bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Multiomics Profiling of Angioimmunoblastic T-Cell Lymphoma
Authors: Xu Mina , Halene Stephanie , Fan Rong , Enninful Archibald
Published: December 2023

Introduction:

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of non-Hodgkin lymphoma (NHL) characterized primarily by a T follicular helper cell (TFH) phenotype. AITL presents with a highly complex tumor microenvironment with the tumor cells on a scaffold of highly arborized CD21+ follicular dendritic cells found in proximity to high endothelial venules (HEVs). The organized structure of the lymph node with distinct B cell and T cell zones is disrupted in the lymph node samples from patients with AITL. Lymphoid follicles in most AITL cases tend to be depleted, not hyperplastic as in other lymphomas. AITL tumor cells express CD10, BCL6, PD1, CXCL13, C-X-C motif chemokine receptor 5 (CXCR5), ICOS, and signaling lymphocytic activation molecule-associated protein (SAP) with diagnosis based on the expression of at least 2 of these markers. Our study uses novel spatial omics technology (Deterministic Barcoding in Tissue (DBiT-seq) and multiplexed immunofluorescence staining (CODEX)) to fully characterize the transcriptional and proteomic landscape of AITL.

Methods:

In this study, initial FFPE biopsy specimens from 22 patients with AITL were collected from archives. 10 µm thick tissue sections on poly-L-lysine coated slides were prepared for the performance of multiplexed immunofluorescence imaging (CODEX) for 12 immune-related markers: Podoplanin, CD20, CD4, CD8, CD68, CD45RO, CD3e, GranzymeB, PD1, Ki67, CD21 and CD34 using the PhenoCycler-Fusion system. We also validated anti-EBV Latent Membrane Protein 1 antibody. Cell segmentation was performed using a Stardist-based model in QuPath and downstream analysis done using the Seurat package. On an adjacent tissue section, we used Spatial CITE-seq to co-map the whole transcriptome and ~160 proteins.

Results:

From the multiplexed immunofluorescence staining, we observed CD21+ Follicular dendritic cells in close proximity to HEVs as expected from the spatial architecture of AITL. We also found 11 spatially distinct clusters differentially expressing the marker proteins. We observed a lower number of CD8+ cytotoxic T cells relative to CD4+ Helper T cells. We also identified cellular neighborhoods and their composition found a population of FDCs that directly interact with the tumor cells. From spatial CITE-seq, we average of ~670 genes were found in each spot. We also found the expression of CXCL13, TET2, DNMT3A and PDCP1 which are markers associated with AITL. There was a strong correlation between the transcript signals detected in Spatial CITE-seq and the protein expression from CODEX.

Conclusions:

Our study revealed the spatial organization of the tumor microenvironment of AITL. We envision that combining multiplexed immunofluorescence and Spatial CITE-seq will further our understanding of the AITL tumor environment and could lead to the discovery of novel clinical targets.
Incidence and Outcomes of Pneumocystis Pneumonia Following Chimeric Antigen Receptor T-Cell Therapy: A Real-World Analysis
Authors: Wang Jiasheng , Daunov Michael , Cooper Brenda W
Published: December 2023

Background: Pneumocystis Pneumonia (PCP) is a known opportunistic infection after chimeric antigen receptor (CAR) T-cell therapy. However, the incidence and outcomes of PCP are poorly understood, and there has been no clear consensus on the optimal duration for PCP prophylaxis post-CAR T-cell treatment.

Methods: From a large real-world database, TriNetX Research Network, we identified patients who underwent commercial anti-CD19 and anti-BCMA CAR T-cell therapy between January 2019 and January 2023. The diagnosis of PCP was established using the ICD-10-CM code B59 (pneumocystosis) or through Logical Observation Identifiers Names and Codes (LOINC) documentation of positive microbiologic tests from respiratory samples.

Results: Among the 1,107 and 280 patients who received anti-CD19 and anti-BCMA CAR T-cell therapies, 19 (1.7%) and 4 (1.4%) patients developed PCP, respectively. Altogether, a total of 23 (1.7%) patients developed PCP within a median of 139 days (range 19 to 732 days) post-infusion. (Figure) Demographics, the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and the initial choice for PCP prophylaxis, were similar for patients with and without PCP. Patients who developed PCP were more likely to have used dexamethasone (65 vs 43%, p=0.02) and have a shorter duration of trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis (median 9 [range 1 to 45] vs 19 [range 1 to 106] weeks, p=0.002). In the univariate analysis, patients who received TMP/SMX prophylaxis for less than 3 months showed a trend of a higher incidence of PCP compared to those who received it for more than 3 months (hazard ratio [HR] 3.54, 95% confidence interval [CI] 0.87 to 14.3, p=0.06). (Table) Regarding survival outcomes, patients with and without PCP had similar time-to-next-treatment or death (median 84 vs 68 days, HR 0.96, 95%CI 0.61 to 1.51) and overall survival (median 518 days vs not-reached, HR 1.61, 95%CI 0.91 to 2.88).

Conclusions: In real-world conditions with routine prophylaxis, PCP is an infrequent opportunistic infection following anti-CD19 or anti-BCMA CAR T-cell therapy. Patients with and without PCP were associated with similar survival outcomes.
Survival of Hematopoietic Stem Cell Transplantation in the National Institute of Neoplastic Diseases, Lima-Perú between 2012 to 2022: 10 Years of Experience
Authors: Quintana Shirley , López Córdova Naty , Lopez Chavez Lourdes ISABEL , Alcarraz Cindy , Mallma Soto Victor IVAN , Calderon Monica , Chavez Sharon , Vidaurre Tatiana , Flores Claudio , Vasquez Jule F
Published: December 2023

Introduction:

Hematopoietic stem cell transplantation (HSCT) is part of standard treatment in a great number of hematologic malignancies and some solid tumors. The National Institute of Neoplastic Diseases (INEN) started the HSCT program in 2012, performing over 600 HSCT so far. In this study, we report the overall survival (OS) at 5 years of patients who undergone this procedure in our institution through 10 years of experience.

Methods:

We analyzed retrospectively the survival of all patients admitted to the HCST program at INEN between 2012 and 2022. Clinical and pathological data were collected from the medical records and the unit's transplant patient registry. The OS was determined through the Kaplan-Meier method and the comparisons of survival curves were performed using the log-rank or Breslow test.

Results:

During the study period, a total of 647 transplants were performed. The median age was 39 years (range: 1 - 70), 73.4% of patients were between 18 and 60 years, and 57.1% were men.

Most transplants (n = 591, 91.3%) were performed in the adult population and 8.6% (n = 56) in pediatric population. According to the type of transplant, 68% (n=440) were autologous and 32% (n=207) allogeneic from related donor.

The most frequent diagnosis were acute leukemia (n = 221, 34.2%), multiple myeloma (n = 190, 29.3%), non-Hodgkin lymphoma (n = 105, 16,2%; of these, 22 were T- cell lymphomas), Hodgkin lymphoma (n = 69, 10.7%) and germinal cell tumor (n = 33, 5.1%); in the pediatric population, leukemia was the most common diagnosis (66.1%).

The median follow-up of the patients was 3.7 years (95% CI: 3.4, 3.9), 25.2% (n = 163) of the patients died due to disease progression. The median overall survival (OS) for the entire cohort was not reached and the OS rate at 5 years was 68.3%. The 5-year OS rate by transplant subtype was 53.9% and 75.3% (p < 0.001) for allogeneic and autologous transplants, respectively; and according to the pathology, the patients who had a better 5-year OS were HL (87.5%) and NHL (77.5%), while in leukemias it was 56.1%. Survival by age group (<40 vs >40) and sex (female vs. male) did not present a significant difference (p > 0.05).

Conclusions:

The survival of the transplanted patients was similar to that reported in other series. Leukemia was the most frequent hematological malignancy admitted to the HSCT program. HL and NHL were the malignant tumors with the highest survival rates at 5 years. Nearly a third of transplants were allogeneic, all from matched related donors. HSCT in our series has shown an improvement in OS at 5 years in both autologous and allogeneic transplant patients compared to non-transplanted patients, according to international reports.
Global research trends in CRISPR-related technologies associated with extracellular vesicles from 2015 to 2022: a bibliometric, dynamic, and visualized study
Authors: Lin Jianjing , Jia Shicheng , Jiao Zilu , Chen Jiayou , Li Wei , Cao Fuyang , Zhang Xintao
Published: December 2023

Purpose

This study aims to explore the emerging trends, dynamic development, and research hotspots of clustered regularly interspaced short palindromic repeats (CRISPR) technology associated with extracellular vesicles during the past 7 years and demonstrate them by visualization.

Methods

A total of 219 records related to CRISPR technology associated with extracellular vesicles from 2015 to 2022 in the Web of Science Core Collection (WoSCC) database were collected. R language, VOSviewer, CiteSpace, and GraphpadPrism software packages were used to analyze the history of this research, the general characteristics of the literature, and keywords. Finally, the hotspots and latest trends in CRISPR technology associated with extracellular vesicles are predicted.

Results

A total of 219 articles were collected for this study. The production of publications about CRISPR technology associated with extracellular vesicles has increased annually. Researchers from China, the USA, and Germany made the most important contributions to this trend, while RLUK Research Libraries UK offers the largest amount of literature in this field. Shenzhen University, Nanjing Medicine University, and Peking University exhibited the closest cooperation. Additionally, active topics burst during different periods, as identified according to 317 keywords belonging to 39 disciplines. Keywords were clustered into seven research subareas, namely exosome, nanovesicles, DNA, gene editing, gene therapy, cancer therapy, and endometrial stromal cells. The alluvial map of keywords reveals that the most enduring concepts are gene therapy, nanovesicles, etc., while the emerging keywords are genome, protein delivery, plasma, etc.

Conclusions

We reviewed 219 previous publications and conducted the first bibliometric study of CRISPR technology related to extracellular vesicles from 2015 to 2022. This comprehensive summary constructed a knowledge map and demonstrates the trends in this area. The current trends and potential hotpots for this topic are also identified, which will be a great help for researchers in the future.
Musashi-2 Deficiency Triggers Colorectal Cancer Ferroptosis by Downregulating the MAPK Signaling Cascade to Inhibit HSPB1 Phosphorylation
Authors: Meng Xiaole , Peng Xiao , Ouyang Wanxin , Li Hui , Na Risi , Zhou Wenting , You Xuting , Li Yuhuan , Pu Xin , Zhang Ke , Xia Junjie , Wang Jie , Zhuang Guohong , Tang Huamei , Peng Zhihai
Published: December 2023

Background

Musashi-2 (MSI2) is a critical RNA-binding protein (RBP) whose ectopic expression drives the pathogenesis of various cancers. Accumulating evidence suggests that inducing ferroptosis of tumor cells can inhibit their malignant biological behavior as a promising therapeutic approach. However, it is unclear whether MSI2 regulates cell death in colorectal cancer (CRC), especially the underlying mechanisms and biological effects in CRC ferroptosis remain elusive.

Methods

Experimental methods including qRT‒PCR, immunofluorescence, flow cytometry, western blot, co-immunoprecipitation, CCK-8, colony formation assay, in vitro cell transwell migration and invasion assays, in vivo xenograft tumor experiments, liver and lung CRC metastasis models, CAC mice models, transmission electron microscopy, immunohistochemistry, histopathology, 4D label-free proteomics sequencing, bioinformatic and database analysis were used in this study.

Results

Here, we investigated that MSI2 was upregulated in CRC and positively correlated with ferroptosis inhibitor molecules. MSI2 deficiency suppressed CRC malignancy by inhibiting cell proliferation, viability, migration and invasion in vitro and in vivo; and MSI2 deficiency triggered CRC ferroptosis by changing the intracellular redox state (ROS levels and lipid peroxidation), erastin induced cell mortality and viability, iron homeostasis (intracellular total irons and ferrous irons), reduced glutathione (GSH) levels and mitochondrial injury. Mechanistically, through 4D-lable free proteomics analysis on SW620 stable cell lines, we demonstrated that MSI2 directly interacted with p-ERK and MSI2 knockdown downregulated the p-ERK/p38/MAPK axis signaling pathway, which further repressed MAPKAPK2 and HPSB1 phosphorylation, leading to decreased expression of PCNA and Ki67 and increased expression of ACSL4 in cancer cells. Furthermore, HSPB1 could rescue the phenotypes of MSI2 deficiency on CRC ferroptosis in vitro and in vivo.

Conclusions

This study indicates that MSI2 deficiency suppresses the growth and survival of CRC cells and promotes ferroptosis by inactivating the MAPK signaling pathway to inhibit HSPB1 phosphorylation, which leads to downregulation of PCNA and Ki67 and upregulation of ACSL4 in cancer cells and subsequently induces redox imbalance, iron accumulation and mitochondrial shrinkage, ultimately triggering ferroptosis. Therefore, targeted inhibition of MSI2/MAPK/HSPB1 axis to promote ferroptosis might be a potential treatment strategy for CRC.
Comparison of erector spinae plane block and serratus anterior plane block for postoperative analgesia in uniportal thoracoscopic lobectomy: a randomized controlled trial
Authors: Wu Wei , Xu Huan , Chen Xue , He Wenxin , Shi Hong
Published: December 2023

Background

Postoperative pain remains a significant concern following uniportal thoracoscopic surgery. The analgesic efficacy of erector spinae plane block (ESPB) and serratus anterior plane block (SAPB) in terms of postoperative opioid consumption in uniportal thoracoscopic surgery still needs further studies.

Methods

A randomized controlled trial was conducted, enrolling 150 patients who underwent uniportal thoracoscopic lobectomy. The patients were randomly allocated to three groups in a 1:1:1 ratio: the ESPB group (administered 20 ml of 0.5% ropivacaine), the SAPB group (administered 20 ml of 0.5% ropivacaine), and the standard care (control) group. The primary endpoint was the consumption of sufentanil during the first 24 h following surgery. Secondary endpoints assessed the area under the curve (AUC) of pain numerical rating scale (NRS) scores, occurrence of moderate to severe pain, time to initial sufentanil request, and postoperative adverse events.

Results

No significant difference was observed in the consumption of sufentanil during the first 24 h following surgery between the ESPB and SAPB groups (adjusted difference, 1.53 [95% CI, -5.15 to 2.08]). However, in comparison to the control group, both intervention groups demonstrated a significant decrease in sufentanil consumption, with adjusted differences of -9.97 [95% CI, -13.10 to -6.84] for the ESPB group and -12.55 [95% CI, -15.63 to -9.47] for the SAPB group. There were no significant differences in AUC of NRS scores during rest and movement between the ESPB and SAPB groups, with adjusted differences of -7.10 [95% CI, 1.33 to -15.55] for the rest condition and 5.61 [95% CI, -13.23 to 2.01] for the movement condition. At 6 h postoperatively, there were fewer patients with moderate to severe pain in the ESPB group compared with those in the SAPB group (adjusted difference, -1.37% [95% CI, -2.29% to -0.45%]. The time to first sufentanil request significantly differed among the three groups (ESPB vs Control P < 0.01, SAPB vs Control P < 0.01, ESPB vs SAPB P = 0.015).

Conclusions

In patients undergoing uniportal thoracoscopic lobectomy, although the differences between the two groups are not statistically significant, both the ESPB and SAPB demonstrate effective reduction in postoperative opioid consumption and the need for rescue analgesics compared to the control group. Moreover, the ESPB group experienced a significantly lower incidence of moderate to severe pain at 6 h postoperatively compared to the SAPB group.

Trial registration

The study was registered in the Chinese Clinical Trial Registry (registration No: ChiCTR1900021695, Date of registration: March 5th, 2019).
The perception of childbearing sense of coherence among Chinese couples: a qualitative study
Authors: Li Bingbing , Yuan Mengmei , Zhang Ke , Ni Sha , Zhao Huimin , Lang Xi , Hu Zhenjing , Zeng Tieying
Published: December 2023

Background

Although childbearing health care is wellness-based and promotes normal physiology, it is in a medical model and focuses on risk aversion and disease prevention. The salutogenic theory might provide an alternative perspective to health care concerning childbearing, supporting health-promoting factors, not solely on avoiding adverse events. However, there is a dearth of qualitative research exploring couples’ perceptions of childbearing from the salutogenic lens. This study aimed to explore perceptions and experiences concerning childbearing among couples in the perinatal period and identify salutogenic aspects of it.

Methods

The qualitative descriptive study adopted a directed content analysis to analyse data from a semi-structured and individual interview with 25 purposively selected Chinese couples between July 2022 and December 2022. The concepts of the sense of coherence (SOC) from the salutogenic theory were used as the theory framework for coding.

Results

Definitions and content for the salutogenic aspects of Chinese couples’ perception of childbearing sense of coherence were developed. For comprehensibility of childbearing, four subthemes were extracted (the challenge to health and endurance; transition to and identification with the new role; conflict and reconciliation in relationships; resistance and compromise between social culture and personal development). For manageability of childbearing, two subthemes were extracted (helplessness and hope of childbearing; self-doubt and self-assurance of childbearing). For meaningfulness of childbearing, three subthemes were extracted (personal realisation; family bonding and harmony; the continuation of life).

Conclusions

The findings of this study could give a greater understanding in maintaining couples’ health in the perinatal period from the salutogenic lens and provide a guide to further research that the salutogenic theory could bring a health and wellness-focused agenda in practice and policy-making in the perinatal period.
Assessing inter- and intra-examiner reliability of orthodontists in devising incisor position objectives on cephalograms: a comparative study between senior and junior practitioners
Authors: Li Xue , Tang Zhenxing , Li Yu , Niu Xiaowen , Zhou Fang
Published: December 2023

Background

Effective orthodontic treatment planning hinges on accurately defining incisor position objectives (IPO) in cephalograms. The purpose of this study was to estimate the inter-examiner and intra-examiner reliability of different orthodontists in devising IPOs on cephalograms.

Methods

Ten orthodontists, who were divided into to the senior group (N = 5) and the junior group (N = 5) based on their clinical experience, formulated IPOs for 60 pre-treatment cephalograms twice with an interval of 2 weeks, utilizing SmartOrtho software. The type and magnitude of movement were read directly in the software. A pairedt-test assessed the absolute differences between the first and second IPO devising within each group and between the senior and junior groups in each time’s IPO devising. The intra-examiner and inter-examiner reliabilities were calculated.

Results

There were significant differences in all types of upper incisor movement and lower incisor protrusion/retraction movement between the first and second IPO devising of the senior group. The junior group exhibited significant differences in the twice the upper incisor extrusion/intrusion movement and upper incisor torque movement devising. Additionally, significant differences in all types of incisor movement between the senior and junior groups in each time’s IPO devising. Intra-examiner reliabilities were excellent for both two groups and moderate for the junior group in most types of incisor movement, respectively. The inter-examiner reliability between the two groups ranged from moderate to good across different types of incisor movement.

Conclusions

Among orthodontists, both senior and junior practitioners displayed the best inter-examiner reliability in lower incisor extrusion/intrusion movement. In terms of intra-examiner reliability, senior orthodontists had better intra-examiner reliability in upper incisor position objectives devising than the junior orthodontists. Furthermore, senior orthodontists tended to adopt a more recessive, intrusive, and lingually torqued incisor position approach compared to junior orthodontists.
Association between risk factors and migraine in Pakistani females
Authors: Razzak Nida , Khan Hina , Tariq Huma , Aslam Muhammad
Published: December 2023

Background

Migraine is a typical cripple issue of the brain identified with cerebral pain which is an indication of numerous health conditions. About 18% of women (27 million) and 6% of men (10 million) are afflicted by migraine in the United States. Based on a case-control study, to explore the different risk factors, causing migraine in females and examine the association between risk factors and migraine.

Methods

A sample of 1055 individuals were selected in different areas of Lahore from September 2019 to March 2020. The information was obtained by using the direct interview method and questionnaire method. Descriptive analysis, bivariate analysis and binary logistic regression analysis were carried out in data analysis.

Results

Among 1055 individuals 740 cases and 315 controls were included. In a binary logistic regression model, physical activities, stress, summer season, menstruation and morning were the risk factors that cause migraine and these were found to be positively significant with the odds ratios and 95% confidence interval of odds ratios (1.399; 1.122–1.746), (1.510; 1.187–1.922), (1.595; 1.374–1.851), (1.513; 1.247–1.836) and (1.309; 1.028–1.665) respectively. Nausea, isolation and back head pain were caused by migraine and these were found positively significant with the odds ratios and 95% confidence interval of odds ratios(1.290; 1.122–1.484), (1.882; 1.617–2.190) and (1.285; 1.123–1.471) respectively.

Conclusions

Stress, physical Activities and Menstruation increase the risk of migraine but weight loss, Breakfast, lunch, thirst, injury and Second trimester during pregnancy reduce the risk of migraine.
Cost-effectiveness of human papillomavirus (HPV) vaccination in Burkina Faso: a modelling study
Authors: Kiendrébéogo Joël Arthur , Sidibe Annick Raissa O. , Compaoré Ghislain Bertrand , Nacanabo Relwendé , Sory Orokia , Ouédraogo Issa , Nawaz Saira , Schuind Anne E , Clark Andrew
Published: December 2023

Background

Africa has some of the highest cervical cancer incidence and mortality rates globally. Burkina Faso launched a human papillomavirus (HPV) vaccination programme for 9-year-old girls in 2022 with support from Gavi, the Vaccine Alliance (Gavi). An economic evaluation of HPV vaccination is required to help sustain investment and inform decisions about optimal HPV vaccine choices.

Methods

We used a proportionate outcomes static cohort model to evaluate the potential impact and cost-effectiveness of HPV vaccination for 9-year-old girls over a ten-year period (2022–2031) in Burkina Faso. The primary outcome measure was the cost (2022 US$) per disability-adjusted life year (DALY) averted from a limited societal perspective (including all vaccine costs borne by the government and Gavi, radiation therapy costs borne by the government, and all other direct medical costs borne by patients and their families). We evaluated four vaccines (CERVARIX®, CECOLIN®, GARDASIL-4®, GARDASIL-9®), comparing each to no vaccination (and no change in existing cervical cancer screening and treatment strategies) and to each other. We combined local estimates of HPV type distribution, healthcare costs, vaccine coverage and costs with GLOBOCAN 2020 disease burden data and clinical trial efficacy data. We ran deterministic and probabilistic uncertainty analyses.

Results

HPV vaccination could prevent 37–72% of cervical cancer cases and deaths. CECOLIN® had the most favourable cost-effectiveness (cost per DALY averted < 0.27 times the national gross domestic product [GDP] per capita). When cross-protection was included, CECOLIN® remained the most cost-effective (cost per DALY averted < 0.20 times the national GDP per capita), but CERVARIX® provided greater health benefits (66% vs. 48% reduction in cervical cancer cases and deaths) with similar cost-effectiveness (cost per DALY averted < 0.28 times the national GDP per capita, with CECOLIN® as the comparator). We estimated the annual cost of the vaccination programme at US$ 2.9, 4.1, 4.4 and 19.8 million for CECOLIN®, GARDASIL-4®, CERVARIX® and GARDASIL-9®, respectively. A single dose strategy reduced costs and improved cost-effectiveness by more than half.

Conclusion

HPV vaccination is cost-effective in Burkina Faso from a limited societal perspective. A single dose strategy and/or alternative Gavi-supported HPV vaccines could further improve cost-effectiveness.
Establishment of microbial model communities capable of removing trace organic chemicals for biotransformation mechanisms research
Authors: Cao Lijia , Garcia Sarahi L. , Wurzbacher Christian
Published: December 2023

Background

Removal of trace organic chemicals (TOrCs) in aquatic environments has been intensively studied. Some members of natural microbial communities play a vital role in transforming chemical contaminants, however, complex microbial interactions impede us from gaining adequate understanding of TOrC biotransformation mechanisms. To simplify, in this study, we propose a strategy of establishing reduced-richness model communities capable of removing diverse TOrCs via pre-adaptation and dilution-to-extinction.

Results

Microbial communities were adapted from tap water, soil, sand, sediment deep and sediment surface to changing concentrations of 27 TOrCs mixture. After adaptation, the communities were further diluted to reduce diversity into 96 deep well plates for high-throughput cultivation. After characterizing microbial structure and TOrC removal performance, thirty taxonomically non-redundant model communities with different removal abilities were obtained. The pre-adaptation process was found to reduce the microbial richness but to increase the evenness and phylogenetic diversity of resulting model communities. Moreover, phylogenetic diversity showed a positive effect on the number of TOrCs that can be transformed simultaneously. Pre-adaptation also improved the overall TOrC removal rates, which was found to be positively correlated with the growth rates of model communities.

Conclusions

This is the first study that investigated a wide range of TOrC biotransformation based on different model communities derived from varying natural microbial systems. This study provides a standardized workflow of establishing model communities for different metabolic purposes with changeable inoculum and substrates. The obtained model communities can be further used to find the driving agents of TOrC biotransformation at the enzyme/gene level.
Prognostic significance of Lymphocyte-activation gene 3 (LAG3) in patients with solid tumors: a systematic review, meta-analysis and pan-cancer analysis
Authors: Li Rongyang , Qiu Jianhao , Zhang Zhan , Qu Chenghao , Tang Zhanpeng , Yu Wenhao , Tian Yu , Tian Hui
Published: December 2023

Background

Lymphocyte-activation gene 3 (LAG3) is a recently discovered immune checkpoint molecule that has been linked to immunosuppression and the advancement of cancer in different types of solid tumors. This study aimed to evaluate the prognostic importance of LAG3 and its role in the immune system within solid tumors.

Methods

Extensive literature searches were conducted using the Pubmed, EMBASE, and Cochrane Library databases to identify relevant studies exploring the effect of LAG3 on survival outcomes. Pooled hazard ratios (HRs) with its 95% confidence intervals (CIs) were calculated to evaluate the prognostic values of LAG3. Afterwards, subgroup analysis and sensitivity analysis were conducted. Pan-cancer analysis investigated the possible relationships between LAG3 expression and genetic alterations, RNA methylation modification-related genes, genomic instability, immune checkpoint genes, and infiltration of immune cells.

Results

A total of 43 studies with 7,118 patients were included in this analysis. Higher expression of LAG3 was associated with worse overall survival (HR = 1.10, 95% CI 1.01–1.19, P = 0.023), but not disease-free survival (HR = 1.41, 95% CI 0.96–2.07, P = 0.078), progression-free survival (HR = 1.12, 95% CI 0.90–1.39, P = 0.317) or recurrence-free survival (HR = 0.98, 95% CI 0.81–1.19, P = 0.871). Subgroup analysis showed that LAG3 might play different prognostic roles in different solid tumors. LAG3 expression was positively associated with immune cell infiltration and immune checkpoint genes in all of the cancers included. LAG3 expression was also found to be associated with microsatellite instability (MSI), copy number variation (CNV), simple nucleoside variation (SNV), tumor mutation burden (TMB), and neoantigen in various types of cancers.

Conclusions

Elevated expression of LAG3 is linked to poorer prognosis among patients diagnosed with solid cancers. LAG3 might play varying prognostic roles in different types of solid tumors. Given its substantial involvement in cancer immunity and tumorigenesis, LAG3 has garnered attention as a promising prognostic biomarker and a potential target for immunotherapy.
Association of cardiometabolic factors and insulin resistance surrogates with mortality in participants from the Korean Genome and Epidemiology Study
Authors: Kityo Anthony , Lee Sang-Ah
Published: December 2023

Background

Simple biochemical and anthropometric measurements such as fasting blood glucose (FBG), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), waist circumference (WC), and body mass index (BMI) are used to formulate insulin resistance (IR) indices. Whether these indices provide new predictive information for mortality remains unknown. This study examined the relationships of biochemical, anthropometric, and IR indices with mortality risk, as well as their predictive performance.

Methods

The data source was the Korean Genome and Epidemiology Study (2004–2020) involving 114,957 participants whose data were linked to death records. The IR indices- triglyceride-glucose index (TyG), TyG-BMI, TyG-WC, visceral adiposity index (VAI), lipid accumulation product (LAP), and metabolic score for insulin resistance (METS-IR) were computed using standard formulae. The associations were examined using restricted cubic splines. The predictive performance was compared using the log-likelihood ratio chi-square test.

Results

Body mass index was U-shaped, HDL-C was reverse J-shaped, and FBG and TG levels were J-shaped associated with all-cause mortality. Results showed U-shaped (TyG), J-shaped (TyG-BMI, VAI, LAP, and METS-IR), and reverse J-shaped (TyG-WC) associations with all-cause mortality. The percentages of new predictive information for all-cause mortality explained by the FBG level, BMI, TyG-BMI, and METIR were 3.34%, 2.33%, 1.47%, and 1.37%, respectively. Other IR indices and biochemical and anthropometric measurements provided < 1.0% of new predictive information. For cardiovascular disease mortality, the FBG, BMI, METIR, TyG-BMI, and HDL-C levels explained 2.57%, 2.12%, 1.59%, 1.30%, and 1.27% of new predictive information respectively. Moreover, the risks of cancer mortality explained by FBG level, VAI, and HDL-C level were 2.05%, 1.49%, and 1.28%, respectively.

Conclusions

Fasting blood glucose level is a superior predictor of mortality risk and may be used as a simple predictive and preventative factor.
Optimal timing of surgery for gastric cancer after neoadjuvant chemotherapy: a systematic review and meta-analysis
Authors: Ling Qi , Huang Shi-Ting , Yu Tian-Hang , Liu Han-Lin , Zhao Lin-Yong , Chen Xiao-Long , Liu Kai , Chen Xin-Zu , Yang Kun , Hu Jian-Kun , Zhang Wei-Han
Published: December 2023

Background

Following neoadjuvant chemotherapy, surgical resection is one of the most preferred treatment options for locally advanced gastric cancer patients. However, the optimal time interval between chemotherapy and surgery is unclear. This review aimed to identify the optimal time interval between neoadjuvant chemotherapy and surgery for advanced gastric cancer.

Methods

Beginning on November 12, 2022, we searched the PubMed, Cochrane Library, Web of Science databases, and Embase.com databases for relevant English-language research. Two authors independently screened the studies, assessed their quality, extracted the data, and analyzed the results. The primary goal was to investigate the relationship between the time interval to surgery (TTS) and long-term survival outcomes for patients. This study has been registered with PROSPERO (CRD42022365196).

Results

After an initial search of 4880 articles, the meta-analysis review ultimately included only five retrospective studies. Ultimately, this meta-analysis included 1171 patients, of which 411 patients had TTS of < 4 weeks, 507 patients had TTS of 4–6 weeks, and 253 patients had TTS of > 6 weeks. In survival analysis, patients with TTS of > 6 weeks had poorer overall survival outcomes than patients with TTS of 4–6 weeks (HR = 1.34, 95% CI: 1.03–1.75, P = 0.03). No significant differences were found in terms of disease-free survival the groups.

Conclusion

Based on the current clinical evidence, patients with locally advanced gastric cancer may benefit better with a TTS of 4–6 weeks; however, this option still needs additional study.
The enrichment of Fanconi anemia/homologous recombination pathway aberrations in ATM/ATR-mutated NSCLC was accompanied by unique molecular features and poor prognosis
Authors: Wei Wei , Shi Fangfang , Xu Yang , Jiao Yang , Zhang Ying , Ou Qiuxiang , Wu Xue , Yang Lingyi , Lai Jinhuo
Published: December 2023

Background

ATM and ATR are two critical factors to regulate DNA damage response (DDR), and their mutations were frequently observed in different types of cancer, including non-small cell lung cancer (NSCLC). Given that the majority of identified ATM/ATR mutations were variants of uncertain significance, the clinical/molecular features of pathogenic ATM/ATR aberrations have not been comprehensively investigated in NSCLC.

Methods

Next-generation sequencing (NGS) analyses were conducted to investigate the molecular features in 191 NSCLC patients who harbored pathogenic/likely pathogenic ATM/ATR mutations and 308 NSCLC patients who did not have any types of ATM/ATR variants. The results were validated using an external cohort of 2727 NSCLC patients (including 48 with ATM/ATR pathogenic mutations).

Results

Most pathogenic ATM/ATR genetic alterations were frameshift and nonsense mutations that disrupt critical domains of the two proteins. ATM/ATR-mutated patients had significantly higher tumor mutational burdens (TMB; P < 0.001) and microsatellite instabilities (MSI; P = 0.023), but not chromosomal instabilities, than those without any ATM/ATR variations. In particular, KRAS mutations were significantly enriched in ATM-mutated patients (P = 0.014), whereas BRCA2 mutations (P = 0.014), TP53 mutations (P = 0.014), and ZNF703 amplification (P = 0.008) were enriched in ATR-mutated patients. Notably, patients with ATM/ATR pathogenic genetic alterations were likely to be accompanied by mutations in Fanconi anemia (FA) and homologous recombination (HR) pathways, which were confirmed using both the study (P < 0.001) and validation (P < 0.001) cohorts. Furthermore, the co-occurrence of FA/HR aberrations could contribute to increased TMB and MSI, and patients with both ATM/ATR and FA/HR mutations tended to have worse overall survival.

Conclusions

Our results demonstrated the unique clinical and molecular features of pathogenic ATM/ATR mutations in NSCLC, which helps better understand the cancerous involvement of these DDR regulators, as well as directing targeted therapies and/or immunotherapies to treat ATM/ATR-mutated NSCLC, especially those with co-existing FA/HR aberrations.
A comparative study on ctDNA and tumor DNA mutations in lung cancer and benign cases with a high number of CTCs and CTECs
Authors: Xie Jianzhu , Hu Binjie , Gong Yanping , He Sijia , Lin Jun , Huang Qian , Cheng Jin
Published: December 2023

Background

Liquid biopsy provides a non-invasive approach that enables detecting circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) using blood specimens and theoretically benefits early finding primary tumor or monitoring treatment response as well as tumor recurrence. Despite many studies on these novel biomarkers, their clinical relevance remains controversial. This study aims to investigate the correlation between ctDNA, CTCs, and circulating tumor-derived endothelial cells (CTECs)  while also evaluating whether mutation profiling in ctDNA is consistent with that in tumor tissue from lung cancer patients. These findings will help the evaluation and utilization of these approaches in clinical practice.

Methods

104 participants (49 with lung cancer and 31 with benign lesions) underwent CTCs and CTECs detection using integrating subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) strategy. The circulating cell-free DNA (cfDNA) concentration was measured and the mutational profiles of ctDNA were examined by Roche AVENIO ctDNA Expanded Kit (targeted total of 77 genes) by next generation sequencing (NGS) in 28 patients (20 with lung cancer and 8 with benign lesions) with highest numbers of CTCs and CTECs. Mutation validation in matched tumor tissue DNA was then performed in 9 patients with ctDNA mutations using a customized xGen pan-solid tumor kit (targeted total of 474 genes) by NGS.

Results

The sensitivity and specificity of total number of CTCs and CTECs for the diagnosis of NSCLC were 67.3% and 77.6% [AUC (95%CI): 0.815 (0.722–0.907)], 83.9% and 77.4% [AUC (95%CI): 0.739 (0.618–0.860)]. The concentration of cfDNA in plasma was statistically correlated with the size of the primary tumor (r = 0.430, P = 0.022) and CYFRA 21–1 (r = 0.411, P = 0.041), but not with the numbers of CTCs and CTECs. In this study, mutations were found to be poorly consistent between ctDNA and tumor DNA (tDNA) in patients, even when numerous CTCs and CTECs were present.

Conclusion

Detection of CTCs and CTECs could be the potential adjunct tool for the early finding of lung cancer. The cfDNA levels are associated with the tumor burden, rather than the CTCs or CTECs counts. Moreover, the poorly consistent mutations between ctDNA and tDNA require further exploration.
Family planning integration in Ethiopia’s primary health care system: a qualitative study on opportunities, challenges and best practices
Authors: Titiyos Addisalem , Mehretie Yohannes , Alemayehu Yibeltal Kiflie , Ejigu Yohannes , Yitbarek Kiddus , Abraham Zelalem , O’Connell Kathryn A. , Kassaw Jemal
Published: December 2023

Background

Family planning (FP) service integration into primary health care (PHC) is an effective approach to realize reproductive autonomy, increase the use of contraceptives, and improve maternal and child health outcomes. The Ethiopian government promotes integration of FP services into primary health care (PHC). However, there is paucity of evidence on the status of FP service integration. The aim of this study is to explore the state of FP integration into PHC services and identify facilitators and barriers to integration.

Methods

A qualitative study nested with a larger national study was conducted from July to October 2022. A total of 60 interviews were conducted with FP stakeholders including, government organizations, non-governmental organizations, donors, service providers, and clients. Interviews were audio recorded, transcribed, and coded using OpenCode 4.03. The coded data were analyzed using framework analysis approach, using the Primary Health Care Performance Initiative (PHCPI) framework. Direct quotes and results from the coding and categorization were used to develop the report.

Results

Family planning is largely provided in designated units by dedicated staff within PHC facilities. The provision of integrated FP service within each service unit is in its early stage. Successful examples of integration include integration of FP with postnatal care, abortion care, and youth-friendly service centers. Facilitators of integration include commitment of the government and partners, the presence of policies and guidelines, and positive attitude of service providers and clients. However, integration of FP also faces challenges that are largely related to challenges of the FP program even before integration. These include resource shortage, health workers shortage, health workers’ capacity/skill gaps, misconceptions about FP, religious and socio-cultural norms, and lack of awareness.

Conclusions

Integration of FP with PHC services in the Ethiopian public health facilities is viable. Pre-existing challenges of the FP program continued to be barriers to integration. Expanding the experiences of good practices in the integration of FP with post abortion care, post-natal care, and youth-friendly service centers to other components of PHC warrants attention. Addressing both supply- and demand-side challenges of the FP program is needed to facilitate the integration of FP with other PHC services.
Mixed methods usability evaluation of an assistive wearable robotic hand orthosis for people with spinal cord injury
Authors: Dittli Jan , Meyer Jan T. , Gantenbein Jessica , Bützer Tobias , Ranzani Raffaele , Linke Anita , Curt Armin , Gassert Roger , Lambercy Olivier
Published: December 2023

Background

Robotic hand orthoses (RHO) aim to provide grasp assistance for people with sensorimotor hand impairment during daily tasks. Many of such devices have been shown to bring a functional benefit to the user. However, assessing functional benefit is not sufficient to evaluate the usability of such technologies for daily life application. A comprehensive and structured evaluation of device usability not only focusing on effectiveness but also efficiency and satisfaction is required, yet often falls short in existing literature. Mixed methods evaluations, i.e., assessing a combination of quantitative and qualitative measures, allow to obtain a more holistic picture of all relevant aspects of device usability. Considering these aspects already in early development stages allows to identify design issues and generate generalizable benchmarks for future developments.

Methods

We evaluated the short-term usability of the RELab tenoexo, a RHO for hand function assistance, in 15 users with tetraplegia after a spinal cord injury through a comprehensive mixed methods approach. We collected quantitative data using the Action Research Arm Test (ARAT), the System Usability Scale (SUS), and timed tasks such as the donning process. In addition, qualitative data were collected through semi-structured interviews and user observations, and analyzed with a thematic analysis to enhance the usability evaluation. All insights were attributed and discussed in relation to specifically defined usability attributes such as comfort, ease of use, functional benefit, and safety.

Results

The RELab tenoexo provided an immediate functional benefit to the users, resulting in a mean improvement of the ARAT score by 5.8 points and peaking at 15 points improvement for one user (clinically important difference: 5.7 points). The mean SUS rating of 60.6 represents an adequate usability, however, indicating that especially the RHO donning (average task time = 295 s) was perceived as too long and cumbersome. The participants were generally very satisfied with the ergonomics (size, dimensions, fit) of the RHO. Enhancing the ease of use, specifically in donning, increasing the provided grasping force, as well as the availability of tailoring options and customization were identified as main improvement areas to promote RHO usability.

Conclusion

The short-term usability of the RELab tenoexo was thoroughly evaluated with a mixed methods approach, which generated valuable data to improve the RHO in future iterations. In addition, learnings that might be transferable to the evaluation and design of other RHO were generated, which have the potential to increase the daily life applicability and acceptance of similar technologies.
An observational study of an adjusted patient blood management protocol intended to lower rates of transfusion following total knee arthroplasty in patients with preoperative anemia
Authors: Hourlier Hervé , Fennema Peter
Published: December 2023

Background

Patients with preoperative anemia have a higher risk of requiring blood transfusion after major orthopedic surgery due to increased blood loss and closer transfusion thresholds. Various patient blood management (PBM) policies aim to reduce transfusion rates. This observational study aimed to investigate blood loss and evaluate the effectiveness of an adjusted surgical PBM protocol in patients with anemic chronic disease (ACD) undergoing elective total knee arthroplasty (TKA).

Methods

A consecutive cohort of patients underwent elective unilateral TKA with an adjusted PBM protocol. The protocol consisted of epoetin (EPO) alfa therapy prescribed by the surgeon, routine administration of tranexamic acid (TXA), and standardized postoperative pharmacologic prophylaxis for thromboembolism. The performance of this PBM protocol was analyzed in patients with a baseline hemoglobin level of less than 12 g/dl. Hemoglobin levels were controlled at admission, on postoperative day (POD) 1, and on POD 7 ± 1. A bleeding index (BI-7) was used as an estimate of blood loss up until POD 7. Multiple linear regression was used to assess whether there were any differences in BI-7 between ACD– and ACD + patients.

Results

A total of 751 patients with complete hemoglobin monitoring were included in the study. Of these patients, 68 (9.1%) had a baseline hemoglobin concentration of less than 12 g/dl (ACD group). In this group, 28 patients (41.2%) received preoperative EPO therapy. The mean adjusted BI-7 for the study population was 3.0 (95% CI, 2.9 to 3.0) g/dl in the ACD– group and 2.3 (95% CI, 2.0–2.6) g/dl in the ACD + group. The difference in BI-7 was statistically significant (difference, 0.6 [95% CI: 0.3 to 0.9] g/dl, p < 0.001). No major complications occurred in the ACD + group, whereas there were three complications in the ACD– group (p = 1.00).

Conclusions

ACD patients undergoing TKA did not have an increased risk of bleeding or bleeding complications with the use of the adjusted PBM protocol. None of ACD patients required transfusion. ACD patients undergoing TKA experienced significantly less blood loss than patients with no preoperative anemia with the use of the adjusted PBM. We now consider the use of EPO in ACD patients with no nutritional deficiencies undergoing TKA at a baseline hemoglobin level of 11 g/dl. However, this should be validated in larger cohorts with a higher prevalence of ACD patients.