Johns Hopkins University School of Medicine

About: Johns Hopkins University School of Medicine is a healthcare organization based out in Baltimore, Maryland, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 44277 authors who have published 79222 publications receiving 4788882 citations.

Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity.

Abstract: The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.

MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2.

Abstract: During their lifespan, immature cells normally pass through sequential transitions to a differentiated state and eventually undergo cell death. This progression is aberrant in cancer, although the transition to differentiation can be reestablished in inducible leukemia cell lines. This report describes a gene, MCL1, that we isolated from the ML-1 human myeloid leukemia cell line during phorbol ester-induced differentiation along the monocyte/macrophage pathway. Our results demonstrate that expression of MCL1 increases early in the induction, or "programming," of differentiation in ML-1 (at 1-3 hr), before the appearance of differentiation markers and mature morphology (at 1-3 days). They further show that MCL1 has sequence similarity to BCL2, a gene involved in normal lymphoid development and in lymphomas with the t(14;18) chromosome translocation. MCL1 and BCL2 do not fall into previously known gene families. BCL2 differs from many oncogenes in that it inhibits programmed cell death, promoting viability rather than proliferation; this parallels the association of MCL1 with the programming of differentiation and concomitant maintenance of viability but not proliferation. Thus, in contrast to proliferation-associated genes, expression of MCL1 and BCL2 relates to the programming of differentiation and cell viability/death. The discovery of MCL1 broadens our perspective on an emerging MCL1/BCL2 gene family and will allow further comparison with oncogene families.

Sound- and/or Pressure-Induced Vertigo Due to Bone Dehiscence of the Superior Semicircular Canal

Abstract: Objectives: To present symptoms, patterns of nystagmus, and computed tomographic scan identification of patients with sound- and/or pressure-induced vertigo due to dehiscence of bone overlying the superior semicircular canal. To describe anatomical findings and outcome in 2 patients undergoing plugging of the superior semicircular canal for treatment of these symptoms. Design and Setting: Prospective study of a case series in a tertiary care referral center. Patients and Results: Eight patients with vertigo, oscillopsia, and/or disequilibrium related to sound, changes in middle ear pressure, and/or changes in intracranial pressure were identified in a 2-year period. Seven of these patients also had vertical-torsional eye movements induced by these sound and/or pressure stimuli. The direction of the evoked eye movements could be explained by excitation or inhibition of the superior semicircular canal in the affected ear. Computed tomographic scans of the temporal bones identified dehiscence of bone overlying the affected superior semicircular canal in each case. Disabling disequilibrium in 2 patients prompted plugging of the dehiscent superior canal through a middle cranial fossa approach. Symptoms were improved in each case. One patient developed recurrent symptoms requiring an additional plugging procedure and developed sensorineural hearing loss several days after this second procedure. Conclusions: We have identified patients with a syndrome of vestibular symptoms induced by sound in an ear or by changes in middle ear or intracranial pressure. These patients can also experience chronic disequilibrium. Eye movements in the plane parallel to that of the superior semicircular canal were evoked by stimuli that have the potential to cause ampullofugal or ampullopetal deflection of this canal’s cupula in the presence of a dehiscence of bone overlying the canal. The existence of such deshiscences was confirmed with computed tomographic scans of the temporal bones. Surgical plugging of the affected canal may be beneficial in patients with disabling symptoms.

MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1

Abstract: Adhesion molecules expressed by activated endothelial cells play a key role in regulating leukocyte trafficking to sites of inflammation. Resting endothelial cells normally do not express adhesion molecules, but cytokines activate endothelial cells to express adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1), which mediate leukocyte adherence to endothelial cells. We now show that endothelial cells express microRNA 126 (miR-126), which inhibits VCAM-1 expression. Transfection of endothelial cells with an oligonucleotide that decreases miR-126 permits an increase in TNF-α-stimulated VCAM-1 expression. Conversely, overexpression of the precursor to miR-126 increases miR-126 levels and decreases VCAM-1 expression. Additionally, decreasing endogenous miR-126 levels increases leukocyte adherence to endothelial cells. These data suggest that microRNA can regulate adhesion molecule expression and may provide additional control of vascular inflammation.