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Autologous treatment for ALS with implication for broad neuroprotection

Translational Neurodegeneration 2022年第1期11卷 718-736页

作者： Daehwan Kim Subin Kim Ashley Sung Neetika Patel Nathan Wong michael j.conboy Irina M.conboy Department of Bioengineering and QB3 Institute University of CaliforniaBerkeleyCA 94720USA

Background: Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of motor neurons (MNs), leading to paralysis, respiratory failure and death within 2-5 years of diagnosis. The exact mechanisms of sporadic ALS, which comprises 90% of all cases, remain unknown. In familial ALS, mutations in superoxide dismutase (SOD1) cause 10% of cases. Methods: ALS patient-derived human-induced pluripotent stem cells (ALS hiPSCs, harboring the SOD1AV4 mutation), were differentiated to MNs (ALS-MNs). The neuroprotective effects of conditioned medium (CM) of hESCs (H9), wt hiPSCs (WTC-11) and the ALS iPSCs, on MN apoptosis and viability, formation and maintenance of neurites, mitochon-drial activity and expression of inflammatory genes, were examined. For in vivo studies, 200 μl of CM from the ALS iPSCs (CS07 and CS053) was injected subcutaneously into the ALS model mice (transgenic for the human SOD1G93A mutation). Animal agility and strength, muscle innervation and mass, neurological score, onset of paralysis and lifes-pan of the ALS mice were assayed. After observing significant disease-modifying effects, the CM was characterized biochemically by fractionation, comparative proteomics, and epigenetic screens for the dependence on pluripotency. CM of fibroblasts that were differentiated from the wt hiPSCs lacked any neuroprotective activity and was used as a negative control throughout the studies. Results: The secretome of PSCs including the ALS patient iPSCs was neuroprotective in the H2O2 model. In the model with pathogenic SOD1 mutation, ALS iPSC-CM attenuated all examined hallmarks of ALS pathology, rescued human ALS-MNs from denervation and death, restored mitochondrial health, and reduced the expression of inflam-matory genes. The ALS iPSC-CM also improved neuro-muscular health and function, and delayed paralysis and mor-bidity in ALS mice. Compared side by side, cyclosporine (CsA), a mitochondrial membrane blocker that prevents the leakage of mitochondrial DNA, failed to avert the death of ALS-MNs, al

关键词： Neurodegeneration Amyotrophic lateral sclerosis SOD1 mutation Pluripotent stem cells Secretome

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Drivers and breaks in the cholangiocarcinoma immune microenvironment

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Hepatobiliary Surgery and Nutrition 2022年第2期11卷 320-323页

作者： Caitlin B.conboy Sumera I.Ilyas Gregory j.Gores Division of Medical Oncology Mayo ClinicRochesterMinnesotaUSA Division of Gastroenterology and Hepatology Mayo ClinicRochesterMNUSA

Clinically effective immune checkpoint inhibitors(ICI)have transformed cancer treatment over the last decade.This progress was built on a foundation of understanding tumor immunology,immune checkpoint biology,and biomarkers for sensitivity to ICI(1).Monoclonal antibodies disrupting the PD-L1/PD-1 axis or CTLA-4 are highly effective in tumors that are primed for an anti-tumor immune response but suppressed by immune checkpoints(1).This is the case for cancer types with abundant neoantigens,such as melanoma and lung cancer,and in tumors regardless of histology that have elevated tumor mutation burden(TMB)or microsatellite instability(MSI)due to mismatch repair deficiency(dMMR).Elevated expression of PD-L1 is a biomarker of immunosuppression and predicts sensitivity to PD-(L)1 blockade in several tumor types,including lung and gastroesophageal cancer.In cholangiocarcinoma(CCA),the immune landscape and factors predicting response to immunotherapy are less well understood(2).

关键词： lung elevated landscape

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