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1.
Ultrasound J ; 16(1): 42, 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39283362

ABSTRACT

BACKGROUND: Ultrasound can detect fluid in the alveolar and interstitial spaces of the lung using the presence of artifacts known as B-lines. The aim of this study was to determine whether a deep learning algorithm generated B-line severity score correlated with pulmonary congestion and disease severity based on clinical assessment (as identified by composite congestion score and Rothman index) and to evaluate changes in the score with treatment. Patients suspected of congestive heart failure underwent daily ultrasonography. Eight lung zones (right and left anterior/lateral and superior/inferior) were scanned using a tablet ultrasound system with a phased-array probe. Mixed effects modeling explored the association between average B-line score and the composite congestion score, and average B-line score and Rothman index, respectively. Covariates tested included patient and exam level data (sex, age, presence of selected comorbidities, baseline sodium and hemoglobin, creatinine, vital signs, oxygen delivery amount and delivery method, diuretic dose). RESULTS: Analysis included 110 unique subjects (3379 clips). B-line severity score was significantly associated with the composite congestion score, with a coefficient of 0.7 (95% CI 0.1-1.2 p = 0.02), but was not significantly associated with the Rothman index. CONCLUSIONS: Use of this technology may allow clinicians with limited ultrasound experience to determine an objective measure of B-line burden.

2.
Nat Commun ; 15(1): 8146, 2024 Sep 25.
Article in English | MEDLINE | ID: mdl-39322643

ABSTRACT

Mutant selective drugs targeting the inactive, GDP-bound form of KRASG12C have been approved for use in lung cancer, but resistance develops rapidly. Here we use an inhibitor, (RMC-4998) that targets RASG12C in its active, GTP-bound form, to treat KRAS mutant lung cancer in various immune competent mouse models. RAS pathway reactivation after RMC-4998 treatment could be delayed using combined treatment with a SHP2 inhibitor, which not only impacts tumour cell RAS signalling but also remodels the tumour microenvironment to be less immunosuppressive. In an immune inflamed model, RAS and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory. In an immune excluded model, combined RAS and SHP2 inhibition sensitises tumours to immune checkpoint blockade, leading to efficient tumour immune rejection. These preclinical results demonstrate the potential of the combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade.


Subject(s)
Immune Checkpoint Inhibitors , Lung Neoplasms , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Proto-Oncogene Proteins p21(ras) , Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Animals , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Mice , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Humans , Cell Line, Tumor , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Mice, Inbred C57BL , Female , Signal Transduction/drug effects , Mutation
3.
MedEdPORTAL ; 20: 11432, 2024.
Article in English | MEDLINE | ID: mdl-39247162

ABSTRACT

Introduction: Anesthesiologists develop anesthetic plans according to the surgical procedure, patient's medical history, and physical exams. Patients with ischemic heart disease are predisposed to intraoperative cardiac complications from surgical blood loss. Unanticipated events can lead to intraoperative complications despite careful anesthesia planning. Methods: This anesthetic management simulation was developed for the anesthesiology residency curriculum during the first clinical anesthesia year (CA 1/PGY 2 residents). A total of 23 CA 1 residents participated. A 50-minute encounter focused on a 73-year-old male who presents for an elective total hip replacement and develops acute myocardial stunning in the setting of critical acute blood loss and a delay in the transportation of blood products. Results: One hundred percent of the residents felt the simulation was educationally valuable in the immediate postsimulation survey (Kirkpatrick level 1). The follow-up survey showed that 100% of residents felt the simulation increased their knowledge of managing acute cardiac ischemia (Kirkpatrick level 2), and 93% felt it increased awareness and confidence in similar real-life situations that positively affected patient outcomes (Kirkpatrick level 3). Discussion: Our simulation provides a psychologically safe environment for anesthesiology residents to develop management skills for acute critical anemia and cardiogenic shock and foster communication skills with a surgery team.


Subject(s)
Anemia , Anesthesiology , Internship and Residency , Humans , Internship and Residency/methods , Anesthesiology/education , Male , Aged , Curriculum , Simulation Training/methods , Surveys and Questionnaires , Clinical Competence , Myocardial Ischemia
4.
Biosensors (Basel) ; 14(8)2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39194613

ABSTRACT

Diffuse correlation spectroscopy (DCS) is a non-invasive technology for the evaluation of blood perfusion in deep tissue. However, it requires high computational resources for data analysis, which poses challenges in its implementation for real-time applications. To address the unmet need, we developed a novel device-on-chip solution that fully integrates all the necessary computational components needed for DCS. It takes the output of a photon detector and determines the blood flow index (BFI). It is implemented on a field-programmable gate array (FPGA) chip including a multi-tau correlator for the calculation of the temporal light intensity autocorrelation function and a DCS analyzer to perform the curve fitting operation that derives the BFI at a rate of 6000 BFIs/s. The FPGA DCS system was evaluated against a lab-standard DCS system for both phantom and cuff ischemia studies. The results indicate that the autocorrelation of the light correlation and BFI from both the FPGA DCS and the reference DCS matched well. Furthermore, the FPGA DCS system was able to achieve a measurement rate of 50 Hz and resolve pulsatile blood flow. This can significantly lower the cost and footprint of the computational components of DCS and pave the way for portable, real-time DCS systems.


Subject(s)
Spectrum Analysis , Humans , Lab-On-A-Chip Devices , Equipment Design , Biosensing Techniques
6.
Prev Med ; 186: 108070, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39029743

ABSTRACT

OBJECTIVE: Accumulating more steps/day is associated with a lower risk of cancer mortality and composite cancer outcomes. However, less is known about the relationship of steps/day with the risk of multiple site-specific cancers. METHODS: This study included >22,000 women from the Women's Health Accelerometry Collaboration Cohort (2011-2022), comprised of women from the Women's Health Study and Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Steps/day and step intensity were collected with accelerometry. Incident cancer cases and deaths were adjudicated. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of steps/day and step intensity with incident breast, colon, endometrial, lung, and ovarian cancers, a composite of 13 physical activity-related cancers, total invasive cancer, and fatal cancer. RESULTS: On average, women were 73.4 years old, accumulated 4993 steps/day, and had 7.9 years of follow-up. There were small nonsignificant inverse associations with the risks of colon cancer (HR = 0.94, 95% CI: 0.83, 1.05), endometrial cancer (HR = 0.91, 95% CI: 0.82, 1.01), and fatal cancer (HR = 0.95 95% CI: 0.90, 1.00) per 1000 steps/day. More minutes at ≥40 steps/min and a faster peak 10- and 30-min step cadence were associated with a lower risk of endometrial cancer, but findings were attenuated after adjustment for body mass index and steps/day. CONCLUSIONS: Among women 62-97 years, there were small nonsignificant inverse associations of colon, endometrial, and fatal cancer with more steps/day. Epidemiologic studies with longer follow-up and updated assessments are needed to further explore these associations.


Subject(s)
Accelerometry , Neoplasms , Women's Health , Humans , Female , Aged , Neoplasms/epidemiology , Neoplasms/mortality , Middle Aged , Exercise , Risk Factors , Cohort Studies , Walking , Proportional Hazards Models , Prospective Studies
7.
Neurophotonics ; 11(2): 024210, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38948888

ABSTRACT

Significance: The choroid plexus (ChP) epithelial network displays diverse dynamics, including propagating calcium waves and individuated fluctuations in single cells. These rapid events underscore the possibility that ChP dynamics may reflect behaviorally relevant and clinically important changes in information processing and signaling. Optogenetic and chemogenetic tools provide spatiotemporally precise and sustained approaches for testing such dynamics in vivo. Here, we describe the feasibility of a novel combined opto- and chemogenetic tool, BioLuminescent-OptoGenetics (BL-OG), for the ChP in vivo. In the "LuMinOpsin" (LMO) BL-OG strategy, a luciferase is tethered to an adjacent optogenetic element. This molecule allows chemogenetic activation when the opsin is driven by light produced through luciferase binding a small molecule (luciferin) or by conventional optogenetic light sources and BL-OG report of activation through light production. Aim: To test the viability of BL-OG/LMO for ChP control. Approach: Using transgenic and Cre-directed targeting to the ChP, we expressed LMO3 (a Gaussia luciferase-VChR1 fusion), a highly effective construct in neural systems. In mice expressing LMO3 in ChP, we directly imaged BL light production following multiple routes of coelenterazine (CTZ: luciferin) administration using an implanted cannula system. We also used home-cage videography with Deep LabCut analysis to test for any impact of repeated CTZ administration on basic health and behavioral indices. Results: Multiple routes of CTZ administration drove BL photon production, including intracerebroventricular, intravenous, and intraperitoneal injection. Intravenous administration resulted in fast "flash" kinetics that diminished in seconds to minutes, and intraperitoneal administration resulted in slow rising activity that sustained hours. Mice showed no consistent impact of 1 week of intraperitoneal CTZ administration on weight, drinking, motor behavior, or sleep/wake cycles. Conclusions: BL-OG/LMO provides unique advantages for testing the role of ChP dynamics in biological processes.

8.
Cell Rep ; 43(7): 114233, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-38905102

ABSTRACT

Perceptual success depends on fast-spiking, parvalbumin-positive interneurons (FS/PVs). However, competing theories of optimal rate and correlation in pyramidal (PYR) firing make opposing predictions regarding the underlying FS/PV dynamics. We addressed this with population calcium imaging of FS/PVs and putative PYR neurons during threshold detection. In primary somatosensory and visual neocortex, a distinct PYR subset shows increased rate and spike-count correlations on detected trials ("hits"), while most show no rate change and decreased correlations. A larger fraction of FS/PVs predicts hits with either rate increases or decreases. Using computational modeling, we found that inhibitory imbalance, created by excitatory "feedback" and interactions between FS/PV pools, can account for the data. Rate-decreasing FS/PVs increase rate and correlation in a PYR subset, while rate-increasing FS/PVs reduce correlations and offset enhanced excitation in PYR neurons. These findings indicate that selection of informative PYR ensembles, through transient inhibitory imbalance, is a common motif of optimal neocortical processing.


Subject(s)
Interneurons , Neocortex , Pyramidal Cells , Animals , Neocortex/physiology , Pyramidal Cells/physiology , Pyramidal Cells/metabolism , Interneurons/physiology , Interneurons/metabolism , Mice , Neural Inhibition/physiology , Parvalbumins/metabolism , Male , Action Potentials/physiology , Female
9.
Nat Commun ; 15(1): 5377, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38918389

ABSTRACT

Polyploidy, the result of whole-genome duplication (WGD), is a major driver of eukaryote evolution. Yet WGDs are hugely disruptive mutations, and we still lack a clear understanding of their fitness consequences. Here, we study whether WGDs result in greater diversity of genomic structural variants (SVs) and how they influence evolutionary dynamics in a plant genus, Cochlearia (Brassicaceae). By using long-read sequencing and a graph-based pangenome, we find both negative and positive interactions between WGDs and SVs. Masking of recessive mutations due to WGDs leads to a progressive accumulation of deleterious SVs across four ploidal levels (from diploids to octoploids), likely reducing the adaptive potential of polyploid populations. However, we also discover putative benefits arising from SV accumulation, as more ploidy-specific SVs harbor signals of local adaptation in polyploids than in diploids. Together, our results suggest that SVs play diverse and contrasting roles in the evolutionary trajectories of young polyploids.


Subject(s)
Evolution, Molecular , Gene Duplication , Genome, Plant , Polyploidy , Genome, Plant/genetics , Genomic Structural Variation/genetics , Mutation
10.
Infect Prev Pract ; 6(2): 100355, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38854705

ABSTRACT

Background: In sub-Saharan Africa, the provision of infection prevention and control (IPC) measures are often limited by resource constraints. Aim: To determine the association of supportive supervision activities with the availability of the WHO core components for IPC at health facilities in Southwestern Uganda. Methods: We employed a before and after quality improvement study design. We conducted a baseline assessment of the availability of the WHO IPC core components and provided supportive supervision activities, which was followed by a second IPC assessment. We included health centers II-IV, which have increasing clinical care capacity, and regional hospitals. Findings: Of 244 regional health facilities, baseline assessment occurred at 111 (45%) of which 23 (21%) were reassessed. The number of facilities in the Red (<70%) category for each core component stayed the same or decreased at each facility type, but there was an increase from five to six health center III facilities scoring Red (<70%) for PPE. The number of facilities in the Green (>85%) category for each core component stayed the same or was increased at each facility type, but there was a decrease from four to two health center III facilities scoring Green (>85%) for instrument processing. There was an increase in the median (interquartile range [IQR]) overall score for all facilities (65 [54-72] vs 75 [68-83], P=0.0001). Conclusion: Supportive supervision activities were associated with improved availability of the core components of IPC at health facilities in Southwestern Uganda. PPE should be prioritized in health care facilities in Southwestern Uganda.

11.
JAMA Intern Med ; 184(7): 718-725, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38767892

ABSTRACT

Importance: Current US physical activity (PA) guidelines prescribe moderate to vigorous PA (MVPA) time of at least 150 minutes per week for health. An analogous step-based recommendation has not been issued due to insufficient evidence. Objective: To examine the associations of MVPA time and step counts with all-cause mortality and cardiovascular disease (CVD). Design, Setting, and Participants: This cohort study analyzed data from an ongoing follow-up study of surviving participants of the Women's Health Study, a randomized clinical trial conducted from 1992 to 2004 in the US to evaluate use of low-dose aspirin and vitamin E for preventing cancer and CVD. Participants were 62 years or older who were free from CVD and cancer, completed annual questionnaires, and agreed to measure their PA with an accelerometer as part of a 2011-2015 ancillary study. Participants were followed up through December 31, 2022. Exposures: Time spent in MVPA and step counts, measured with an accelerometer for 7 consecutive days. Main Outcomes and Measures: The associations of MVPA time and step counts with all-cause mortality and CVD (composite of myocardial infarction, stroke, and CVD mortality) adjusted for confounders. Cox proportional hazards regression models, restricted mean survival time differences, and area under the receiver operating characteristic curve (AUC) were used to evaluate the associations. Results: A total of 14 399 women (mean [SD] age, 71.8 [5.6] years) were included. The median (IQR) MVPA time and step counts were 62 (20-149) minutes per week and 5183 (3691-7001) steps per day, respectively. During a median (IQR) follow-up of 9.0 (8.0-9.9) years, the hazard ratios (HR) per SD for all-cause mortality were 0.82 (95% CI, 0.75-0.90) for MVPA time and 0.74 (95% CI, 0.69-0.80) for step counts. Greater MVPA time and step counts (top 3 quartiles vs bottom quartile) were associated with a longer period free from death: 2.22 (95% CI, 1.58-2.85) months and 2.36 (95% CI, 1.73-2.99) months at 9 years follow-up, respectively. The AUCs for all-cause mortality from MVPA time and step counts were similar: 0.55 (95% CI, 0.52-0.57) for both metrics. Similar associations of these 2 metrics with CVD were observed. Conclusion and Relevance: Results of this study suggest that among females 62 years or older, MVPA time and step counts were qualitatively similar in their associations with all-cause mortality and CVD. Step count-based goals should be considered for future guidelines along with time-based goals, allowing for the accommodation of personal preferences.


Subject(s)
Cardiovascular Diseases , Exercise , Humans , Female , Cardiovascular Diseases/mortality , Cardiovascular Diseases/prevention & control , Middle Aged , Aged , Time Factors , Accelerometry , Follow-Up Studies , United States/epidemiology , Cohort Studies , Women's Health , Cause of Death
12.
Article in English | MEDLINE | ID: mdl-38781057

ABSTRACT

We present a machine learning method to directly estimate viscoelastic moduli from displacement time-series profiles generated by viscoelastic response (VisR) ultrasound excitations. VisR uses two colocalized acoustic radiation force (ARF) pushes to approximate tissue viscoelastic creep response and tracks displacements on-axis to measure the material relaxation. A fully connected neural network is trained to learn a nonlinear mapping from VisR displacements, the push focal depth, and the measurement axial depth to the material elastic and viscous moduli. In this work, we assess the validity of quantitative VisR (QVisR) in simulated materials, propose a method of domain adaption to phantom VisR displacements, and show in vivo estimates from a clinically acquired dataset.

13.
Neurophotonics ; 11(2): 024209, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38725801

ABSTRACT

Significance: Pain comprises a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms. Aim: We aimed to develop and validate tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations was targeted to developing novel imaging hardware that addresses the many challenges of multisite imaging. The second key set of innovations was targeted to enabling bioluminescent (BL) imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity, and decreased resolution due to scattering of excitation signals. Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for BL imaging and developed a novel modified miniscope optimized for these signals (BLmini). Results: We describe "universal" implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of BL signals in both foci and a new miniscope, the "BLmini," which has reduced weight, cost, and form-factor relative to standard wearable miniscopes. Conclusions: The combination of 3D-printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a coalition of methods for understanding spinal cord-brain interactions. Our work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior.

14.
Article in English | MEDLINE | ID: mdl-38700961

ABSTRACT

The reliability of automated image interpretation of point-of-care (POC) echocardiography scans depends on the quality of the acquired ultrasound data. This work reports on the development and validation of spatiotemporal deep learning models to assess the suitability of input ultrasound cine loops collected using a handheld echocardiography device for processing by an automated quantification algorithm (e.g. ejection fraction estimation). POC echocardiograms (n=885 DICOM cine loops from 175 patients) from two sites were collected using a handheld ultrasound device and annotated for image quality at the frame-level. Attributes of high-quality frames for left ventricular (LV) quantification included a temporally-stable LV, reasonable coverage of LV borders, and good contrast between the borders and chamber. Attributes of low-quality frames included temporal instability of the LV and/or imaging artifacts (e.g., lack of contrast, haze, reverberation, acoustic shadowing). Three different neural network architectures were investigated - (a) frame-level convolutional neural network (CNN) which operates on individual echo frames (VectorCNN), (b) single-stream sequence-level CNN which operates on a sequence of echo frames (VectorCNN+LSTM) and (c) two-stream sequence-level CNNs which operate on a sequence of echo and optical flow frames (VectorCNN+LSTM+Average, VectorCNN+LSTM+MinMax, and VectorCNN+LSTM+ConvPool). Evaluation on a sequestered test dataset containing 76 DICOM cine loops with 16,914 frames showed that VectorCNN+LSTM can effectively utilize both spatial and temporal information to regress the quality of an input frame (accuracy: 0.925, sensitivity = 0.860, specificity = 0.952), compared to the frame-level VectorCNN that only utilizes spatial information in that frame (accuracy: 0.903, sensitivity = 0.791, specificity = 0.949). Furthermore, an independent sample t-test indicated that the cine loops classified to be of adequate quality by the VectorCNN+LSTM model had a statistically significant lower bias in the automatically estimated EF (mean bias = - 3.73 ± 7.46 %, versus a clinically obtained reference EF) compared to the loops classified as inadequate (mean bias = -15.92 ± 12.17 %) (p = 0.007). Thus, cine loop stratification using the proposed spatiotemporal CNN model improves the reliability of automated point-of-care echocardiography image interpretation.

15.
PLoS One ; 19(5): e0302874, 2024.
Article in English | MEDLINE | ID: mdl-38722910

ABSTRACT

Lyme disease is the most common wildlife-to-human transmitted disease reported in North America. The study of this disease requires an understanding of the ecology of the complex communities of ticks and host species involved in harboring and transmitting this disease. Much of the ecology of this system is well understood, such as the life cycle of ticks, and how hosts are able to support tick populations and serve as disease reservoirs, but there is much to be explored about how the population dynamics of different host species and communities impact disease risk to humans. In this study, we construct a stage-structured, empirically-informed model with host dynamics to investigate how host population dynamics can affect disease risk to humans. The model describes a tick population and a simplified community of three host species, where primary nymph host populations are made to fluctuate on an annual basis, as commonly observed in host populations. We tested the model under different environmental conditions to examine the effect of environment on the interactions of host dynamics and disease risk. Results show that allowing for host dynamics in the model reduces mean nymphal infection prevalence and increases the maximum annual prevalence of nymphal infection and the density of infected nymphs. Effects of host dynamics on disease measures of nymphal infection prevalence were nonlinear and patterns in the effect of dynamics on amplitude in nymphal infection prevalence varied across environmental conditions. These results highlight the importance of further study of the effect of community dynamics on disease risk. This will involve the construction of further theoretical models and collection of robust field data to inform these models. With a more complete understanding of disease dynamics we can begin to better determine how to predict and manage disease risk using these models.


Subject(s)
Lyme Disease , Population Dynamics , Lyme Disease/epidemiology , Animals , Humans , Ixodes/microbiology , Ixodes/physiology , Models, Theoretical , Ticks/microbiology , Ticks/physiology , Models, Biological , Borrelia burgdorferi/physiology , Borrelia burgdorferi/pathogenicity , Host-Parasite Interactions , Nymph
16.
Antimicrob Agents Chemother ; 68(7): e0034624, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38771031

ABSTRACT

While the Plasmodium falciparum malaria parasite continues to cause severe disease globally, Mozambique is disproportionally represented in malaria case totals. Acquisition of copy number variations (CNVs) in the parasite genome contributes to antimalarial drug resistance through overexpression of drug targets. Of interest, piperaquine resistance is associated with plasmepsin 2 and 3 CNVs (pfpmp2 and pfpmp3, respectively), while CNVs in the multidrug efflux pump, multidrug resistance-1 (pfmdr1), increase resistance to amodiaquine and lumefantrine. These antimalarials are partner drugs in artemisinin combination therapies (ACTs) and therefore, CNV detection with accurate and efficient tools is necessary to track ACT resistance risk. Here, we evaluated ~300 clinically derived samples collected from three sites in Mozambique for resistance-associated CNVs. We developed a novel, medium-throughput, quadruplex droplet digital PCR (ddPCR) assay to simultaneously quantify the copy number of pfpmp3, pfpmp2, and pfmdr1 loci in these clinical samples. By using DNA from laboratory parasite lines, we show that this nanodroplet-based method is capable of detecting picogram levels of parasite DNA, which facilitates its application for low yield and human host-contaminated clinical surveillance samples. Following ddPCR and the application of quality control standards, we detected CNVs in 13 of 229 high-quality samples (prevalence of 5.7%). Overall, our study revealed a low number of resistance CNVs present in the parasite population across all three collection sites, including various combinations of pfmdr1, pfpmp2, and pfpmp3 CNVs. The potential for future ACT resistance across Mozambique emphasizes the need for continued molecular surveillance across the region.


Subject(s)
Antimalarials , DNA Copy Number Variations , Drug Resistance , Malaria, Falciparum , Plasmodium falciparum , Protozoan Proteins , Antimalarials/pharmacology , Mozambique , Plasmodium falciparum/genetics , Plasmodium falciparum/drug effects , Humans , Drug Resistance/genetics , DNA Copy Number Variations/genetics , Malaria, Falciparum/parasitology , Malaria, Falciparum/drug therapy , Protozoan Proteins/genetics , Polymerase Chain Reaction/methods , Quinolines/pharmacology , Amodiaquine/pharmacology , Multidrug Resistance-Associated Proteins/genetics , Aspartic Acid Endopeptidases/genetics , Artemisinins/pharmacology , Lumefantrine/pharmacology , Piperazines
17.
Cancer Res ; 84(14): 2231-2246, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38635884

ABSTRACT

Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells. Oncogenic KRAS potently induced COX2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX2/PGE2 remodeled the tumor microenvironment by inducing proinflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer. Significance: COX2 signaling via prostaglandin E2 is a major mediator of immune evasion driven by oncogenic KRAS that promotes immunotherapy and KRAS-targeted therapy resistance, suggesting effective combination treatments for KRAS-mutant lung cancer.


Subject(s)
CRISPR-Cas Systems , Cyclooxygenase 2 , Drug Resistance, Neoplasm , Immunotherapy , Lung Neoplasms , Proto-Oncogene Proteins p21(ras) , Animals , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Lung Neoplasms/drug therapy , Cyclooxygenase 2/metabolism , Cyclooxygenase 2/genetics , Mice , Proto-Oncogene Proteins p21(ras)/genetics , Humans , Drug Resistance, Neoplasm/genetics , Immunotherapy/methods , Dinoprostone/metabolism , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/therapy , Tumor Microenvironment/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Cell Line, Tumor , Mice, Inbred C57BL , Female
18.
Neurophotonics ; 11(2): 024208, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38559366

ABSTRACT

Significance: Luminopsins (LMOs) are bioluminescent-optogenetic tools with a luciferase fused to an opsin that allow bimodal control of neurons by providing both optogenetic and chemogenetic access. Determining which design features contribute to the efficacy of LMOs will be beneficial for further improving LMOs for use in research. Aim: We investigated the relative impact of luciferase brightness, opsin sensitivity, pairing of emission and absorption wavelength, and arrangement of moieties on the function of LMOs. Approach: We quantified efficacy of LMOs through whole cell patch clamp recordings in HEK293 cells by determining coupling efficiency, the percentage of maximum LED induced photocurrent achieved with bioluminescent activation of an opsin. We confirmed key results by multielectrode array recordings in primary neurons. Results: Luciferase brightness and opsin sensitivity had the most impact on the efficacy of LMOs, and N-terminal fusions of luciferases to opsins performed better than C-terminal and multi-terminal fusions. Precise paring of luciferase emission and opsin absorption spectra appeared to be less critical. Conclusions: Whole cell patch clamp recordings allowed us to quantify the impact of different characteristics of LMOs on their function. Our results suggest that coupling brighter bioluminescent sources to more sensitive opsins will improve LMO function. As bioluminescent activation of opsins is most likely based on Förster resonance energy transfer, the most effective strategy for improving LMOs further will be molecular evolution of luciferase-fluorescent protein-opsin fusions.

19.
PLoS One ; 19(4): e0301233, 2024.
Article in English | MEDLINE | ID: mdl-38573893

ABSTRACT

BACKGROUND: Describing correlates of physical activity (PA) and sedentary behavior (SB) among postmenopausal cancer survivors can help identify risk profiles and can be used to support development of targeted interventions to improve PA and reduce SB in this population. OBJECTIVE: To describe PA/SB and identify correlates of PA/SB among cancer and cancer-free post-menopausal women. METHODS: Women from the Women's Health Study (N = 16,629) and Women's Health Initiative/Objective Physical Activity and Cardiovascular Health Study (N = 6,079) were asked to wear an accelerometer on the hip for 7 days. Multiple mixed-effects linear regression models were used to identify sociodemographic-, health-, and chronic condition-related correlates (independent variables) associated with PA and SB (dependent variables) among women with (n = 2,554) and without (n = 20,154) a history of cancer. All correlates were mutually adjusted for each other. RESULTS: In unadjusted analyses, women with a history of cancer took fewer mean daily steps (4,572 (standard deviation 2557) vs 5,029 (2679) steps/day) and had lower mean moderate-to-vigorous PA (74.9 (45.0) vs. 81.6 (46.7) minutes/day) than cancer-free women. In adjusted analyses, for cancer and cancer-free women, age, diabetes, overweight, and obesity were inversely associated with all metrics of PA (average vector magnitude, time in moderate-to-vigorous PA, step volume, time at ≥40 steps/minutes, and peak 30-minute step cadence). In unadjusted analyses, mean SB was similar for those with and without cancer (529.7 (98.1) vs. 521.7 (101.2) minutes/day). In adjusted analyses, for cancer and cancer-free women, age, diabetes, cardiovascular disease, current smoking, overweight, and obesity were positive correlates of SB, while Black or Hispanic race/ethnicity, weekly/daily alcohol intake, and excellent/very good/good self-rated health were inverse correlates of SB. CONCLUSION: Several sociodemographic, health, and chronic conditions were correlates of PA/SB for postmenopausal women with and without cancer. Future studies should examine longitudinal relationships to gain insight into potential determinants of PA/SB.


Subject(s)
Cancer Survivors , Diabetes Mellitus , Neoplasms , Humans , Female , Sedentary Behavior , Overweight , Exercise , Women's Health , Obesity , Accelerometry , Neoplasms/epidemiology
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