bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

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 < 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

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 < 0.001) and objective response rate (ORR; 21.9% vs 3.5%; P < 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

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

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

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.
43 Epigenomic profiling of translocation renal cell carcinoma via liquid biopsy
Authors: Garinet Simon , Semaan Karl , Canniff John , Phillips Noa , Davidsohn Matthew , Berchuck Jacob , Li Jiao , Sadagopan Ananthan , Fortunato Brad , O’toole Jillian , Gwo-shu Mary , Horst Jack , Freeman Dory , Seo Ji-Heui , Freedman Matthew , Choueiri Toni , Baca Sylvan , Viswanathan Srinivas
Published: August 2024

Background

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer usually driven by a fusion involving the TFE3 gene. Due to histologic overlap with other subtypes of RCC, tRCC is frequently misclassified. Methods for accurate diagnosis and detection of this molecularly distinct entity are therefore a pressing need.

Epigenomic profiling of ctDNA via plasma chromatin immunoprecipitation and sequencing (ChIP-seq) has recently emerged as a powerful tool to detect and molecularly subtype cancers and may offer a more sensitive and specific detection of molecular fusions. We aimed to detect tRCC in plasma and to discriminate tRCC from ccRCC based on epigenomic profiling of cfDNA.

Methods

We first identified differentially expressed gene, methylated regions (DMRs) and regulatory elements (REs) specific to tRCC vs. ccRCC via RNA-seq, methylated DNA immunoprecipitation sequencing (MeDIP-seq) and ChIP-Seq, of 4 tRCC and 5 ccRCC cell lines. We collected 16 plasma samples from metastatic patients with tRCC, 11 with ccRCC and 9 healthy patients (HP). Ultra low pass whole genome sequencing (ulpWGS) was performed to infer ctDNA fraction (TF), and cfMeDIP-seq, H3K4me3/H3K27ac cfChIP-seq for epigenomic profiling. Signal at tRCC-specific regions derived from cell lines profiling was aggregated for each mark and normalized to common active REs and DMRs, then compared between classes using a Wilcoxon rank-sum test. Classification performance was evaluated using the area under the receiver operating characteristic (AUROC) curve.

Results

Overall 8/16 tRCC and 5/12 ccRCC samples had >3% TF by ulpWGS. H3K4me3 and H3K27ac cfChIP-seq signal was significantly higher in all tRCC samples compared to healthy patients (p<10-6, AUROC =1), at tRCC-specific promoters and tRCC-specific REs respectively. Furthermore, H3K27ac signal in plasma was also significantly higher at tRCC-specific REs in tRCC samples compared to ccRCC (p<10-4, AUROC=0.95). MeDIP-seq could not discriminate between tRCC and ccRCC.

Conclusions

Although a majority of tRCC plasma samples profiled had TF < 3%, all could be distinguished from healthy samples on the basis of cfChIP. H3K27ac cfChIP-Seq was also discriminatory for tRCC vs. ccRCC. Epigenomic profiling of cfDNA appears as a powerful tool for both detection of tRCC and discrimination from ccRCC/healthy plasma, with potential implications for diagnosis and guiding therapy.
55 Influence of gender on immunosurveillance in a novel mouse model of clear cell renal cell carcinoma
Authors: Zheng Ms Doris
Published: August 2024

Background

Renal Cell Carcinoma (RCC) is a cancer that exhibits sex dimorphism. Males have twice the incidence rate of their female counterparts and more than twice the mortality rate. They frequently present with larger, higher-grade tumors, greater metastatic spread, and earlier diagnosis of disease. Many hormonal, genetic, and environmental reasons have been explored, however a considerable amount of uncertainty remains.

Methods

Here, we explored the immunologic differences using a novel syngeneic mouse model of ccRCC. Tumors were orthotopically implanted by sub-renal capsular injection in immunocompetent WT C57Bl/6 and immunodeficient mice NOD/Scid/Gamma (NSG) mice, and tumor growth was longitudinally monitored using ultrasound imaging. At necropsy, liver and lung metastases were quantified and immune populations in the tumor and peripheral blood were analyzed by flow cytometry.

Results

In the immune-competent model, female mice had lower tumor penetrance as well as delayed tumor growth compared to male mice. In contrast, in the immune-deficient model female mice had similar tumor penetrance and growth rates as males suggesting that the female immune system may be protective against tumor development. No metastases were seen in either sex in the immune-competent model, whereas both lung and liver masses were found in the immune-deficient model suggesting the immune system is critical for restricting metastatic development. Interestingly, increased lung metastases were observed in females compared with male counterparts in NSG mice, suggesting that perhaps hormonal or other non-adaptive immunity-mediated mechanisms can promote metastatic seeding into the lungs.

Flow cytometry characterization revealed higher peripheral B- and T-cells in females, with a higher CD8/CD4 T-cell ratio. Tumors from females had more activated and cytotoxic CD8 T cells and were more frequently metastatic to the lung compared to male mice.

Conclusions

Our findings suggest sex-related immunologic differences in immunosurveillance and metastatic tropism that warrants further interrogation.

DOD CDMRP Funding: yes
74 Unraveling the Complexities of Obesity in Clear Cell Renal Cell Carcinoma Carcinogenesis
Authors: Rodriguez Olivia , Wride Joseph , Tufts Mathew , Peterson Connor , Quinteros Badí , McRae Elisa , Khanderao Gayatri , Tan Aik Choon , Firpo Matthew , Sanchez Alejandro
Published: August 2024

Background

Obesity has been identified as an established risk factor in the development of clear cell renal cell carcinoma (ccRCC). ccRCC arises from the proximal convoluted tubule (PCT) of the kidney which is also the site of obesity-associated chronic kidney disease. Obesity can lead to chronic cellular insults which may lead to DNA injury and whether these mechanisms are critical to cancer initiation in the kidney is unclear. One potential way that obesity can lead to cancer is by altering lipid metabolism, including increasing circulating saturated fatty acids. In particular, palmitic acid is known to be lipotoxic to proximal tubules of the kidney. Understanding how free fatty acids initiate cancer is critical to understanding the role of obesity in cancer initiation and development. We hypothesize that chronic injury and repair due to excess FFA exposure could lead to ccRCC carcinogenesis and aim to define the metabolic phenotype of obesity associated ccRCC.

Methods

Using publicly available data from The KIRC Cancer Genome Atlas Program (TCGA) and clinicopathologic data, we compared the RNAseq profiles of obese (BMI >= 30) to normal weight (BMI =< 25) sample origins. Of the 337, a total of 333 had BMI available for analysis. We evaluated differences in Hallmark and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Using DESeq, we adjusted for age and sex. In vitro, HK PCT cells were cultured in DMEM+10%FBS treated with bovine serum albumin (BSA)-palmitic acid complex for 48 hrs. We measured cell viability using Alamar Blue. Results were normalized to controls with BSA only. We extracted protein and performed western blots to identify DNA damage (pATM, H2AX) and endoplasmic reticulum stress (ATF4, eFI2alpha).

Results

Most of the patients in our clinical data cohort are male (64.4%), while 45.4% of patients are categorized by BMI as obese and 33.2% are categorized as normal. We utilized 333 individuals from the Kyoto Encyclopedia of Genes and Genomes (KEGG) to link genomic information to pathways associated with fatty acid metabolism as well as other cancer-associated hallmark metabolic pathways. We confirmed that excess free fatty acid supplementation leads to decreased cell viability in renal proximal tubule cells and renal embryonal cells and aim to assess differences in gene expression and metabolomic variation with fatty acid supplementation.

Conclusions

Through the investigation of these questions, we hope to improve understanding of obesity associated ccRCC and ultimately impact oncological outcomes for patients with this cancer. Understanding changes in lipid metabolism around ccRCC initiation will help identify novel pathways for pharmacologic intervention at earlier stages of the disease.

DOD CDMRP Funding: yes
Conflicting identities: cosmopolitan or anxious? Appreciating concerns of host country population improves attitudes towards immigrants
Authors: Heidland Tobias , Wichardt Philipp C
Published: August 2024

This paper connects insights from the literature on cosmopolitan worldviews and the effects of perspective-taking in political science, (intergroup) anxiety in social psychology, and identity economics in a vignette-style experiment. In particular, we asked German respondents about their attitudes towards a Syrian refugee, randomizing components of his description (N = 662). The main treatment describes the refugee as being aware of and empathetic towards potential worries in the German population about cultural change, costs, and violence associated with refugee inflows. This perspective-taking by the refugee increases the reported ability to empathize with the refugee and, especially for risk-averse people, reported sympathy and trust. We argue that acknowledging the potential concerns of the host population relieves the tension between an anxious and a cosmopolitan/open part of people’s identities. Moreover, relieved tension renders people less defensive; i.e. when one aspect of identity is already acknowledged (expressing anxieties), it has less influence on actual behavior (expressing sympathy). In addition, previous contact with foreigners and a higher willingness to take risks are important factors in determining an individual’s willingness to interact with refugees.
G protein coupled receptor in apoptosis and apoptotic cell clearance
Authors: Li Xinyan , Li Chao , Kang Yang , Zhang Rui , Li Peiyao , Zheng Qian , Wang Hui , Xiao Hui , Yuan Lei
Published: August 2024

Apoptosis is a genetically programmed form of cell death that is substantially conserved across the evolutionary tree. Apoptotic cell elimination includes recognition, phagocytosis, and degradation. Failure to clear apoptotic cells can ultimately cause a series of human diseases, such as systemic lupus erythematosus, Alzheimer's disease, atherosclerosis, and cancer. Consequently, the timely and effective removal of apoptotic cells is crucial to maintaining the body's homeostasis. GPCRs belong to the largest membrane receptor family. Its intracellular domain exerts an effect on the trimer G protein. By combining with a variety of ligands, the extracellular domain of G protein initiates the dissociation of G protein trimers and progressively transmits signals downstream. Presently, numerous G protein‐coupled receptors (GPCRs) have been identified as participants in the apoptosis signal transduction pathway and the apoptotic cell clearance pathway. Therefore, studies on the mechanism of GPCRs in the clearance of apoptotic cells is important for the development of GPCRs therapeutics.
The Influence of Adolescent Health-related Behaviors on Degenerative Low Back Pain Hospitalizations and Surgeries in Adulthood
Authors: Vaajala Matias , Teuho Alisa , Liukkonen Rasmus , Ponkilainen Ville , Rimpelä Arja , Koivusilta Leena K. , Mattila Ville M.
Published: August 2024

Study Design.

Retrospective longitudinal study.

Objective.

This study aims to investigate the influence of adolescent health-related behaviors (physical activity, high BMI, drunkenness, smoking), self-reported chronic disease, and low socioeconomic status (SES) on the development of low back pain requiring hospitalization or surgery.

Background.

The baseline data were surveys gathered biennially in 1981–1997 (the Adolescent Health and Lifestyle Survey) and individually linked with outcome data, degenerative low back pain hospitalizations, and spine surgeries retrieved from the Care Register for Health Care. A total of 47,724 participants were included. Explanatory variables included physical activity, high BMI, smoking, monthly drunkenness, chronic diseases, and family SES.

Materials and Methods.

A logistic regression model was used to analyze the influence of adolescent health-related behaviors (physical activity, high BMI, drunkenness, smoking), self-reported chronic disease, and low SES on degenerative low back pain hospitalization, lumbar disc herniation (LDH) hospitalization, and/or spine surgery. Covariates were selected using directed acyclic graphs (DAGs).

Results.

A total of 5538 participants had degenerative low back pain hospitalizations, 2104 had LDH hospitalizations, and 913 had spinal surgery over an average of 27-year follow-up. High BMI [adjusted odds ratio (aOR): 1.25, CI: 1.12–1.38], smoking (aOR: 1.53, CI: 1.43–1.62), monthly drunkenness (aOR: 1.17, CI: 1.10–1.26), and chronic diseases (aOR: 1.47, CI: 1.35–1.61) in adolescence increased the odds of hospitalizations during follow-up. In addition, high BMI (aOR: 1.37, CI: 1.09–1.72), smoking (aOR: 1.40, CI: 1.21–1.61), and monthly drunkenness (aOR: 1.19, CI: 1.01–1.39) increased the odds of spine surgeries.

Conclusions.

We found that smoking, high BMI, monthly drunkenness, chronic diseases, and low family SES in adolescence increased the likelihood of degenerative low back pain hospitalizations in adulthood. In addition, high BMI, smoking, and monthly drunkenness in adolescence increased the odds of spinal surgeries.
Simultaneous Determination of Ripretinib and Its Desmethyl Metabolite in Human Plasma Using LC-MS/MS
Authors: Qian Zhou-Yi , Wang Ping , Wang Zi-Yi , Zhao Yang , Du Tian-Tian , Xu Hao , Wang Yong-Qing , Sun Lu-Ning
Published: August 2024

Background:

Ripretinib, a recently developed tyrosine kinase inhibitor with switch-control abilities, can inhibit both primary and secondary activation of KIT (KIT proto-oncogene receptor tyrosine kinase) and platelet-derived growth factor receptor alpha (PDGFRA) mutants, which contribute to gastrointestinal stromal tumor progression.

Methods:

In this study, a high-performance liquid chromatography–tandem mass spectrometry method to measure the concentrations of ripretinib and its active desmethyl metabolite DP-5439 in human plasma was developed and validated. Plasma samples were extracted and recovered by precipitation with acetonitrile containing the internal standard and diluted with acetonitrile before analysis. Ripretinib and DP-5439 were separated using chromatography on a Waters ACQUITY UPLC HSS T3 column (2.1 mm × 50 mm, 1.8 μm) with gradient elution using 0.1% formic acid and 5 mM ammonium formate in water as mobile phase A and acetonitrile as mobile phase B. The mobile phase was set to a flow rate of 0.5 mL/min.

Results:

The calibration curves were linear across the following concentration range: 7.5 to 3000 ng/mL for ripretinib and 10 to 4000 ng/mL for DP-5439. The intraday and interday precisions were approximately 15% for all analytes in the quality control samples. The relative matrix effects in extracted plasma samples (90.3%–108.8% at different levels) were considered acceptable.

Conclusions:

This method will be a useful tool in oncology to facilitate the further clinical development of ripretinib.
Model-Informed Dosing Optimization of Tacrolimus for Concomitant Administration with Itraconazole to Japanese Lung Transplant Recipients
Authors: Takahashi Ren , Itohara Kotaro , Nakagawa Shunsaku , Katada Yoshiki , Sugimoto Mitsuhiro , Umemura Keisuke , Matsumura Katsuyuki , Hira Daiki , Tsuda Masahiro , Katsube Yurie , Tanaka Satona , Ohsumi Akihiro , Nakajima Daisuke , Nagao Miki , Date Hiroshi , Terada Tomohiro
Published: August 2024

Background:

Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients.

Methods:

This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed.

Results:

A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug–drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation.

Conclusions:

This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.
Menopause in adult women with human papillomavirus: health-related quality of life and determinants
Authors: Calvo-Torres Javier , Rejas Javier , Ramírez-Mena Mar , González-Granados Carmen , Bradbury Melissa , del Pino Marta , Procas Beatriz , Rubio-Arroyo Mar , Presa-Lorite Jesús , Gippini Isabel , Fasero María , Fiol Gabriel , Romero Pablo , Cohen Aaron , Coronado Pluvio J. ,   on behalf of the HPV-QoL Study group
Published: August 2024

Objective

Human papillomavirus (HPV) infection and menopause entail a considerable impairment in health-related quality of life (HRQoL). The objective of the present study was to analyze the impact of the menopause status on HRQoL in women with HPV infection.

Methods

A cross-sectional, nationwide, multicenter sample of women with HPV infection was conducted throughout clinics of gynecology representative of the Spanish population with regard to age, geographic density, and autonomous regions. Demographic and clinical characteristics and the specific HPV-QoL questionnaire score with its domains were compared according to reproductive status: premenopausal and peri-/postmenopausal. Correlation with other validated patient-reported outcomes measurements was also tested, including General Health Questionnaire-12 (GHQ-12), Female Sexual Function Index (FSFI), and Hospital Anxiety and Depression Scale (HADS).

Results

A sample of 1,016 noninstitutionalized women, aged 18‐80 y, was recorded, 191 (18.8%) peri-/postmenopausal and 825 (81.2%) premenopausal. Total HPV-QoL scoring was significantly lower in peri-/postmenopausal (38.8, 95% CI [35.2-42.4]) compared to premenopausal (46.4, 95% CI [45.0‐47.8]) women, and also in every domain of the scale (P < 0.05), except in social well-being and health domains, with a small effect size of 0.39. In women with sexual dysfunction according to FSFI, adjusted total scoring and domains sexuality, general well-being, and psychological well-being scored significantly higher in premenopause women (P < 0.01), although the magnitude of differences were of small to moderate size.

Conclusions

HRQoL was impaired during menopause in women with HPV infection according to HPV-QoL questionnaire. The sexuality domain was the most differentiating dimension between these populations.
The effects of motivational interviewing on sexual quality of life and sexual self-efficacy in postmenopausal women with sexual dysfunction
Authors: Kamalak Hülya , Aksoy Derya Yeşim
Published: August 2024

Objective

This study was conducted to determine the effects of motivational interviewing on sexual quality of life and sexual self-efficacy in postmenopausal women with sexual dysfunction.

Methods

This randomized controlled study was conducted with 164 postmenopausal women with sexual dysfunction who presented to the gynecology outpatient clinic of a university hospital in Kahramanmaras, Türkiye (82 experimental, 82 control). The data were collected using a personal information form, the Arizona Sexual Experiences Scale–Female Version Questionnaire, the Sexual Quality of Life–Female Questionnaire, and the Sexual Self-Efficacy Scale. Four motivational interview sessions were conducted with the postmenopausal women in the experimental group at 1-week intervals, and those in the control group did not receive any intervention. The data were analyzed using descriptive statistics, Pearson's chi-squared test, and independent samples and paired samples t tests.

Results

Both the sexual quality of life and sexual self-efficacy levels of the participants in the experimental and control groups were similar in the pretest stage (P > 0.05). After the motivational interviews with those in the experimental group, the rate of sexual dysfunction was determined as 82.9% in the experimental group and 98.8% in the control group. Additionally, after the motivational interviews, the sexual dysfunction scores of the participants in the experimental group decreased significantly, and their sexual quality of life and sexual self-efficacy levels increased significantly compared to those in the control group (P < 0.001).

Conclusions

The results of this study revealed that motivational interviewing decreased sexual dysfunction and increased sexual quality of life and sexual self-efficacy in postmenopausal women with sexual dysfunction.
Simulating the Morphological Changes of Facial Deformities after Using 3D-printed Polyether Ether Ketone Facial Implants
Authors: Ahmad Ahmad Fayez , Yacoub Hekmat , Khalil Ali
Published: August 2024

Background:

Patient-specific implants (PSIs) have been presented as an effective solution for diseases that require reconstruction. PSIs are designed to precisely fit anatomical defects or deformities in terms of shape and size. In addition to the possibility of predicting the results of surgery regarding soft tissue changes.

Methods:

A research sample consisting of 10 patients with facial deformities underwent maxillofacial reconstructive surgery between 2020 and 2021 in the Tishreen University Hospital, Syria. All patients underwent computed tomography scans; then, the design of the required facial implant was carried out, and the three-dimensional soft tissues were reconstructed using the ExoCad 3.0 program based on the computed tomography. The final form of the facial implant was printed from polyether ether ketone, and then surgical work was performed. The patients were followed up after 6 months. Then, a comparison was made between the virtual design and the real result.

Results:

The absolute difference between the expected soft tissue changes result and the actual result did not exceed three-tenths for all patients, and only two of 10 patients had measurements higher than 20%.

Conclusions:

This technique can be relied upon with the placement of implants to predict the outcome of the surgical procedure in terms of morphological changes in the facial soft tissues covering PSI polyether ether ketone. Therefore, it is possible to make a virtual design based on the cosmetic requirements of the patient.
Evaluation of Posthospital Brain Injury Rehabilitation Outcomes With Quasi-Experimental Controls
Authors: Parrott Devan , Salisbury David B. , Altman Irwin M. , Logan Daniel M. , McGrath Claire , Walters G. Joseph , Malec James F.
Published: August 2024

Objective:

To further evaluate, using quasi-experimental methodologies, posthospital brain injury rehabilitation outcomes described in an accompanying report of a large observational study (n = 2120).

Setting:

Data from Intensive Rehabilitation (IR: Residential Neurobehavioral, Residential Neurorehabilitation, Home and Community Neurorehabilitation, Day Treatment, Outpatient Neurorehabilitation) and Supported Living (SL) programs serving individuals with acquired brain injury (ABI).

Participants:

Two hundred twenty-eight individuals with traumatic brain injury, stroke, or other ABI in propensity score analysis; 1344 in analysis by extent of recommended treatment completed (TC) rating.

Main Measures:

Sex, age, time since injury, Mayo-Portland Adaptability Inventory—4th edition (MPAI-4) Rasch-derived T-scores, and TC rating.

Design:

Analyses of covariance (1) of discharge MPAI-4 Total, index, and subscale T-scores on propensity score-matched samples of IR and SL participants controlling for admission scores and (2) of MPAI-4 T-scores by TC rating and diagnostic category.

Results:

Propensity score-matched groups showed superior outcomes for IR participants compared to SL participants on MPAI-4 Total T-score (F = 77.21, P < .001; partial η2 = 0.257) and all MPAI-4 index and subscale T-scores controlling for sex, age, and baseline scores. Participants with traumatic brain injury and stroke who completed the recommended course of rehabilitation had superior outcomes on all MPAI-4 T-scores compared to those who completed less than or much less than the recommended treatment. No additional benefit was apparent for those who completed more than the recommended course. The association between TC rating and outcome was not significant for the other ABI group.

Conclusions:

These analyses using quasi-experimental controls provide more scientifically rigorous evidence of the benefit of IR provided through posthospital brain injury rehabilitation programs after acute inpatient care, consistent with the results of numerous observational studies. However, improved internal validity limits external validity and generalization. The absence of a significant association between TC rating and outcomes for the other ABI group most likely reflects the difficulty prescribing rehabilitation for this highly heterogeneous group.
Aqueous-Deficient Dry Eye Increases Lipid Layer Thickness Measured by Dynamic Tear Interferometry
Authors: Ahn Hyunmin , Kim Sang Yeop , Jun Ikhyun , Kim Tae-im , Seo Kyoung Yul
Published: August 2024

Purpose:

To investigate the impact of aqueous deficiency on lipid layer thickness (LLT) measurement in dry eye disease before and after treatment of aqueous-deficient dry eye (ADDE) using dynamic tear interferometry.

Methods:

This prospective comparative study included 230 eyes from 230 patients with ADDE. The treatment group with punctal plug insertion was compared with the control group. The average LLT (LLTave) was measured with a LipiView II tear interferometer at baseline and after 1 month. Correlation analyses were performed with the indices of the dynamics of the tear film lipid layer (TFLL).

Results:

Baseline LLTave values were 116.1 ± 26.7 and 112.3 ± 27.6 nm in the treatment group (n = 121) and the control group (n = 109), respectively. At 1 month, LLTave significantly decreased in the treatment group (difference −41.8 [95% confidence interval (CI) −47.2 to −36.3], P = 0.003). The values of tear meniscus height (TMH) at baseline and 1-month follow-up were negatively correlated with LLTave (both P < 0.001). Spreading time of TFLL to equilibrium and the deviation of TFLL were positively correlated with LLTave (all P < 0.001) and negatively correlated with TMH (P < 0.001 and 0.009). In multivariate analysis (adjusted R2 = 0.411, P < 0.001), LLTave was associated with TMH (B = −1.068; P < 0.001), adjusting for age, sex, and meibomian gland expressibility.

Conclusions:

In ADDE, the TFLL was measured to be thicker than the normal range of 60 to 99 nm and became thinner with treatment. LLT was affected by not only meibum secretion but also aqueous status due to changes in the dynamics of TFLL.