60 research outputs found
jason-weirather/AlignQC: AlignQC 2.0.4
No full text<p>An across the board improvement on stability. Better cross-platform compatibility. Docker added. Now <code>-t</code> or <code>--no_transcriptome</code> has replace <code>-a</code>, and <code>-g</code> or <code>--genome</code> has replaced <code>-r</code> to reduce the ambiguity. Now by default <code>-t</code> takes a GTF format file. with optional <code>--gpd</code> flag to indicate GPD format.</p>
Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma
No full textAbstract T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types
Study of parasite kinetics with antileishmanial drugs using real-time quantitative PCR in Indian visceral leishmaniasis
No full textObjectives This study describes parasite kinetics in the blood of visceral leishmaniasis patients treated with liposomal amphotericin B (L-AmB) or a preformed fat emulsion of amphotericin B (ApL) using real-time quantitative PCR (qPCR).
Methods Forty-six patients were treated with a single dose (15 mg/kg of body weight) of either L-AmB (n = 13) or ApL (n = 33). qPCR was used to estimate parasite kinetics by detection of Leishmania donovani DNA using kinetoplast DNA-specific primers in peripheral blood samples using an absolute quantification method.
Results The mean parasite load decreased from baseline (day 0) values of 894.07 and 980.48 to 71.72 and 211.52 parasite genomes/mL at day 7 in L-AmB and ApL groups, respectively, and at day 30 these further declined to 8.30 and 133.98 parasite genomes/mL, respectively. At day 30 post-treatment evaluation, the decline in parasite load was significantly greater (P = 0.024) with L-AmB compared with ApL. Four of 33 patients in the ApL group failed treatment (1 primary failure and 3 relapses) with the presence of parasites, whereas all patients in the L-AmB group were cured at 6 month follow-up.
Conclusions qPCR can be a tool to measure parasite dynamics accurately and provide a marker to measure the efficacy of various drugs. It can be used as a test of cure, allowing us to do away with invasive and risky methods such as splenic or bone marrow aspiration
Associação entre a carga de parasitária e falha terapêutica em pacientes com Leishmaniose Tegumentar Americana
No full textA Leishmania (Viannia) braziliensis é o agente causador de leishmaniose cutânea (LC), leishmaniose mucosa (LM) e leishmaniose disseminada (LD). Como os parasitas são escassos no tecido e há uma resposta inflamatória exuberante, a patologia relacionada à infecção por L. braziliensis tem sido associada, principalmente, à resposta inflamatória do hospedeiro. Diante da necessidade em se obter um diagnóstico rápido e preciso em áreas afetadas pela leishmaniose, um estudo de associação da carga parasitária com a gravidade da doença faz-se necessário para uma melhor avaliação, e dessa maneira, diagnóstico e tratamento mais precisos. Este é um estudo de coorte retrospectiva, no qual investigamos a influência da carga parasitária na expressão da doença de pacientes com leishmaniose tegumentar americana (LTA) provenientes de Corte de Pedra-BA
Abstract 5289: Enhance both precision and sensitivity of fusion gene detection by hybrid sequencing
No full textComprehensive comparison of Pacific Biosciences and Oxford Nanopore Technologies and their applications to transcriptome analysis
No full textSingle cell expression analysis of primate-specific retroviruses-derived HPAT lincRNAs in viable human blastocysts identifies embryonic cells co-expressing genetic markers of multiple lineages
No full textChromosome instability and aneuploidies occur very frequently in human embryos, impairing proper embryogenesis and leading to cell cycle arrest, loss of cell viability, and developmental failures in 50–80% of cleavage-stage embryos. This high frequency of cellular extinction events represents a significant experimental obstacle challenging analyses of individual cells isolated from human preimplantation embryos. We carried out single cell expression profiling of 241 individual cells recovered from 32 human embryos during the early and late stages of viable human blastocyst (VHB) differentiation. Classification of embryonic cells was performed solely based on expression patterns of human pluripotency-associated transcripts (HPAT), which represent a family of primate-specific transposable element-derived lincRNAs highly expressed in human embryonic stem cells and regulating nuclear reprogramming and pluripotency induction. We then validated our findings by analyzing transcriptomes of 1,708 individual cells recovered from more than 100 human embryos and 259 mouse cells from more than 40 mouse embryos at different stages of preimplantation embryogenesis. HPAT's expression-guided spatiotemporal reconstruction of human embryonic development inferred from single-cell expression analysis of VHB differentiation enabled identification of telomerase-positive embryonic cells co-expressing key pluripotency regulatory genes and genetic markers of three major lineages. Follow-up validation analyses confirmed the emergence in human embryos prior to lineage segregation of telomerase-positive cells co-expressing genetic markers of multiple lineages. Observations reported in this contribution support the hypothesis of a developmental pathway of creation embryonic lineages and extraembryonic tissues from telomerase-positive pre-lineage cells manifesting multi-lineage precursor phenotype
Durvalumab, tremelimumab alone or in combination with low-dose or hypofractionated targeted radiotherapy in metastatic non-small cell lung cancer refractory to prior PD(L)-1 therapy: a multicentre, open-label, randomised, phase 2 trial
No full textBACKGROUND: Patients with PD(L)-1 therapy resistant non-small cell lung cancer (NSCLC) have poor outcomes. Studies suggest radiotherapy may enhance anti-tumor immunity. Therefore, we investigated combined PD-L1 (durvalumab) and CTLA-4 inhibition (tremelimumab) alone or combined with radiation. METHODS: This multicentre, randomised, open-label phase 2 NCI Experimental Therapeutics Clinical Trials Network trial was conducted at 18 U.S. sites. Patients aged >=18 years with metastatic NSCLC, Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were randomised (1:1:1) using a permuted block scheme, without stratification to durvalumab/tremelimumab (1500mg/75mg every 4 weeks, 4 cycles, intravenous) alone (noRT) or with low-dose (LDFRT) or hypofractionated (HFRT) radiotherapy followed by durvalumab until 52 weeks or progression. The primary endpoint was the rate of complete/partial response in patients who initiated study treatment. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete. FINDINGS: 90 patients were randomised and 78 patients treated between 24 August 2017 and 29 March 2019. Median follow up was 12.4 months (IQR 7.8-15.1). There were no differences in response rates between the noRT arm (3 [11.5%] of 26, 90% CI 1.2-21.8) and the LDFRT (2 [7.7%] of 26, 0-16.3, p=0.64) or HFRT (3 [11.5%] of 26, 90% CI 1.2-21.8, p=0.99) arms. The most common grade 3-4 adverse event was dyspnea (2 [8%] of 26 NoRT, 3 [11%] LDFRT, and 3 [11%] HFRT). Serious adverse events occurred in 4 (15%, NoRT), 8 (31%, LDFRT) and 3 (12%, HFRT) patients. There was 1 grade-5 respiratory failure potentially related to therapy (LDFRT arm). INTERPRETATION: Radiation should not be used to increase response to PD-L1/CTLA-4 inhibition in PD(L)-1-resistant NSCLC patients. However, PD-L1/CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting. FUNDING: US National Institutes of Health, Dana-Farber Cancer Institut
Immune checkpoint inhibitor-associated risk for venous thromboembolism: a comprehensive analysis
No full textBackground The relationship between venous thromboembolism (VTE) and immune checkpoint inhibitor therapy (ICI) is unclear. This analysis investigates the incidence of and risk factors for VTE in VTE-naive patients with cancer receiving ICI treatment.Methods A retrospective cohort study of patients receiving any type or combination of ICI from 2009 to 2022 at Dana-Farber Cancer Institute was conducted to identify VTE occurring after initiation of ICI treatment. Cumulative incidences of VTE were determined using Fine and Gray’s methods. Associations between VTE, ICI regimens, and clinical risk factors were evaluated using propensity-score stratified, multivariable Cox proportional hazards models.Results In 10,638 patients without a prior history of VTE, the 6-month cumulative incidence of VTE was 7.6% (95% CI: 7.1% to 8.1%) and 11.1% (95% CI: 10.5% to 11.8%) at 12 months. Clinical risk factors included: age 15–59 (HR 1.27; 95% CI: 1.12 to 1.43; p=0.002), obesity (HR: 1.41; 95% CI: 1.16 to 1.71), and history of anticoagulation prior to ICI start (HR: 1.43; 95% CI: 1.26 to 1.61). Compared with pembrolizumab, treatment with ipilimumab/nivolumab increased the risk of VTE (HR: 1.36; 95% CI: 1.02 to 1.82), while durvalumab conveyed lower risk (HR: 0.52; 95% CI: 0.31 to 0.87). Treatment with programmed cell death ligand 1 had significantly reduced risk of VTE (HR: 0.79; 95% CI: 0.63 to 0.99) compared with programmed cell death 1 monotherapy. Dual ICI blockade with cytotoxic T lymphocyte antigen 4/PD-1 significantly increased the risk of VTE (HR: 1.43; 95% CI 1.12 to 1.84). Initiation of anticoagulation after starting ICI for indications other than VTE reduced the risk by 40% (HR: 0.60, 95% CI: 0.48 to 0.73).Conclusions ICI treatment appears to be independently associated with a high incidence of VTE in patients with cancer warranting further investigation
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