The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson's disease (PD). Nevertheless, the molecular features associated ...with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration.
Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated ...cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas.
Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1–6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10–18 mg/kg) (Regimen B).
Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders.Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab.
Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing.
NCT01148849.
Low oxygen (O2) diffusion into large tissue engineered scaffolds hinders the therapeutic efficacy of transplanted cells. To overcome this, we previously studied hollow, hyperbarically-loaded ...microtanks (μtanks) to serve as O2 reservoirs. To adapt these for bone regeneration, we fabricated biodegradable μtanks from polyvinyl alcohol and poly (lactic-co-glycolic acid) and embedded them to form 3D-printed, porous poly-ε-caprolactone (PCL)-μtank scaffolds. PCL-μtank scaffolds were loaded with pure O2 at 300–500 psi. When placed at atmospheric pressures, the scaffolds released O2 over a period of up to 8 h. We confirmed the inhibitory effects of hypoxia on the osteogenic differentiation of human adipose-derived stem cells (hASCs and we validated that μtank-mediated transient hyperoxia had no toxic impacts on hASCs, possibly due to upregulation of endogenous antioxidant regulator genes. We assessed bone regeneration in vivo by implanting O2-loaded, hASC-seeded, PCL-μtank scaffolds into murine calvarial defects (4 mm diameters × 0.6 mm height) and subcutaneously (4 mm diameter × 8 mm height). In both cases we observed increased deposition of extracellular matrix in the O2 delivery group along with greater osteopontin coverages and higher mineral deposition. This study provides evidence that even short-term O2 delivery from PCL-μtank scaffolds may enhance hASC-mediated bone tissue regeneration.
Cellular perturbations underlying Alzheimer’s disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of ...cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes—which we refer to as the early cortical amyloid response—were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with β-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.
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•Single-nucleus profiling of human cortex biopsies uncovers amyloid-associated states•Upper-layer pyramidal neurons show hyperactivity prior to degeneration•Microglial states correlate with pathological and clinical progression•Signatures of amyloid production identified in both neurons and oligodendrocytes
Generating single-nucleus atlas from cortical biopsies of living individuals at early stage of Alzheimer’s disease, cell states of neurons, microglia, and oligodendrocytes associated with AD pathology are identified.
Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, ...evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative.
Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer.
At least 1GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%).
GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.
Aim: To evaluate the mortality experience of a cohort of employees of a perfluorooctanesulphonyl fluoride (POSF) based fluorochemical production facility. Methods: A retrospective cohort mortality ...study followed all workers with at least one year of cumulative employment at the facility. The jobs held by cohort members were assigned to one of three exposure subgroups; high exposed, low exposed, and non-exposed, based on biological monitoring data for perfluorooctane sulphonate (PFOS). Results: A total of 145 deaths were identified in the 2083 cohort members. Sixty five deaths occurred among workers ever employed in high exposed jobs. The overall mortality rates for the cohort and the exposure subcohorts were lower than expected in the general population. Two deaths from liver cancer were observed in the workers with at least one year of high or low exposure (standardised mortality ratio (SMR) 3.08, 95% CI 0.37 to 11.10). The risk of death from bladder cancer was increased for the entire cohort (three observed, SMR 4.81, 95% CI 0.99 to 14.06). All three bladder cancers occurred among workers who held a high exposure job (SMR 12.77, 95% CI 2.63 to 37.35). The bladder cancer cases primarily worked in non-production jobs, including maintenance and incinerator and wastewater treatment plant operations. Conclusion: Workers employed in high exposure jobs had an increased number of deaths from bladder cancer; however it is not clear whether these three cases can be attributed to fluorochemical exposure, an unknown bladder carcinogen encountered during the course of maintenance work, and/or non-occupational exposures. With only three observed cases the possibility of a chance finding cannot be ruled out.
Purpose: To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. Patients and methods: Seventy-four patients were ...enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a ≥50% reduction in pain intensity, ≥50% reduction in daily analgesic consumption, or ≥20 point improvement in KPS that was sustained for ≥4 consecutive weeks. Results: Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0% The median duration of Clinical Benefit Response was 14 weeks (range: 4–69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3–18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. Conclusion: Systematic assessment of subjective out comes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.
We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or ...without radiotherapy in patients with advanced solid tumors.
Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B.
In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional.
Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited.
NCT03724890.
•Genomic instability induced by the disruption of DNA damage response pathways can increase sensitivity to immunotherapies.•Peposertib, a DNA-dependent protein kinase inhibitor, had preclinical antitumor efficacy in combination with radiotherapy.•We assessed the safety and antitumor activity of peposertib + avelumab ± radiotherapy in advanced solid tumors.•Peposertib was well tolerated at doses ≤200 mg b.i.d. with avelumab and ≤250 mg q.d. with avelumab + radiotherapy.•Peposertib + avelumab ± radiotherapy had limited clinical activity.
The Center for Law and the Public's Health at Georgetown and Johns Hopkins Universities drafted the Model State Emergency Health Powers Act (MSEHPA or Model Act) at the request of the Centers for ...Disease Control and Prevention. The Model Act provides state actors with the powers they need to detect and contain bioterrorism or a naturally occurring disease outbreak. Legislative bills based on the MSEHPA have been introduced in 34 states. Problems of obsolescence, inconsistency, and inadequacy may render current state laws ineffective or even counterproductive. State laws often date back to the early 20th century and have been built up in layers over the years. They frequently predate the vast changes in the public health sciences and constitutional law. The Model Act is structured to reflect 5 basic public health functions to be facilitated by law: (1) preparedness, comprehensive planning for a public health emergency; (2) surveillance, measures to detect and track public health emergencies; (3) management of property, ensuring adequate availability of vaccines, pharmaceuticals, and hospitals, as well as providing power to abate hazards to the public's health; (4) protection of persons, powers to compel vaccination, testing, treatment, isolation, and quarantine when clearly necessary; and (5) communication, providing clear and authoritative information to the public. The Model Act also contains a modernized, extensive set of principles and requirements to safeguard personal rights. Law can be a tool to improve public health preparedness. A constitutional democracy must balance the common good with respect for personal dignity, toleration of groups, and adherence to principles of justice.
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