Jared Rosenblum

Neurosimplicity LLC

Paediatric phaeochromocytomas and paragangliomas (PPGLs), though rare tumours, are associated with significant disability and death in the most vulnerable of patients early in their lives. However, unlike cryptogenic and insidious disease states, the clinical presentation of paediatric patients with PPGLs can be rather overt, allowing early diagnos...

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease. We s...

This article is a summary of the plenary lecture presented by Jared Rosenblum MD that was awarded the Manger Prize at the 6th International Symposium on Pheochromocytoma/paraganglioma held on October 22-25, 2022 in Prague, Czech Republic. Herein, review our initial identification of a new syndrome of multiple paragangliomas, somatostatinomas, and p...

Mapping cranial vasculature and adjacent neurovascular interfaces in their entirety will enhance our understanding of central nervous system function in any physiologic state. We present a workflow to visualize in situ murine vasculature and surrounding cranial structures using terminal polymer casting of vessels, iterative sample processing and im...

Originally approved in 1979, a specific grading classification for central nervous system (CNS) tumors was devised by the World Health Organization (WHO) in an effort to guide cancer treatment and better understand prognosis. These “blue books” have since undergone several iterations based on tumor location, advancements in histopathology, and most...

Carrimycin is a synthetic macrolide antibiotic that has been shown to have anti-cancer activity; however, its exact mechanism of action and molecular target were previously unknown. It was recently elucidated that Isovalerylspiramycin I (ISP I), the active component of carrimycin, targets selenoprotein H (SelH), a nucleolar reactive oxygen species-...

BACKGROUND Reports of cerebrovascular ischemia and stroke occurring as predominant neurological sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), are increasingly evident within the literature. While various pathophysiological mechanisms have been postulated, includ...

A 13-year-old male presented with a 10-day history of left eye swelling and pain. These symptoms prompted presentation to the emergency department. He had no significant past medical history and no preceding fevers or chills. He was found on examination of the eyes and the orbit to have left supraorbital erythema, edema, and pain with upward and me...

Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization. Protein phosphatase 2A (PP2A) is highly conserved and is the predominant serine/threonine phosphatase in the nervous system, constituting more than 70% of all neuronal phosphatases. PP2A is involved in diverse re...

Pediatric medulloblastoma (MB) is the most common pediatric brain tumor with varying prognoses depending on the distinct molecular subtype. The four consensus subgroups are WNT, Sonic hedgehog (SHH), Group 3, and Group 4, which underpin the current 2021 WHO classification of MB. While the field of knowledge for treating this disease has significant...

Chiari Malformation Type I (CMI) is a congenital malformation diagnosed by MRI findings of at least 5 mm of cerebellar ectopy below the foramen magnum. CM1 is frequently associated with syringomyelia. Herein, we discuss the history of CMI and syringomyelia, including early pathological and surgical studies. We also describe recent investigations in...

Understanding physiologic and pathologic central nervous system function depends on our ability to map the entire in situ cranial vasculature and neurovascular interfaces. To accomplish this, we developed a non-invasive workflow to visualize murine cranial vasculature via polymer casting of vessels, iterative sample processing and micro-computed to...

Human endogenous retroviruses (HERVs), which are critical to normal embryologic development and downregulated during normal maturation, have been implicated in a variety of cancers. Abnormal persistent production of HERVs has been suggested to play a role in oncogenesis and to confer stem cell properties to cells. We recently demonstrated that the...

Atypical teratoid rhabdoid tumor (ATRT) is a pediatric brain tumor with a high mortality rate characterized by mutations in/ deletions of SWI/SNF matrix-associated actin-dependent regulator of chromatin sub-family B member 1 (SMARCB1). We previously showed that loss of SMARCB1 causes up-regulation and release of HML-2 subfamily of human endogenous...

We recently described a previously unknown trans-tentorial venous system (TTVS) connecting venous drainage throughout the brain in humans. Prior to this finding, it was believed that the embryologic tentorial plexus regresses, resulting in a largely avascular tentorium. Our finding contradicted this understanding and necessitated further investigat...

The inner ear is a complex organ housed within the petrous bone of the skull. Its intimate relationship with the brain enables the transmission of auditory and vestibular signals via cranial nerves. Development of this structure from neural crest begins in utero and continues into early adulthood. However, the anatomy of the murine inner ear has on...

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1 , a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human gen...

Quantifying terabyte-scale multi-modal human and animal imaging data requires scalable analysis tools. We developed CloudReg, an open-source, automatic, terabyte-scale, cloud-based image analysis pipeline that pre-processes and registers cross-modal volumetric datasets with artifacts via spatially-varying polynomial intensity transform. CloudReg ac...

EPAS1, encoding HIF-2α, mutations were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to our institution for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS...

INTRODUCTION Germ line (CCM1-3) and somatic (KRAS, BRAF) mutations were identified in patients with congenital cavernous and sporadic arteriovenous malformations, respectively. We hypothesized that patients with a syndrome of paraganglioma, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation in the gene EPAS1, encoding...

BACKGROUND AND PURPOSE: A new transtentorial venous system consisting of medial, intermediate, and lateral tentorial veins, connecting infra- and supratentorial compartments, was recently shown in 2 cadaver dissections and 2 patient scans. We sought to characterize the venous patterns within the tentorium and their relation to measures of skull dev...

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias...

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the...

Introduction: Recently, we described a trans-tentorial venous system consisting of the medial, intermediate, and lateral tentorial veins, connecting infra- and supratentorial compartments in two cadaver dissections and two patient scans. Based on this, we investigated tentorial venous anatomy in a larger normal population. Methods: Tentorial venous...

Introduction: We previously reported two cases of Chiari I malformation with spina bifida occulta in a EPAS1- gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia. This syndrome is caused by somatic, post-zygotic, gain-of-function mutation of EPAS1, encoding hypoxia-inducible factor-2-alpha; (HIF-2...

Objective To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 ( EPAS1 ) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and pol...

Chimeric antigen receptor (CAR)-engineered T cells represent a promising modality for treating glioblastoma. Recently, we demonstrated that CAR-T cells targeting carbonic anhydrase IX (CAIX), a protein involved in HIF-1a hypoxic signaling, is a promising CAR-T cell target in an intracranial murine glioblastoma model. Anti-CAIX CAR-T cell therapy is...

Heat shock protein 90 (HSP-90) has been identified in many disease processes including cancer, neurodegeneration, autoimmune diseases, and cancers. Great effort has been expended in the development of specific inhibitors of the N-terminal and C-terminal domains. Inhibitors of post-translational modification have also been developed. Herein, we expl...

OBJECTIVE Patients with neurofibromatosis type 1 (NF1) are predisposed to visceral neurofibromas, some of which can progress to premalignant atypical neurofibromas (ANFs) and malignant peripheral nerve sheath tumors (MPNSTs). Though subtotal resection of ANF may prevent malignant transformation and thus deaths with no neural complications, local re...

Patients with von Hippel Lindau (VHL) disease develop multiple central nervous system hemangioblastomas (HB). The surgical resection of VHL-HBs is the standard of clinical care when these HBs become symptomatic due to tumor growth, edema, or cyst formation. VHL-HBs frequently present at the obex of the brainstem, making this a challenging surgical...

Hepatocellular carcinoma (HCC) is a terminal, yet preventable, outcome of untreated infection with hepatitis B virus (HBV). HBV is endemic in many areas of Latin America and the Caribbean, including Haiti. Haitians have the highest incidence of liver cancer among Caribbean immigrants. Unfortunately, many of these patients are not screened, despite...

INTRODUCTION Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas (NF), which can progress to premalignant atypical neurofibromas (ANF) and malignant peripheral nerve sheath tumors (MPNST). Subtotal resection of ANF may prevent metastases and deaths, but local recurrences require reoperation. Here, we assess the surgical morbidi...

Background: Glioblastoma survival remains unchanged despite continuing therapeutic innovation. Herein, we aim to 1) develop CAR-T cells with a specificity to a unique antigen, carbonic anhydrase IX (CAIX), which is expressed in the hypoxic microenvironment characteristic of glioblastoma, and 2) demonstrate its efficacy with limited off-target effe...

Background: Described variations of tentorial venous anatomy impact surgical sectioning of the tentorium in skull base approaches; however, described configurations do not consistently explain post-operative complications. To understand the outcomes of two clinical cases we studied the tentorial venous anatomy of two cadavers. Methods: The venous a...

The need for novel therapies for glioblastoma multiforme (GBM) is well established. Chimeric antigen receptor (CAR)-engineered T cells represent a promising cancer treatment modality for treating GBM. However, CAR-T therapy has limitations, such as low penetration into solid tumors and short duration of CAR-T survival. Protein phosphatase 2A (PP2A)...

A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of EPAS1, encoding HIF-2α, was previously described. HIF-2α has been implicated in endochondral and intramembranous ossification. Abnormal bone growth of the skull base may lead to Chiari malformation type I. We...

Elevated expression of lncRNA H19 (H19) in the setting of hypoxia has been implicated as a promising therapeutic target for various cancers. However, little is known about the impact and underlying mechanism of H19 in ischemic brain stroke. This study found that H19 levels were elevated in the serum of stroke patients, as well as in the ischemic pe...

We previously identified a novel syndrome in patients characterized by paraganglioma, somatostatinoma, and polycythemia. In these patients, polycythemia occurs long before any tumor develops, and tumor removal only partially corrects polycythemia, with recurrence occurring shortly after surgery. Genetic mosaicism of gain-of-function mutations of th...

Introduction : The skull base surgeon may need to manipulate or section the tentorium to widen the surgical corridor. Few studies have examined tentorial venous anatomy and how surgical maneuvers might affect it. Described medial and lateral tentorial sinus configurations inadequately explain intraoperative tentorial vascularity and postoperative c...

Introduction: We previously identified a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia resulting from mosaic gain-of-function EPAS1 mutation, Pacak-Zhuang syndrome. HIF2A, the product of EPAS1, is critical to development, particularly at regions of pseudo-hypoxia, such as the endocardial cushion and the dural venous field....

BACKGROUND The need for novel therapies for GBM treatment is well established. While chimeric antigen receptor (CAR)-engineered T cells represent a promising cancer treatment modality, highly expressed unique cell surface antigens are essential. We postulated that tumor-specific surface antigens related to hypoxia signaling may have potential. Carb...

Previously we identified the p.Thr61Ile mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in a Chinese family with autosomal dominant Parkinson's disease. But the mechanism is still unclear. In this study, we explored the effects of CHCHD2 p.Thr61Ile mutation in cells and its association with coiled-coil-helix-coiled-coil...

Primary adenocarcinoma of the small intestine comprises one of the rarest gastrointestinal malignancies. Further, the terminal ileum is very seldom implicated. This entity occurs sporadically and evades traditional colonoscopic evaluation in which the terminal ileum is not visualized. Herein, a case of interval development of primary terminal ileal...

Background Several cases of Hypertrophic olivary degeneration (HOD) have been reported, none directly following interval bleed of a stable midbrain-pontine cavernous angioma (CA). HOD is a rare phenomenon in the dento-rubro-olivary pathway first described by Oppenheim in 1887. It is a an uncommon condition and creates unique diagnostic, observation...

Background: Hypertrophic olivary degeneration (HOD) is a rare phenomenon in the dento-rubro-olivary pathway due to lesion or disruption of the fibers of the Guillain-Mollaret Triangle. Hemorrhage of pontine and midbrain cavernous angiomas rarely can lead to hypertrophic olivary degeneration (HOD) portending neurological deterioration and possible...

Purpose Radiographic evaluation of a series of brachial plexopathies and comparison to normal anatomy. Materials and Methods Evaluation of the cervical spine and brachial plexus was performed using various modalities including PET, CT and MRI. Patients ranged from neonate to 7th decade. Conclusion This presentation illustrates a spectrum of brachia...

Cyclin dependent kinase-5 (cdk5) was the focus of our last update on neuronal signal transduction wherein its role in neuronal signal transduction was reviewed in the context of spatial and temporal co-localization, or cross-talk, with other pathways and subsequent regulation. This cross-talk was shown to regulate synaptic activity, neuronal system...

Cyclin dependent kinase-5 (cdk5) belongs to the family of cyclin dependent kinases (cdks) based on its sequence homology, varying between 60-70 percent, with the other cdks. However, its activity is primarily restricted to neuronal cells. It is activated by neuron-specific molecules p35 and p39 with molecular weights of 35kD and 39kD, respectively,...