Background
Jeffrey A. Norton could have been a professional football player but instead he chose to pursue a career in medicine and in the process became an outstanding academic surgeon. This story ...recounts his ascent from a small town in Massachusetts to the pinnacle of academic surgery.
Methods
After graduating from high school in Albany, New York, Jeff continued his education at Dartmouth University, the State University of New York Upstate Medical University at Syracuse (SUNY Upstate Medical University), and the Department of Surgery at the Duke University School of Medicine. When he completed the surgical residency, he spent 10 years at the National Cancer Institute (NCI) where he and his colleagues made significant contributions to the diagnosis and treatment of patients with endocrine tumors. After leaving the NCI, he had highly productive years as a Professor in Departments of Surgery at Washington University, the University of California at San Francisco, and Stanford University. He became a member of every major academic surgical society and won numerous awards for his accomplishments in research. His expertise in educating medical students and surgical residents is legendary.
Results
In addition to his academic accomplishments, Jeff trained legions of young surgeons who subsequently made significant contributions in surgical investigation and clinical surgery.
Conclusion
It is most fitting that the Stanford University School of Medicine has assembled a group of Jeffrey Norton’s colleagues in academic medicine and surgery to pay tribute to his achievements as a surgical scientist.
The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association.
The Task Force ...identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document.
The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC.
The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.
Targeted protein degradation has emerged as a new paradigm to manipulate cellular proteostasis. Proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to ...a target protein of interest, promoting its ubiquitination and subsequent degradation. Here, we report the development of antibody-based PROTACs (AbTACs), fully recombinant bispecific antibodies that recruit membrane-bound E3 ligases for the degradation of cell-surface proteins. We show that an AbTAC can induce the lysosomal degradation of programmed death-ligand 1 by recruitment of the membrane-bound E3 ligase RNF43. AbTACs represent a new archetype within the PROTAC field to target cell-surface proteins with fully recombinant biological molecules.
The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which ...accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.
We investigate the Dzyaloshinskii-Moriya interactions (DMIs) in perpendicularly magnetized thin films of Pt/Co/Pt and Pt/Co/Ir/Pt. To study the effective DMI, arising at either side of the ...ferromagnet, we use a field-driven domain wall creep-based method. The use of only magnetic field removes the possibility of mixing with current-related effects such as spin Hall effect or Rashba field, as well as the complexity arising from lithographic patterning. Inserting an ultrathin layer of Ir at the top Co/Pt interface allows us to access the DMI contribution from the top Co/Pt interface. We show that the insertion of a thin Ir layer leads to reversal of the sign of the effective DMI acting on the sandwiched Co layer, and therefore continuously changes the domain wall structure from the right- to the left-handed Neel wall. The use of two DMI-active layers offers an efficient way of DMI tuning and enhancement in thin magnetic films. The comparison with an epitaxial Pt/Co/Pt multilayer sheds more light on the origin of DMI in polycrystalline Pt/Co/Pt films and demonstrates an exquisite sensitivity to the exact details of the atomic structure at the film interfaces.
The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC ...DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression.
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•FOXO1 expression in the germinal center is restricted to dark zone B cells•FOXO1-null mouse germinal centers lack dark zones and lose architectural polarity•FOXO1 deletion impairs affinity maturation and IgG1 class switch recombination•FOXO1 instructs the dark zone gene program directly and by licensing BCL6 activity
The factors that control germinal center polarity and cyclic reentry are unknown. Dalla-Favera and colleagues demonstrate that the transcription factor FOXO1 instructs a gene program that is required for germinal center dark zone development. Mouse germinal centers devoid of FOXO1 expression fail to support affinity maturation and class switch recombination.
Sexual dimorphisms in the brain underlie behavioral sex differences, but the function of individual sexually dimorphic neuronal populations is poorly understood. Neuronal sexual dimorphisms typically ...represent quantitative differences in cell number, gene expression, or other features, and it is unknown whether these dimorphisms control sex-typical behavior exclusively in one sex or in both sexes. The progesterone receptor (PR) controls female sexual behavior, and we find many sex differences in number, distribution, or projections of PR-expressing neurons in the adult mouse brain. Using a genetic strategy we developed, we have ablated one such dimorphic PR-expressing neuronal population located in the ventromedial hypothalamus (VMH). Ablation of these neurons in females greatly diminishes sexual receptivity. Strikingly, the corresponding ablation in males reduces mating and aggression. Our findings reveal the functions of a molecularly defined, sexually dimorphic neuronal population in the brain. Moreover, we show that sexually dimorphic neurons can control distinct sex-typical behaviors in both sexes.
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•Widespread adult sex differences in progesterone receptor (PR)-expressing neurons•Ventrolateral compartment of ventromedial hypothalamus (VMHvl) contains PR+ neurons•PR+ VMHvl neurons exhibit cellular and molecular dimorphisms between the sexes•PR+ VMHvl neurons essential for normal mating in both sexes and fighting in males
Ablating progesterone-receptor-expressing neurons in the ventromedial hypothalamus of mice results in reduced sexual behavior in both sexes but reduces aggression specifically in males, suggesting sexually dimorphic roles for these subsets of neurons.
While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the ...adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions ("don't eat me" signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction ("eat me" signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer-cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.
The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a ...cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family alpha co-receptors (GFRalpha). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy.
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