tbuckley/cabot-search huggingface dataset:
Malignant effusion aspirate for use in constructing organoids model to assist individualized treatment of advanced non-small cell lung cancer.
Authors: Qiong He, Xinmin Yu, Zhenhua Chen, Cuiwei Xie, Hongjiang Xiao
Journal: Journal of Clinical Oncology (2024)

e20526 Background: Organoids derived from cancer patients are considered to represent the overall appearance of the original tumor in lung cancer. With the in-depth study of molecular mechanisms and the development of new drugs, the survival time of advanced non-small cell lung cancer has been greatly extended. However, when it comes to the back-end treatment, they often have limited amounts of fresh tissue samples or cannot complete puncture, which affects the successfully establishment of organoids. Some patients often have malignant pleural effusion (MPE) requiring repeated aspiration, so it is clinically easy to obtain. Our goal was to culture organoids from malignant effusion of advanced NSCLC patients (LCO), and explore and analyze the consistency of drug sensitivity with clinical practice. Methods: In this study, malignant pleural effusion specimens of 39 patients with NSCLC were collected and complete clinical information was obtained.The partially paired successfully modeled organoids and the original malignant effusion were sequenced by WES(N = 7) and RNA(N = 6) for genetic background consistency.All successfully cultured organoids were subjected to drug sensitivity test, and the drug sensitivity results were compared with the actual therapeutic effect of clinical patients. Results: We successfully established 34 LCOs with a success rate of 87.2% . LCOs retained the mutation spectrum of the matching primary tumor. TP53 and EGFR were the most frequently mutated genes, occurring in 83.3% (5 of 6) and 66.7% (4 of 6) of effusion samples. On average, LCOs retained an 93.2% overlap of the most frequently lung cancer gene mutational variants from the parental MPE samples.The gene expression in the paired LCOs and effusion samples were compared, demonstrating an average 80% overlap in gene expression between the LCOs and the matching effusion samples.The clinical outcomes of the 25 patients (27 rounds of treatment) and their LCOs pharmaco-phenotyping results are analyzed. Notably, 94.7% of the treatments, which include at least one drug that was tested to be sensitive or moderately responsive by LCOs, achieved partial response or stable disease. However, 62.5% of the treatments, which do not include any drug that was tested to be sensitive or moderately responsive by LCOs, developed progressive disease. Overall, the LCO pharmaco-phenotyping results are highly correlated with clinical outcomes, with 85.2% accuracy (95% CI, 67.5–94.1%), 85.7% sensitivity (95% CI, 62.6–96.2%), and 83.3% specificity (95% CI, 36.5–99.1%). Conclusions: The effusion and LCOs have high concordance of genomic profiling. Organoid culture from malignant effusions of lung cancer can be used as a platform for drug sensitivity testing. These LCOs may be helpful in individualized treatment of NSCLC.
Are the clinical trials in lung cancer an advantage for patients in developing countries?
Authors: Cihan Erol, Mutlu Hizal, Seda Kahraman, Murat Bardakci, Didem Sener Dede, Muhammed Bulent Akinci, Bulent Yalcin, Mehmet Ali Nahit Sendur
Journal: Journal of Clinical Oncology (2024)

e20523 Background: Clinical trials are critical to developing new drugs. This study examined the characteristics of patients diagnosed with metastatic non-small cell lung cancer (mNSCLC) and who wanted to participate in clinical trials. This study aims to compare the outcomes of patients who enrolled in clinical trials or not. Methods: The data of the patients who applied to Ankara Yildirim Beyazit University Medical Oncology Department to participate in the first-line treatment-related clinical trials in mNSCLC were retrospectively reviewed. Survival outcomes of patients included in clinical trials (CT) and patients who signed informed consent for clinical trials but could not enroll (standard treatment-ST) were compared. Results: Data from 155 patients who applied to participate in clinical trials were analyzed. Patients who died during the screening process and who lacked systemic treatment information were excluded (n = 14). While 55.3% (n = 78) of the patients participated in the clinical trials, 44.7% (n = 63) could not. Not meeting the inclusion criteria (pathological and clinical) was the most common reason for screen-fail. At a median follow-up of 29 months, median overall survival was 17.1 months (95%CI, 15.1 to 19.1) in the CT group and 9.6 months (95%CI, 7.1 to 12.1) in the ST group (p = 0.015). Median progression-free survival was 11.6 (95% CI, 5.9 - 17.4) and 5.4 (95% CI, 3.7 - 7.2) months, respectively (p = 0.014). Conclusions: Being able to take part in clinical trials is not unfavorable, and it may even improve survival for patients with metastatic non-small cell lung cancer (mNSCLC), particularly in areas of the world where access to novel and effective treatments is limited.
Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and lung cancer metastasis.
Authors: Liang Liu, Xiaodong Chen, Kaizong Huang, Zhenyi Wang, Yaolin Zheng, Cheng Zheng, Zhenshan Zhang, Dongping Wei, Xu Yaping
Journal: Journal of Clinical Oncology (2024)

e20520 Background: The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. Methods: Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. Results: This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. Conclusions: These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9's function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.
Early life adversities, psychopathologies and novel pharmacological strategies
Authors: Annamaria Cattaneo, Veronica Begni, Valentina Zonca, Marco A. Riva
Journal: Pharmacology & Therapeutics (2024)

Exposure to adversities during early life stages (early life adversities - ELA), ranging from pregnancy to adolescence, represents a major risk factor for the vulnerability to mental disorders. Hence, it is important to understand the molecular and functional underpinning of such relationship, in order to develop strategies aimed at reducing the psychopathologic burden associated with ELA, which may eventually lead to a significant improvement in clinical practice. In this review, we will initially recapitulate clinical and preclinical evidence supporting the link between ELA and psychopathology and we will primarily discuss the main biological mechanisms that have been described as potential mediators of the effects of ELA on the psychopathologic risk, including the role for genetic factors as well as sex differences. The knowledge emerging from these studies may be instrumental for the development of novel therapeutic strategies aimed not only at correcting the deficits that emerge from ELA exposure, but also in preventing the manifestation of a full-blown psychopathologic condition. With this respect, we will specifically focus on adolescence as a key time frame for disease onset as well as for early therapeutic intervention. We believe that incorporating clinical and preclinical research data in the context of early life adversities can be instrumental to elucidate the mechanisms contributing to the risk for psychopathology or that may promote resilience. This will ultimately allow the identification of 'at risk' individuals who may benefit from specific forms of interventions that, by interfering with disease trajectories, could result in more benign clinical outcomes.
Occurrence of in vivo carbapenem-resistant Campylobacter coli mediated by porA point mutation and overexpression of blaOXA-489 under meropenem treatment
Authors: Charles Maurille, François Guérin, Quentin Jehanne, Alexandra Audemard-Verger, Christophe Isnard, Renaud Verdon, Philippe Lehours, Richard Bonnet, Jean-Christophe Giard, Simon Le Hello, François Gravey
Journal: Clinical Microbiology and Infection (2024)
Spotlight on plasticity-related genes: Current insights in health and disease
Authors: Nicola Brandt, Franziska Köper, Jens Hausmann, Anja U. Bräuer
Journal: Pharmacology & Therapeutics (2024)

The development of the central nervous system is highly complex, involving numerous developmental processes that must take place with high spatial and temporal precision. This requires a series of complex and well-coordinated molecular processes that are tighly controlled and regulated by, for example, a variety of proteins and lipids. Deregulations in these processes, including genetic mutations, can lead to the most severe maldevelopments. The present review provides an overview of the protein family Plasticity-related genes (PRG1-5), including their role during neuronal differentiation, their molecular interactions, and their participation in various diseases. As these proteins can modulate the function of bioactive lipids, they are able to influence various cellular processes. Furthermore, they are dynamically regulated during development, thus playing an important role in the development and function of synapses. First studies, conducted not only in mouse experiments but also in humans, revealed that mutations or dysregulations of these proteins lead to changes in lipid metabolism, resulting in severe neurological deficits. In recent years, as more and more studies have shown their involvement in a broad range of diseases, the complexity and broad spectrum of known and as yet unknown interactions between PRGs, lipids, and proteins make them a promising and interesting group of potential novel therapeutic targets.
Timing decisions as the next frontier for collective intelligence
Authors: Albert B. Kao, Shoubhik Chandan Banerjee, Fritz A. Francisco, Andrew M. Berdahl
Journal: Trends in Ecology & Evolution (2024)

The past decade has witnessed a growing interest in collective decision making, particularly the idea that groups can make more accurate decisions compared with individuals. However, nearly all research to date has focused on spatial decisions (e.g., food patches). Here, we highlight the equally important, but severely understudied, realm of temporal collective decision making (i.e., decisions about when to perform an action). We illustrate differences between temporal and spatial decisions, including the irreversibility of time, cost asymmetries, the speed–accuracy tradeoff, and game theoretic dynamics. Given these fundamental differences, temporal collective decision making likely requires different mechanisms to generate collective intelligence. Research focused on temporal decisions should lead to an expanded understanding of the adaptiveness and constraints of living in groups.
Short- and long-term effects of imatinib in hospitalized COVID-19 patients: A randomized trial
Authors: Alex L E Halme, Sanna Laakkonen, Jarno Rutanen, Olli P O Nevalainen, Marjatta Sinisalo, Saana Horstia, Jussi M J Mustonen, Negar Pourjamal, Aija Vanhanen, Tuomas Rosberg, Andreas Renner, Markus Perola, Erja-Leena Paukkeri, Riitta-Liisa Patovirta, Seppo Parkkila, Juuso Paajanen, Taina Nykänen, Jarkko Mäntylä, Marjukka Myllärniemi, Tiina Mattila, Maarit K Leinonen, Alvar Külmäsu, Pauliina Kuutti, Ilari Kuitunen, Hanna-Riikka Kreivi, Tuomas P Kilpeläinen, Heikki Kauma, Ilkka E J Kalliala, Petrus Järvinen, Riina Hankkio, Taina Hammarén, Thijs Feuth, Hanna Ansakorpi, Riikka Ala-Karvia, Gordon H Guyatt, Kari A O Tikkinen
Journal: Journal of Infection (2024)
Metabolic changes due to dexamethasone premedication in patients with breast cancer.
Authors: Vanessa Armenio Scontre, Milena Degaspari Gonzales Lapate, Laura Testa, Gabriel Watarai, Maria Del Pilar Estevez-Diz
Journal: Journal of Clinical Oncology (2024)

e24127 Background: The treatment for patients diagnosed with breast cancer is based, in the curative intent scenario, on chemotherapy (CT) such as anthracyclines and taxanes. We are aware that some drugs are widely used and necessary before CT administration to avoid unwanted side effects. Dexamethasone is part of the arsenal of these medications, however, pathological conditions resulting from high doses of administration of this corticosteroid are clinically evident in these patients. In this study we aim to evaluate whether omitting a dose of corticosteroid therapy as a premedication after the second week of treatment with taxane can prevent or reduce the incidence of metabolic changes, and its impact on a patient's quality of life (QoL). Methods: A prospective, randomized, open label study. Breast cancer patients with indication for adjuvant or neoadjuvant treatment with doxorubicin, cyclophosphamide and paclitaxel + trastuzumab (AC-T+ TTZ) chemotherapy were randomized to standard arm, with dexamethasone 10 mg IV administered pre-paclitaxel in all cycles and experimental arm, where dexamethasone was omitted from the premedication from the third to the last taxane application. Results: 86 patients were included, 43 patients in each arm. Premedication was administered every cycle and/ or week before the administration of chemotherapy drugs. Patients had lab analysis and QoL EORTC QLQ-C30 before the beginning of the CT, before the third application of Paclitaxel and 24 hours after the last administration. We observed an increase in ACTH in the experimental group, which is predictable since high doses of corticosteroids suppress the hormone pathway; a drop of insulin levels in its levels in the experimental group and stability in its serum levels in the control group; a stability of GH and IGF-1 in the control group and a more pronounced drop in circulating levels of this hormone in the experimental group. The control group had a greater increase in the excretion of aldosterone, probably due water retention caused by the use of dexamethasone. There were no adverse events reported in the experimental group and also hypersensitivity or anaphylactic reactions were not observed. The EORTC-QLQ-C30 scores related to diarrhea, constipation, inappetence and insomnia were better in the experimental group, as well the average score for global health. Conclusions: The omission of dexamethasone in patients in the experimental group improved QOL scores related to common AEs during CT, mainly GI and also insomnia. Insulin levels were also lower in this group. The potential reduction of the incidence of metabolic syndrome seems palusible but would require larger sample size. The short term safety and tolerability of this regimen warrants its use in larger populations. Clinical trial information: NCT04350229 .
Can vitamin D deficiency be considered a risk factor be considered a risk factor in luminal breast cancer?
Authors: Laura Fernández Madrigal, María Yeray Rodríguez Garcés, Miguel Angel Castaño López, Juan Lucas Bayo Calero
Journal: Journal of Clinical Oncology (2024)

e24122 Background: The relationship of vitamin D (VD) with cancer is controversial. Its antiproliferative function by inhibiting the cell cycle has been described, as well as its characteristics as an inhibitor of angiogenesis, inducer of apoptosis and its ability to reduce inflammation, invasion and metastasis. Deficiency of this vitamin is very prevalent, affecting 40% of the population under 65 years of age, and there are some studies that relate it to the increase in the incidence of breast cancer (BC), colon or prostate cancer. VD deficiency is defined as a serum level of 25-hydroxy VD &lt; 20 ng/mL. We analyzed whether VD deficiency can be considered a risk factor for BC, given that it is the most frequent tumor in the world. Methods: A single-center, retrospective, descriptive and analytical study of female patients diagnosed with localized luminal BC (stage I-II and III) in the year 2023 and a control group of healthy women. Baseline VD levels were determined in both groups. Statistical analysis (IBM SPSS Statistics 22) of demographic and clinical characteristics and multivariate analysis using a logistic regression model for the study of VD deficiency, according to the variables age, menopausal status and previous chemotherapy. Results: We analyzed 231 patients (p) with luminal BC and a control group of 324 healthy women. In the BC group the median age was 62 years (range 34 - 88 years), 72% (168 p) in postmenopausal stage. 52% (121 p) had stage I, 37% (86 p) stage II, and 11% stage III. 59.7 % (138 p) had luminal A phenotype and 40.2 % luminal B phenotype. 27.7 % (64 p) had received chemotherapy. In the control group the median age was 65 years (range 45 - 78 years), 90% (287 women) in postmenopausal state. VD deficiency was present in 50.6 % of the BC group with a mean VD value of 21 ng / ml. In the control group the deficit was 33 % with a mean VD value of 24 ng / ml. Therefore, this deficit is significantly higher in breast cancer patients than in healthy patients, with OR of 2.08 with 95% CI (1.4 - 2.7). In the overall multivariate analysis postmenopausal women have 5.1 more risk of presenting VD deficit, with p = 0.04. The variable age did not reach statistical significance. Logistic regression was performed to determine the effects of age, menopausal status, and having received previous chemotherapy, on the probability of BC patients presenting a VD deficit, without reaching statistical significance. Conclusions: VD deficiency is more prevalent in women with BC than the normal population, which is consistent with previous studies. Further well-designed studies are needed to assess the effect of VD supplementation in the female population as prevention of BC.
The efficacy and safety of ruxolitinib as an add-on therapy to corticosteroids for patients with severe checkpoint inhibitor pneumonitis.
Authors: Yan Xu, Hui Huang, Xiaoxing Gao, Xiaoyan Liu, Ruxuan Chen, Minjiang Chen, Jing Zhao, Wei Zhong, Junzhen Gao, Mengzhao Wang
Journal: Journal of Clinical Oncology (2024)

e24121 Background: Although immune checkpoint inhibitors (ICIs) have improved survival of patients with malignancies, they also bring forth the immune-related adverse events (irAEs). Checkpoint inhibitor pneumonitis (CIP) stands out as a prominent complication following ICI therapy, while a substantial proportion of CIP cases present with severe manifestations, often leading to life-threatening outcomes. The management of severe and refractory CIP is challenging. This study was aimed to evaluate the efficacy and safety of ruxolitinib as an add-on therapy to corticosteroids for patients with severe CIP. Methods: In this investigator-initiated, multicenter, randomized, open-label, phase 2 trial, cancer patients with CTCAE grade (G) 3 or G4 CIP after ICIs therapy were enrolled. CIP patients were randomly assigned in a 1:1 ratio (randomized block method) to corticosteroids administration (the initial dosage was more than prednisone 1mg/kg/d or equivalent) or corticosteroids with add-on ruxolitinib administration (5mg twice a day for 2 weeks, followed by 5mg once a day for 2 weeks). The primary end point was the proportion of patients with a prednisone daily dosage of no more than 10mg and improvement to G1 CIP at week 8. Results: From April 2023 to Jan 2024, 19 patients were enrolled. There were 17 cases of G3 CIP and two cases of G4 CIP. Eleven cases were assigned to corticosteroids group (C group), and 8 cases were assigned to corticosteroids with add-on ruxolitinib administration group (R group). Fourteen patients completed 8 weeks of follow-up. Five cases (5/6, 83.3%) in the R group and three cases (3/8, 37.5%) in the C group improved to G1 CIP and received ≤prednisone 10mg daily at week 8. One patient in the R group and three cases in the C group failed to taper to 10mg/d prednisone or had G2-3 CIP. Two patients in the C group died from CIP. Two cases in R group and three cases in C group were still under follow-up. The G3 or higher treatment-related AEs (TRAEs) occurred in three patients, including one case of aspiration pneumonia in C group and two cases of COVID-19 (one in each group). Conclusions: Corticosteroids with add-on ruxolitinib administration could improve clinical responsiveness for severe CIP patients. The safety profile was controllable and favorable. Ruxolitinib could provide a valuable promising therapeutic option for cancer patients with severe CIP. Clinical trial information: NCT05899725 .