tbuckley/cabot-search huggingface dataset:
Stool Microbiome Signature Associated with Response to Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Cancer
Authors: Filippo Pederzoli, Michela Riba, Chiara Venegoni, Laura Marandino, Marco Bandini, Elisa Alchera, Irene Locatelli, Daniele Raggi, Patrizia Giannatempo, Paolo Provero, Dejan Lazarevic, Marco Moschini, Roberta Lucianò, Andrea Gallina, Alberto Briganti, Francesco Montorsi, Andrea Salonia, Andrea Necchi, Massimo Alfano
Journal: European Urology (2024)

Neoadjuvant pembrolizumab has been shown to be a valid treatment for patients affected by muscle-invasive bladder cancer (MIBC), as demonstrated in the PURE-01 clinical trial (NCT02736266). Among the tumor-extrinsic factors influencing immunotherapy efficacy, extensive data highlighted that the microbiome is a central player in immune-mediated anticancer activity. This report aimed to investigate the composition and role of stool microbiome in patients enrolled in the PURE-01 clinical trial. An orthotopic animal model of bladder cancer (MB49-Luc) was used to support some of the findings from human data. An analysis of stool microbiome before pembrolizumab was conducted for 42 patients, of whom 23 showed a pathologic response. The information in the preclinical model of orthotopic bladder cancer treated with anti–PD-1 antibody or control isotype was validated. Linear discriminant analysis effect size and linear models were used to identify the bacterial taxa enriched in either responders or nonresponders. The identified taxa were also tested for their association with event-free survival (EFS). Survival at 31 d after tumor instillation was used as the study endpoint in the preclinical model. Responders and nonresponders emerged to differ in terms of enrichment for 16 bacterial taxa. Of these, the genus Sutterella was enriched in responders, while the species Ruminococcus bromii was enriched in nonresponders. The negative impact of R. bromii on anti–PD-1 antibody activity was also observed in the preclinical model. EFS and survival of the preclinical model showed a negative role of R. bromii. We found different stool bacterial taxa associated with the response or lack of response to neoadjuvant pembrolizumab. Moreover, we provided experimental data about the negative role of R. bromii on immunotherapy response. Further studies are needed to externally validate our findings and provide mechanistic insights about the host-pathogen interactions in MIBC. Using prepembrolizumab stool samples collected from patients enrolled in the PURE-01 clinical trials, we identified some bacterial taxa that were enriched in patients who either responded or did not respond to immunotherapy. Using an animal model of bladder cancer, we gathered further evidence of the negative impact of the Ruminococcus bromii on immunotherapy efficacy. Further studies are needed to confirm the current findings and test the utility of these bacteria as predictive markers of immunotherapy response.
Inventory study on completeness of tuberculosis case notifications in Poland in 2018
Authors: Teresa Domaszewska, Maria Korzeniewska-Kosela, Barbara Hauer, Nita Perumal, Stefan Wesolowski, Walter Haas, Stefan Kroeger
Journal: Eurosurveillance (2024)

Background Evaluating tuberculosis (TB) notification completeness is important for monitoring TB surveillance systems, while estimating the TB disease burden is crucial for control strategies. Aim We conducted an inventory study to assess TB reporting completeness in Poland in 2018. Methods Using a double-pronged inventory approach, we compared notifications of culture-positive TB cases in the National TB Register to records of diagnostic laboratories. We calculated under-reporting both with observed and capture–recapture (CRC)-estimated case numbers. We further compared the notifications by region (i.e. voivodship), sex, and age to aggregated data from hospitalised TB patients, which provided an independent estimate of reporting completeness. Results In 2018, 4,075 culture-positive TB cases were notified in Poland, with 3,789 linked to laboratory records. Laboratories reported further 534 TB patients, of whom 456 were linked to notifications from 2017 or 2019. Thus, 78 (534 – 456) cases were missing in the National TB Register, yielding an observed TB under-reporting of 1.9% (78/(4,075 + 78) × 100). CRC-modelled total number of cases in 2018 was 4,176, corresponding to 2.4% ((4,176 – 4,075)/4,176 × 100) under-reporting. Based on aggregated hospitalisation data from 13 of 16 total voivodeships, under-reporting was 5.1% (3,482/(3,670 – 3,482) × 100), similar in both sexes but varying between voivodeships and age groups. Conclusions Our results suggest that the surveillance system captures ≥ 90% of estimated TB cases in Poland; thus, the notification rate is a good proxy for the diagnosed TB incidence in Poland. Reporting delays causing discrepancies between data sources could be improved by the planned change from a paper-based to a digital reporting system.
Relative vaccine effectiveness against COVID-19 hospitalisation in persons aged ≥ 65 years: results from a VEBIS network, Europe, October 2021 to July 2023
Authors: Mario Fontán-Vela, Esther Kissling, Nathalie Nicolay, Toon Braeye, Izaak Van Evercooren, Christian Holm Hansen, Hanne-Dorthe Emborg, Massimo Fabiani, Alberto Mateo-Urdiales, Ala'a AlKerwi, Susanne Schmitz, Jesús Castilla, Iván Martínez-Baz, Brechje de Gier, Susan Hahné, Hinta Meijerink, Jostein Starrfelt, Baltazar Nunes, Constantino Caetano, Tarik Derrough, Anthony Nardone, Susana Monge
Journal: Eurosurveillance (2024)

To monitor relative vaccine effectiveness (rVE) against COVID-19-related hospitalisation of the first, second and third COVID-19 booster (vs complete primary vaccination), we performed monthly Cox regression models using retrospective cohorts constructed from electronic health registries in eight European countries, October 2021–July 2023. Within 12 weeks of administration, each booster showed high rVE (≥ 70% for second and third boosters). However, as of July 2023, most of the relative benefit has waned, particularly in persons ≥ 80-years-old, while some protection remained in 65–79-year-olds.
Reliability of blood eosinophil count in steady-state bronchiectasis
Authors: M.A. Martínez-García, C. Olveira, R. Girón, M. García-Clemente, L. Máiz, O. Sibila, R. Golpe, J.L. Rodríguez-Hermosa, E. Barreiro, Raúl Méndez, C. Prados, J. Rodríguez-López, G. Oscullo, D. de la Rosa
Journal: Pulmonology (2024)

The baseline value of eosinophils in peripheral blood (BEC) has been associated with different degrees of severity, prognosis and response to treatment in patients with bronchiectasis. It is not known, however, if this basal value remains constant over time. The aim of this study was to assess whether the BEC remains stable in the long term in patients with bronchiectasis. Patients from the RIBRON registry of bronchiectasis diagnosed by computed tomography with at least 2 BEC measurements one year apart were included in the study. Patients with asthma and those taking anti-eosinophilic drugs were excluded. Reliability was assessed using the intra-class correlation coefficient (ICC). A patient with a BEC of at least 300 cells/uL or less than 100 cells/uL was considered eosinophilic or eosinopenic, respectively. Group changes over time were also calculated. Seven hundred and thirteen patients were finally included, with a mean age of 66.5 (13.2) years (65.8 % women). A total of 2701 BEC measurements were performed, with a median number of measurements per patient of 4 (IQR: 2–5) separated by a median of 12.1 (IQR: 10.5–14.3) months between two consecutive measurements. The ICC was good (>0.75) when calculated between two consecutive measurements (approximately one year apart) but had dropped significantly by the time of the next annual measurements. Similarly, the change from an eosinophilic or eosinopenic patient to a non-eosinophilic or non-eosinopenic patient, respectively, was less than 30 % during the first year with respect to the baseline value but was close to 50 % in later measurements. Given the significant changes observed in the baseline value of the BEC over time, its monitoring is necessary in patients with bronchiectasis in order to more reliably assess its usefulness.
Interrupted gender transitions: underlying motivations as correlates of psychosocial risks
Authors: N. Eugene Walls, Jarrod Call, Brendon T. Holloway, Tural Mammadli, Darren L. Whitfield
Journal: International Journal of Transgender Health (2024)

Previous research on what is often termed "detransitioning" experiences among transgender and nonbinary individuals has frequently lacked conceptual clarity, failed to differentiate interrupted gender transition experiences by underlying motivations, and failed to examine correlations with psychosocial risks by the various motivations. Utilizing a proposed conceptual framework that captures motivational differences between various interrupted gender transition experiences, this examination seeks to provide a more nuanced understanding of these interrupted gender transitions and their associations with psychosocial risks, underscoring the importance of improved conceptual clarity and empirical precision in this body of scholarship. This secondary data analysis of the 2015 US Transgender Study (N = 26,026) examines how three specific interrupted gender transitions (i.e. interpersonal adaptive gender transitions, structural adaptive gender transitions, and gender recalibration) are correlated with a series of lifetime (i.e. suicide attempts and physical relational violence) and recent (i.e. illicit drug use, fear-based avoidance of medical providers, homelessness, and arrests) psychosocial risks. Multivariate models examine the relationships of interest controlling for age, gender identity, sexual orientation, race/ethnicity, partner status, education, employment status, and household income. Across all six examined risks, we find that interrupted gender transitions due to interpersonal pressure from others (interpersonal adaptive gender transition) and structural barriers facing transgender and nonbinary people (structural adaptive gender transition) are associated with the highest likelihoods of risks. Transgender and nonbinary (TNB) respondents who experience an interrupted gender transition due to a shift in their gender identity from one identity to another identity within the TNB umbrella (gender recalibration) are not significantly different than TNB respondents who had never undergone a gender transition in the first place. The study's findings underscore not only the importance of disaggregation of gender transition interruptions by their underlying motivation, but also highlight one other way in which interpersonal and structural transphobia negatively impact the lived experiences of TNB people.
Nitrate reduction capacity of the oral microbiota is impaired in periodontitis: potential implications for systemic nitric oxide availability
Authors: Bob T. Rosier, William Johnston, Miguel Carda-Diéguez, Annabel Simpson, Elena Cabello-Yeves, Krystyna Piela, Robert Reilly, Alejandro Artacho, Chris Easton, Mia Burleigh, Shauna Culshaw, Alex Mira
Journal: International Journal of Oral Science (2024)

The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with periodontal health, but the impact of periodontitis on nitrate-reducing capacity (NRC) and, therefore, nitric oxide availability has not been evaluated. The current study aimed to evaluate how periodontitis affects the NRC of the oral microbiota. First, 16S rRNA sequencing data from five different countries were analyzed, revealing that nitrate-reducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals (P < 0.05 in all five datasets with n = 20-82 samples per dataset). Secondly, subgingival plaque, saliva, and plasma samples were obtained from 42 periodontitis patients before and after periodontal treatment. The oral NRC was determined in vitro by incubating saliva with 8 mmol/L nitrate (a concentration found in saliva after nitrate-rich vegetable intake) and compared with the NRC of 15 healthy individuals. Salivary NRC was found to be diminished in periodontal patients before treatment (P < 0.05) but recovered to healthy levels 90 days post-treatment. Additionally, the subgingival levels of nitrate-reducing bacteria increased after treatment and correlated negatively with periodontitis-associated bacteria (P < 0.01). No significant effect of periodontal treatment on the baseline saliva and plasma nitrate and nitrite levels was found, indicating that differences in the NRC may only be revealed after nitrate intake. Our results suggest that an impaired NRC in periodontitis could limit dietary nitrate-derived nitric oxide levels, and the effect on systemic health should be explored in future studies.
Isolation and characterization of a novel lytic <i>Parabacteroides distasonis</i> bacteriophage φPDS1 from the human gut
Authors: Adrián Cortés-Martín, Rémi Denise, Emma Guerin, Stephen R. Stockdale, Lorraine A. Draper, R. Paul Ross, Andrey N. Shkoporov, Colin Hill
Journal: Gut Microbes (2024)

The human gut microbiome plays a significant role in health and disease. The viral component (virome) is predominantly composed of bacteriophages (phages) and has received significantly less attention in comparison to the bacteriome. This knowledge gap is largely due to challenges associated with the isolation and characterization of novel gut phages, and bioinformatic hurdles such as the lack of a universal phage marker gene and the absence of sufficient numbers of homologs in viral databases. Here, we describe the isolation from human feces of a novel lytic phage with siphovirus morphology, φPDS1, infecting Parabacteroides distasonis APCS2/PD, and classified within a newly proposed Sagittacolavirus genus. In silico and biological characterization of this phage is presented in this study. Key to the isolation of φPDS1 was the antibiotic-driven selective enrichment of the bacterial host in a fecal fermenter. Despite producing plaques and lacking genes associated with lysogeny, φPDS1 demonstrates the ability to coexist in liquid culture for multiple days without affecting the abundance of its host. Multiple studies have shown that changes in Parabacteroides distasonis abundance can be linked to various disease states, rendering this novel phage-host pair and their interactions of particular interest.
CXCR4/CXCL12 axis: “old” pathway as “novel” target for anti‐inflammatory drug discovery
Authors: Liuxin Lu, Junjie Li, Xiaoying Jiang, Renren Bai
Journal: Medicinal Research Reviews (2024)

Inflammation is the body's defense response to exogenous or endogenous stimuli, involving complex regulatory mechanisms. Discovering anti-inflammatory drugs with both effectiveness and long-term use safety is still the direction of researchers' efforts. The inflammatory pathway was initially identified to be involved in tumor metastasis and HIV infection. However, research in recent years has proved that the CXC chemokine receptor type 4 (CXCR4)/CXC motif chemokine ligand 12 (CXCL12) axis plays a critical role in the upstream of the inflammatory pathway due to its chemotaxis to inflammatory cells. Blocking the chemotaxis of inflammatory cells by CXCL12 at the inflammatory site may block and alleviate the inflammatory response. Therefore, developing CXCR4 antagonists has become a novel strategy for anti-inflammatory therapy. This review aimed to systematically summarize and analyze the mechanisms of action of the CXCR4/CXCL12 axis in more than 20 inflammatory diseases, highlighting its crucial role in inflammation. Additionally, the anti-inflammatory activities of CXCR4 antagonists were discussed. The findings might help generate new perspectives for developing anti-inflammatory drugs targeting the CXCR4/CXCL12 axis.
<i>Collinsella aerofaciens</i> as a predictive marker of response to probiotic treatment in non-constipated irritable bowel syndrome
Authors: Giorgio Gargari, Giacomo Mantegazza, Cesare Cremon, Valentina Taverniti, Alice Valenza, Maria Raffaella Barbaro, Giovanni Marasco, Robin Duncan, Walter Fiore, Roberto Ferrari, Valerio De Vitis, Giovanni Barbara, Simone Guglielmetti
Journal: Gut Microbes (2024)

Probiotics are exploited for adjuvant treatment in IBS, but reliable guidance for selecting the appropriate probiotic to adopt for different forms of IBS is lacking. We aimed to identify markers for recognizing non-constipated (NC) IBS patients that may show significant clinical improvements upon treatment with the probiotic strain Lacticaseibacillus paracasei DG (LDG). To this purpose, we performed a post-hoc analysis of samples collected during a multicenter, double-blind, parallel-group, placebo-controlled trial in which NC-IBS patients were randomized to receive at least 24 billion CFU LDG or placebo capsules b.i.d. for 12 weeks. The primary clinical endpoint was the composite response based on improved abdominal pain and fecal type. The fecal microbiome and serum markers of intestinal (PV1 and zonulin), liver, and kidney functions were investigated. We found that responders (R) in the probiotic arm (25%) differed from non-responders (NR) based on the abundance of 18 bacterial taxa, including the families Coriobacteriaceae, Dorea spp. and Collinsella aerofaciens, which were overrepresented in R patients. These taxa also distinguished R (but not NR) patients from healthy controls. Probiotic intervention significantly reduced the abundance of these bacteria in R, but not in NR. Analogous results emerged for C. aerofaciens from the analysis of data from a previous trial on IBS with the same probiotic. Finally, C. aerofaciens was positively correlated with the plasmalemmal vesicle associated protein-1 (PV-1) and the markers of liver function. In conclusion, LDG is effective on NC-IBS patients with NC-IBS with a greater abundance of potential pathobionts. Among these, C. aerofaciens has emerged as a potential predictor of probiotic efficacy.
Selected Articles from This Issue
Journal: Clinical Cancer Research (2024)

Highlights| January 05 2024 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2024 American Association for Cancer Research2024American Association for Cancer Research Clin Cancer Res (2024) 30 (1): 7. https://doi.org/10.1158/1078-0432.CCR-30-1-HI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record January 5 2024 Citation Selected Articles from This Issue. Clin Cancer Res 1 January 2024; 30 (1): 7. https://doi.org/10.1158/1078-0432.CCR-30-1-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Therapies targeting HER2 have become a standard of care (SOC) treatment for patients with HR+ HER2+ breast cancer; however, resistance can arise through multiple mechanisms. Those who progress on HER2 therapies may benefit from further treatment with a combination of cytotoxic chemotherapy and additional HER2-directed agents. Initial results from the monarcHER trial found that abemaciclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, combined with the HER2-targeting immunotherapeutic trastuzumab and the selective estrogen receptor degrader fulvestrant improved progression free survival (PFS) in patients with HR+ HER2+ advanced breast cancer (ABC) compared to chemotherapy plus trastuzumab. In this update to the phase II monarcHER trial, Tolaney and colleagues assessed overall survival (OS) in patients with HR+ HER2+ with ABC treated with abemaciclib, trastuzumab, and fulvestrant (Arm A), abemaciclib plus trastuzumab (Arm B), or SOC chemotherapy plus trastuzumab (Arm C). The authors report a median OS of 31.1... You do not currently have access to this content.
Project Confirm: Accelerated Drug Approvals for CML—Letter
Authors: Jan H. Beumer, Salvatore J. Salamone
Journal: Clinical Cancer Research (2024)

In reviewing CML drug development, Sweet and colleagues touch on the importance of dose optimization and lament that "TKI dose-finding trials… determine the MTD", and that "it is unlikely that most patients… require the MTD" (1). While we agree with the latter, dose optimization of the first TKI certainly did not stop at the MTD.Novartis' efforts to personalize imatinib dosing through Therapeutic Drug Monitoring (TDM) of plasma concentrations is unprecedented and never-repeated (2). The FDA's reaction disincentivized such efforts, and locked the industry into the one-dose-fits-all approach. Project Optimus merely suggests shifting a single dose, usually lower (3). We propose aiming for an optimal exposure range (therapeutic window), at whatever individual dose required. Lowering the dose will certainly reduce the number of patients above the therapeutic window; but other patients will move to below the therapeutic window, depriving them of benefit (Fig. 1), while the number of patients within the therapeutic window may not change. Reduced toxicity with equal activity may then be celebrated as a success. But optimal it is not. From the imatinib exposure response relationships (4), the CML field has now come full circle with ponatinib which has a 48% CV interindividual pharmacokinetic variability, corresponding to a roughly 5-fold range in exposures when everyone is given the same dose (5).The plasma exposure of a 15-mg ponatinib dose increase imparts odds ratios of 1.63 for MR1, and 2.05 for ≥MR1 response. The exposure increase of 15 mg imparts a HR of 2.05 for arterial occlusive events (AOE, causing its temporary market withdrawal) and 1.31 for grade ≥3 thrombocytopenia (5). Decreasing the dose for everyone reduces risk of toxicity for some, and reduces probability of response for others. The updated dosing for ponatinib (45 then 15 mg) merely reduces the time some patients are exposed to toxic concentrations and has a limited impact on OAEs. Dosing individual patients to a therapeutic window would have resulted in a distribution of doses beyond 15–45 mg, and might have been both more tolerable and more active.The authors point to idiosyncratic side effect profiles of TKIs with effects in some patients and none in others, and also stress the need for response biomarkers, suggesting early molecular response, T-cell subsets, NK-cell activity, or combinations. We suggest they revisit the TDM principles already established with their first revolutionary drug imatinib. Plasma exposure may be the best biomarker yet and therapeutic windows should be part of drug labeling.See the Response, p. 237S.J. Salamone reports other support from Saladax Biomecical, Inc. outside the submitted work. No disclosures were reported by the other author.