this trial will be published in peer-reviewed journals and presentations at national and international conferences relevant to this topic.

Trial registration

chiCTR2200057867. Date of registration is March 20 2022.
Efficacy of an oral formulation of afoxolaner and milbemycin oxime against Tunga penetrans in naturally infected dogs
Authors: dos Santos Katharine Costa , Tielemans Eric , Cutolo Andre Antonio , Guedes Paula Elisa Brandão , Harvey Tatiani Vitor , de Carvalho Teixeira Jamille Bispo , Vitor Rebeca Costa , da Paixão Sevá Anaiá , de Melo Navarro Adan William , Lima Ana Carolina Ribeiro , Botteon Karin Denise , Bittar Thammy Vieira , Albuquerque George Rêgo , de Almeida Borges Fernando , Beugnet Frederic , Carlos Renata Santiago Alberto
Published: December 2023

Background

The sand flea Tunga penetrans is one of the agents of tungiasis, an important parasitic skin disease affecting humans and several mammalian species. Tungiasis is mainly observed in disadvantaged rural and peripheral urban communities in Latin America and sub-Saharan Africa. The dog is a major reservoir of Tunga fleas. Hematophagous adult female Tunga spp. embed and grow in their host’s epidermis and cause cutaneous inflammatory disorders. NexGard Spectra® is an orally administered endectocide for dogs, a co-formulation of the isoxazoline afoxolaner and the macrocyclic lactone milbemycin oxime. The objective of this study was to assess the efficacy of this product against canine tungiasis.

Methods

A blinded, negative-controlled field trial was conducted in a Brazilian community known to be highly endemic for tungiasis. Sixty-six dogs naturally infected with live T. penetrans were randomly allocated to a treated group (44 dogs) and an untreated control group (22 dogs). In a first phase, dogs from the treated group were treated on days 0, 30, and 60. Efficacy was evaluated on the basis of the macroscopic parasitic skin lesions (Fortaleza classification) on days 7, 14, 21, 30, 45, 60, 75, and 90. In a second phase, to evaluate natural reinfections, all dogs were treated on day 90 and evaluated every 2 weeks thereafter until at least 30% of dogs were infected with live sand fleas.

Results

During the first phase, efficacy (reduction in live sand fleas) of 92.4% was demonstrated on day 7. From day 14 until day 90, the efficacy of NexGard Spectra® was 100%. In the second phase, all dogs were free of live T. penetrans from 15 until 45 days after the day 90 treatment; 60 days post-treatment, 11% of dogs were reinfected, and 75 days post-treatment, 40% of dogs were reinfected.

Conclusions

NexGard Spectra® was demonstrated to be highly effective against canine tungiasis. In addition to an obvious beneficial effect on the health and welfare of the treated dog, the use of this product may have a one-health benefit on human cases by controlling the main reservoir of sand fleas.

Graphical Abstract
Predictors for CD4 cell count and hemoglobin level with survival time to default for HIV positive adults under ART treatment at University of Gondar Comprehensive and Specialized Hospital, Ethiopia
Authors: Muhie Nurye Seid , Tegegne Awoke Seyoum
Published: December 2023

Background

HIV/AIDS is the most known powerful risk factor for morbidity and mortality in the world. The greatest biological markers in HIV patients are CD4 cell count and hemoglobin level, as they are independent predictors of survival of HIV patients. The objective of this study was to investigate the common socio-demographic, clinical, and behavioral Predictor’s affecting the CD4 cell count, and hemoglobin level with survival time to default from ART treatment among HIV positive adults under ART treatment at university of Gondar comprehensive and specialized hospital, North-west Ethiopia.

Method

This study was conducted at University of Gondar comprehensive specialized hospital by using a retrospective cohort follow up study design. The source of data in this study was secondary data obtained from patients chart. Bayesian joint models were employed to get wide-ranging information about HIV/AIDS progression.

Result

From a total of 403 HIV positive adults, about 44.2% were defaulted from therapy and the rest were actively followed ART treatment. The estimate of the association parameter for the current true value of CD4 cell count ($${\alpha }_{1}$$

α
1

), and hemoglobin level ($${\alpha }_{2}$$

α
2

), trend of CD4 cell count ($${\alpha }_{2}$$

α
2

) and hemoglobin level ($${b}_{2}$$

b
2

) is positive. Positive values indicating that the higher CD4 cell count and hemoglobin level is related with the higher time of defaulting from ART. Predictor’s hematocrit, weight, platelet cell count, lymphocyte count, sex, adherence, and WHO clinical stage were joint determinate risk factors affecting CD4 cell count, hemoglobin level and time to default at 5% level of significance.

Conclusion

Current study results revealed that hematocrit, weight, BMI, platelet cell count, lymphocyte count, sex (female), and good treatment adherence were significantly associated with higher CD4 cell count, hemoglobin level and time to default while having advanced WHO clinical stage-IV had significantly decreased CD4 cell, hemoglobin level, and time to default from treatment. Patients with HIV should be given special attention based on these important factors to improve their health and prolong their lives.
Clinico-biological-radiomics (CBR) based machine learning for improving the diagnostic accuracy of FDG-PET false-positive lymph nodes in lung cancer
Authors: Ren Caiyue , Zhang Fuquan , Zhang Jiangang , Song Shaoli , Sun Yun , Cheng Jingyi
Published: December 2023

Background

The main problem of positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging is the high false positive rate (FPR). Thus, we aimed to explore a clinico-biological-radiomics (CBR) model via machine learning (ML) to reduce FPR and improve the accuracy for predicting the hypermetabolic mediastinal–hilar LNs status in lung cancer than conventional PET/CT.

Methods

A total of 260 lung cancer patients with hypermetabolic mediastinal–hilar LNs (SUVmax ≥ 2.5) were retrospectively reviewed. Patients were treated with surgery with systematic LN resection and pathologically divided into the LN negative (LN-) and positive (LN +) groups, and randomly assigned into the training (n = 182) and test (n = 78) sets. Preoperative CBR dataset containing 1738 multi-scale features was constructed for all patients. Prediction models for hypermetabolic LNs status were developed using the features selected by the supervised ML algorithms, and evaluated using the classical diagnostic indicators. Then, a nomogram was developed based on the model with the highest area under the curve (AUC) and the lowest FPR, and validated by the calibration plots.

Results

In total, 109 LN− and 151 LN + patients were enrolled in this study. 6 independent prediction models were developed to differentiate LN− from LN + patients using the selected features from clinico-biological-image dataset, radiomics dataset, and their combined CBR dataset, respectively. The DeLong test showed that the CBR Model containing all-scale features held the highest predictive efficiency and the lowest FPR among all of established models (p < 0.05) in both the training and test sets (AUCs of 0.90 and 0.89, FPRs of 12.82% and 6.45%, respectively) (p < 0.05). The quantitative nomogram based on CBR Model was validated to have a good consistency with actual observations.

Conclusion

This study presents an integrated CBR nomogram that can further reduce the FPR and improve the accuracy of hypermetabolic mediastinal–hilar LNs evaluation than conventional PET/CT in lung cancer, thereby greatly reducing the risk of overestimation and assisting for precision treatment.
Efficacy of pharmacotherapies for bulimia nervosa: a systematic review and meta-analysis
Authors: Yu Sijie , Zhang Yuhan , Shen Chongkai , Shao Fei
Published: December 2023

Objective

The main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN).

Methods

Randomized controlled trials (RCTs) were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase from inception to November 2022. Primary outcomes were changes in the frequency of binge eating episodes and vomiting episodes from baseline to endpoint. Secondary outcomes were differences in the improvement of scores in depressive symptoms, tolerability (dropout due to adverse events) and weight change.

Results

The literature search ultimately included 11 drugs, 33 studies and 6 types of drugs, 8 trials with TCAs (imipramine, desipramine), 14 with SSRIs (fluoxetine, citalopram and fluvoxamine), 6 with MAOIs (phenelzine, moclobemide and brofaromine), 3 with antiepileptic drugs (topiramate), 1 with mood stabilizers (lithium), and 1 with amphetamine-type appetite suppressant (fenfluramine). The reduction in binge eating episodes was more likely due to these drugs than the placebo, and the SMD was -0.4 (95% CI -0.61 ~ -0.19); the changes in the frequency of vomiting episodes (SMD = -0.16, 95% CI -0.3 ~ -0.03); weight (WMD = -3.05, 95% CI -5.97 ~ -0.13); and depressive symptoms (SMD = -0.32, 95% CI -0.51 ~ -0.13). However, no significant difference was found in dropout due to adverse events (RR = 1.66, 95% CI 1.14 ~ 2.41).

Conclusions

This meta-analysis indicates that most pharmacotherapies decreased the frequency of binge-eating and vomiting episodes, body weight, and depressive symptoms in BN patients, but the efficacy was not significant. In each drug the efficacy is different, treating different aspects, different symptoms to improve the clinical performance of bulimia nervosa.