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The spike D614G mutation increases SARS-CoV-2 infectivity, viral load, and transmission but the molecular mechanism underlying these effects remains unclear. We report here that spike is trafficked to lysosomes and that the D614G mutation enhances the lysosomal sorting of spike and the lysosomal accumulation of spike-positive punctae in SARS-CoV-2-infected cells. Spike trafficking to lysosomes is an endocytosis-independent, V-ATPase-dependent process, and spike-containing lysosomes drive lysosome clustering but display poor lysotracker labeling and reduced uptake of endocytosed materials. These results are consistent with a lysosomal pathway of coronavirus biogenesis and raise the possibility that a common mechanism may underly the D614G mutation’s effects on spike protein trafficking in infected cells and the accelerated entry of SARS-CoV-2 into uninfected cells.

SUMMARYIndividuals can test positive for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) after no longer being infectious.1-8 Positive SARS-CoV-2 antigen-based testing exhibits a temporal pattern that corresponds with active, replicating virus and could therefore be a more accurate predictor of an individual’s potential to transmit SARS-CoV-2.2,3,9 Using the BD Veritor System for Rapid Detection of SARS-CoV-2 later flow antigen detection test, we demonstrate a higher concordance of antigen-positive test results with the presence of cultured, infectious virus when compared to RT-PCR. When compared to infectious virus isolation, the sensitivity of antigen-based testing is similar to RT-PCR. The correlation between SARS-CoV-2 antigen and SARS-CoV-2 culture represents a significant advancement in determining the risk for potential transmissibility beyond that which can be achieved by detection of SARS-CoV-2 genomic RNA. Coupled with a rapid time-to-result, low cost, and scalability, antigen-based testing should facilitate effective implementation of testing and public health interventions that will better contain COVID-19.

Background: MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE), an anti-microtubulin agent. In preclinical studies, MRG001 demonstrated significant tumor growth inhibition in rituximab-resistant non-Hodgkin's lymphoma (NHL) models. MRG001 is being evaluated in a first-in-human, open-label, multicenter Phase I study for the safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity in patients with CD20-positive relapsed or refractory (R/R) B-cell NHL. Methods: MRG001 was evaluated as a monotherapy for the treatment of patients with confirmed CD20-positive R/R B-cell NHL. The study consists of Phase Ia dose escalation and Ib dose expansion. In the Phase Ia dose-escalation study utilizing a "3+3" design, patients with pathologically confirmed R/R NHL received single agent MRG001 intravenously once every 3 weeks (Q3W) for a maximum of 6 treatment cycles. Six dose levels ranging from 0.15 to 2.5 mg/kg were evaluated for safety, PK and preliminary antitumor activity to determine the MTD/RP2D. Results: From June 25, 2019 to May 31, 2021, a total of 21 subjects with DLBCL (n=8), FL (n=12), and MZL (n=1) who met the eligibility criteria had received at least two cycles of MRG001. As of May 31, 2021, 18 subjects were off treatment and 3 subjects were still on treatment. There were 3 subjects enrolled into the 0.15, 0.3 , 0.6, 1.2 and 2.5 mg/kg cohort respectively, and 6 subjects enrolled into the 1.8 mg/kg cohort. Of the 21 subjects enrolled, 12 subjects were male and 9 subjects were female, with age ranging from 27 to 75 years old. Among the 18 subjects who were off treatment, 5 had completed 6 cycles of treatment, and 13 had drug discontinuation (12 due to progression of disease and 1 subject due to withdrawal of the informed consent for personal reasons). Commonly observed drug-related TEAEs were decreased white blood cell/neutrophil/lymphocyte counts, ALT/AST elevation, pyrexia, hypertension, increased LDH, QT prolongation, and thrombocytopenia.TEAEs (29 cases) ≥ Grade 3 were reported in 9 subjects, including 23 drug-related TEAEs in 8 subjects. The most commonly reported Grade 3 or above TRAEs were leukopenia/neutropenia, lymphopenia, hypertension, and ALT elevation. In the 2.5 mg/kg cohort, two subjects experienced drug-related toxicities that met the DLT definition per protocol, including 1 subject with Grade 3 hyperlipidemia and 1 subject with Grade 4 neutropenia that lasted 5 days. There was no death due to AEs. PK samples of total antibody, MRG001 and MMAE were measured at predefined time points and the results showed that the C max and AUC of total antibody, MRG001 and MMAE increased with dose level increase. The T max of MMAE was non-linear to dose level increase, similar trends could be observed in two other parameters including C max and AUC 0-t, which suggested that MMAE was continuously released from MRG001. Among 21 pts who had at least one tumor assessment, 1 CR (5%), 4 PR (19%), 9 SD (43%), and 7 PD (33%). The investigator assessed ORR was 24% and the DCR was 67%. In the starting dose 0.15 mg/kg cohort, one subject with FL acheived PR. Among six subjects (4 with DLBCL and 2 with FL) enrolled in the 1.8 mg/kg cohort, one DLBCL subject achieved CR and another subject with DLBCL achieved PR, ORR was 33.33% (2 out of 6). Three subjects were enrolled in the 2.5 mg/kg cohort, two subjects with FL had PR, both of them had DLT on cycle 1 and had dose reduction to 1.8 mg/kg from cycle 2, ORR was 66.7% (2 out of 3). Conclusion: The dose escalation study of MRG001 has shown manageable safety profiles and encouraging preliminary antitumor activity in patients with NHL. Based on the safety, tolerability, and pharmacokinetic parameters of MRG001, 1.8 mg/kg was determined to be the RP2D and further investigation of MRG001 in patients with NHL is warranted. Disclosures Peng: Lepu Biopharma Co., Ltd.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Li: Shanghai Miracogen Inc.: Current Employment.

Depressive symptoms are prevalent in the aging population and can negatively impact the health and well-being of older adults. Personality traits may interact with depressive symptoms, but there is currently limited knowledge regarding this relationship in minority aging research. This study aims to explore the associations between two personality traits, neuroticism and conscientiousness, and depressive symptoms in 3,157 U.S. Chinese older adults. Data were obtained from the Population Study of Chinese Elderly in Chicago (PINE) collected between 2011 and 2013. Neuroticism and conscientiousness were measured by the NEO Five-factor Inventory. Depressive symptoms were measured by the nine-item Patient Health Questionnaire (PHQ-9). 45.3% of the participants reported at least one depressive symptom. Controlling for potential confounders, logistic regression analyses showed that both traits were significantly associated with depressive symptoms. One unit increase in neuroticism was associated with 19% increased odds of having any depressive symptoms (odds ratio [OR]=1.19, 95% confidence interval [CI]=1.17-1.22). One unit increase in conscientiousness was associated with 5% decreased odds of having any depressive symptoms (OR=0.95, 95% [CI]=0.94-0.96). Results validate the significant association between both traits and depressive symptoms among U.S. Chinese older adults, adding to the psychological and cultural profiles of those who have experienced mental distress. More in-depth examination using culturally-tailored measurements for personality traits is encouraged in minority aging studies. The NEO inventory was developed from Western populations and hence might not adequately represent personality traits valued by non-Western cultures.

Summary Background There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses. Methods We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape. Findings We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape. Interpretation Our results highlight the need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered. Funding The work was partially funded by The Saban Research Institute at Children’s Hospital Los Angeles intramural support for COVID-19 Directed Research (X.G. and J.D.B.), the Johns Hopkins Center of Excellence in Influenza Research and Surveillance HHSN272201400007C (A.P.), NIH/NIAID R01AI127877 (S.D.B.), NIH/NIAID R01AI130398 (S.D.B.), NIH 1U54CA260517 (S.D.B.), an endowment to S.D.B. from the Crown Family Foundation, an Early Postdoc.Mobility Fellowship Stipend to O.F.W. from the Swiss National Science Foundation (SNSF), and a Coulter COVID-19 Rapid Response Award to S.D.B. L.G. is a SHARE Research Fellow in Pediatric Hematology-Oncology.

In this paper, we propose a two-step data analytic approach to the promotion planning for paid mobile applications (apps). In the first step, we use historical sales data to empirically estimate the app demand model and quantify the effect of price promotions on download volume. The estimation results reveal two interesting characteristics of the relationship between price promotion and download volume of mobile apps: (1) the magnitude of the direct immediate promotion effect is changing within a multi-day promotion; and (2) due to the visibility effect (i.e., apps ranked high on the download chart are more visible to consumers), a price promotion also has an indirect effect on download volume by affecting app rank, and this effect can persist after the promotion ends. Based on the empirically estimated demand model, we formulate the app promotion optimization problem into a Longest Path Problem, which takes into account the direct and indirect effects of promotions. To deal with the tractability of the Longest Path Problem, we propose a Moving Planning Window heuristic, which sequentially solves a series of sub-problems with a shorter time horizon, to construct a promotion policy. Our heuristic promotion policy consists of shorter and more frequent promotions. We show that the proposed policy can increase the app lifetime revenue by around 10%.

Introduction Hyperlipidaemia is a recognized complication of HIV antiretroviral therapy. The interactions among HIV, viral hepatitis, antiretroviral therapies and lipids are poorly understood. Methods Ontario HIV Treatment Network Cohort Study participants with at least one lipid level after highly active antiretroviral therapy (HAART) initiation were assessed. Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-coinfected patients were identified by serology or chart review. HCV antiviral recipients, diabetics and those on lipid-lowering drugs at baseline were excluded from the study. Factors associated with a decreased risk of grade 3 or 4 hyperlipidaemia or lipid-lowering drug use were assessed by multivariate logistic regression. Results A total of 1587 HIV-monoinfected, 190 HIV/HBV-coinfected and 255 HIV/HCV-coinfected patients were evaluated. Most were male (85–92% for the 3 groups evaluated: HIV, HIV/HBV, HIV/HCV). The median [interquartile range (IQR)] age at HAART initiation was 48 (44–56) years and was similar between groups. The median (IQR) CD4 count at HAART initiation was 245 (120–370) cells/μL in HIV-monoinfected participants, 195 (110–330) cells/μL in HIV/HBV-coinfected participants and 268 (140–409) cells/μL in HIV/HCV-coinfected participants. Factors associated with a decreased risk of grade 3 or 4 hyperlipidaemia or lipid-lowering drug use included HIV/HCV coinfection [odds ratio (OR) 0.46; 95% confidence interval (CI) 0.34, 0.61; P

We studied the association of once-daily dosing with self-reported adherence among participants of the Ontario Cohort Study who were currently taking ART and who had completed a 90-min interviewer-administered questionnaire. Suboptimal adherence was defined as missing ≥1 dose of ART in the 4 days prior to the interview. Participants (n = 779) were 85% male, 69% men having sex with men, 67% white, median age 48 years (IQR 42-54), median years of ART 9 (IQR 5-13) and median CD4 count 463 cells/mm(3) (IQR 320-638). Fifteen percent of participants reported suboptimal adherence in the 4 days prior to the interview. In a multivariable logistic regression model, participants on once daily regimens were half as likely to miss a dose during the 4 days prior to the interview. Other independent correlates of suboptimal adherence were younger age, lower positive social interaction and increased frequency of consuming > 6 alcoholic drinks on one occasion.

Studies have reported that soy isoflavones inhibit growth in a number of carcinoma cell lines. The overexpression of Akt, a prosurvival pathway, and vimentin, a mesenchymal marker, in urological carcinomas has been associated with tumor progression and poor prognosis. Our study investigated the effects of a soy isoflavone concentrate (ISF) on the expression of Akt and vimentin in a) cultured human prostate cancer cells and b) xenograft tumors in mice. METHODS: Human prostate cancer PC-3 cells, which are androgen-insensitive and do not express p53 or PTEN, were grown in culture. Hypoxia exposure was at 1% oxygen vs room air for 48 hours. Akt, phosphorylated-Akt (phosAkt), carbonic anhydrase IX (CAIX) and vimentin expression in cells was measured by Western immunoblot analysis. Male nude mice on a soy-free control diet were injected with PC-3 cells into the hind flank. On day 5, half the mice were placed on a diet containing 0.5% soy isoflavone concentrate (ISF). Tumor size was monitored biweekly. Resected tumors were fixed in formalin and paraffin-embedded. Immunohistochemical (IHC) analysis of tumors used antibodies against PCNA, TUNEL, CAIX, Akt, phosAkt, and vimentin. RESULTS: In culture, PC-3 cells constitutively express high levels of Akt and vimentin proteins, which is not altered by hypoxia; in contrast, phosAkt and CAIX proteins are highly expressed only under hypoxic conditions. ISF caused dose-dependent inhibition of DNA synthesis and cell viability without evidence of apoptotic cell death. In culture, ISF decreased the constitutive expression of vimentin, as well as the hypoxia-mediated induction of pAkt and CAIX. In mice, the soy ISF diet significantly inhibited xenograft tumor growth. At 39 days, median tumor size was 862 mm3 in soy-free controls, and 520 mm3 in mice on the ISF diet (p=0.02). IHC analysis of tumors shows that ISF decreased the expression of nuclear PCNA, while TUNEL positive apoptotic cells was increased 4-fold. The ISF diet markedly suppressed levels of total Akt and activated phosAkt. In contrast, staining for CAIX protein was not different in control vs ISF-tumors. Vimentin was clearly expressed in PC-3 tumors and was increased by exposure to irradiation (IR, 2Gy). Interestingly, ISF suppressed IR-induced vimentin expression. Thus, soy ISF treatment inhibited PC-3 cell proliferation both in vitro and in vivo, but different mechanisms are involved in the regulation of expression of the dominant Akt prosurvival signaling pathway, as well as a major mesenchymal marker vimentin. CONCLUSIONS: Together, data indicate that a soy ISF diet strongly inhibits the growth of prostate xenograft tumors which is mediated by differential effects on hypoxia-regulated genes in the tumor microenvironment. (Supported by NIH CA102386 and the Maren Foundation) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2886.