The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities ...primarily online. The open innovation platform titled “International Natural Product Sciences Taskforce” (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools.
In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week “2021 INPST Twitter Networking Event” (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST.
The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events.
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Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and ...metastasis
. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.
Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain–related gene A, ...MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio HR, 1.83; 95% confidence interval CI, 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.
•Matching for MICA significantly reduces the incidence of acute and chronic GVHD in otherwise HLA 10/10-matched unrelated-donor HCT.•Our results formally define MICA as a novel major histocompatibility complex-encoded human transplantation antigen.
Biopsies taken at deceased donor kidney procurement continue to be cited as a leading reason for discard; however, the reproducibility and prognostic capability of these biopsies are controversial.
...We compiled a retrospective, single-institution, continuous cohort of deceased donor kidney transplants performed from 2006 to 2009. Procurement biopsy information-percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease-was obtained from the national transplant database. Using univariable, multivariable, and time-to-event analyses for death-censored graft survival, we compared procurement frozen section biopsy reports with reperfusion paraffin-embedded biopsies read by trained kidney pathologists (
=270). We also examined agreement for sequential procurement biopsies performed on the same kidney (
=116 kidneys).
For kidneys on which more than one procurement biopsy was performed (
=116), category agreement was found in only 64% of cases (
=0.14). For all kidneys (
=270), correlation between procurement and reperfusion biopsies was poor: overall, biopsies were classified into the same category (optimal versus suboptimal) in only 64% of cases (
=0.25). This discrepancy was most pronounced when categorizing percentage of glomerulosclerosis, which had 63% agreement (
=0.15). Interstitial fibrosis/tubular atrophy and vascular disease had agreement rates of 82% (
=0.13) and 80% (
=0.15), respectively. Ninety-eight (36%) recipients died, and 56 (21%) allografts failed by the end of follow-up. Reperfusion biopsies were more prognostic than procurement biopsies (hazard ratio for graft failure, 2.02; 95% confidence interval, 1.09 to 3.74 versus hazard ratio for graft failure, 1.30; 95% confidence interval, 0.61 to 2.76), with procurement biopsies not significantly associated with graft failure.
We found that procurement biopsies are poorly reproducible, do not correlate well with paraffin-embedded reperfusion biopsies, and are not significantly associated with transplant outcomes.
Melorheostosis is a very rare sclerosing bone dysplasia characterized by asymmetrical and progressive cortical hyperostosis, usually with involvement of soft tissues surrounding the lesions. Recently ...Kang et al. identified somatic mosaicism for variants (p.Gln56Pro, p.Lys57Asn, or p.Lys57Glu) in the negative regulatory domain of MAP2K1, resulting in increased ERK1/2 signalling in affected tissues. In our study, we employed several sequencing technologies to unravel genetic variants (only present in affected tissues) from four sporadic melorheostosis patients. In the exome of two patients, we identified the same variants (p.K57N and p.K57E) as previously described by Kang et al. WGS and RNAseq analysis in a third patient demonstrated the presence of a novel variant (p.Cys121Ser) in the catalytic domain of MAP2K1. In addition, gene set enrichment analysis of the transcriptome data demonstrated upregulation of proliferative pathways. Interestingly, increased proliferation of MAP2K1 p.Lys57Asn-positive osteoblasts has been reported by Kang et al. The variants located in the hotspot region of the negative regulatory domain as well as this newly identified p.Cys121Ser variant have all been classified as MAP2K1 variants that can constitutively activate the downstream effector Erk. Finally, in a fourth patient with classical radiographic features of melorheostosis, no pathogenic variants could be identified in MAP2K1 or the other candidate genes for melorheostosis (SMAD3; LEMD3; KRAS). In conclusion, our study strongly suggests that not only somatic variants in the regulatory domain of MAP2K1 but also in the catalytic domain can cause melorheostosis. Our observations confirm that mutations in MAP2K1 are a major cause of melorheostosis and also suggest further locus heterogeneity for this disorder.
•In 3/4 patients with melorheostosis a somatic causal variant in MAP2K1 was found.•The catalytic domain of MAP2K1 is also important for melorheostosis.•Evidence for a third locus for melorheostosis•GSEA of transcriptome data underscores the pathogenicity of the p.Cys121Ser variant.
Unfavorable histology on procurement biopsies is the most common reason for deceased donor kidney discard. We sought to assess the reproducibility of procurement biopsy findings.
We compiled a ...continuous cohort of deceased donor kidneys transplanted at our institution from 1/1/2006 to 12/31/2016 that had at least one procurement biopsy performed, and excluded cases with missing biopsy reports and those used in multiorgan transplants. Suboptimal histology was defined as the presence of advanced sclerosis in greater than or equal to one biopsy compartment (glomeruli, tubules/interstitium, vessels). We calculated
coefficients to assess agreement in optimal versus suboptimal classification between sequential biopsy reports for kidneys that underwent multiple procurement biopsies and used time-to-event analysis to evaluate the association between first versus second biopsies and patient and allograft survival.
Of the 1011 kidneys included in our cohort, 606 (60%) had multiple procurement biopsies; 98% had first biopsy performed at another organ procurement organization and their second biopsy performed locally. Categorical agreement was highest for vascular disease (
=0.17) followed by interstitial fibrosis and tubular atrophy (
=0.12) and glomerulosclerosis (
=0.12). Overall histologic agreement (optimal versus suboptimal) was
=0.15. First biopsy histology had no association with allograft survival in unadjusted or adjusted analyses. However, second biopsy optimal histology was associated with a higher probability of death-censored allograft survival, even after adjusting for donor and recipient factors (adjusted hazard ratio, 0.50; 95% confidence interval, 0.34 to 0.75;
=0.001).
Deceased donor kidneys that underwent multiple procurement biopsies often displayed substantial differences in histologic categorization in sequential biopsies, and there was no association between first biopsy findings and post-transplant outcomes.
The role of reduced intensity allogeneic stem cell transplantation for the treatment of relapsed/refractory Hodgkin's lymphoma remains controversial. We retrospectively analyzed 191 patients who ...underwent reduced intensity allogeneic stem cell transplantation between 1998 and 2008 for relapsed or refractory Hodgkin's lymphoma and whose data were reported to the French registry. The median follow-up was 36 months. The estimated 3-year overall survival rate, progression-free survival rate, cumulative incidence of relapse and cumulative incidence of non-relapse mortality were 63%, 39%, 46%, and 16%, respectively. There was no difference in outcome between patients in complete response and in partial response at the time of transplantation with regards to overall survival (70% versus 74%, no significant difference) and progression-free survival (51% versus 42%, no significant difference). Patients with chemoresistant disease had a shorter overall survival (39% at 3 years; P=0.0003) and progression-free survival (18% at 3 years; P=0.001) than patients in complete remission. The use of umbilical cord blood as the source of stem cells was associated with a poor outcome with an increased risk of death with a hazard ratio of 3.49 (95% confidence interval: 1.26 to 9.63; P=0.016). The use of peripheral blood was associated with a better outcome for patients who where alive 1 year after transplantation with a hazard ratio of 0.38 (95% confidence interval: 0.17 to 0.83; P=0.016). Disease status at transplantation remains the most important risk factor for outcome. Our data suggest that the use of peripheral blood should be preferred whereas umbilical cord blood should be used with caution.
Abstract
Background
Invasive mucormycosis (IM) is associated with high mortality and morbidity. MAT2203 is an encochleated oral formulation of amphotericin B which has been shown to be safe and ...effective against murine aspergillosis and murine cryptococcal meningoencephalitis. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM.
Methods
ICR mice were immunosuppressed with cyclophosphamide and cortisone acetate on days -2, -3 and +8, relative to infection with intratracheally instilled Rhizopus delemar 99-880 or M. circinelloides f. jenssenii DI15-131. Treatment with placebo (diluent control), oral MAT2203 (5 to 45 mg/kg, given qd or bid for 7 days) or LAMB (10 mg/kg, iv, qd for 4 days), began 16 h post infection. Survival (n=10-20/group from 1/2 experiments) through Day +21 and tissue fungal burden of lungs or brain (n=10/group) euthanized on Day +4 post infection (conidial equivalents using qPCR) served as a primary and secondary endpoint, respectively.
Results
For Rhizopus delemar infection, doses of MAT2203 5,15 mg/kg qd or 7.5 mg/kg bid, significantly prolonged median survival time (MST) and enhanced overall survival vs. placebo-treated mice (MST of 9 Days and 0% survival for placebo-treated mice vs. 13 Days, and 20-40% for MAT2203 doses, P< 0.05 by Log-Rank). Importantly, MAT2203 treatments were as effective as LAMB (MST of 16 days and overall survival of 45%). For mice infected with M. circinelloides, MAT2203 at 15 mg/kg, qd significantly prolonged MST and enhanced overall survival vs. placebo-treated mice (MST of 5 Days and 0% survival, for placebo-treated mice vs. 13.5 Days and 50% survival for MAT2203, P< 0.05). In both infection models MAT2203 treatment of 15 mg/kg or LAMB resulted in significant ∼1.0-1.5 log reduction and ∼2.0-2.2 log reduction in lung and brain fungal burden vs. placebo, respectively (Wilcoxon Rank Sum).
Conclusion
MAT2203 demonstrated in vivo efficacy in treating R. delemar or M. circinelloides pulmonary infection in immunosuppressed mice, which was equivalent to the LAMB current standard of care. Continued investigation and development of MAT2203 as a novel, and oral formulation of amphotericin antifungal agent against mucormycosis is warranted.
Disclosures
Theresa Matkovits, PhD, Matinas BioPharma: Employee Jenel Cobb, PhD, Matinas BioPharma: Employee Raphael J. Mannino, PhD, Matinas BioPharma: Employee Ashraf S. Ibrahim, PhD, Matinas BioPharma: Advisor/Consultant|Matinas BioPharma: Grant/Research Support|SFunga: Grant/Research Support.
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