The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role ...of chemotherapy in modulating the tumor immune microenvironment (TIME).
We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1-high (PD-1
) CD8
peripheral T cells and examination of a cytolytic gene signature in whole blood.
In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden.
We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
Numerous protected areas (PAs) have been created in Africa to safeguard wildlife and other natural resources. However, significant threats from anthropogenic activities and decline of wildlife ...populations persist, while conservation efforts in most PAs are still minimal. We assessed the impact level of the most common threats to wildlife within PAs in tropical Africa and the relationship of conservation activities with threat impact level. We collated data on 98 PAs with tropical forest cover from 15 countries across West, Central and East Africa. For this, we assembled information about local threats as well as conservation activities from published and unpublished literature, and questionnaires sent to long-term field workers. We constructed general linear models to test the significance of specific conservation activities in relation to the threat impact level. Subsistence and commercial hunting were identified as the most common direct threats to wildlife and found to be most prevalent in West and Central Africa. Agriculture and logging represented the most common indirect threats, and were most prevalent in West Africa. We found that the long-term presence of conservation activities (such as law enforcement, research and tourism) was associated with lower threat impact levels. Our results highlight deficiencies in the management effectiveness of several PAs across tropical Africa, and conclude that PA management should invest more into conservation activities with long-term duration.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Perseverance rover landed in Jezero crater, Mars, in February 2021. We used the Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) instrument to ...perform deep-ultraviolet Raman and fluorescence spectroscopy of three rocks within the crater. We identify evidence for two distinct ancient aqueous environments at different times. Reactions with liquid water formed carbonates in an olivine-rich igneous rock. A sulfate-perchlorate mixture is present in the rocks, which probably formed by later modifications of the rocks by brine. Fluorescence signatures consistent with aromatic organic compounds occur throughout these rocks and are preserved in minerals related to both aqueous environments.
Alcohol use in adolescence may increase susceptibility to substance use disorders (SUDs) in adulthood. This study determined if voluntary ethanol (EtOH) consumption during adolescence, combined with ...social isolation, alters the trajectory of EtOH and nicotine intake during adulthood, as well as activating brain neuroinflammation.
Adolescent male isolate- and group-housed rats were given 0.2 % saccharin/20 % EtOH (Sacc/EtOH) or water using intermittent 2-bottle choice; controls were given water in both bottles (n=17–20 per group). Some rats from each group (n=5–6) were euthanized one week later to measure autoradiographic 3HPK-11195 binding, an indicator of microglial reactivity, and the remainder (n=11–14 per group) were tested in adulthood in 2-bottle choice, followed by nicotine self-administration using an incremental fixed ratio (FR) schedule with Sacc/EtOH and water concurrently available.
Isolation housing increased adolescent intake of Sacc/EtOH, but the increase did not produce an observable neuroimmunological response in brain. Adolescent EtOH exposure decreased adult intake of both Sacc/EtOH and unsweetened EtOH, with isolate-housed rats showing a greater effect than group-housed rats. In the co-use model, a cross-price economic demand analysis revealed a substitutional relationship between Sacc/EtOH and nicotine, but no effect of adolescent Sacc/EtOH exposure. Compared to group-housed rats, isolate-housed rats were more sensitive to the changing price of nicotine and showed greater substitutability of Sacc/EtOH for nicotine.
The current results suggest that adolescent EtOH exposure per se, with or without isolation stress, does not likely explain the enhanced risk for either alcohol or nicotine use later in life.
•Isolation stress in adolescence increases voluntary sweetened ethanol consumption.•Voluntary ethanol intake in adolescence does not activate a neuroimmune response.•Voluntary ethanol intake in adolescence decreases adult EtOH drinking.•Isolation stress increases adult nicotine self-administration.•Alcohol serves as an economic substitute for nicotine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The recurring association of specific genetic lesions with particular types of cancer is a fascinating and largely unexplained area of cancer biology. This is particularly true of clear cell renal ...cell carcinoma (ccRCC) where, although key mutations such as loss of VHL is an almost ubiquitous finding, there remains a conspicuous lack of targetable genetic drivers. In this study, we have identified a previously unknown protumorigenic role for the
genes in this disease setting. Analysis of patient tumor biopsies together with loss-of-function studies in preclinical models established the importance of RUNX1 and RUNX2 in ccRCC. Patients with high RUNX1 (and RUNX2) expression exhibited significantly poorer clinical survival compared with patients with low expression. This was functionally relevant, as deletion of RUNX1 in ccRCC cell lines reduced tumor cell growth and viability
and
. Transcriptional profiling of RUNX1-CRISPR-deleted cells revealed a gene signature dominated by extracellular matrix remodeling, notably affecting
, and
signaling. Finally, RUNX1 deletion in a genetic mouse model of kidney cancer improved overall survival and reduced tumor cell proliferation. In summary, these data attest to the validity of targeting a RUNX1-transcriptional program in ccRCC. SIGNIFICANCE: These data reveal a novel unexplored oncogenic role for
genes in kidney cancer and indicate that targeting the effects of RUNX transcriptional activity could be relevant for clinical intervention in ccRCC.
Abstract
Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, ...we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
Graphical Abstract
Graphical Abstract
Abstract Previous work has shown that acupuncture stimulation evokes deactivation of a limbic–paralimbic–neocortical network (LPNN) as well as activation of somatosensory brain regions. This study ...explores the activity and functional connectivity of these regions during acupuncture vs. tactile stimulation and vs. acupuncture associated with inadvertent sharp pain. Acupuncture during 201 scans and tactile stimulation during 74 scans for comparison at acupoints LI4, ST36 and LV3 was monitored with fMRI and psychophysical response in 48 healthy subjects. Clusters of deactivated regions in the medial prefrontal, medial parietal and medial temporal lobes as well as activated regions in the sensorimotor and a few paralimbic structures can be identified during acupuncture by general linear model analysis and seed-based cross correlation analysis. Importantly, these clusters showed virtual identity with the default mode network and the anti-correlated task-positive network in response to stimulation. In addition, the amygdala and hypothalamus, structures not routinely reported in the default mode literature, were frequently involved in acupuncture. When acupuncture induced sharp pain, the deactivation was attenuated or became activated instead. Tactile stimulation induced greater activation of the somatosensory regions but less extensive deactivation of the LPNN. These results indicate that the deactivation of the LPNN during acupuncture cannot be completely explained by the demand of attention that is commonly proposed in the default mode literature. Our results suggest that acupuncture mobilizes the anti-correlated functional networks of the brain to mediate its actions, and that the effect is dependent on the psychophysical response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cannulation technique: femoro-femoral Burrell, Aidan J C; Ihle, Joshua F; Pellegrino, Vincent A ...
Journal of thoracic disease
10, Issue:
Suppl 5
Journal Article
Open access
The cannulation technique used during veno-venous extracorporeal membrane oxygenation (VV ECMO) insertion can have a major impact on a patients' overall outcome. We have developed a technique that ...aims to combine speed and effectiveness, with minimal risk. The steps include: (I) percutaneous cannulation using the Seldinger technique; (II) ultrasound guided access and positioning of cannulas; (III) femoro-femoral circuit configuration with a later option of high flow; (IV) a no skin cut serial dilation technique; (V) non-suturing securing of cannulas and (VI) a non-surgical manual pressure technique of explantation. The following is a discussion around these techniques and their various advantages and disadvantages.
Phaseolus vulgaris L. is considered one of the most essential legume crops in Kenya. Alternaria alternata is an economically significant plant pathogen that causes Alternaria leaf spot which accounts ...for over 70% yield losses of beans in Kenya. Chemical fungicides based on copper and sulfur are used to control Alternaria leaf spot in bean plants, but their prolonged use has adversely affected the environment and the health of workers. Herein, we tested the biocontrol potential of bacterial agents from soil planted with Rosecoco bean plants infected with A. alternata. Using bacterial suspensions at different time intervals, we evaluated the putative bacterial biocontrol activity against A. alternata under greenhouse conditions. B. subtilis and B. velezensis bacterial biocontrol agents significantly suppressed disease severity by 20% and 21.2% on the 45th day, respectively. Our study demonstrates that B. subtilis and B. velezensis are promising biocontrol agents that could be integrated in the management of Alternaria leaf spot.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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