Sphingobacterium spiritivorum bacteremia due to cellulitis in an elderly man with chronic obstructive pulmonary disease and congestive heart failure: a case report

Sphingobacterium spiritivorum is a glucose non-fermenting Gram-negative rod, formerly classified as one of the Flavobacterium species. It is characterized by a large number of cellular...

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Overt Skeletal Metastases in a Patient of Occult (Microscopic) Follicular Thyroid Carcinoma: a Rare Case

Abstract

Occult follicular thyroid carcinoma (FTC) presenting as distant metastases is a rare occurrence. However, despite being occult in majority of these cases, primary tumor can be detected on thyroid imaging or during surgery. Here, we present an extremely rare case of an occult FTC with overt skeletal metastases in which primary tumor was discernible only on microscopic examination.

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Overt Skeletal Metastases in a Patient of Occult (Microscopic) Follicular Thyroid Carcinoma: a Rare Case

Abstract

Occult follicular thyroid carcinoma (FTC) presenting as distant metastases is a rare occurrence. However, despite being occult in majority of these cases, primary tumor can be detected on thyroid imaging or during surgery. Here, we present an extremely rare case of an occult FTC with overt skeletal metastases in which primary tumor was discernible only on microscopic examination.

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MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Timothy S. Cliff, Tianming Wu, Benjamin R. Boward, Amelia Yin, Hang Yin, John N. Glushka, James H. Prestegaard, Stephen Dalton
As human pluripotent stem cells (hPSCs) exit pluripotency, they are thought to switch from a glycolytic mode of energy generation to one more dependent on oxidative phosphorylation. Here we show that, although metabolic switching occurs during early mesoderm and endoderm differentiation, high glycolytic flux is maintained and, in fact, essential during early ectoderm specification. The elevated glycolysis observed in hPSCs requires elevated MYC/MYCN activity. Metabolic switching during endodermal and mesodermal differentiation coincides with a reduction in MYC/MYCN and can be reversed by ectopically restoring MYC activity. During early ectodermal differentiation, sustained MYCN activity maintains the transcription of "switch" genes that are rate-limiting for metabolic activity and lineage commitment. Our work, therefore, shows that metabolic switching is lineage-specific and not a required step for exit of pluripotency in hPSCs and identifies MYC and MYCN as developmental regulators that couple metabolism to pluripotency and cell fate determination.

Graphical abstract

Teaser

Cliff et al. show that, contrary to prior understanding, a metabolic switch away from glycolysis is not a required step for human pluripotent stem cell differentiation, and that, in fact, differentiation to ectoderm requires maintenance of high glycolytic flux via MYC/MYCN activity, indicating its role as a developmental regulator.


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Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Maria Kleppe, Matthew H. Spitzer, Sheng Li, Corinne E. Hill, Lauren Dong, Efthymia Papalexi, Sofie De Groote, Robert L. Bowman, Matthew Keller, Priya Koppikar, Franck T. Rapaport, Julie Teruya-Feldstein, Jorge Gandara, Christopher E. Mason, Garry P. Nolan, Ross L. Levine
JAK1 is a critical effector of pro-inflammatory cytokine signaling and plays important roles in immune function, while abnormal JAK1 activity has been linked to immunological and neoplastic diseases. Specific functions of JAK1 in the context of hematopoiesis, and specifically within hematopoietic stem cells (HSCs), have not clearly been delineated. Here, we show that conditional Jak1 loss in HSCs reduces their self-renewal and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient HSCs exhibit decreased competitiveness in vivo and are unable to rescue hematopoiesis in the setting of myelosuppression. They exhibit increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and a marked reduction in cytokine sensing, including in response to type I interferons and IL-3. Moreover, Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Together, these data highlight an essential role for Jak1 in HSC homeostasis and stress responses.

Graphical abstract

Teaser

Selective JAK1 inhibition has emerged as a potential strategy for treating autoimmune and hematological diseases. Levine and colleagues show that Jak1 integrates multiple cytokine signals in normal and malignant HSCs to regulate their self-renewal and quiescence, highlighting further potential therapeutic benefits and risks of Jak1 inhibition.


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Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Anjali Jacob, Michael Morley, Finn Hawkins, Katherine B. McCauley, J.C. Jean, Hillary Heins, Cheng-Lun Na, Timothy E. Weaver, Marall Vedaie, Killian Hurley, Anne Hinds, Scott J. Russo, Seunghyi Kook, William Zacharias, Matthias Ochs, Katrina Traber, Lee J. Quinton, Ana Crane, Brian R. Davis, Frances V. White, Jennifer Wambach, Jeffrey A. Whitsett, F. Sessions Cole, Edward E. Morrisey, Susan H. Guttentag, Michael F. Beers, Darrell N. Kotton
Lung alveoli, which are unique to air-breathing organisms, have been challenging to generate from pluripotent stem cells (PSCs) in part because there are limited model systems available to provide the necessary developmental roadmaps for in vitro differentiation. Here we report the generation of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, from human PSCs. Using multicolored fluorescent reporter lines, we track and purify human SFTPC+ alveolar progenitors as they emerge from endodermal precursors in response to stimulation of Wnt and FGF signaling. Purified PSC-derived SFTPC+ cells form monolayered epithelial "alveolospheres" in 3D cultures without the need for mesenchymal support, exhibit self-renewal capacity, and display additional AEC2 functional capacities. Footprint-free CRISPR-based gene correction of PSCs derived from patients carrying a homozygous surfactant mutation (SFTPB^121ins2) restores surfactant processing in AEC2s. Thus, PSC-derived AEC2s provide a platform for disease modeling and future functional regeneration of the distal lung.

Graphical abstract

Teaser

Jacob et al. differentiate human pluripotent stem cells (PSCs) into type II alveolar cells (iAEC2s). They find that iAEC2s display many of the functions, transcriptomic features, and surfactant-processing capacities that characterize primary cells. Finally, they derive AEC2s from gene-edited, patient-specific PSCs to model surfactant protein B deficiency in vitro.


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The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Alexander M.M. Eggermont, Reinhard Dummer
The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C–IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node–positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.



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