ABSTRACT Intensity mapping, which images a single spectral line from unresolved galaxies across cosmological volumes, is a promising technique for probing the early universe. Here we present ...predictions for the intensity map and power spectrum of the CO(1-0) line from galaxies at -2.8, based on a parameterized model for the galaxy-halo connection, and demonstrate the extent to which properties of high-redshift galaxies can be directly inferred from such observations. We find that our fiducial prediction should be detectable by a realistic experiment. Motivated by significant modeling uncertainties, we demonstrate the effect on the power spectrum of varying each parameter in our model. Using simulated observations, we infer constraints on our model parameter space with an MCMC procedure, and show corresponding constraints on the - relation and the CO luminosity function. These constraints would be complementary to current high-redshift galaxy observations, which can detect the brightest galaxies but not complete samples from the faint end of the luminosity function. By probing these populations in aggregate, CO intensity mapping could be a valuable tool for probing molecular gas and its relation to star formation in high-redshift galaxies.
With the rapidly expanding pandemic of SARS‐CoV‐2, there is concern that solid organ transplant recipients will be particularly vulnerable to infection and may experience a more severe clinical ...course. We report four cases of COVID‐19 in solid organ transplant recipients including recipients of kidney, liver, lung, and heart transplants. We describe each patient's medical history including transplantation history, their clinical presentation and workup, and their course from diagnosis to either hospital discharge or to improvement in symptoms. These reports demonstrate a range of symptoms, clinical severity, and disease course in solid organ transplant recipients with COVID‐19, including two hospitalized patients and two patients managed entirely in the outpatient setting.
The authors report four cases of SARS‐CoV‐2 infection in kidney, liver, lung, and heart transplant recipients in Seattle, Washington, with a range of disease severity and favorable outcomes.
We combine recent simulation work on the SFR-C ii correlation at high redshift with empirical modeling of the galaxy-halo connection (via UniverseMachine) to forecast C ii auto power spectra from z ∼ ...4 to z ∼ 8. We compare these to sensitivities realistically expected from various instruments expected to come online in the next decade. If the predictions of our model are correct, C ii should be detectable up to z ∼ 6 in this generation of surveys, but detecting C ii past the end of reionization will require a generational leap in line-intensity survey capabilities.
Predicting cancer patients’ response to therapy is essential for curing disease and improving quality of life. Garraway and colleagues demonstrate that the frequency and number of neoantigens, ...non-synonymous mutations, and adaptive immune genes, but not the assessment of individual recurrent neoantigens or mutations, predicts patient responses to immunotherapy.
Predicting cancer patients’ response to therapy is essential for curing disease and improving quality of life. Garraway and colleagues demonstrate that the frequency and number of neoantigens, non-synonymous mutations, and adaptive immune genes, but not the assessment of individual recurrent neoantigens or mutations, predicts patient responses to immunotherapy.
Bisulfite sequencing detects 5mC and 5hmC at single-base resolution. However, bisulfite treatment damages DNA, which results in fragmentation, DNA loss, and biased sequencing data. To overcome these ...problems, enzymatic methyl-seq (EM-seq) was developed. This method detects 5mC and 5hmC using two sets of enzymatic reactions. In the first reaction, TET2 and T4-BGT convert 5mC and 5hmC into products that cannot be deaminated by APOBEC3A. In the second reaction, APOBEC3A deaminates unmodified cytosines by converting them to uracils. Therefore, these three enzymes enable the identification of 5mC and 5hmC. EM-seq libraries were compared with bisulfite-converted DNA, and each library type was ligated to Illumina adaptors before conversion. Libraries were made using NA12878 genomic DNA, cell-free DNA, and FFPE DNA over a range of DNA inputs. The 5mC and 5hmC detected in EM-seq libraries were similar to those of bisulfite libraries. However, libraries made using EM-seq outperformed bisulfite-converted libraries in all specific measures examined (coverage, duplication, sensitivity, etc.). EM-seq libraries displayed even GC distribution, better correlations across DNA inputs, increased numbers of CpGs within genomic features, and accuracy of cytosine methylation calls. EM-seq was effective using as little as 100 pg of DNA, and these libraries maintained the described advantages over bisulfite sequencing. EM-seq library construction, using challenging samples and lower DNA inputs, opens new avenues for research and clinical applications.
Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary ...colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.
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•Inter- and intra-metastatic immune infiltrates are heterogeneous in colorectal cancer•T cell densities from metastases increase following anti-EGFR treatment•Immunoscore (IS) outperforms PDL1 staining in metastatic biopsy diagnostic accuracy•IS and TB score from the least-infiltrated metastasis are most survival associated
Van den Eynde et al. quantify immune cell types in metastases and primary colorectal tumors. They show that high Immunoscore (IS) associates with fewer metastases, that anti-EGFR treatment significantly increases T cell density in the core of metastases, and that the predictive accuracy of IS better than PDL1.
This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients.
Complete curative resection of metastases (n = 441) ...was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided.
The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not.
Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.
Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of ...mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations. Similar patterns of cancer-related gene expression levels were observed between patients. No cancer-associated genes or pathways were associated with M stage. Instead, mutations of FBXW7 were associated with the absence of metastasis and correlated with increased expression of T cell proliferation and antigen presentation functions. Analyzing the tumor microenvironment, we observed two hallmarks of the metastatic process: decreased presence of lymphatic vessels and reduced immune cytotoxicity. These events could be the initiating factors driving both synchronous and metachronous metastases. Our data demonstrate the protective impact of the Immunoscore, a cytotoxic immune signature, and increased marginal lymphatic vessels, against the generation of distant metastases, regardless of genomic instability.
B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. ...Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA
) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA
with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA
rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.
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