14 research outputs found
Exploring the mycobacteriophage metaproteome: Phage genomics as an educational platform
Bacteriophages are the most abundant forms of life in the biosphere and carry genomes characterized by high genetic diversity and mosaic architectures. The complete sequences of 30 mycobacteriophage genomes show them collectively to encode 101 tRNAs, three tmRNAs, and 3,357 proteins belonging to 1,536 "phamilies" of related sequences, and a statistical analysis predicts that these represent approximately 50% of the total number of phamilies in the mycobacteriophage population. These phamilies contain 2.19 proteins on average; more than half (774) of them contain just a single protein sequence. Only six phamilies have representatives in more than half of the 30 genomes, and only three - encoding tape-measure proteins, lysins, and minor tail proteins - are present in all 30 phages, although these phamilies are themselves highly modular, such that no single amino acid sequence element is present in all 30 mycobacteriophage genomes. Of the 1,536 phamilies, only 230 (15%) have amino acid sequence similarity to previously reported proteins, reflecting the enormous genetic diversity of the entire phage population. The abundance and diversity of phages, the simplicity of phage isolation, and the relatively small size of phage genomes support bacteriophage isolation and comparative genomic analysis as a highly suitable platform for discovery-based education. © 2006 Hatfull et al
Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study
BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.
METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.
RESULTS: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.
CONCLUSIONS: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.
FUNDING: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.
CLINICAL TRIAL NUMBER: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701
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Patterns of Response to 200 Mg Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma: Longer Follow-Up of the Linker-MM1 Study
Background Linvoseltamab, a B-cell maturation antigen (BCMA)×CD3 bispecific antibody, demonstrated promising efficacy and generally manageable safety as therapy for relapsed/refractory multiple myeloma (RRMM; Lee et al. ASCO 2023). Here we report additional analysis of efficacy, including response pattern over time, and safety. Methods To enroll into LINKER-MM1 (NCT03761108) patients (pts) had to have multiple myeloma (MM) that either progressed on/after ≥3 lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody; or that was ≥triple-class (PI/IMiD/anti-CD38 antibody) refractory. Pts received intravenous linvoseltamab once a week through week 14, then once every two weeks. In the 200 mg phase 2 expansion cohort, pts achieving very good partial response (VGPR) or better received linvoseltamab once every four weeks after week 24. Primary endpoint was objective response rate (ORR). Key secondary endpoints included progression free survival (PFS) and overall survival. Treatment-emergent adverse events (TEAEs) reported are those that occurred from first dose until 30 days after the end of study treatment. Results As of February 28, 2023, 117 MM pts enrolled into the 200 mg cohort; median age was 70 (range: 37-91) with 26% ≥75, 26% were non-white, 14% had extramedullary (excluding paramedullary) plasmacytomas ≥2 cm, 36% had a high-risk cytogenetics, 22% had bone marrow plasma cells ≥50%, and 74% were ≥triple-class refractory. Median duration of follow-up was 5.6 months (interquartile range [Q1-Q3]: 3.02-8.34) ORR was 71% with ≥complete response (CR) rate of 30%. Responses deepen over time: median time to ≥partial response (PR) was 0.95 months (Q1-Q3: 0.76-1.87); median time to ≥VGPR was 1.87 months (0.79-3.55); and median time to ≥CR was 5.32 months (3.71-7.69). Moreover, high ORR and high rates of ≥CR were observed in many subgroups of difficult-to-treat MM pts. Specifically, ORR and ≥CR rates were: 70% and 29% in pts with ≥triple-class refractory disease; 68% and 26% in pts ≥75 years old; 62% and 26% in pts with high cytogenetic risk; and 47% and 18% in pts with International Staging System stage III. High rates of overall response and ≥CR were also observed in patients with high tumor burden as determined by various measures including bone marrow plasmacytosis ≥50% (50% and 31%) and soluble BCMA at baseline ≥ 0.4mg/L (55% and 25%). Kaplan-Meier (KM) estimated median duration of response was not reached (NR) (95% confidence interval [CI] non-evaluable [NE], NE), and probability of response at 12 months was 79% (95% CI 63, 89). KM estimated median PFS was NR (95% CI NE, NE) and probability of PFS at 12 months was 66% (95% CI 52, 77). TEAEs occurred in all patients with Grade [Gr] ≥3 in 79%. The most common TEAE was cytokine release syndrome (any grade: 45%, Gr3-4: 1%, Gr5: 0; tocilizumab was utilized to treat these symptoms in 16 [13.7%] pts). Other common TEAEs were cough (33%, 0, and 0), neutropenia (32%, 31%, and 0), diarrhea (32%, 2%, and 0), and fatigue (32%, 0, and 0). Rate of infections of any grade was 59.8% with ≥Gr3 in 36.8%. The most common infections were pneumonia (any grade 17.1%, ≥Gr3 13.7%), upper respiratory tract infection (12.0%, and 2.6%), and COVID-19 (12.0%, 5.1%). Opportunistic infections (any grade) were observed in 9 (7.7%) pts including 7 (6.0%) pts ≥Gr3. Twenty-six of 117 (22%) pts were treated with intravenous immunoglobulin. Conclusions Linvoseltamab 200 mg induced deep responses in patients with RRMM including those with high-risk myeloma and high tumor burden, and deepened responses over time while maintaining a generally manageable safety profile. More mature data with longer follow-up will be reported at the meeting
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Health-Related Quality of Life (HRQoL) Among Patients with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Linvoseltamab in Linker-MM1: Interim Assessment up to 36 Weeks of Treatment
Background Patients with multiple myeloma (MM) have worsened HRQoL that deteriorates with progression or with increasing lines of therapy (Fonseca et al. Clin Lymphoma Myeloma Leuk. 2023). Assessing HRQoL in patients with RRMM provides insights on the full benefit of treatment. LINKER-MM1 (NCT03761108) is an ongoing open-label, multicenter Phase 1/2 dose-escalation and dose-expansion trial evaluating linvoseltamab, a B-cell maturation antigen (BCMA)×CD3 bispecific antibody that targets CD3 on T-cells and BCMA on myeloma cells resulting in T-cell-mediated cytotoxicity. Results have demonstrated promising efficacy and generally manageable safety for linvoseltamab in patients with RRMM (Lee et al. ASCO. 2023). Patient-reported outcomes (PRO) from the Phase 1 portion have shown improvements in quality of life (QoL) and pain symptoms. We report PRO for the combined Phase 1/2 cohort receiving the linvoseltamab 5-25-200 mg dosing regimen. Methods Patients in LINKER-MM1 (June 7, 2023 data cut-off with a July 20, 2023 data extraction) who were enrolled to receive the 5-25-200 mg dosing regimen during Phase 1 (n=12) and Phase 2 (n=105) were included in the analysis. Patients were ≥18 years of age with RRMM after triple-class exposure to a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody. Linvoseltamab was administered at Week 1 (5 mg), Week 2 (25 mg), and Week 3 (200 mg), followed by weekly dosing through Week 14 (Phase 2) or Week 16 (Phase 1), then every 2 weeks thereafter until progression. Patients in Phase 2 who achieved a very good partial response by Week 24 could transition to every 4 week dosing from Week 24. The PRO instruments included the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma module (QLQ-MY20), and European Quality of Life 5 Dimensions 3 Level questionnaire (EQ-5D-3L) administered at baseline, Week 4, and every 4 weeks thereafter. Six scales across the three instruments were pre-specified in the clinical statistical analysis plan. We present analyses of the first 36 weeks of treatment. Least squares (LS) mean change from baseline to each assessment visit in PRO scores was estimated using a mixed effects model for repeated measures. Clinically meaningful improvements for EORTC QLQ-C30 were defined based on the minimally important difference (MID) of ≥10 points, with higher scores indicating better global health status (GHS)/QoL and physical functioning (PF). For EORTC QLQ-C30 fatigue (MID ≥10 points) and EORTC QLQ-MY20 Disease Symptoms (MID ≥16 points) and Side Effects of Treatment symptom scales (MID ≥6 points), lower scores indicate a lower symptom burden. For EQ-5D-3L visual analog scale (VAS), changes ≥12 points were considered clinically meaningful, with higher scores indicating better health status. LS mean change from baseline was considered statistically significant if the 95% confidence interval (CI) did not cross 0. No adjustment for multiplicity was performed, hence all statistical significance is nominal. Results PRO completion rates were high with ≥85% for the majority of time points among expected visits. Estimated mean changes from baseline by time point were statistically significant for GHS/QoL from Week 12 up to Week 36, with a LS mean change of 9.97 (95% CI 5.51, 14.43) at Week 36 (Figure 1A). Statistically significant improvements were observed for fatigue at Week 16 up to Week 36 with a LS mean change of −9.66 (95% CI −13.35, −5.98) at Week 36. Notably, both statistically significant and clinically meaningful improvements were observed for pain at Week 20 (−18.43; 95% CI −23.54, −13.32) through Week 36 (−12.28; 95% CI −18.15, −6.42) (Figure 1B). Statistically significant improvements were observed in PF at Week 20 up to Week 36 (Figure 1A) and most assessment time points for the EORTC QLQ-MY20 Disease Symptoms and Side Effects of Treatment scales during the 36-week period, although these changes did not reach the MID thresholds for clinically meaningful improvement. Scores on the EQ-5D-3L VAS were maintained from baseline throughout the 36-week period. Conclusions During 36 weeks of treatment, improvements in measures of HRQoL, including pain, were reported among patients with RRMM receiving linvoseltamab. These PRO findings support a favorable benefit-risk profile of linvoseltamab consistent with clinical results
Complex Relationships within Highly Abundant Mycobacteriophage Phamilies
<div><p>(A) Complex relationships among members of the Pham7 (Lysin A) phamily. The output of a BLAST comparison of Wildcat gp49 against other mycobacteriophage proteins shows that only 16 other mycobacteriophage proteins are matched and that these correspond to different parts of Wildcat gp49. Colored bars represent the strength of the matches, with red being the strongest, followed by purple, blue, and black.</p><p>(B) Phylogenetic relationships between members of mycobacteriophage Pham23 (tape-measure protein; Tmp). Amino acid sequences for each of the 30 constituent members of Pham23 were aligned using ClustalW and the unrooted phylogenetic relationships represented using NJTree. Bootstrap values from 1,000 reiterations are shown.</p><p>(C) Chimerism in Pham28 (minor tail) proteins. Llij gp18 is related to both gp18 and gp19 of phage Che8 at high levels of amino acid sequence identity, and these proteins are related in turn to other members of Pham28 as shown.</p></div
Size and Distribution of Mycobacteriophage Phamilies
<div><p>All 3,357 mycobacteriophage genes were assorted into 1,536 phamilies based on amino acid sequence similarity with a BLAST E value of 0.001 or better to at least one other member of the phamily.</p><p>(A) The distribution of phamilies is shown ranked according to the number of mycobacteriophage genomes containing at least one phamily member. Examples of specific phams and the total number of mycobacteriophage genes within that pham are shown.</p><p>(B) Pie-chart representation of the phamily-size distribution. Phamilies with eight or more members represent about 2% of the total.</p></div
Nucleotide Sequence Comparison of 30 Mycobacteriophage Genomes as Illustrated in a Dotter Plot Using a Sliding Window of 25 bp [63]
<p>The lower triangle represents the relationships at an elevated level of gray-scale relative to the upper triangle, revealing weaker sequence relationships.</p
Estimating the Number of Mycobacteriophage Phams
<p>A subset of the 30 phages was randomly selected without replacement, and the total number of Phams was determined; this was repeated 10,000 times with the mean shown as a blue circle. For each subset, an additional phage was then randomly chosen, and the average number of new Phams found in that phage was determined; these data are shown as red squares. The total number of Phams was fit to a hyperbolic function, with the best-fit equation determined by least-squares regression.</p
Relationships between Mycobacteriophage Phams and Previously Sequenced Proteins
<p>The number and size of mycobacteriophage phamilies with sequence similarity to nonmycobacteriophage genes are shown. The numbers of Phams shared by mycobacteriophages, other phages, and nonphage genomes are shown, along with the average pham size, defined as the number of mycobacteriophage genomes containing at least one member of that phamily. The red circle represents mycobacteriophage genomes, the green circle represents all dsDNA phage genomes other than the mycobacteriophages, and the blue circle represents all nonphage genomes. The number of phams shared between these groups and the mean mycobacteriophages pham size of those phams are shown, with arrows indicating whether they are shared by mycobacteriophages (red circle), nonmycobacteriophage phage genomes (green circle), or nonphage genomes (blue circle).</p