bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial community composition predicts bacterial production across ocean ecosystems
Authors: Connors Elizabeth , Dutta Avishek , Trinh Rebecca , Erazo Natalia , Dasarathy Srishti , Ducklow Hugh , Weissman J L , Yeh Yi-Chun , Schofield Oscar , Steinberg Deborah , Fuhrman Jed , Bowman Jeff S 
Published: August 2024

Abstract
Microbial ecological functions are an emergent property of community composition. For some ecological functions, this link is strong enough that community composition can be used to estimate the quantity of an ecological function. Here, we apply random forest regression models to compare the predictive performance of community composition and environmental data for bacterial production (BP). Using data from two independent long-term ecological research sites—Palmer LTER in Antarctica and Station SPOT in California—we found that community composition was a strong predictor of BP. The top performing model achieved an R2 of 0.84 and RMSE of 20.2 pmol L−1 hr−1 on independent validation data, outperforming a model based solely on environmental data (R2 = 0.32, RMSE = 51.4 pmol L−1 hr−1). We then operationalized our top performing model, estimating BP for 346 Antarctic samples from 2015 to 2020 for which only community composition data were available. Our predictions resolved spatial trends in BP with significance in the Antarctic (P value = 1 × 10−4) and highlighted important taxa for BP across ocean basins. Our results demonstrate a strong link between microbial community composition and microbial ecosystem function and begin to leverage long-term datasets to construct models of BP based on microbial community composition.
In vitro activity of olorofim against 507 filamentous fungi including antifungal drug-resistant strains at a tertiary laboratory in Australia: 2020–2023
Authors: Halliday Catriona L , Tay Enoch , Green Wendy , Law Derek , Lopez Ronald , Faris Silvia , Meehan Lauren , Harvey Emma , Birch Mike , Chen Sharon C A 
Published: August 2024

Abstract

Background
New antifungal agents are required to mitigate against azole-resistant Aspergillus and drug-resistant non-Aspergillus moulds. The novel orotomide, olorofim (F2G, Manchester, UK), has potent fungicidal activity against Aspergillus including azole-resistant Aspergillus fumigatus, Lomentospora prolificans and Scedosporium spp. Development of olorofim-specific clinical breakpoints/epidemiological cut-off values requires reliable MIC data.

Objectives
Determine the in vitro activity of olorofim compared with standard antifungals against mould pathogens at an Australian hospital.

Materials and methods
Olorofim MICs were determined for 507 clinical mould isolates using the CLSI M38-A3 standard. MICs of amphotericin B, anidulafungin, posaconazole, voriconazole and isavuconazole were obtained using Sensititre™ YeastOne YO10 and AUSNMRCI panels (Thermo-Fisher Scientific).

Results
A. fumigatus sensu stricto was the commonest species (33.3%) followed by L. prolificans (18.3%), Scedosporium (11.4%) and Fusarium (6%) species. Olorofim modal MICs were ≤0.25 mg/L (MIC90 0.25 mg/L) for all Aspergillus except Aspergillus Section Usti (1 mg/L); MICs for nine azole-resistant/non-wild-type A. fumigatus ranged from 0.008 to 0.125 mg/L. The MIC90 of olorofim for L. prolificans was 0.5 mg/L, 0.25–0.5 mg/L for Scedosporium spp. and 8 mg/L for the F. solani complex but with modal MICs of 0.25 and 0.008 mg/L for F. oxysporum and F. proliferatum complexes, respectively. For Verruconis gallopava (n = 10), the olorofim MIC90 was 0.06 mg/L (voriconazole MIC90 2 mg/L, isavuconazole MICs of 4–&gt;8 mg/L). Olorofim had little activity against other dematiaceous moulds including Exophiala species.

Conclusions
Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus, L. prolificans, Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava.
The G-protein alpha subunit AaGA1 positively regulates vegetative growth, appressorium-like formation, and pathogenicity in Alternaria alternata
Authors: Nan Yuanping , Zhang Miao , Li Yongcai , Bi Yang 
Published: August 2024

Abstract

Aims
The Gα subunit is a major component of heterotrimeric G proteins, which play a crucial role in the development and pathogenicity of several model fungi. However, its detailed function in the causal agent of pear black spot (Alternaria alternata) is unclear. Our aim was to understand the characteristics and functions of AaGA1 in A. alternata.

Methods and results
AaGA1 was cloned from A. alternata in this study, which encodes 353 amino acids and has a “G-alpha” domain. Mutant ΔAaGA1 resulted in reduced vegetative growth, conidiation, and spore germination. Especially, mutant ΔAaGA1 produced only fewer conidia on the V8A medium, and spore formation-related genes AbaA, BrlA, and WetA were significantly downregulated. More tolerance against cell wall-inhibiting agents was observed after the deletion of AaGA1. Moreover, AaGA1 deletion led to a significant reduction in melanin and toxin production. Interestingly, deletion of AaGA1 resulted in defective appressorium-like formations, complete loss of the ability to penetrate cellophane, and decreased infection on non-wound inoculated tobacco leaves. Cell wall-degrading enzyme-related genes PME, CL, Cut2, and LC were significantly downregulated in mutant ΔAaGA1 mutant, significantly reducing virulence on wound-inoculated pear fruits.

Conclusions
The G protein alpha subunit AaGA1 is indispensable for fungal development, appressorium-like formations, and pathogenicity in A. alternata.
A novel CFA + EFA model to detect aberrant respondents
Authors: Cao Niccolò , Finos Livio , Lombardi Luigi , Calcagnì Antonio 
Published: August 2024

Abstract
Aberrant respondents are common but yet extremely detrimental to the quality of social surveys or questionnaires. Recently, factor mixture models (FMMs) have been employed to identify individuals providing deceptive or careless responses. We propose a comprehensive FMM for continuous outcomes that combines confirmatory and exploratory factor models to classify both the nonaberrant and aberrant respondents. The flexibility of the proposed classification model allows for the identification of two of the most common aberrant response styles, namely faking and careless responding. We validated our approach by means of two simulations and two case studies. The results indicate the effectiveness of the proposed model in dealing with aberrant responses in social and behavioural surveys.
Assessing Wolbachia-mediated sterility for dengue control: emulation of a cluster-randomized target trial in Singapore
Authors: Lim Jue Tao , Mailepessov Diyar , Chong Chee-Seng , Dickens Borame , Lai Yee Ling , Ng Youming , Deng Lu , Lee Caleb , Tan Li Yun , Chain Grace , Ho Soon Hoe , Chang Chia-Chen , Ma Pei , Bansal Somya , Lee Vernon , Sim Shuzhen , Tan Cheong Huat , Ng Lee Ching 
Published: August 2024

Abstract

Background
Matings between male Aedes aegypti mosquitoes infected with wAlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing wAlbB-infected Ae. aegypti male mosquitoes to suppress dengue.

Methods
We specified the protocol of a two-arm cluster-randomized test-negative controlled trial (cRCT) and emulated it using a nationally representative test-negative/positive database of individuals reporting for febrile illness to any public hospital, general practitioner or polyclinic. We retrospectively built a cohort of individuals who reside in Wolbachia locations vs a comparator control group who do not reside in Wolbachia locations, using a nationally representative database of all individuals whom report for febrile illness and were tested for dengue at the Environmental Health Institute/hospital laboratories/commercial diagnostic laboratories, through general practitioner clinic, polyclinic or public/private hospital from epidemiological week (EW) 1 2019 to EW26 2022. We emulated a constrained randomization protocol used in cRCTs to balance dengue risk between intervention and control arms in the pre-intervention period. We used the inverse probability weighting approach to further balance the intervention and control groups using a battery of algorithmically selected sociodemographic, environmental and anthropogenic variables. Intention-to-treat analyses were conducted to estimate the risk reduction of dengue given Wolbachia exposure.

Results
Intention-to-treat analyses revealed that, compared with controls, Wolbachia releases for 3, 6 and ≥12 months was associated to 47% (95% confidence interval: 25–69%), 44% (33–77%) and 61% (38–78%) protective efficacy against dengue, respectively. When exposed to ≥12 months of Wolbachia releases, protective efficacies ranged from 49% (13–72%) to 77% (60–94%) across years. The proportion of virologically confirmed dengue cases was lower overall in the intervention arm. Protective efficacies were found across all years, age and sex subgroups, with higher durations of Wolbachia exposure associated to greater risk reductions of dengue.

Conclusion
Results demonstrated that Wolbachia-mediated sterility can strengthen dengue control in tropical cities, where dengue burden is the greatest.
Cometary ion drift energy and temperature at comet 67P/Churyumov–Gerasimeko
Authors: Williamson Hayley N , Johansson Annie , Canu-Blot Romain , Stenberg Wieser Gabriella , Nilsson Hans , Johansson Fredrik L , Moeslinger Anja 
Published: August 2024

ABSTRACT
The Ion Composition Analyzer (ICA) on the Rosetta spacecraft observed both the solar wind and the cometary ionosphere around comet 67P/Churyumov–Gerasimenko for nearly two years. However, observations of low energy cometary ions were affected by a highly negative spacecraft potential, and the ICA ion density estimates were often much lower than plasma densities found by other instruments. Since the low energy cometary ions are often the highest density population in the plasma environment, it is nonetheless desirable to understand their properties. To do so, we select ICA data with densities comparable to those of Rosetta’s Langmuir Probe (LAP)/Mutual Impedance Probe (MIP) throughout the mission. We then correct the cometary ion energy distribution of each energy-angle scan for spacecraft potential and fit a drifting Maxwell–Boltzmann distribution, which gives an estimate of the drift energy and temperature for 3521 scans. The resulting drift energy is generally between 11–18 eV and the temperature between 0.5–1 eV. The drift energy shows good agreement with published ion flow speeds from LAP/MIP during the same time period and is much higher than the cometary neutral speed. We see additional higher energy cometary ions in the spectra closest to perihelion that would be well described by a second Maxwellian-like distribution. The energy and temperature are negatively correlated with heliocentric distance, with a stronger dependence on heliocentric distance for temperature. It cannot be quantitatively determined whether this trend is primarily due to heliocentric distance or spacecraft distance to the comet, which increased with decreasing heliocentric distance.
17 CDK4/6 inhibition with Abemaciclib in in patients (pts) with previously treated advanced renal carcinoma (RCC)
Authors: McGregor Bradley , Xie Wanling , Xu Wenxin , Berg Stephanie , Viswanathan Srinivas R , McDermott David , Signoretti Sabina , Kaelin William , Choueiri Toni 
Published: August 2024

Abstract

Background
Preclinical data suggests rationale for CDK4/6 alone and in combination with HIF-2 inhibitors; single agent activity for CDK4/6 inhibitors in RCC has not been reported. Abemaciclib is an oral CDK4/6 inhibitor approved in combination with hormonal therapy for metastatic breast cancer. In our phase 1b clinical trial (NCT04627064), we investigated the safety and clinical efficacy of abemaciclib monotherapy in pts with advanced pretreated RCC with clear cell component.

Methods
In this single center trial, adult pts with advanced RCC with a clear cell component and ECOG status of ≤1 progressing after at least one prior regimen including immunotherapy and a VEGF TKI received abemaciclib 200 mg twice daily in 4-week cycles until progression or unacceptable toxicity. Primary objective was to evaluate the objective response rate (ORR) of abemaciclib with secondary endpoint of safety. First imaging was performed after 2 cycles. Response assessed per RECIST 1.1 and toxicity per CTCAE v5.0.

Results
11 pts (10 clear cell RCC and 1 translocation RCC) were enrolled between 12/31/2020 and 10/03/2023. Median age was 62 years (range 54-68) with 18% (n=2) showing sarcomatoid features. 73% (n=8) had IMDC intermediate risk disease and one patient had translocation RCC (tRCC) with a clear cell component. Median number of prior therapies was 4 (range 1-9). Seven patients received 2 cycles and 4 patients received &lt; 2 cycles. ORR was 0% (0/11; 8 progressive disease, 1 stable disease in tRCC stopping for clinical progression, 2 pts not evaluable with clinical progression). 27% (n=3) experienced grade ≥3 treatment-related adverse events (diarrhea n=1, nausea n=1, neutropenia n=1).

Conclusions
In pts with heavily pretreated RCC, abemaciclib had manageable toxicity profile but no clinically meaningful activity as monotherapy. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2 inhibitors.
42 Belzutifan versus everolimus for previously treated advanced clear cell renal cell carcinoma: Subgroup analysis of the phase 3 LITESPARK-005 study
Authors: Albiges Laurence , Choueiri Toni K , Peltola Katriina , de Velasco Guillermo , Burotto Mauricio , Suarez Cristina , Ghatalia Pooja , Iacovelli Roberto , Lam Elaine T , Verzoni Elena , Gumus Mahmut , Stadler Walter M , Kollmannsberger Christian , Melichar Bohuslav , Venugopal Balaji , Xing Aiwen , Perini Rodolfo F , Vickery Donna , Rini Brian , Powles Thomas 
Published: August 2024

Abstract

Background
Belzutifan monotherapy is approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) based on the results of the phase 3 LITESPARK-005 study (NCT04195750). In LITESPARK-005, belzutifan improved progression-free survival (PFS; HR 0.75; 95% CI, 0.63-0.90; P &lt; 0.001) and objective response rate (ORR; 21.9% vs 3.5%; P &lt; 0.00001) versus everolimus at first interim analysis (IA1); overall survival (OS) did not reach statistical significance at IA2 (HR 0.88; 95% CI, 0.73-1.07; P = 0.1). We present efficacy outcomes by prespecified subgroups from IA2.

Methods
Patients with clear cell RCC whose disease progressed after anti–PD-(L)1 and VEGF-targeted therapies and who had 1-3 prior systemic regimens were randomly assigned 1:1 to belzutifan 120 mg by mouth once daily or everolimus 10 mg by mouth once daily until progression or intolerable toxicity. The dual primary end points of PFS by central review per RECIST v1.1 and OS and the key secondary end point of ORR were evaluated by prespecified baseline characteristic subgroups: IMDC risk (favorable vs intermediate/poor), prior VEGF-TKIs (1 vs 2-3), and number of prior lines of therapy (1 vs 2 vs 3). These analyses were not controlled for multiplicity and no formal statistical testing occurred. The database cutoff date was June 13, 2023.

Results
Overall, 746 patients were assigned to belzutifan (n = 374) or everolimus (n = 372). Baseline characteristics were balanced between groups. Median follow-up was 25.7 months (range, 16.8-39.1). Across analyzed subgroups, PFS and OS results were consistent with the primary analysis (Table). ORR favored belzutifan over everolimus for all subgroups: IMDC favorable risk (22.8% vs 6.0%), IMDC intermediate/poor risk (22.7% vs 2.8%), 1 prior VEGF-TKI (19.7% vs 3.7%), 2 prior VEGF-TKIs (25.7% vs 3.3%), 1 prior line of therapy (28.3% vs 5.8%), 2 prior lines (19.1% vs 2.4%), and 3 prior lines (24.6% vs 3.9%).

Conclusions
Consistent with the intention-to-treat population of LITESPARK-005, PFS and ORR favored belzutifan over everolimus across prespecified subgroups. These results support belzutifan as a new treatment option for patients with advanced clear cell RCC after prior anti–PD-(L)1 and VEGF-targeted therapies.
34 Impact of Latino Ethnicity on the gut microbiome composition of patients with metastatic renal cell cancer (mRCC)
Authors: Barragan-Carrillo Regina 
Published: August 2024

Abstract

Background
Latinos with mRCC may have poorer outcomes with frontline immune checkpoint inhibition (ICI) compared to their non-Latino counterparts (Chehrazi-Raffle et al Oncologist 2023). Recent studies have shown that the composition of the gut microbiome can impact outcomes with ICI (Routy et al Science 2018). Therefore, we aimed to investigate the differences in gut microbiome composition between Latino and non-Latino patients with mRCC.

Methods
Stool specimens were prospectively collected in treatment-naïve patients with mRCC. We dichotomized patients into Latino vs non-Latino groups. Patients provided a stool sample (OMNIgene Gut) at baseline. Whole metagenome sequencing was performed on stool specimens collected. Taxonomic profiling was conducted using MetaPhlAn 4. ANCOM-BC analysis was used to identify differences in the relative abundance of bacterial species between groups. Alpha-diversity was evaluated using the Shannon diversity index and Evenness analysis, employing the Kruskal-Wallis test. Beta-diversity was assessed using the Bray-Curtis and Jaccard dissimilarity measures. The ratio of Firmicutes/Bacteroidetes (F/B), a measure of gut dysbiosis, was computed at baseline in the two cohorts.

Results
Among 59 patients assessed, 27 and 32 were Latino and non-Latino, respectively. Median age of the cohort was 60 (range, 36-90). Most were male (71%), had clear cell RCC (88%) and had intermediate/poor risk disease (79%). ANCOM-BC analysis showed an enrichment of 14 bacterial species and a depletion in 3 species at baseline in the Latino group (p ≤ 0.05). Three Roseburia spp. were enriched in the Latino patients, namely R. faecis (log-fold change [LFC]: 2.6), R. hominis (LFC: 2.0) and R. inulinivorans (LFC: 1.8). Additionally, E. rectale was also enriched in the Latino group (LFC: 2.0). In contrast, in non-Latino patients Methylobacterium spp. was enriched (LFC: 1.3). The F/B ratio was higher in the Latino group as compared to the non-Latino group (1.00 vs 0.92). We did not observe any differences in alpha and beta diversity.

Conclusions
Our examination of the gut microbiota of pts with mRCC revealed significant differences based on ethnicity at baseline. Specifically, the Latino group exhibited an enhancement of Roseburia spp. and E. rectale, species previously linked to favorable outcomes with ICIs. Our findings suggest that clinical trials related to the microbiome should potentially account for baseline differences in ethnicity.
9 Delving into molecular underpinnings of sarcomatoid/rhabdoid dedifferentioation in renal cancers using spatial profiling
Authors: Riazalhosseini Yasser 
Published: August 2024

Abstract

Background
Renal cell carcinomas (RCC) are characterized by their largely diverse clinical outcomes. Leveraging genomic diversity among individual tumors, our research during the past decade has concentrated on developing personalized medicine approaches for the most common and the most aggressive type of RCC, clear cell renal carcinoma (ccRCC). We generated the largest dataset of ccRCC including somatic genomic and clinical annotations for over 940 ccRCC patients, and developed a genomic classifier, based on mutational status of 12 RCC-relevant genes, which is able to stratify patients according to their risk of relapse after nephrectomy and/or death due to RCC. Furthermore, we noticed the presence of mesenchymal-like cellular phenotypes in tumors of high-risk patients, representsing a de-differentiation process, known as sarcomatoic or rhabdoid (S/R) de-differentation.

Methods
The current knowledge about molecular mechanisms that may drive S/R de-differentiation is primarily generated from molecular profiling of bulk tumors, collecting data from a mixture of cells that co-exist in the tumor milieu. Therefore, high-resolution studies that precisely define molecular characteristics of different cellular phenotypes associated with S/R features are missing. We have used spatial transcriptomic profiling to investigate molecular mechanisms that underline S/R de-differentationin RCC. While preserving tissue context, we applied spatial whole human transcriptome profiling to areas exhibiting S/R or clear cell phenotypes within the same tumor specimens to generate phenotype-specific transcriptome profiles. In addition, we applied whole-exome sequencing (WES) to independent areas that exhibit different differentiation phenotype withing same tumors.

Results
Pathway and network analysis of genesets with upregulation in each area have revealed meaningful differences in cellular pathways which are active in each phenotype. Specifically, we observed that dysregulation of extracellular matrix (ECM) is a hallmark of S/R areas within RCC tumors. Furthermore, WES of phenotypically-distinct areas within each tumor has shed new light son the genome evoltuion of S/R phenotypes.

Conclusions
S/R dedifferentiation in RCC tumors is characterized by specific genomic evolutionary patterns and substantial dysregulation of ECM components.
DOD CDMRP Funding: yes
18 Unraveling the Impact of Tumor Microenvironment on Immunotherapy Response/Resistance in Human Sarcomatoid Clear Cell Renal Cell Carcinoma: Insights from a Novel Mouse Model
Authors: Jiang Hui 
Published: August 2024

Abstract

Background
Renal cell carcinoma (RCC) with histological sarcomatoid de-differentiation (sRCC) has a historically poor prognosis across all RCC subtypes. Recently, immunotherapy with anti-PD1 + anti-CTLA4 combo has significantly improved disease-specific survival, and complete response are seen in upwards of 20% of patients. However, half of sRCC patients still have no response to this immunotherapy, and the mechanism of response remains unclear.

Methods
Our preliminary bulk RNA sequencing data reveal a distinct tumor microenvironment (TME) in human sRCC tumors, characterized by heightened immune cell infiltration, particularly enriched for regulatory T cells (Tregs). Subsequently, we delineated the spatial gene expression topography within sRCC and clear cell renal cell carcinoma (ccRCC) regions, culminating in the development of the sRCC signature. Concurrently, we established an innovative immunocompetent murine model of sRCC. Leveraging CRISPR technology, we replicated the human sRCC genotype by knocking out Vhl, Bap1, and Cdkn2a/2b genes in a mouse telomerase reverse transcriptase (mTERT) overexpressing renal proximal tubule epithelial cell line. This effort yielded a successfully engineered mouse implantable sRCC cell line bearing VhlMutBap1DelCdkn2aDelCdkn2bDel (HJRCC68N).

Results
The syngeneic mouse sRCC model we developed faithfully replicates human sRCC histology and tumor microenvironment and recapitulates the sRCC signature identified in human sRCC regions. Importantly, like in humans, mouse sRCC tumors exhibit a heterogeneous response to anti-PD1 + anti-CTLA4 combination, and anti-CTLA4 monotherapy, reflecting the clinical variability observed in human patients. Furthermore, transcriptomic analysis from our mouse model reveals the involvement of type 1 immunity in responder, providing insights into overcoming immunotherapy resistance.

Conclusions
In conclusion, our study unveiled distinct changes in the TME at the transcriptomic and spatial gene expression levels in human sRCC. Leveraging our novel murine model, which faithfully replicates human sRCC histology, TME characteristics, and mixed response to immunotherapy, we elucidated the involvement of type 1 immunity in treatment response. These insights offer valuable pathways for overcoming immunotherapy resistance and pave the way for the development of tailored treatment strategies aimed at improving outcomes for sRCC patients.