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Patients with relapsed/refractory germ cell tumors (GCT) have limited treatment options and poor survival outcomes. We describe our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) as an outpatient regimen for 35 patients with relapsed/refractory GCT between 2017 and 2022. Twenty-four patients received nonpalliative intent ATP, with a median of 2 lines of prior therapy, 23 (96%) having received at least 1 cisplatin-based regimen and 1 (4%) with a prior stem cell transplant. The objective response rate for the nonpalliative intent cohort was 37.5% (1 complete response and 8 partial responses). Post-ATP, 12 patients underwent stem cell transplant, 7 patients had surgical resections, and 4 patients received radiation. The median PFS was 4.3 months (95% CI: 3.8, 32.7) and median OS of 13.1 months (95% CI: 10.7, NA) for the nonpalliative intent cohort. Eleven patients received palliative intent ATP, with a median of 4 lines of prior therapy, all having received at least 1 cisplatin-based regimen, and 7 (64%) having received prior stem cell transplants. Within the palliative intent cohort, the objective response rate was 9% (1 partial response). Patients who received palliative intent ATP had a median PFS of 0.92 months (95% CI 0.46, NA) and median OS of 5.2 months (95% CI 3.3, NA). Treatment toxicities occurred in 5 (14%) patients who required dose reductions and 5 (14%) patients who were admitted for treatment related toxicities, most commonly for myelosuppression. Our results support the use of ATP in a primarily anthracycline naïve patient population and show the safety of continued cisplatin use in patients who have previously received cisplatin-based regimens. Therefore, ATP is a feasible and well tolerated chemotherapy regimen in the salvage setting and can serve as a bridge to other treatments for patients with relapsed/refractory GCT. We report our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) in 35 patients with relapsed/refractory germ cell tumors (GCT) between 2017-2022. In the non-palliative intent cohort, the objective response rate was 37.5% (median PFS 4.3 months, median OS 13.1 months), while in the palliative intent cohort, the response rate was 9% (median PFS 0.92 months, median OS 5.2 months). ATP is a feasible, well-tolerated salvage regimen. [ABSTRACT FROM AUTHOR]

Comprehensive bioinformatic analysis and filtering techniques are employed to identify a single-nucleotide coding variant in the feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) which causes posterior column ataxia and retinitis pigmentosa (PCARP). The findings for aberrant FLVCR1 which causes a selective degeneration of a subpopulation of neurons in the retina and the posterior columns of the spinal cord via dysregulation of heme or iron homeostasis provide better insight into the molecular basis of sensory neural signaling to include common mechanisms that involve proprioception and vision.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.11.018 Byline: Carl P. Wonders (a), Lauren Taylor (b), Jelle Welagen (b), Ihunanya C. Mbata (c), Jenny Z. Xiang (d), Stewart A. Anderson (b) Keywords: MGE; Somatostatin; Parvalbumin; Microarray; Interneuron subtypes Abstract: Although it is well established that the ventral telencephalon is the primary source of GABAergic cortical interneurons in rodents, little is known about the specification of specific interneuron subtypes. It is also unclear whether the potential to achieve a given fate is established at their place of origin or by signals received during their migration to or during their maturation within the cerebral cortex. Using both in vivo and in vitro transplantation techniques, we find that two major interneuron subgroups have largely distinct origins within the MGE. Somatostatin (SST)-expressing interneurons are primarily generated within the dorsal MGE, while parvalbumin (PV)-expressing interneurons primarily originate from the ventral MGE. In addition, we show that significant heterogeneity exists between gene expression patterns in the dorsal and ventral MGE. These results suggest that, like the spinal cord, neuronal fate determination in the ventral telencephalon is largely the result of spatially segregated, molecularly distinct microdomains arranged on the dorsal-ventral axis. Author Affiliation: (a) Graduate Program in Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA (b) Department of Psychiatry, Weill Medical College of Cornell University, 1300 York Ave., Box 244, New York, NY 10021, USA (c) Gateways to the Laboratory Program, Weill Medical College of Cornell University, New York, NY 10021, USA (d) Departments of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA Article History: Received 19 December 2006; Revised 14 November 2007; Accepted 14 November 2007

Summary Genome-wide association studies (GWASs) have identified many disease-associated variant alleles, but understanding whether and how different genes/loci interact requires a platform for probing how the variant alleles act mechanistically. Isogenic mutant human embryonic stem cells (hESCs) provide an unlimited resource to derive and study human disease-relevant cells. Here, we focused on CDKAL1 , linked by GWASs to diabetes. Through transcript profiling, we find that expression of the metallothionein ( MT ) gene family, also linked by GWASs to diabetes, is significantly downregulated in CDKAL1 −/− cells that have been differentiated to insulin-expressing pancreatic beta-like cells. Forced MT1E expression rescues both hypersensitivity of CDKAL1 mutant cells to glycolipotoxicity and pancreatic beta-cell dysfunction in vitro and in vivo. MT1E functions at least in part through relief of ER stress. This study establishes an isogenic hESC-based platform to study the interaction of GWAS-identified diabetes gene variants and illuminate the molecular network impacting disease progression. [ABSTRACT FROM AUTHOR]

It is urgent to develop disease models to dissect mechanisms regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA sequencing (RNA-seq) analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting hypoxia inducible factor 1 subunit alpha (HIF1α), which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium. [Display omitted] • hPSC-derived airway organoids (hPSC-AOs) are permissive to SARS-CoV-2 infection • An hPSC-AO-based high content screen identifies GW6471 blocking SARS-CoV-2 infection • Chemical and genetic perturbation of HIF1α blocks SARS-CoV-2 infection • Glycolysis is necessary for SARS-CoV-2 infection of human airway epithelium Duan et al. develop an hPSC-derived airway organoid-based platform to monitor SARS-CoV-2 infection and screen for anti-viral drugs. From a high content chemical screen, they identify GW6471 that blocks SARS-CoV-2 infection in hPSC-derived airway organoids and hPSC-derived colonic organoids by inhibiting the HIF1α-glycolysis axis. [ABSTRACT FROM AUTHOR]

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans -integrated stress response inhibitor (trans -ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19. [Display omitted] • SARS-CoV-2 viral antigen is detected in beta cells of autopsies of COVID-19 subjects • SARS-CoV-2 infection causes beta cell transdifferentiation • SARS-CoV-2-induced beta cell transdifferentiation is mediated by eIF2 pathway • Trans -ISRIB reverses SARS-CoV-2 infection-induced beta cell transdifferentiation Here, Tang et al. reported the detection of SARS-CoV-2 viral antigen in autopsy samples from COVID-19 subjects. In addition, SARS-CoV-2 infection induces eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that can be reversed by trans -ISRIB. [ABSTRACT FROM AUTHOR]

[Display omitted] Store-operated calcium entry (SOCE) is essential for cellular signaling. Earlier studies of the pyrazole derivative BTP2, an efficient inhibitor SOCE, identified that SOCE blockade suppresses proinflammatory gene expression. The impact of SOCE blockade on gene expression at the whole transcriptome level, however, is unknown. To fill this gap, we performed RNA sequencing (RNA-seq) and investigated at the whole transcriptome level the effect of BTP2 on gene expression in human peripheral blood mononuclear cells signaled with phytohemagglutinin. Our global gene expression analysis identified that SOCE blockade spares activation-induced expression of anti-inflammatory genes (e.g., IL10, TGFB1, FOXP3, and CTLA4) whereas the induced expression of proinflammatory genes such as IFNG and cytopathic genes such as GZMB are inhibited. We validated the differential expression of immunoregulatory genes identified by RNA-seq using preamplification-enhanced RT-qPCR assays. Because IL-2/IL2RA interaction is essential for T cell clonal expansion, we investigated and confirmed that BTP2 inhibits IL2RA expression at the protein level using multiparameter flow cytometry. Our elucidation that SOCE blockade spares activation-induced expression of anti-inflammatory genes while blocking pro-inflammatory gene expression suggests that SOCE blockers may represent a novel class of immunoregulatory drugs of value for treating autoimmune disease states and organ transplantation. [ABSTRACT FROM AUTHOR]

The molecular drivers of classic Hodgkin Lymphoma (HL) underlying its pathologic and clinical distinctions from non-Hodgkin lymphoma (NHL) have been challenging to uncover. The study of HL has been impeded by the rarity of the Hodgkin Reed-Sternberg (HRS) cells within a dense tumor microenvironment. Previously, we developed a FACS approach to isolate the HRS cells and profiled their whole exomes and genomes. This work revealed a clonally-complex tumor, with no HRS-specific mutational signature, but rather mutations overlapping with those of NHL. This suggested that non-genetic factors such as the underlying cell state may cooperate with somatic mutations to induce HL. To assess this, we applied the Genotyping of Transcriptomes (GoT) platform, that links whole transcriptomes and somatic mutations within the same thousands of individual cells, to primary HL samples after FACS-isolation of HRS cells. We identified the expected cell types including immune and HRS cells. The HRS cells displayed highly heterogeneous cell states, like cycling or inflammatory states. Unexpectedly, we also identified an HRS state with features of neuronal-glial (NG) transdifferentiation. To assess the degree of heritability of the cell states, we integrated VDJ sequencing with GoT, whereby somatic hypermutations served as endogenous barcodes. Phylogenetic reconstructions revealed that HRS cell states were distributed across clades, unveiling a plastic interchange of cell states. Single nuclei ATAC-seq on HRS-enriched HL samples revealed that HRS cells displayed enhanced accessibility for binding motifs of NG transcription factors, revealing the regulators of the lineage infidelity program. Altogether, this single-cell multi-omics study indicated that an epigenetically encoded NG program may cooperate with lymphoma driving mutations to drive HL, paving novel avenues of therapy. [ABSTRACT FROM AUTHOR]

Summary: Microvascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. These libraries identify attributes that confer ECs with their organotypic features. We show that clusters of transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by ECs of each organ. Furthermore, ECs respond distinctly in tissue regeneration models, hepatectomy, and myeloablation. To test the data set, we developed a transplantation model that employs generic ECs differentiated from embryonic stem cells. Transplanted generic ECs engraft into regenerating tissues and acquire features of organotypic ECs. Collectively, we demonstrate the utility of informational databases of ECs toward uncovering the extravascular and intrinsic signals that define EC heterogeneity. These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration. [ABSTRACT FROM AUTHOR]