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Cells respond to double-strand breaks (DSBs) by activating DNA damage response pathways, including cell cycle arrest. We have previously shown that a single double-strand break generated via CRISPR/Cas9 is sufficient to delay cell cycle progression and compromise cell viability. However, we also found that the cellular response to DSBs can vary, independent of the number of lesions. This implies that not all DSBs are equally toxic, and raises the question if the location of a single double-strand break could influence its toxicity. To systematically investigate if DSB-location is a determinant of toxicity we performed a CRISPR/Cas9 screen targeting 6237 single sites in the human genome. Next, we developed a data-driven framework to design CRISPR/Cas9 sgRNA (crRNA) pools targeting specific chromatin features. The chromatin context was defined using ChromHMM states, Lamin-B1 DAM-iD, DNAseI hypersensitivity, and RNA-sequencing data. We computationally designed 6 distinct crRNA pools, each containing 10 crRNAs targeting the same chromatin state. We show that the toxicity of a DSB is highly similar across the different ChromHMM states. Rather, we find that the major determinants of toxicity of a sgRNA are cutting efficiency and off-target effects. Thus, chromatin features have little to no effect on the toxicity of a single CRISPR/Cas9-induced DSB.

BACKGROUND: The endocannabinoid system is present in multiple organ systems and is involved in smooth muscle regulation, immune function, neuroendocrine modulation, and metabolism of tissues. Limited data are available regarding the presence and role of this system in reproductive tissues. Components of the endocannabinoid system have been identified in myometrial and placental tissues. However, no study has investigated differential expression of the endocannabinoid system in labor. OBJECTIVES: The purpose of this study was to identify and quantify two components of the endocannabinoid system, the CB(1) cannabinoid receptor and cannabinoid receptor interacting protein 1a (CRIP1a) in uterine and placental tissues, and to determine if there is differential expression in tissues exposed to labor. We hypothesized that CB(1) cannabinoid receptor concentration would be altered in uterine and placental tissue exposed to labor compared with tissues not exposed to labor. STUDY DESIGN: Uterine and placental tissue samples were collected in nine laboring and 11 nonlaboring women undergoing cesarean delivery. CB(1) cannabinoid receptor and CRIP1a presence and quantification were evaluated using western blot, immunohistochemistry, and real-time quantitative polymerase chain reaction. Statistical comparisons of laboring and nonlaboring subjects were made for uterine and placental tissue using a Mann–Whitney test. RESULTS: Immunohistochemistry demonstrated positive staining for CB(1) cannabinoid receptors and CRIP1a in uterine tissue. The protein abundance of CB(1) cannabinoid receptor in uterine tissue was significantly lower in tissues exposed to labor (p=0.01). The protein abundance of CRIP1a was lower in uterine tissue exposed to labor but did not reach statistical significance (p=0.06). mRNA expression of CB(1) cannabinoid receptor (p=0.20) and CRIP1a (p=0.63) did not differ in labored compared with nonlabored uterine tissues. CONCLUSIONS: Our findings of diminished protein density of CB(1) cannabinoid receptor in uterine tissue exposed to labor support the hypothesis that the endocannabinoid system plays a role in parturition. Our data add to the growing body of evidence indicating the endocannabinoid system is of importance for successful reproduction and support the need for additional research investigating this complex system as it pertains to labor. ClinicalTrials.gov ID: NCT03752021.

Dysferlinopathy demonstrates heterogeneity in muscle weakness between patients, which can progress at different rates over time. Changing muscle strength due to disease progression or from an investigational product is associated with changing functional ability. The purpose of this study was to compare three methods of strength testing used in the Clinical Outcome Study (COS) for dysferlinopathy to understand which method and which muscle groups were most sensitive to change over time.Patients were evaluated at each study visit using functional scales, manual muscle testing, and handheld dynamometry (HHD) at all 15 sites. A fixed-frame system (Fixed) was used at a subset of seven sites. Screening and baseline visits were evaluated for reliability. Data over a 1-year period were analyzed to determine sensitivity to change among strength modalities and individual muscle groups.HHD and Fixed captured significant change across 1 year in summed muscle strength score of four muscle groups (P .01). Strength summed scores were significantly correlated with functional scales (rho = 0.68-0.92, P .001). Individual muscle groups, however, showed high levels of variability between visits.Although both HHD and Fixed demonstrate change over 12 months, HHD is a less expensive option that provides data on a continuous scale and may be easier to implement. Due to variability in strength measures, researchers should carefully consider use of strength testing as an outcome and may wish to select functional measures with less variability as clinical trial endpoints.

This perspective is a companion to a recent editorial on the use of Bayesian analysis in clinical research. We aim to introduce and highlight the relevance and advantages that Bayesian inference offers to clinical trials using the data on the amyloid antibody aducanumab presented at a Food and Drug Administration hearing in November 2020 as an applied example. We apply Bayesian analysis of model plausibility and effect sizes based on simulated data of the two phase 3 trials of aducanumab in prodromal and mild dementia stages of Alzheimer's disease (AD). Bayesian analysis can quantify evidence in favor of, or against, the presence of an effect (i.e., provide evidence of absence), as well as assess the strength of the effect. This is in contrast to the binary conclusions provided by frequentist tests.

OBJECTIVES: To determine whether the full spectrum of hypertensive disorders of pregnancy (HDP) -- comprising gestational hypertension; preeclampsia with or without severe features; eclampsia; and Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) Syndrome -- is increased at high (≥2500 m, 8250 ft) compared with lower altitudes in Colorado independent of maternal background characteristics, and if so their relationship to neonatal well-being. METHODS: A retrospective cohort study was conducted using statewide birth-certificate data to compare the frequency of gestational hypertension, preeclampsia (with or without severe features), eclampsia, HELLP Syndrome, or all HDP combined in 617,958 Colorado women who lived at high vs. low altitude (2500 m)- vs. low (

Navigating parental leave can be challenging in all fields of medicine, but it can be especially challenging for leaders balancing clinical, research, and administrative duties. As women take on more leadership roles, we have the opportunity to better define the current challenges and identify potential strategies for navigating successful parental leave while balancing the demands of leadership. This manuscript provides a commentary on the challenges and strategies for navigating parental leave in leadership positions in radiology, an important topic for shaping how parental leave is both viewed and valued in the future. Specifically, we highlight challenges and strategies for administrative responsibilities, reporting personnel, emails, microaggressions, research, empowerment, and prioritization.

Fourteen cadaveric specimens were separated into two groups: (1) L3 pedicle subtraction osteotomy (PSO) with transforaminal lumbar interbody fusion (TLIF) or (2) lateral lumbar interbody fusion (LLIF). A 2-rod configuration (2R) was compared with two supplemental rod configurations: 4-rod (4R) with accessory rods (ARs) using connectors or 4R with satellite rods (SRs) without connectors.Compare PSO constructs with different rod configurations and adjacent-level interbody support.Supplemental rods and anterior column support enhance biomechanical performance.Pure moments were applied in (1) intact, (2) pedicle screws and rods, (3) PSO + 2R, (4) 4R AR, and (5) 4R SR conditions. Primary and supplemental rods had strain gauges across the index level. Sacral screw bending moments and range of motion (ROM) were recorded.For TLIF, AR decreased ROM during flexion (P = 0.02) and extension (P 0.001) versus 2R. For LLIF, AR and SR decreased motion versus 2R during left (AR: P = 0.03; SR: P = 0.04) and right (AR: P = 0.002; SR: P = 0.01) axial rotation. For LLIF, sacral screw strain increased with SR compared with AR in compression and right lateral bending (P ≤ 0.03). During lateral bending, rod strain increased with PSO+TLIF+SR versus PSO+LLIF+2R and PSO+LLIF+AR (P ≤ 0.02). For LLIF, SR configuration increased rod strain versus AR during flexion, extension, and lateral bending (P≤ 0.01); for TLIF, rod strain increased with SR versus AR during extension (P = 0.03). For LLIF, AR configuration increased posterior supplemental rod strain versus SR during flexion (P = 0.02) and lateral bending (P 0.001).Both supplemental rod configurations reduced motion in both groups. Constructs with the SR configuration increased the primary rod strain and the sacral screw bending moment compared with AR constructs, which can share strain. Deep-seated SRs, which have become increasingly popular, may be more vulnerable to failure than ARs. LLIF provided more stability in sagittal plane. Protective effect of supplemental rods on rod strain was more effective with TLIF.Level of Evidence: NA.

Purpose of Review A clear link between excessive alcohol consumption and cardiovascular disease (CVD) has been established, but no consensus exists on the effects of moderate alcohol consumption on CVD. Recent Findings A lower risk of coronary heart disease and myocardial infarction among moderate drinkers compared to abstainers has been consistently observed in epidemiological studies and meta-analyses of these studies. However, ambiguity remains on the effect of alcohol on other CVDs and all-cause mortality. Short-term randomized controlled trials (RCT) have identified potentially beneficial effects of alcohol consumption on cardiovascular risk factors, but studies investigating genetic polymorphisms that influence alcohol consumption (i.e., Mendelian randomization) have yielded inconclusive results. To date, a long-term RCT providing causal evidence is lacking but urgently needed. Summary Triangulation of evidence from different study designs, including long-term RCTs, pragmatic trials and the evaluation of policy measures, combined will lead to the best available evidence.

Introduction: Gait speed is a simple and safe measure with strong predictive value for negative health outcomes in clinical practice, yet in-laboratory gait speed seems not representative for daily-life gait speed. This study aimed to investigate the interrelation between and robustness of in-laboratory and daily-life gait speed measures over 12 months in 61- to 70-year-old adults. Methods: Gait speed was assessed in laboratory through standardized stopwatch tests and in daily life by 7 days of trunk accelerometry in the PreventIT cohort, at baseline, and after 6 and 12 months. The interrelation was investigated using Pearson’s correlations between gait speed measures at each time point. For robustness, changes over time and variance components were assessed by ANOVA and measurement agreement over time by Bland-Altman analyses. Results: Included were 189 participants (median age 67 years [interquartile range: 64–68], 52.2% females). In-laboratory and daily-life gait speed measures showed low correlations (Pearson’s r = 0.045–0.455) at each time point. Moreover, both in-laboratory and daily-life gait speed measures appeared robust over time, with comparable and smaller within-subject than between-subject variance (range 0.001–0.095 m/s and 0.032–0.397 m/s, respectively) and minimal differences between measurements over time (Bland-Altman) with wide limits of agreement (standard deviation of mean difference range: 0.12–0.34 m/s). Discussion/Conclusion: In-laboratory and daily-life gait speed measures show robust assessments of gait speed over 12 months and are distinct constructs in this population of high-functioning adults. This suggests that (a combination of) both measures may have added value in predicting health outcomes.

Lay abstract CAR-T therapy is a treatment option for patients with diffuse large B-cell lymphoma that has not responded to at least two other kinds of treatments. CAR-T therapies are manufactured from a patient’s white blood cells, modified to attack lymphoma cells. A CAR-T therapy takes time to manufacture after these cells are collected. CAR-T therapies can result in the reduction or disappearance of lymphoma tumors and can increase the chances of survival, but also cause serious side effects for a few patients. One of these is cytokine release syndrome (CRS), in which high levels of inflammation throughout the body may cause fever, heart problems or difficulty breathing. Another is the development of temporary but serious neurological problems such as confusion, seizures and memory problems. To understand how important physicians consider certain features of CAR-T therapies to be when deciding whether to recommend them, we asked physicians to choose between two treatment options resembling CAR-T therapies in a series of questions, with the CAR-T features varying in each question. Their answers indicated whether disappearance of tumors, a patient’s chances of survival after 1 and 2 years of treatment, manufacturing time, or the risk of CRS or neurological problems was the most important factor. Physicians most wanted to reduce manufacturing time from 113 to 16 days, but also were willing to accept a20% increase in risk of severe CRS and a 15% increase in risk of severe neurological events to increase a patient’s chance of survival from 40 to 55% at 2 years.

Background Burkholderia cenocepacia is an opportunistic pathogen that can cause acute and chronic infections in patients with weakened immune systems and in patients with cystic fibrosis. B. cenocepacia is resistant to many antibiotics making treatment challenging. Consequently, there is a critical need for alternative strategies to treat B. cenocepacia infections such as using bacteriophages and/or bacteriophages with subinhibitory doses of antibiotic called phage-antibiotic synergy. Results We isolated a bacteriophage, KP1, from raw sewage that infects B. cenocepacia. Its morphological characteristics indicate it belongs in the family Siphoviridae, it has a 52 Kb ds DNA genome, and it has a narrow host range. We determined it rescued infections in Lemna minor (duckweed) and moderately reduced bacterial populations in our artificial sputum medium model. Conclusion These results suggest that KP1 phage alone in the duckweed model or in combination with antibiotics in the ASMDM model improves the efficacy of reducing B. cenocepacia populations.

Background Organisms in the wild can acquire disease- and stress-resistance traits that outstrip the programs endogenous to humans. Finding the molecular basis of such natural resistance characters is a key goal of evolutionary genetics. Standard statistical-genetic methods toward this end can perform poorly in organismal systems that lack high rates of meiotic recombination, like Caenorhabditis worms. Results Here we discovered unique ER stress resistance in a wild Kenyan C. elegans isolate, which in inter-strain crosses was passed by hermaphrodite mothers to hybrid offspring. We developed an unbiased version of the reciprocal hemizygosity test, RH-seq, to explore the genetics of this parent-of-origin-dependent phenotype. Among top-scoring gene candidates from a partial-coverage RH-seq screen, we focused on the neuronally-expressed, cuticlin-like gene cutl-24 for validation. In gene-disruption and controlled crossing experiments, we found that cutl-24 was required in Kenyan hermaphrodite mothers for ER stress tolerance in their inter-strain hybrid offspring; cutl-24 was also a contributor to the trait in purebred backgrounds. Conclusions These data establish the Kenyan strain allele of cutl-24 as a determinant of a natural stress-resistant state, and they set a precedent for the dissection of natural trait diversity in invertebrate animals without the need for a panel of meiotic recombinants.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

Up to 60% of older adults have a lifestyle characterized by low physical activity (PA) and high sedentary behavior (SB). This can amplify age-related declines in physical and cognitive functions and may therefore affect the ability to complete basic and instrumental activities of daily living (ADL and IADL, respectively), which are essential for independence. This systematic review aims to describe the association of objectively measured PA and SB with ADL and IADL in community-dwelling older adults. Six databases (PubMed, Embase, the Cochrane library, CINAHL, PsychINFO, SPORTDiscuss) were searched from inception to 21/06/2020 for articles meeting our eligibility criteria: 1) observational or experimental study, 2) participants’ mean/median age ≥60 years, 3) community-dwelling older adults, 4) PA and SB were measured with a(n) accelerometer/pedometer, 5) PA and SB were studied in relation to ADL and/or IADL. Risk of bias was assessed in duplicate using modified versions of the Newcastle–Ottawa scale. Effect direction heat maps provided an overview of associations and standardized regression coefficients (βs) were depicted in albatross plots. Thirty articles (6 longitudinal; 24 cross-sectional) were included representing 24,959 (range: 23 to 2749) community-dwelling older adults with mean/median age ranging from 60.0 to 92.3 years (54.6% female). Higher PA and lower SB were associated with better ability to complete ADL and IADL in all longitudinal studies and overall results of cross-sectional studies supported these associations, which underscores the importance of an active lifestyle. The median [interquartile range] of βs for associations of PA/SB with ADL and IADL were, respectively, 0.145 [0.072, 0.280] and 0.135 [0.093, 0.211]. Our strategy to address confounding may have suppressed the true relationship of PA and SB with ADL or IADL because of over-adjustment in some included studies. Future research should aim for standardization in PA and SB assessment to unravel dose–response relationships and inform guidelines.

This protocol describes a complete data acquisition, analysis and computational forecasting pipeline for employing quantitative MRI data to predict the response of locally advanced breast cancer to neoadjuvant therapy in a community-based care setting. The methodology has previously been successfully applied to a heterogeneous patient population. The protocol details how to acquire the necessary images followed by registration, segmentation, quantitative perfusion and diffusion analysis, model calibration, and prediction. The data collection portion of the protocol requires ~25 min of scanning, postprocessing requires 2–3 h, and the model calibration and prediction components require ~10 h per patient depending on tumor size. The response of individual breast cancer patients to neoadjuvant therapy is forecast by application of a biophysical, reaction–diffusion mathematical model to these data. Successful application of the protocol results in coregistered MRI data from at least two scan visits that quantifies an individual tumor’s size, cellularity and vascular properties. This enables a spatially resolved prediction of how a particular patient’s tumor will respond to therapy. Expertise in image acquisition and analysis, as well as the numerical solution of partial differential equations, is required to carry out this protocol.

Objective: The later-age shift towards physical inactivity and sedentary behaviour is associated with comorbidity and reduced function: markers of frailty. Whether these behaviours relate to frailty has yet to be thoroughly studied using objective measurements. This study aimed to summarise the associations of objectively measured habitual physical activity and sedentary behaviour with frailty in community-dwelling older adults. Study Design and Setting: Six databases were searched from inception to July 21st 2020. Articles analyzing objectively measured physical activity and/or sedentary behaviour with frailty in community-dwelling adults ≥60 years old were included. Synthesis of included articles was performed using effect direction heat maps and albatross plots. Results: The search identified 23 articles across 18 cohorts, including 7,696 total participants with a mean age of 69.3±8.1 years, and 56.9% female. All but one article were cross-sectional. Lower moderate-to-vigorous and total physical activity, steps, postural transitions, and energy expenditure were associated with frailty. The use of multifactorial or physical frailty definitions did not alter associations. Median effect sizes for the associations of all physical activity and sedentary behaviour measures with frailty were β = -0.272 [-0.381, -0.107] and β = 0.100 [0.001, 0.249], respectively. Conclusion: Objective measures of physical activity are associated with frailty, regardless of frailty definition.

The main neurotransmitters in the brain—dopamine, γ-aminobutyric acid (GABA), glutamate, and opioids—are recognized to be the most important for the regulation of aggression and addiction. The aim of this work was to study differentially expressed genes (DEGs) in the main reward-related brain regions, including the ventral tegmental area (VTA), dorsal striatum (STR), ventral striatum (nucleus accumbens, NAcc), prefrontal cortex (PFC), and midbrain raphe nuclei (MRNs), in male mice with 20-day positive fighting experience in daily agonistic interactions. Expression of opioidergic, catecholaminergic, glutamatergic, and GABAergic genes was analyzed to confirm or refute the influence of repeated positive fighting experience on the development of “addiction-like” signs shown in our previous studies. High-throughput RNA sequencing was performed to identify differentially expressed genes in the brain regions of chronically aggressive mice. In the aggressive mice, upregulation of opioidergic genes was shown (Oprk1 in VTA, Pdyn in NAcc, Penk in PFC, and Oprd1 in MRNs and PFC), as was downregulation of genes Opcml and Oprk1 in STR and Pomc in VTA and NAcc. Upregulation of catecholaminergic genes in VTA (Ddc and Slc6a2) and in NAcc (Th and Drd2) and downregulation of some differentially expressed genes in MRNs (Th, Ddc, Dbh, Drd2, Slc18a2, and Sncg) and in VTA (Adra2c, Sncg, and Sncb) were also documented. The expression of GABAergic and glutamatergic genes that participate in drug addiction changed in all brain regions. According to literature data, the proteins encoded by genes Drd2, Oprk1, Oprd1, Pdyn, Penk, and Pomc are directly involved in drug addiction in humans. Thus, our results confirm our earlier claim about the formation of addiction-like signs following repeated positive fighting experience in mice, as shown previously in our biobehavioral studies.

Dental erosion is an irreversible condition of loss of teeth hard tissues caused by intrinsic or extrinsic acids attack, without bacterial involvement. Common soft drinks have an acid pH and they release hydrogen ions and act as chelating agents, dissolving teeth mineral component. The aim of the study was to investigate the correlation between the consumption of soft drinks in children and the degree of dental erosion.A questionnaire of 15 multiple choice questions was addressed to the parents of the 231 children needing different dental treatments. Responses were compared with the level of dental erosion of their child, that was clinically investigated using the Basic Erosive Wear Examination (BEWE) index.About 26.8% of subjects fall into a high-risk category of dental erosion while 24.2% in a low risk level. Socioeconomic status and oral hygiene habits are able to affect the degree of dental erosion. Toothpastes containing fluoride have not proved effective in preventing this phenomenon and no significant correlations were found between the type of toothbrush used and its frequency of use.It is necessary to apply preventive measures such as information on the processes and causes of erosion, instruction about right home oral hygiene maneuvers and the possible use of specific products, to avoid the development of problems related to severe dental wear.

The aim: To determine changes in endothelial dysfunction and immunological response in patients with rheumatoid arthritis with and without coronary heart disease. Materials and methods: The study involved 151 patients with RA and coronary heart disease. The ED was assessed by examining the NO system in RA for determination of the content in the blood of the product of NO synthase – the final metabolites of NO2– and NO3– and the level of VEGF and CD28 in the serum. Results: The results of the study of the levels of metabolites NO2– and NO3– in the first and second groups showed their increased content. Analysis of the content of VEGF in the blood for patients with different durations of the disease showed that the concentration of the studied protein grows larger with increasing duration of the disease. The maximum of sCD28 concentration was found in middle-aged patients, and the minimum (the difference was significant) – in the elderly. Conclusions: As the duration of the disease increases, the content of VEGF in the blood of patients increases, which, at the same time, did not show age dependence on RA and did not change further with concomitant coronary heart disease. Detected concentrations of sCD28 are higher in patients with less prolonged RA, and begin to decrease with increasing duration of the disease.

Language production has often been described as impaired in psychiatric diseases such as in psychosis. Nevertheless, little is known about the characteristics of linguistic difficulties and their relation with other cognitive domains in patients with a first episode of psychosis (FEP), either affective or non-affective. To deepen our comprehension of linguistic profile in FEP, 133 patients with FEP (95 non-affective, FEP-NA; 38 affective, FEP-A) and 133 healthy controls (HC) were assessed with a narrative discourse task. Speech samples were systematically analyzed with a well-established multilevel procedure investigating both micro- (lexicon, morphology, syntax) and macro-linguistic (discourse coherence, pragmatics) levels of linguistic processing. Executive functioning and IQ were also evaluated. Both linguistic and neuropsychological measures were secondarily implemented with a machine learning approach in order to explore their predictive accuracy in classifying participants as FEP or HC. Compared to HC, FEP patients showed language production difficulty at both micro- and macro-linguistic levels. As for the former, FEP produced shorter and simpler sentences and fewer words per minute, along with a reduced number of lexical fillers, compared to HC. At the macro-linguistic level, FEP performance was impaired in local coherence, which was paired with a higher percentage of utterances with semantic errors. Linguistic measures were not correlated with any neuropsychological variables. No significant differences emerged between FEP-NA and FEP-A (p≥0.02, after Bonferroni correction). Machine learning analysis showed an accuracy of group prediction of 76.36% using language features only, with semantic variables being the most impactful. Such a percentage was enhanced when paired with clinical and neuropsychological variables. Results confirm the presence of language production deficits already at the first episode of the illness, being such impairment not related to other cognitive domains. The high accuracy obtained by the linguistic set of features in classifying groups support the use of machine learning methods in neuroscience investigations.

Determination of treatment response to immunotherapy in glioblastoma multiforme (GBM) is a process which can take months. Detection of CD8+ T cell recruitment to the tumor with a noninvasive imaging modality such as positron emission tomography (PET) may allow for tumor characterization and early evaluation of therapeutic response to immunotherapy. In this study, we utilized 89Zr-labeled anti-CD8 cys-diabody-PET to provide proof-of-concept to detect CD8+ T cell immune response to oncolytic herpes simplex virus (oHSV) M002 immunotherapy in a syngeneic GBM model. Immunocompetent mice (n = 16) were implanted intracranially with GSC005 GBM tumors, and treated with intratumoral injection of oHSV M002 or saline control. An additional non-tumor bearing cohort (n = 4) receiving oHSV M002 treatment was also evaluated. Mice were injected with 89Zr-labeled anti-CD8 cys-diabody seven days post oHSV administration and imaged with a preclinical PET scanner. Standardized uptake value (SUV) was quantified. Ex vivo tissue analyses included autoradiography and immunohistochemistry. PET imaging showed significantly higher SUV in tumors which had been treated with M002 compared to those without M002 treatment (p = 0.0207) and the non-tumor bearing M002 treated group (p = 0.0021). Accumulation in target areas, especially the spleen, was significantly reduced by blocking with the non-labeled diabody (p + cell trafficking patterns after oHSV treatment. This PET imaging strategy could aid in distinguishing responders from non-responders during immunotherapy of GBM.

Background Fluoroscopic‐guided lumbar procedures have increased in daily pain practice because the lumbar spine is one of the most common sources of pain. Interventional pain fellows must develop a minimum number of skills during their training in order to achieve the competences without neglecting radiological safety. However, medical training in fluoroscopic‐guided interventions is being affected by the current coronavirus disease 2019 (COVID‐19) situation. Methods The objective of this study was to evaluate the use of a phantom model for lumbar injection as a training strategy during the COVID‐19 pandemic in fellows of interventional pain. The study was divided into theoretical and practical modules. The hands‐on practice was performed in a lumbar model phantom where fellows were evaluated in four fluoroscopically guided approaches: intra‐articular facet block (IAFB), medial branch block (MBB), transforaminal block (TFB), and interlaminar block (ILB) divided in 5 sessions. The aim was to make as many punctures as possible in every session. We measured total procedural performance (TPP), total needle hand time (TNH), and total radiation dose generated by the fluoroscopic machine (TRD) during each procedure. Additionally, a survey was applied to evaluate confidence and satisfaction before and after training. Results A total of 320 lumbar punctures were completed. The results were statistically significant in all approaches attempted (p

Chimeric antigen receptor (CAR) T-cell therapy has become a novel approach in the treatment of many hematologic malignancies. However, ocular adverse effects have not been well described. This report presents a case of a pediatric patient with relapsed B-cell acute lymphoblastic leukemia with ocular involvement treated with CAR T-cell therapy who developed an exudative retinal detachment likely secondary to an inflammatory response to CAR T-cell therapy. [ Ophthalmic Surg Lasers Imaging Retina . 2022;53:113–115.]

Background We investigated the causal associations between the genetic liability to cardiovascular and lifestyle risk factors and peripheral artery disease (PAD), using a Mendelian randomization approach. Methods and Results We performed a 2‐sample inverse‐variance weighted Mendelian randomization analysis, multiple sensitivity analyses to assess pleiotropy and multivariate Mendelian randomization analyses to assess mediating/confounding factors. European‐ancestry genomic summary data ( P −8 ) for type 2 diabetes, lipid‐fractions, smoking, alcohol and coffee consumption, physical activity, sleep, and education level were selected. Genetic associations with PAD were extracted from the Million‐Veteran‐Program genome‐wide association studies (cases=31 307, controls=211 753, 72% European‐ancestry) and the GoLEAD‐SUMMIT genome‐wide association studies (11 independent genome‐wide association studies, European‐ancestry, cases=12 086, controls=449 548). Associations were categorized as robust (Bonferroni‐significant ( P P value: 0.00294–0.05, associations in 1 PAD‐cohort/inconsistent sensitivity analyses) or not present. Robust evidence for genetic liability to type 2 diabetes, smoking, insomnia, and inverse associations for higher education level with PAD were found. Suggestive evidence for the genetic liability to higher low‐density lipoprotein cholesterol, triglyceride‐levels, alcohol consumption, and inverse associations for high‐density lipoprotein cholesterol, and increased sleep duration were found. No associations were found for physical activity and coffee consumption. However, effects fully attenuated for low‐density lipoprotein cholesterol and triglycerides after correcting for apoB, and for insomnia after correcting for body mass index and lipid‐fractions. Nonsignificant attenuation by potential mediators was observed for education level and type 2 diabetes. Conclusions Detrimental effects of smoking and type 2 diabetes, but not of low‐density lipoprotein cholesterol and triglycerides, on PAD were confirmed. Lower education level and insomnia were identified as novel risk factors for PAD; however, complete mediation for insomnia and incomplete mediation for education level by downstream risk factors was observed.

High-altitude (2500 m or 8200 ft) residence reduces uterine artery blood flow during pregnancy, contributing to an increased incidence of preeclampsia and intrauterine growth restriction. However, not all pregnancies are affected by the chronic hypoxic conditions of high-altitude residence. K

Withdrawal syndrome (WS) a musculoskeletal pain after discontinuation of tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) has been described in the treatment-free remission (TFR) studies. The pathophysiological mechanisms and predisposing factors of WS have not been well established.Our aim was to evaluate clinical features and factors associated with WS in the Russian cohort of CML patients who discontinued TKI therapy.WS was evaluated in total of 183 CML patients with chronic phase and sustained deep molecular response (DMR). WS was defined as a musculoskeletal pain newly observed after TKI cessation or as a worsening of previously observed symptoms.DMR loss free survival at 36 months was 49% and 43% in prospective and retrospective groups respectively (p=0.96) with mеdian (Me) time of observation 33 months (range 1136). WS was observed in 49 (27%) patients: grade 12 was in 45 (92%) patients, grade 3 in 4 (8%) patients. Me time to WS occurrence was 2 months (range 17), Ме duration of WS was 5 months (range 135). WS was resolved in 14 of 15 patients with molecular relapse after 13 months of TKI re-initiation and was decreased in 1 patient. WS was completely resolved in 31 of 34 patients who continued remained in TFR and decreased in 3 patients. WS was resolved spontaneously or with nonsteroidal anti-inflammatory drugs in 14 (45%) and 17 (55%) patients accordingly. Older age (p0.0001), longer duration of TKI therapy (p0.0001) and presence of locomotion system diseases (p=0.022) were observed in patients with WS. No WS was observed in pregnant patients (р0.001). Survival without DMR loss at 12 months after TKI stop was 66 and 42% in patients with and without WS accordingly (р=0.095).The rate of WS was 27% that is in a good concordance with the data of the other TFR studies. A longer period of TKI exposure, older age and the history of locomotion system diseases were associated with the development of the WS. We found for the first time that WS was not observed in patients with pregnancy. There was no association of WS development and the rate of molecular relapses.Обоснование. Синдром отмены (СО) после прекращения приема ингибиторов тирозинкиназ (ИТК) у пациентов с хроническим миелоидным лейкозом (ХМЛ) описан в исследованиях ремиссии без лечения (РБЛ). Патофизиологические механизмы и факторы развития СО точно не установлены. Цель. Определить клинические особенности СО и факторы его развития у больных ХМЛ после отмены терапии ИТК в российской когорте пациентов. Материалы и методы. Анализ выполнен в группе 183 больных ХМЛ со стабильным большим молекулярным ответом (БМО). СО определяли как впервые возникший после отмены ИТК скелетно-мышечный болевой синдром или увеличение степени выраженности ранее имевшихся симптомов. Результаты. Выживаемость без потери БМО через 36 мес после отмены ИТК составила 49 и 43% в проспективной и ретроспективной группах пациентов соответственно (p=0,96) при медиане (Me) наблюдения 33 (от 1 до 136) мес. СО наблюдался у 49 (27%) больных: 12-й степени у 45 (92%) человек, 3-й степени у 4 (8%) пациентов. Ме времени до появления СО составила 2 (от 1 до 7) мес, Ме длительности СО 5 (от 1 до 35) мес. После возобновления терапии в связи с молекулярным рецидивом СО полностью разрешился у 14 из 15 пациентов в течение 13 мес, выраженность проявлений уменьшилась у 1 пациента. СО полностью разрешился у 31 из 34 пациентов с продолжением наблюдения в РБЛ; у 3 больных уменьшилась выраженность его симптомов. СО купировался самостоятельно либо на фоне применения нестероидных противовоспалительных препаратов у 14 (45%) и 17 (55%) пациентов соответственно. У больных с СО статистически значимо чаще отмечены более старший возраст (р0,0001), длительный срок терапии ИТК (р0,0001) и наличие заболеваний опорно-двигательного аппарата (р=0,022). Развитие СО не зарегистрировано у беременных пациенток (p0,001). Выживаемость без потери БМО к 12 мес без терапии составила 66 и 42% в группах больных с наличием СО и без него соответственно (р=0,095). Заключение. Доля больных ХМЛ с СО после отмены ИТК составила 27%, что сопоставимо с данными других исследователей по наблюдению в РБЛ. Более длительный период терапии ИТК, старший возраст и наличие заболеваний опорно-двигательного аппарата ассоциированы с развитием СО. Впервые отмечено, что развитие СО не характерно для пациенток с беременностью. Взаимосвязи между развитием СО и молекулярными рецидивами не установлено.

Long diagnostic wait times hinder international efforts to address antibiotic resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution. However, generalizability and clinical adoption have been limited by a lack of interpretability, especially in deep learning methods. Here, we present two deep convolutional neural networks that predict antibiotic resistance phenotypes of M. tuberculosis isolates: a multi-drug CNN (MD-CNN), that predicts resistance to 13 antibiotics based on 18 genomic loci, with AUCs 82.6-99.5% and higher sensitivity than state-of-the-art methods; and a set of 13 single-drug CNNs (SD-CNN) with AUCs 80.1-97.1% and higher specificity than the previous state-of-the-art. Using saliency methods to evaluate the contribution of input sequence features to the SD-CNN predictions, we identify 18 sites in the genome not previously associated with resistance. The CNN models permit functional variant discovery, biologically meaningful interpretation, and clinical applicability.

Aims. Evaluation of (hc knowledge and behavioral risks relatcd lo sexually transmiltcd infections (STIs) among the student population of the degree course in nursing at the University of Palermo. Materials and Methods. An anonymous online a survey was provided to students that investigate to socio-demographic information. sexual habits and the level of knowledge of the STIs. Multivariable logistic regression was performed. considering it as a dependent variable "Do you permanently have unprotected sex (without a condom)? Yes", in order to evaluate the role of the variables of the questionnaire. Results are expressed as adjusted Odds Ratio (aOR). Results. The sample size consists of 405. The average age of the sample is 21.65 years (standard deviation±3.24). The analysis shows that the risk of having permanently unprotected sex (without condom) is significantly associatcd with the following variables: "Are you engaged or single? Engagcd" (aOR 3.24,95% CI 1.66 - 6.33); "Sexual orientation. Homosexual or Bisexual (aOR4.45, 95% CI 1.30-15.29); "Have you occasionally had unprotected sex (without a condom)? Yes" (aOR 5.09, 95% CI 2.69 - 9.62); "How would you define your knowledge of sexually transmitted discases? Good" (aOR 2.07, 95% CI 1.05 -4.08); "How would you define your knowledge about contraceptive methods? Good" (aOR 2.51, 95% CI 1.23 - 5.15); "Have you or have you ever had a sexually transmitted discase? Yes (aOR 4.43,95% CI 1.71 - 11.53); "Do you know that men can also undergo HPV vaccination? Yes" (aOR 2.57,95% CI 1.03 -6.40); "Age. As the unit inercase" (aOR 1.14,95% CI 1.02- 1.26). Conclusions. These results highlight the importance of involving university students in programs aimed at improving the knowledge in terms of STIs and inercase of Sexual and reproductive health. Further. because STIs prevention is based mainly on human behavior. tailored intervention is needed especially because behavior change remains a complex challenge.

The risk of interlaminar passage of a dilator into the lumbar spinal canal in minimally invasive approaches is currently unknown. Among anthropometric data reported in the medical literature, there is no cadaveric report of the interlaminar dimensions of the lumbar spine.To report the lumbar interlaminar dimensions in neutral, flexion, and extension postures.A total of 8 spines were sectioned into lumbar segments. Digitized coordinate data defining the locations and movements of chosen anatomic points on the laminar edges at a given spinal level were used to measure changes in the opening dimensions during static neutral posture and flexion-extension movements. Interlaminar dimensions were averaged and categorized for each vertebral level and spinal posture.The mean interlaminar distance increased from neutral posture to flexion across all vertebral levels. The mean interlaminar distances in the neutral posture ranged from 12.21 mm (L5-S1) to 14.88 mm (L1-L2). In flexion, the range was from 17.15 mm (L5-S1) to 18.50 mm (L4-L5). These measurements are greater than the first several diameters of dilators in all minimally invasive dilator sets.The precise measurements of the lumbar interlaminar space are valuable to minimally invasive spine surgeons for the dilatation phase of the operation. The risk of interlaminar passage of a minimally invasive dilator is greatest in flexion with dilators that have a diameter of 16 mm or less. There is considerably less risk of interlaminar passage in patients positioned on an extended Jackson table.

Introduction High-altitude (>2500 m) residence augments the risk of intrauterine growth restriction (IUGR) and preeclampsia likely due, in part, to uteroplacental hypoperfusion. Previous genomic and transcriptomic studies in humans and functional studies in mice and humans suggest a role for AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR. AMPK is a metabolic sensor activated by hypoxia that is ubiquitously expressed in vascular beds and placenta. Methods We measured gene expression and protein levels of AMPK and its upstream regulators and downstream targets in human placentas from high (>2500 m) vs. moderate (~1700 m) and low (~100 m) altitude. Results We found that phosphorylated AMPK protein levels and its downstream target TSC2 were increased in placentas from high and moderate vs. low altitude, whereas the phosphorylated form of the downstream target translation repressor protein 4E-BP1 was increased in high compared to moderate as well as low altitude placentas. Mean birth weights progressively fell with increasing altitude but no infants, by study design, were clinically growth-restricted. Gene expression analysis showed moderate increases in PRKAG2, encoding the AMPK γ2 subunit, and mechanistic target of rapamycin, MTOR, expression. Discussion These results highlight a differential regulation of placental AMPK pathway activation in women residing at low, moderate or high altitude during pregnancy, suggesting AMPK may be serving as a metabolic regulator for integrating hypoxic stimuli with placental function.

Background The combination of traumatic simultaneous diaphragmatic rupture and chest wall herniation remains rare, with 42 cases of traumatic transdiaphragmatic intercostal hernia (TDIH) reported in the literature since 1946. An accurate count of cases is difficult to obtain, as TDIH nomenclature has been variable. 1 - 5 Risk factors for traumatic TDIH are not well established. As these injuries are uncommon, best management techniques have yet to be established. Reported repair techniques include primary closure, closure with mesh, and implantation of prosthetic or autologous material. We present our single-center series of 7 patients, the largest reported to our knowledge, and discuss the challenges of repairing these difficult injuries. Methods After obtaining institutional review board approval, data were abstracted from the electronic medical record on all adults who underwent evaluation and treatment for traumatic TDIH between July 2014 and January 2019. Results Of the 7 cases of traumatic TDIH, 6 patients developed TDIH secondary to cough; the seventh patient presented with chronic chest wall pain after an episode of heavy lifting. All patients were obese or overweight. Pain and a “popping sensation” were the most common presenting symptoms. All patients underwent operative intervention with primary repair of the diaphragm and suture approximation of the ribs. 3 patients had onlay mesh repair of the chest wall and/or abdominal wall. 1 patient had plating of his rib fracture. 3 patients had a recurrence of the intercostal portion of the hernia No patients have undergone reoperation thus far. Discussion While previously thought to more commonly occur on the left side due to the protective effects of the diaphragm, 2 the majority in this series had right-sided injuries. Herniation through the ninth-10th interspace remains the most common location. 4 Computed tomography imaging should be used for diagnosis and operative planning. It is best to manage these hernias acutely to re-establish normal anatomy. Mesh may be required in delayed reconstructions of if the chest wall cannot be re-approximated. Rib plating should be considered in cases of instability or flail. High rates of complications are not unexpected given the complicated and rare nature of the injury. Given the high rate of intercostal hernia recurrence, it is likely that mesh repair or should be more often used in the treatment of this injury.

The ability to accurately predict response and then rigorously optimize a therapeutic regimen on a patient-specific basis, would transform oncology. Toward this end, we have developed an experimental-mathematical framework that integrates quantitative magnetic resonance imaging (MRI) data into a biophysical model to predict patient-specific treatment response of locally advanced breast cancer to neoadjuvant therapy. Diffusion-weighted and dynamic contrast-enhanced MRI data is collected prior to therapy, after 1 cycle of therapy, and at the completion of the first therapeutic regimen. The model is initialized and calibrated with the first 2 patient-specific MRI data sets to predict response at the third, which is then compared to patient outcomes (N = 18). The model's predictions for total cellularity, total volume, and the longest axis at the completion of the regimen are significant within expected measurement precision (P< 0.05) and strongly correlated with measured response (P < 0.01). Further, we use the model to investigate, in silico, a range of (practical) alternative treatment plans to achieve the greatest possible tumor control for each individual in a subgroup of patients (N = 13). The model identifies alternative dosing strategies predicted to achieve greater tumor control compared to the standard of care for 12 of 13 patients (P < 0.01). In summary, a predictive, mechanism-based mathematical model has demonstrated the ability to identify alternative treatment regimens that are forecasted to outperform the therapeutic regimens the patients clinically. This has important implications for clinical trial design with the opportunity to alter oncology care in the future.

Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. This study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, IHC, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired t test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared with 5-ALA (P = 0.0079). SDs for core and margin regions of interest in 5-ALA–treated tissues were significantly higher than those found in panitumumab-IRDye800CW–treated tissues (P = 0.0240 and P = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were more than 10% higher than those of 5-ALA. Higher AUC for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared with 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescence intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in patients with GBM compared with 5-ALA.

Inflammatory breast cancer (IBC), a rare form of breast cancer associated with increased angiogenesis and metastasis, is largely driven by tumor-stromal interactions with the vasculature and the extracellular matrix (ECM). However, there is currently a lack of understanding of the role these interactions play in initiation and progression of the disease. In this study, we developed the first three-dimensional, in vitro, vascularized, microfluidic IBC platform to quantify the spatial and temporal dynamics of tumor-vasculature and tumor-ECM interactions specific to IBC. Platforms consisting of collagen type 1 ECM with an endothelialized blood vessel were cultured with IBC cells, MDA-IBC3 (HER2+) or SUM149 (triple negative), and for comparison to non-IBC cells, MDA-MB-231 (triple negative). Acellular collagen platforms with endothelialized blood vessels served as controls. SUM149 and MDA-MB-231 platforms exhibited a significantly (p < .05) higher vessel permeability and decreased endothelial coverage of the vessel lumen compared to the control. Both IBC platforms, MDA-IBC3 and SUM149, expressed higher levels of vascular endothelial growth factor (p < .05) and increased collagen ECM porosity compared to non-IBCMDA-MB-231 (p < .05) and control (p < .01) platforms. Additionally, unique to the MDA-IBC3 platform, we observed progressive sprouting of the endothelium over time resulting in viable vessels with lumen. The newly sprouted vessels encircled clusters of MDA-IBC3 cells replicating a key feature of in vivo IBC. The IBC in vitro vascularized platforms introduced in this study model well-described in vivo and clinical IBC phenotypes and provide an adaptable, high throughput tool for systematically and quantitatively investigating tumor-stromal mechanisms and dynamics of tumor progression.

High-altitude (>2,500 m) residence increases the incidence of intrauterine growth restriction (IUGR) due, in part, to reduced uterine artery blood flow and impaired myometrial artery (MA) vasodilator response. A role for the AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR is suggested by genomic and transcriptomic studies in humans and functional studies in mice. AMPK is a hypoxia-sensitive metabolic sensor with vasodilatory properties. Here we hypothesized that AMPK-dependent vasodilation was increased in MAs from high versus low-altitude (2,500 m) with appropriate for gestational age pregnancies but not in IUGR pregnancies at any altitude.

Background:Pulmonary vascular disease resulting from CHDs may be the most preventable cause of pulmonary artery hypertension worldwide. Many children in developing countries still do not have access to early closure of clinically significant defects, and the long-term outcomes after corrective surgery remain unclear. Focused on long-term results after isolated ventricular septal defect repair, our review sought to determine the most effective medical therapy for the pre-operative management of elevated left-to-right shunts in patients with an isolated ventricular septal defect.Methods:We identified articles specific to the surgical repair of isolated ventricular septal defects. Specific parameters included the pathophysiology and pre-operative medical management of pulmonary over-circulation and outcomes.Results:Studies most commonly focused on histologic changes to the pulmonary vasculature and levels of thromboxanes, prostaglandins, nitric oxide, endothelin, and matrix metalloproteinases. Only 2/44 studies mentioned targeted pharmacologic management to any of these systems related to ventricular septal defect repair; no study offered evidence-based guidelines to manage pulmonary over-circulation with ventricular septal defects. Most studies with long-term data indicated a measurable frequency of pulmonary artery hypertension or diminished exercise capacity late after ventricular septal defect repair.Conclusion:Long-term pulmonary vascular and respiratory changes can occur in children after ventricular septal defect repair. Research should be directed at providing an evidenced-based approach to the medical management of infants and children with ventricular septal defects (and naturally all CHDs) to minimise consequences of pulmonary artery hypertension, particularly as defect repair may occur late in underprivileged societies.

Background Therapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer. Trastuzumab, a monoclonal antibody that targets HER2, has been shown pre-clinically to induce vascular changes that can increase delivery of chemotherapy. To quantify the role of immune modulation in treatment-induced vascular changes, this study identifies temporal changes in myeloid cell infiltration with corresponding vascular alterations in a preclinical model of HER2+ breast cancer following trastuzumab treatment. Methods HER2+ tumor-bearing mice (N = 46) were treated with trastuzumab or saline. After extraction, half of each tumor was analyzed by immunophenotyping using flow cytometry. The other half was quantified by immunohistochemistry to characterize macrophage infiltration (F4/80), vascularity (CD31 and α-SMA), proliferation (Ki67) and cellularity (H&E). Additional mice (N = 10) were used to quantify differences in tumor cytokines between control and treated groups. Results Immunophenotyping showed an increase in macrophage infiltration 24 h after trastuzumab treatment (P ≤ 0.05). With continued trastuzumab treatment, the M1 macrophage population increased (P = 0.02). Increases in vessel maturation index (i.e., the ratio of α-SMA to CD31) positively correlated with increases in tumor infiltrating M1 macrophages (R = 0.33, P = 0.04). Decreases in VEGF-A and increases in inflammatory cytokines (TNF-α, IL-1β, CCL21, CCL7, and CXCL10) were observed with continued trastuzumab treatment (P ≤ 0.05). Conclusions Preliminary results from this study in a murine model of HER2+ breast cancer show correlations between immune modulation and vascular changes, and reveals the potential for anti-HER2 therapy to reprogram immunosuppressive components of the tumor microenvironment. The quantification of immune modulation in HER2+ breast cancer, as well as the mechanistic insight of vascular alterations after anti-HER2 treatment, represent novel contributions and warrant further assessment for potential clinical translation.