Thrombocytopenia is one of the complications for in vivo administration of adenovirus serotype 5 (Ad5) vectors after intravenous injection. In this paper, we investigated the mechanism of Ad5-induced ...thrombocytopenia and how these effects are attenuated by polyethylene glycol (PEG) modification of Ad5 (Ad-PEG). After intravenous injection, accelerated platelet loss was observed in Ad-injected mice but not in their Ad-PEG-injected counterparts. This platelet loss induced by Ad5 corresponded with increases in coagulation D-dimer levels, splenomegaly, and, later, production of megakaryocytes in the bone marrow. In contrast, these responses were blunted or ablated after injection of Ad-PEG. Ad5 activated both platelets and endothelial cells directly in vitro as evidenced by induction of P-selectin and the formation of von Willebrand factor-platelet strings and in vivo as evidenced by the induction of E-selectin messenger RNA. PEGylation blunted these observed activations. These data suggest that Ad5 may induce thrombocytopenia by direct activation of endothelial cells in addition to its direct effects on platelets. This link provides an important clue for the understanding of the mechanisms of thrombocytopenia associated with Ad5. Given that PEGylation blunted interactions of Ad with platelets and endothelial cells, reduced D-dimer formation, reduced thrombocytopenia, and reduced splenomegaly, these data suggest that this simple vector modification may have utility to improve the safety of Ad vectors for human gene therapy.
We complete the survey for finite-source/point-lens (FSPL) giant-source events in 2016-2019 KMTNet microlensing data. The 30 FSPL events show a clear gap in Einstein radius, 9 as < E < 26 as, which ...is consistent with the gap in Einstein timescales near tE ~ 0.5 days found by Mróz et al. (2017) in an independent sample of point-source/point-lens (PSPL) events. We demonstrate that the two surveys are consistent. We estimate that the 4 events below this gap are due to a power-law distribution of free-floating planet candidates (FFPs) dNFFP/d log M = (0.4 ± 0.2) (M/38 M⊕)-p/star, with 0.9 ≲ p ≲ 1.2. There are substantially more FFPs than known bound planets, implying that the bound planet power-law index = 0.6 is likely shaped by the ejection process at least as much as by formation. The mass density per decade of FFPs in the Solar neighborhood is of the same order as that of 'Oumuamua-like objects. In particular, if we assume that 'Oumuamua is part of the same process that ejected the FFPs to very wide or unbound orbits, the power-law index is p = 0.89 ± 0.06. If the Solar System's endowment of Neptune-mass objects in Neptune-like orbits is typical, which is consistent with the results of Poleski et al. (2021), then these could account for a substantial fraction of the FFPs in the Neptune-mass range.
To determine the association between cow's milk-fat and non−high-density lipoprotein (non-HDL) cholesterol, a marker of cardiovascular disease (CVD) risk in young children, and whether this ...association is mediated by the typical volume of cow's milk consumed.
A longitudinal study in 2- to 8-year-old children (n = 2890) was conducted through The Applied Research Group for Kids (TARGet Kids!), a practice-based research network in Toronto, Canada. Generalized estimating equations were used to examine the relationship between parent-reported cow's milk-fat percentage intake and serum non-HDL cholesterol concentrations as well as having high non-HDL cholesterol (≥3.75 mmol/L 145 mg/dL), adjusting for covariates including age, sex, body mass index z score, breastfeeding duration, mother's ethnicity, and parental history of CVD. Bootstrap resampling (10 000 repetitions) was used to assess whether typical volume consumed mediated the association between cow's milk-fat percentage and non-HDL cholesterol.
In total, 156 (5.4%) had high non-HDL cholesterol. Each percent increase in cow's milk-fat was associated with a 0.035 mmol/L (1.35 mg/dL) (P < .001) and 0.024 mmol/L (0.92 mg/dL) (P = .01) increase in non-HDL cholesterol, unadjusted and adjusted for covariates respectively. Cow's milk-fat percentage was not associated with greater odds of having high non-HDL cholesterol. Volume of cow's milk partially mediated the association between cow's milk-fat percentage and non-HDL cholesterol, accounting for 28% of the relationship (P < .001).
Consumption of higher-fat cow's milk was associated with a small increase in non-HDL cholesterol but not greater odds of having high non-HDL cholesterol. Further research is needed to assess this relationship with other CVD risk factors in young children.
ClinicalTrials.gov: NCT01869530.
Introduction
In advanced Parkinson’s disease (PD), a high pill burden is associated with poor compliance, reduced control of symptoms, and decreased quality of life. We assessed the impact of ...carbidopa–levodopa enteral suspension (CLES) and deep brain stimulation (DBS) on PD-related pill burden.
Methods
A retrospective cohort analysis was conducted in the IBM MarketScan and Medicare Supplemental databases. Patients with advanced PD, taking only PD medications, and initiating CLES or DBS between 9 January 2015 and 31 July 2019 were identified. CLES patients were matched to DBS patients in a 1:3 ratio based on a propensity score to balance patient characteristics. Pill burden was measured as a 30-day average number of PD-related pills per day and was captured monthly. Pill-free status was evaluated as the percentage of patients receiving CLES or DBS monotherapy. Descriptive statistics were used to compare pill counts and assess the proportion of patients on monotherapy at 6 and 12 months after initiating CLES or DBS.
Results
The cohorts included 34 CLES patients matched to 97 DBS patients. A significant reduction in PD-related pill burden was observed at 6 months after initiation of CLES or DBS (∆CLES: −5.62,
p
< 0.0001; ∆DBS: −1.48,
p
= 0.0022). PD-related pill burden reduction in CLES patients was significantly greater than in matched DBS patients at 6 months (∆: −4.14,
p
< 0.0001), which was sustained at 12 months after initiation. At 12 months, nearly three times more CLES patients were pill free than DBS patients (29.41% and 10.31%, respectively,
p
= 0.0123).
Conclusions
Device-aided therapies such as CLES and DBS are effective in significantly reducing PD-related pill burden. Patients treated with CLES were more likely to achieve pill-free status than patients receiving DBS.
BackgroundPembrolizumab is a standard-of-care first-line treatment for advanced/metastatic NSCLC, either as monotherapy (for patients with PD-L1 tumor proportion score TPS ≥1%) or combined with ...platinum chemotherapy. An improved OS benefit has been demonstrated for both pembrolizumab monotherapy and pembrolizumab plus chemotherapy in patients with higher tumor PD-L1 expression, and for pembrolizumab monotherapy in patients with higher tissue tumor mutation burden (tTMB). Mutations in KRAS occur relatively frequently in patients with nonsquamous NSCLC but infrequently in those with squamous NSCLC; most mutations are in codon 12. Notably, the pembrolizumab OS treatment effect was not diminished in patients with KRAS G12C mutations in phase 3 studies evaluating pembrolizumab monotherapy and pembrolizumab in combination with chemotherapy.1 2 Herein we describe prevalence of KRAS mutations among patients with advanced nonsquamous NSCLC from two phase 3 clinical studies evaluating first-line pembrolizumab (KEYNOTE-042 and KEYNOTE-189) and the relationship of such mutations with select patient characteristics.MethodsKEYNOTE-042 (NCT02220894) evaluated pembrolizumab versus platinum-based chemotherapy for advanced PD-L1–positive NSCLC (any histology) without EGFR/ALK alterations. KEYNOTE-189 (NCT02578680) evaluated pembrolizumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone for metastatic nonsquamous NSCLC without EGFR/ALK alterations irrespective of tumor PD-L1 expression. Whole-exome sequencing of tumor tissue and matched normal DNA (blood) was performed for patients with nonsquamous histology. PD-L1 TPS was evaluated using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA). Prevalence of KRAS mutations and their relationships with TMB, PD-L1 TPS, and smoking status were analyzed descriptively.Results590 patients with nonsquamous NSCLC were included in these analyses (KEYNOTE-042, n=301; KEYNOTE-189, n=289). Overall, 42.9% of patients had tTMB ≥175 mut/exome, 81.4% were current/former smokers and, 40.3%, 42.7%, and 16.9% had PD-L1 TPS ≥50%, 1–49% and <1% respectively. KRAS G12C, G12D, and G12V mutations occurred in 11.0%, 4.1%, and 5.4% of patients, respectively. Prevalence of KRAS mutations by patient characteristics is summarized in the table (table 1). KRAS G12C mutations occurred almost exclusively in current/former smokers. KRAS G12C was enriched in tumors with tTMB ≥175 mut/exome and tumors with PD-L1 TPS ≥50%. Prevalence was highest in tumors with both tTMB ≥175 mut/exome and PD-L1 TPS ≥50%.Abstract 364 Table 1KRAS Mutation PrevalenceConclusions KRAS G12C mutations occurred with moderate frequency in patients with nonsquamous NSCLC, with most occurring in current/former smokers. KRAS G12C mutations occurred at higher frequency in patient subgroups defined by higher tTMB and PD-L1 TPS.AcknowledgementsMedical writing assistance was provided by Christabel Wilson, MSc, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationKEYNOTE-042, ClinicalTrials.gov, NCT02220894; KEYNOTE-189, ClinicalTrials.gov, NCT02578680ReferencesGadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol 2019;30(suppl 11):xi64-xi5.Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042. Ann Oncol 2019;30(suppl 11):xi63-xi4.Ethics ApprovalFor both trials, the protocol and all amendments were approved by the appropriate ethics committee at each center, the study was conducted in accordance with the standards of Good Clinical Practice. Patients provided written informed consent before enrollment.
Dacomitinib (PF-00299804) is a second-generation irreversible HER tyrosine kinase inhibitor (TKI). In preclinical studies, dacomitinib has demonstrated anti-tumor activity in lung cancer cell lines ...with sensitive and resistant EGFR mutations (including the T790 mutation). Safety and well tolerability of dacomitinib were demonstrated in Phase I studies with stomatitis, diarrhea and skin toxicities being the dose-limiting toxicities. The maximum tolerated dose was established to be 45 mg/day. In Phase II and III studies, dacomitinib has shown clinical activity in both HER tyrosine kinase-naive and HER tyrosine kinase failure settings. Further clinical trials are underway to evaluate the efficacy of dacomitinib in non-small-cell lung cancer.
Abstract Because the pulp tissue extirpated during root canal procedures might serve as a valuable resource with which to assess underlying mechanisms of persistent pain, we sought to determine ...whether standard Western blotting techniques could be used to quantify neural proteins in pulp extirpated from teeth with irreversible pulpitis. Pulp harvested from healthy intact teeth extracted for orthodontic reasons was used for comparison. The neural marker PGP9.5 was detectable in all samples tested. A membrane enrichment protocol enabled detection of even low abundance, high molecular weight proteins such as the sodium channel α-subunit NaV 1.8. Importantly, it was possible to quantify a ∼6-fold increase in the relative density of NaV 1.8 in inflamed pulp compared with control pulp. Our results suggest that it should be possible to use extirpated tooth pulp to validate mechanisms of persistent pain implicated in preclinical studies as well as evaluate the therapeutic efficacy of novel antinociceptive interventions.
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