Publications by authors named "Jasmine Lin"

12 Publications

  • Page 1 of 1

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Motion Analytics of Trapezius Muscle Activity in an 18-Year-Old Female with Extended Upper Brachial Plexus Birth Palsy.

J Brachial Plex Peripher Nerve Inj 2021 Jan 26;16(1):e51-e55. Epub 2021 Oct 26.

Department of Orthopaedics, Rutgers New Jersey Medical School, Newark, New Jersey, United States.

 The trapezius muscle is often utilized as a muscle or nerve donor for repairing shoulder function in those with brachial plexus birth palsy (BPBP). To evaluate the native role of the trapezius in the affected limb, we demonstrate use of the Motion Browser, a novel visual analytics system to assess an adolescent with BPBP.  An 18-year-old female with extended upper trunk (C5-6-7) BPBP underwent bilateral upper extremity three-dimensional motion analysis with Motion Browser. Surface electromyography (EMG) from eight muscles in each limb which was recorded during six upper extremity movements, distinguishing between upper trapezius (UT) and lower trapezius (LT). The Motion Browser calculated active range of motion (AROM), compiled the EMG data into measures of muscle activity, and displayed the results in charts.  All movements, excluding shoulder abduction, had similar AROM in affected and unaffected limbs. In the unaffected limb, LT was more active in proximal movements of shoulder abduction, and shoulder external and internal rotations. In the affected limb, LT was more active in distal movements of forearm pronation and supination; UT was more active in shoulder abduction.  In this female with BPBP, Motion Browser demonstrated that the native LT in the affected limb contributed to distal movements. Her results suggest that sacrificing her trapezius as a muscle or nerve donor may affect her distal functionality. Clinicians should exercise caution when considering nerve transfers in children with BPBP and consider individualized assessment of functionality before pursuing surgery.
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http://dx.doi.org/10.1055/s-0041-1731748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548257PMC
January 2021

SARS-CoV-2 Wave Two Surveillance in East Asia and the Pacific: Longitudinal Trend Analysis.

J Med Internet Res 2021 02 1;23(2):e25454. Epub 2021 Feb 1.

Buehler Center for Health Policy and Economics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.

Background: The COVID-19 pandemic has had a profound global impact on governments, health care systems, economies, and populations around the world. Within the East Asia and Pacific region, some countries have mitigated the spread of the novel coronavirus effectively and largely avoided severe negative consequences, while others still struggle with containment. As the second wave reaches East Asia and the Pacific, it becomes more evident that additional SARS-CoV-2 surveillance is needed to track recent shifts, rates of increase, and persistence associated with the pandemic.

Objective: The goal of this study is to provide advanced surveillance metrics for COVID-19 transmission that account for speed, acceleration, jerk, persistence, and weekly shifts, to better understand country risk for explosive growth and those countries who are managing the pandemic successfully. Existing surveillance coupled with our dynamic metrics of transmission will inform health policy to control the COVID-19 pandemic until an effective vaccine is developed. We provide novel indicators to measure disease transmission.

Methods: Using a longitudinal trend analysis study design, we extracted 330 days of COVID-19 data from public health registries. We used an empirical difference equation to measure the daily number of cases in East Asia and the Pacific as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R.

Results: The standard surveillance metrics for Indonesia, the Philippines, and Myanmar were concerning as they had the largest new caseloads at 4301, 2588, and 1387, respectively. When looking at the acceleration of new COVID-19 infections, we found that French Polynesia, Malaysia, and the Philippines had rates at 3.17, 0.22, and 0.06 per 100,000. These three countries also ranked highest in terms of jerk at 15.45, 0.10, and 0.04, respectively.

Conclusions: Two of the most populous countries in East Asia and the Pacific, Indonesia and the Philippines, have alarming surveillance metrics. These two countries rank highest in new infections in the region. The highest rates of speed, acceleration, and positive upwards jerk belong to French Polynesia, Malaysia, and the Philippines, and may result in explosive growth. While all countries in East Asia and the Pacific need to be cautious about reopening their countries since outbreaks are likely to occur in the second wave of COVID-19, the country of greatest concern is the Philippines. Based on standard and enhanced surveillance, the Philippines has not gained control of the COVID-19 epidemic, which is particularly troubling because the country ranks 4th in population in the region. Without extreme and rigid social distancing, quarantines, hygiene, and masking to reverse trends, the Philippines will remain on the global top 5 list of worst COVID-19 outbreaks resulting in high morbidity and mortality. The second wave will only exacerbate existing conditions and increase COVID-19 transmissions.
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http://dx.doi.org/10.2196/25454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857528PMC
February 2021

SPEG binds with desmin and its deficiency causes defects in triad and focal adhesion proteins.

Hum Mol Genet 2021 02;29(24):3882-3891

Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Striated preferentially expressed gene (SPEG), a member of the myosin light chain kinase family, is localized at the level of triad surrounding myofibrils in skeletal muscles. In humans, SPEG mutations are associated with centronuclear myopathy and cardiomyopathy. Using a striated muscle-specific Speg-knockout (KO) mouse model, we have previously shown that SPEG is critical for triad maintenance and calcium handling. Here, we further examined the molecular function of SPEG and characterized the effects of SPEG deficiency on triad and focal adhesion proteins. We used yeast two-hybrid assay, and identified desmin, an intermediate filament protein, to interact with SPEG and confirmed this interaction by co-immunoprecipitation. Using domain-mapping assay, we defined that Ig-like and fibronectin III domains of SPEG interact with rod domain of desmin. In skeletal muscles, SPEG depletion leads to desmin aggregates in vivo and a shift in desmin equilibrium from soluble to insoluble fraction. We also profiled the expression and localization of triadic proteins in Speg-KO mice using western blot and immunofluorescence. The amount of RyR1 and triadin were markedly reduced, whereas DHPRα1, SERCA1 and triadin were abnormally accumulated in discrete areas of Speg-KO myofibers. In addition, Speg-KO muscles exhibited internalized vinculin and β1 integrin, both of which are critical components of the focal adhesion complex. Further, β1 integrin was abnormally accumulated in early endosomes of Speg-KO myofibers. These results demonstrate that SPEG-deficient skeletal muscles exhibit several pathological features similar to those seen in MTM1 deficiency. Defects of shared cellular pathways may underlie these structural and functional abnormalities in both types of diseases.
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http://dx.doi.org/10.1093/hmg/ddaa276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485222PMC
February 2021

Striated Preferentially Expressed Protein Kinase (SPEG)-Deficient Skeletal Muscles Display Fewer Satellite Cells with Reduced Proliferation and Delayed Differentiation.

Am J Pathol 2020 12 11;190(12):2453-2463. Epub 2020 Sep 11.

Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Centronuclear myopathies (CNMs) are a subtype of congenital myopathies characterized by skeletal muscle weakness and an increase in the number of central myonuclei. SPEG (striated preferentially expressed protein kinase) has been identified as the sixth gene associated with CNM, and it has been shown that striated muscle-specific Speg-knockout (KO) mice have defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling. The impact of SPEG deficiency on the survival and function of myogenic cells remains to be deciphered. In this study, the authors examined the overall population, proliferation, and differentiation of myogenic cells obtained from striated muscle-specific Speg-KO mice and compared them with wild-type (WT) controls. SPEG-deficient skeletal muscles contained fewer myogenic cells, which on further study demonstrated reduced proliferation and delayed differentiation compared with those from WT muscles. Regenerative response to skeletal muscle injury in Speg-KO mice was compared with that of WT mice, leading to the identification of similar abnormalities including fewer satellite cells, fewer dividing cells, and an increase in apoptotic cells in KO mice. Overall, these results reveal specific abnormalities in myogenic cell number and behavior associated with SPEG deficiency. Similar satellite cell defects have been reported in mouse models of MTM1- and DNM2-associated CNM, suggestive of shared underlying pathways.
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http://dx.doi.org/10.1016/j.ajpath.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734599PMC
December 2020

Advertise Right by Addressing the Concerns: An Evaluation of Women's/Breast Imaging Radiology Fellowship Website Content for Prospective Fellows.

Curr Probl Diagn Radiol 2021 Jul-Aug;50(4):481-484. Epub 2020 Jun 1.

University of British Columbia, Department of Radiology, Vancouver, Canada; Vancouver General Hospital, Department of Radiology, Vancouver, Canada.

Purpose: Fellowship is an important part of postgraduate medical training as it facilitates advanced training in a subspecialty of interest. Internet is the most readily available and frequently used tool for acquiring information about the fellowship programs by residents worldwide. The aim of this study was to analyze the content of the websites of American and Canadian breast/women's imaging fellowship programs.

Methods: The content of active Canadian and American breast/women's imaging fellowship websites was collected and analyzed in August 2019 using 27 different criteria in the categories of application process, recruitment, education, research, clinical work, and incentives. The fellowship program without a webpage were excluded from the study.

Results: Out of 76 active breast/women's imaging Radiology fellowship programs in the US and Canada, 75 had dedicated fellowship websites available for analysis. One program was excluded due to lack of a dedicated website. On average, websites showcased 11 of the 27 criteria (40.0%). The category with the least prevalent information was incentives especially career placement after completion of the fellowship (1/75, 1.3%). Majority of the programs around 80.0% (60/75) had adequate information about the application process and requirements. The mean number of schools satisfying the different groups of criteria differed (P< 0.01); more schools satisfied the application criteria (60.5/75; 79.6% ± 20.3%) than the incentives (12.8/75; 16.8% ± 8.2%) and recruitment (24.5/75; 32.2% ± 29.7%) criteria.

Conclusion: Majority of the breast and women's imaging fellowship websites lack important information. Providing comprehensive online information about the program and application process may help the applicants to choose the best suited program for their academic needs and career progression.
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http://dx.doi.org/10.1067/j.cpradiol.2020.05.010DOI Listing
October 2021

The discovery of benzoxazine sulfonamide inhibitors of Na1.7: Tools that bridge efficacy and target engagement.

Bioorg Med Chem Lett 2017 08 1;27(15):3477-3485. Epub 2017 Jun 1.

Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.

The voltage-gated sodium channel Na1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat Na1.7 versus human Na1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse Na1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement.
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http://dx.doi.org/10.1016/j.bmcl.2017.05.070DOI Listing
August 2017

Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase.

Bioorg Med Chem Lett 2009 Jan 20;19(2):424-7. Epub 2008 Nov 20.

Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Bldg. 1000, Cambridge, MA 02139, USA.

Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.056DOI Listing
January 2009

Identification of a novel recepteur d'origine nantais/c-met small-molecule kinase inhibitor with antitumor activity in vivo.

Cancer Res 2008 Aug;68(16):6680-7

Department of Oncology Research, Amgen, Inc., Thousand Oaks, California 91320, USA.

Recepteur d'origine nantais (RON) is a receptor tyrosine kinase closely related to c-Met. Both receptors are involved in cell proliferation, migration, and invasion, and there is evidence that both are deregulated in cancer. Receptor overexpression has been most frequently described, but other mechanisms can lead to the oncogenic activation of RON and c-Met. They include activating mutations or gene amplification for c-Met and constitutively active splicing variants for RON. We identified a novel inhibitor of RON and c-Met, compound I, and characterized its in vitro and in vivo activities. Compound I selectively and potently inhibited the kinase activity of RON and c-Met with IC(50)s of 9 and 4 nmol/L, respectively. Compound I inhibited hepatocyte growth factor-mediated and macrophage-stimulating protein-mediated signaling and cell migration in a dose-dependent manner. Compound I was tested in vivo in xenograft models that either were dependent on c-Met or expressed a constitutively active form of RON (RONDelta160 in HT-29). Compound I caused complete tumor growth inhibition in NIH3T3 TPR-Met and U-87 MG xenografts but showed only partial inhibition in HT-29 xenografts. The effect of compound I in HT-29 xenografts is consistent with the expression of the activating b-Raf V600E mutation, which activates the mitogen-activated protein kinase pathway downstream of RON. Importantly, tumor growth inhibition correlated with the inhibition of c-Met-dependent and RON-dependent signaling in tumors. Taken together, our results suggest that a small-molecule dual inhibitor of RON/c-Met has the potential to inhibit tumor growth and could therefore be useful for the treatment of patients with cancers where RON and/or c-Met are activated.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-6782DOI Listing
August 2008

Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458).

J Med Chem 2008 Jul 14;51(13):3688-91. Epub 2008 Jun 14.

Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.

Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.
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http://dx.doi.org/10.1021/jm800401tDOI Listing
July 2008

Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.

J Med Chem 2008 May 22;51(10):2879-82. Epub 2008 Apr 22.

Amgen Inc., Cambridge, MA 02139, USA.

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.
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http://dx.doi.org/10.1021/jm800043gDOI Listing
May 2008

Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists.

J Med Chem 2006 May;49(9):2758-71

Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.

The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1021/jm0509445DOI Listing
May 2006
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