bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bile-induced biofilm formation in
Bacteroides thetaiotaomicron
requires magnesium efflux by an RND pump
Authors: Lopes Anne-Aurélie , Vendrell-Fernández Sol , Deschamps Julien , Georgeault Sonia , Cokelaer Thomas , Briandet Romain , Ghigo Jean-Marc 
Published: March 2024

ABSTRACT

Bacteroides thetaiotaomicron
is a prominent member of the human gut microbiota contributing to nutrient exchange, gut function, and maturation of the host’s immune system. This obligate anaerobe symbiont can adopt a biofilm lifestyle, and it was recently shown that
B. thetaiotaomicron
biofilm formation is promoted by the presence of bile. This process also requires a
B. thetaiotaomicron
extracellular DNase, which is not, however, regulated by bile. Here, we showed that bile induces the expression of several Resistance-Nodulation-Division (RND) efflux pumps and that inhibiting their activity with a global competitive efflux inhibitor impaired bile-dependent biofilm formation. We then showed that, among the bile-induced RND-efflux pumps, only the tripartite BT3337-BT3338-BT3339 pump, re-named BipABC [for Bile Induced Pump A (
BT3337
), B (
BT3338
), and C (
BT3339
)], is required for biofilm formation. We demonstrated that BipABC is involved in the efflux of magnesium to the biofilm extracellular matrix, which leads to a decrease of extracellular DNA concentration. The release of magnesium in the biofilm matrix also impacts biofilm structure, potentially by modifying the electrostatic repulsion forces within the matrix, reducing interbacterial distance and allowing bacteria to interact more closely and form denser biofilms. Our study therefore, identified a new molecular determinant of
B. thetaiotaomicron
biofilm formation in response to bile salts and provides a better understanding on how an intestinal chemical cue regulates biofilm formation in a major gut symbiont.

IMPORTANCE

Bacteroides thetaiotaomicron
is a prominent member of the human gut microbiota able to degrade dietary and host polysaccharides, altogether contributing to nutrient exchange, gut function, and maturation of the host’s immune system. This obligate anaerobe symbiont can adopt a biofilm community lifestyle, providing protection against environmental factors that might, in turn, protect the host from dysbiosis and dysbiosis-related diseases. It was recently shown that
B. thetaiotaomicron
exposure to intestinal bile promotes biofilm formation. Here, we reveal that a specific
B. thetaiotaomicron
membrane efflux pump is induced in response to bile, leading to the release of magnesium ions, potentially reducing electrostatic repulsion forces between components of the biofilm matrix. This leads to a reduction of interbacterial distance and strengthens the biofilm structure. Our study, therefore, provides a better understanding of how bile promotes biofilm formation in a major gut symbiont, potentially promoting microbiota resilience to stress and dysbiosis events.
Hsp90, a team player in protein quality control and the stress response in bacteria
Authors: Wickramaratne Anushka C. , Wickner Sue , Kravats Andrea N. 
Published: March 2024

SUMMARY
Heat shock protein 90 (Hsp90) participates in proteostasis by facilitating protein folding, activation, disaggregation, prevention of aggregation, degradation, and protection against degradation of various cellular proteins. It is highly conserved from bacteria to humans. In bacteria, protein remodeling by Hsp90 involves collaboration with the Hsp70 molecular chaperone and Hsp70 cochaperones. In eukaryotes, protein folding by Hsp90 is more complex and involves collaboration with many Hsp90 cochaperones as well as Hsp70 and Hsp70 cochaperones. This review focuses primarily on bacterial Hsp90 and highlights similarities and differences between bacterial and eukaryotic Hsp90. Seminal research findings that elucidate the structure and the mechanisms of protein folding, disaggregation, and reactivation promoted by Hsp90 are discussed. Understanding the mechanisms of bacterial Hsp90 will provide fundamental insight into the more complex eukaryotic chaperone systems.
Analyzing the safety of the parasiticide fungus
Mucor circinelloides
: first insights on its virulence profile and interactions with the avian gut microbial community
Authors: Lozano João , Cunha Eva , Almeida Cristina , Nunes Mónica , Dias Ricardo , Vicente Eduardo , Sebastião Daniela , Henriques Sérgio , Madeira de Carvalho Luís , Paz-Silva Adolfo , Oliveira Manuela 
Published: March 2024

ABSTRACT

Parasiticide fungi are considered an accurate, sustainable, and safe solution for the biocontrol of animal gastrointestinal (GI) parasites. This research provides an initial characterization of the virulence of the native parasiticide fungus
Mucor circinelloides
(FMV-FR1) and an assessment of its impact on birds’ gut microbes. The genome of this fungus was sequenced to identify the genes coding for virulence factors. Also, this fungus was checked for the phenotypic expression of proteinase, lecithinase, DNase, gelatinase, hemolysin, and biofilm production. Finally, an
in vivo
trial was developed based on feeding
M. circinelloides
spores to laying hens and peacocks three times a week. Bird feces were collected for 3 months, with total genomic DNA being extracted and subjected to long-read 16S and 25S-28S sequencing. Genes coding for an iron permease (FTR1), iron receptors (FOB1 and FOB2), ADP-ribosylation factors (ARFs) (ARF2 and ARF6), and a GTPase (CDC42) were identified in this
M. circinelloides
genome. Also, this fungus was positive only for lecithinase activity. The field trial revealed a fecal microbiome dominated by Firmicutes and Proteobacteria in laying hens, and Firmicutes and Bacteroidetes in peacocks, whereas the fecal mycobiome of both bird species was mainly composed of Ascomycetes and Basidiomycetes fungi. Bacterial and fungal alpha-diversities did not differ between sampling time points after
M. circinelloides
administrations (
P
= 0.62 and
P
= 0.15, respectively). Although findings from this research suggest the lack of virulence of this
M. circinelloides
parasiticide isolate, more complementary
in vitro
and
in vivo
research is needed to conclude about the safety of its administration to birds, aiming at controlling their GI parasites.

IMPORTANCE

A previous study revealed that the native
Mucor circinelloides
isolate (FMV-FR1) can develop parasiticide activity toward coccidia oocysts, one of the most pathogenic GI parasites in birds. However, ensuring its safety for birds is of utmost importance, namely by studying its virulence profile and potential effect on commensal gut microbes. This initial study revealed that although this
M. circinelloides
isolate had genes coding for four types of virulence factors—iron permease, iron receptors, ADP-ribosylation factors, and GTPase—and only expressed phenotypically the enzyme lecithinase, the administration of its spores to laying hens and peacocks did not interfere with the abundances and diversities of their gut commensal bacteria and fungi. Although overall results suggest the lack of virulence of this
M. circinelloides
isolate, more complementary research is needed to conclude about the safety of its administration to birds in the scope of parasite biocontrol programs.
Online tools to predict individualised survival for primary oesophageal cancer patients with and without pathological complete response after neoadjuvant therapy followed by oesophagectomy: development and external validation of two independent nomograms
Authors: Cao Yuqin , Huang Binhao , Tang Han , Dong Dong , Shen Tianzheng , Chen Xiang , Feng Xijia , Zhang Jiahao , Shi Liqiang , Li Chengqiang , Jiao Heng , Tan Lijie , Zhang Jie , Li Hecheng , Zhang Yajie 
Published: March 2024

ObjectiveThis study aimed to develop and validate robust predictive models for patients with oesophageal cancer who achieved a pathological complete response (pCR) and those who did not (non-pCR) after neoadjuvant therapy and oesophagectomy.DesignClinicopathological data of 6517 primary oesophageal cancer patients who underwent neoadjuvant therapy and oesophagectomy were obtained from the National Cancer Database for the training cohort. An independent cohort of 444 Chinese patients served as the validation set. Two distinct multivariable Cox models of overall survival (OS) were constructed for pCR and non-pCR patients, respectively, and were presented using web-based dynamic nomograms (graphical representation of predicted OS based on the clinical characteristics that a patient could input into the website). The calibration plot, concordance index and decision curve analysis were employed to assess calibration, discrimination and clinical usefulness of the predictive models.ResultsIn total, 13 and 15 variables were used to predict OS for pCR and non-pCR patients undergoing neoadjuvant therapy followed by oesophagectomy, respectively. Key predictors included demographic characteristics, pretreatment clinical stage, surgical approach, pathological information and postoperative treatments. The predictive models for pCR and non-pCR patients demonstrated good calibration and clinical utility, with acceptable discrimination that surpassed that of the current tumour, node, metastases staging system.ConclusionsThe web-based dynamic nomograms for pCR (https://predict-survival.shinyapps.io/pCR-eso/) and non-pCR patients (https://predict-survival.shinyapps.io/non-pCR-eso/) developed in this study can facilitate the calculation of OS probability for individual patients undergoing neoadjuvant therapy and radical oesophagectomy, aiding clinicians and patients in making personalised treatment decisions.
Benchmarking digital displays (monitors) for histological diagnoses: the nephropathology use case
Authors: Cazzaniga Giorgio , Mascadri Francesco , Marletta Stefano , Caputo Alessandro , Guidi Gabriele , Gambaro Giovanni , Eccher Albino , Dei Tos Angelo Paolo , Pagni Fabio , L'Imperio Vincenzo 
Published: March 2024

AimThe digital transformation of the pathology laboratory is being continuously sustained by the introduction of innovative technologies promoting whole slide image (WSI)-based primary diagnosis. Here, we proposed a real-life benchmark of a pathology-dedicated medical monitor for the primary diagnosis of renal biopsies, evaluating the concordance between the ‘traditional’ microscope and commercial monitors using WSI from different scanners.MethodsThe College of American Pathologists WSI validation guidelines were used on 60 consecutive renal biopsies from three scanners (Aperio, 3DHISTECH and Hamamatsu) using pathology-dedicated medical grade (MG), professional grade (PG) and consumer-off-the-shelf (COTS) monitors, comparing results with the microscope diagnosis after a 2-week washout period.ResultsMG monitor was faster (1090 vs 1159 vs 1181 min, delta of 6–8%, p<0.01), with slightly better performances on the detection of concurrent diseases compared with COTS (κ=1 vs 0.96, 95% CI=0.87 to 1), but equal concordance to the commercial monitors on main diagnosis (κ=1). Minor discrepancies were noted on specific scores/classifications, with MG and PG monitors closer to the reference report (r=0.98, 95% CI=0.83 to 1 vs 0.98, 95% CI=0.83 to 1 vs 0.91, 95% CI=0.76 to 1, κ=0.93, 95% CI=077 to 1 vs 0.93, 95% CI=0.77 to 1 vs 0.86, 95% CI=0.64 to 1, κ=1 vs 0.50, 95% CI=0 to 1 vs 0.50, 95% CI=0 to 1, for IgA, antineutrophilic cytoplasmic antibody and lupus nephritis, respectively). Streamlined Pipeline for Amyloid detection through congo red fluorescence Digital Analysis detected amyloidosis on both monitors (4 of 30, 13% cases), allowing detection of minimal interstitial deposits with slight overestimation of the Amyloid Score (average 6 vs 7).ConclusionsThe digital transformation needs careful assessment of the hardware component to support a smart and safe diagnostic process. Choosing the display for WSI is critical in the process and requires adequate planning.
Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis
Authors: Patel Jimmy S , Woo Yena , Draper Amber , Jansen Caroline S , Carlisle Jennifer W , Innominato Pasquale F , Lévi Francis A , Dhabaan Layla , Master Viraj A , Bilen Mehmet A , Khan Mohammad K , Lowe Michael C , Kissick Haydn , Buchwald Zachary S , Qian David C 
Published: March 2024

BackgroundRecent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC).MethodsThe treatment records of all patients with stage IV RCC who began ICI therapy within a multicenter academic hospital system between 2015 and 2020 were reviewed. The associations between the proportion of ICI infusions administered prior to noon (denoting morning infusions) and PFS and OS were evaluated using univariate and multivariable Cox proportional hazards regression.ResultsIn this study, 201 patients with mRCC (28% women) received ICIs and were followed over a median of 18 months (IQR 5–30). The median age at the time of ICI initiation was 63 years (IQR 56–70). 101 patients (50%) received ≥20% of their ICI infusions prior to noon (Group A) and 100 patients (50%) received <20% of infusions prior to noon (Group B). Across the two comparison groups, initial ICI agents consisted of nivolumab (58%), nivolumab plus ipilimumab (34%), and pembrolizumab (8%). On univariate analysis, patients in Group A had longer PFS and OS compared with those in Group B (PFS HR 0.67, 95% CI 0.48 to 0.94, Punivar=0.020; OS HR 0.57, 95% CI 0.34 to 0.95, Punivar=0.033). These significant findings persisted following multivariable adjustment for age, sex, performance status, International Metastatic RCC Database Consortium risk score, pretreatment lactate dehydrogenase, histology, and presence of bone, brain, and liver metastases (PFS HR 0.70, 95% CI 0.50 to 0.98, Pmultivar=0.040; OS HR 0.57, 95% CI 0.33 to 0.98, Pmultivar=0.043).ConclusionsPatients with mRCC may benefit from earlier time-of-day receipt of ICIs. Our findings are consistent with established mechanisms of chrono-immunology, as well as with preceding analogous studies in melanoma and lung cancer. Additional prospective randomized trials are warranted.
Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial
Authors: ten Ham Renske M T , Rohaan Maartje W , Jedema Inge , Kessels Rob , Stegeman Wim , Scheepmaker Walter , Nuijen Bastiaan , Nijenhuis Cynthia , Lindenberg Melanie , Borch Troels Holz , Monberg Tine , Donia Marco , Marie Svane Inge , van Harten Wim , Haanen John , Retel Valesca P 
Published: March 2024

IntroductionIn a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC–IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis.MethodsA Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed.ResultsMean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most.ConclusionBased on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC–IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems.
NPEPPS Is a Druggable Driver of Platinum Resistance
Authors: Jones Robert T. , Scholtes Mathijs , Goodspeed Andrew , Akbarzadeh Maryam , Mohapatra Saswat , Feldman Lily Elizabeth , Vekony Hedvig , Jean Annie , Tilton Charlene B. , Orman Michael V. , Romal Shahla , Deiter Cailin , Kan Tsung Wai , Xander Nathaniel , Araki Stephanie P. , Joshi Molishree , Javaid Mahmood , Clambey Eric T. , Layer Ryan , Laajala Teemu D. , Parker Sarah J. , Mahmoudi Tokameh , Zuiverloon Tahlita C.M. , Theodorescu Dan , Costello James C. 
Published: March 2024

Abstract

There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations.

Significance:
Targeting NPEPPS, which induces cisplatin resistance by controlling intracellular drug concentrations, is a potential strategy to improve patient responses to platinum-based therapies and lower treatment-associated toxicities.
Regular Use of Aspirin and Statins Reduces the Risk of Cancer in Individuals with Systemic Inflammatory Diseases
Authors: Lin Jia-Run , Han Duan-Duan , Wei Wei , Zeng Qin , Rong Zi-Xuan , Bai Xue , Zhang Yan-Pei , Wang Jian , Cai Xiao-Ting , Rao Xu-Guang , Ma Si-Cong , Dong Zhong-Yi 
Published: March 2024

Abstract

Aspirin has shown potential for cancer prevention, but a recent large randomized controlled trial found no evidence for a reduction in cancer risk. Given the anti-inflammatory effects of aspirin, systemic inflammatory diseases (SID), such as osteoporosis, cardiovascular diseases, and metabolic diseases, could potentially modify the aspirin-cancer link. To investigate the impact of aspirin in people with SIDs, we conducted an observational study on a prospective cohort of 478,615 UK Biobank participants. Individuals with at least one of the 41 SIDs displayed a higher cancer risk than those without SIDs. Regular aspirin use showed protective effects exclusively in patients with SID, contrasting an elevated risk among their non-SID counterparts. Nonetheless, aspirin use demonstrated preventative potential only for 9 of 21 SID-associated cancer subtypes. Cholesterol emerged as another key mediator linking SIDs to cancer risk. Notably, regular statin use displayed protective properties in patients with SID but not in their non-SID counterparts. Concurrent use of aspirin and statins exhibited a stronger protective association in patients with SID, covering 14 common cancer subtypes. In summary, patients with SIDs may represent a population particularly responsive to regular aspirin and statin use. Promoting either combined or individual use of these medications within the context of SIDs could offer a promising chemoprevention strategy.

Significance:
Individuals with systemic inflammatory diseases derive chemoprotective benefits from aspirin and statins, providing a precision cancer prevention approach to address the personal and public challenges posed by cancer.
Cancer Cells Hijack Physiologic Metabolic Signals to Seed Liver Metastasis
Authors: Rettig Andres R. , Ganesh Karuna 
Published: March 2024

Abstract
Metastasis arises from cancer cell–intrinsic adaptations and permissive tumor microenvironments (TME) that are distinct across different organs. Deciphering the mechanisms underpinning organotropism could provide novel preventive and therapeutic strategies for patients with cancer. Rogava and colleagues identified Pip4k2c as a driver of liver metastasis, acting by sensitizing cancer cells to insulin-dependent PI3K/AKT signaling, which could be reversed by dual pharmacologic inhibition of PI3K and SGLT2 or a ketogenic diet. The study highlights the importance of tumor microenvironment communication in the context of systemic physiology and points toward potential combination therapies.