Glucocorticoids modulate CHO cell glycosylation in chemically-defined media

Product quality attributes are critical to the therapeutic activity of manufactured biologics. One key quality attribute is glycosylation, which can dramatically affect antibody activity, specificity, and/or immunogenicity. As such, a high priority during drug development is to control the glycosylation profile. Glycosylation is significantly influenced by the composition of cell culture media, including sugars, amino acids, vitamins, trace metals, and even metabolic waste products. Formulation of chemically-defined growth and feed media provides the ability to fine tune the concentrations of media components that regulate glycosylation through metabolic shifts and cell signaling. For example, some of the current strategies for modulating glycosylation involve combinations of guanosine, uridine, MnCl2, galactose, and other sugars. While these components can be adjusted to alter glycosylation, they can also negatively impact cell growth or productivity. Therefore, identifying a broad array of glycosylation control strategies is necessary for tailoring media to different cell lines. Glucocorticoids are a class of compounds commonly found in cell culture media that have demonstrated viability enhancing properties in growth of CHO cells. This class of steroid hormones regulates programmed cell death in CHO cells by triggering increased expression of the anti-apoptotic gene Tsc22d3 [Jing et al., Biotechnol Prog. 2012; 28:490496]. Using our chemically-defined media system, we demonstrate an additional property of glucocorticoids as a regulator of antibody glycosylation in CHO cell culture. Our results show reductions in fucosylated and galactosylated glycan species and a concomitant increase in mannosylated glycan species. This is notable because fucosylation and mannosylation affect potency if the mechanism of action relies on antibodydependent, cell-mediated cytotoxicity (ADCC) and galactosylation affects potency if the mechanism of action relies on complement-dependent cytotoxicity (CDC). Therefore, understanding the effect of glucocorticoids on glycosylation is important for tuning cell culture media in the pursuit of more desirable product quality attributes of biologic

Attention-deficit/hyperactivity disorder medication and seizures

OBJECTIVE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures, but there is uncertainty about whether ADHD medication treatment increases risk among patients with and without preexisting seizures. METHODS: We followed a sample of 801,838 patients with ADHD who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases to examine whether ADHD medication increases the likelihood of seizures among ADHD patients with and without a history of seizures. First, we assessed overall risk of seizures among patients with ADHD. Second, within-individual concurrent analyses assessed odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications. Third, within-individual long-term analyses examined odds of seizure events in relation to the duration of months over the previous 2 years patients received medication. RESULTS: Patients with ADHD were at higher odds for any seizure compared with non-ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24-2.42 males; OR = 2.31, 95% CI = 2.22-2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60-0.85) and without (OR = 0.71, 95% CI = 0.62-0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59-1.30) and without (OR = 1.01, 95% CI = 0.80-1.28) a seizure history. CONCLUSIONS: Results reaffirm that patients with ADHD are at higher risk of seizures. However, ADHD medication was associated with lower risk of seizures within individuals while they were dispensed medication, which is not consistent with the hypothesis that ADHD medication increases risk of seizures

Minimizing the impact of model changeovers at a medium-mix high-volume cellular-telephone production line

Thesis (M.S.)--Massachusetts Institute of Technology, Sloan School of Management, 1996, and Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1996.Includes bibliographical references (p. 79-80).by Kwan "Brian" Y. Tan.M.S

High injection and carrier pile-up in lattice matched InGaAs/InP PN diodes for thermophotovoltaic applications

This article analyzes and explains the observed temperature dependence of the forward dark current of lattice matched In0.53Ga0.47As on InP diodes as a function of voltage. The experimental results show, at high temperatures, the characteristic current-voltage (I-V) curve corresponding to leakage, recombination, and diffusion currents, but at low temperatures an additional region is seen at high fields. We show that the onset of this region commences with high injection into the lower-doped base region. The high injection is shown by using simulation software to substantially alter the minority carrier concentration profile in the base, emitter and consequently the quasi-Fermi levels (QFL) at the base/window and the window/cap heterojunctions. We show that this QFL splitting and the associated electron "pile-up" (accumulation) at the window/emitter heterojunction leads to the observed pseudo-n=2 region of the current-voltage curve. We confirm this phenomenon by investigating the I-V-T characteristics of diodes with an InGaAsP quaternary layer (E-g=1 eV) inserted between the InP window (E-g=1.35 eV) and the InGaAs emitter (E-g=0.72 eV) where it serves to reduce the barrier to injected electrons, thereby reducing the "pile-up." We show, in this case that the high injection occurs at a higher voltage and lower temperature than for the ternary device, thereby confirming the role of the "accumulation" in the change of the I-V characteristics from n=1 to pseudo-n=2 in the ternary latticed matched device. This is an important phenomenon for consideration in thermophotovoltaic applications. We, also show that the activation energy at medium and high voltages corresponds to the InP/InGaAs conduction band offset at the window/emitter heterointerface

A confluence of cultures: advance care planning in long-term care settings

Context: While policies may promote Advance Care Planning (ACP) discussions in long-term care (LTC) settings, practices often result in outcomes different from residents’ wishes. We attribute this to a confluence of cultures: healthcare; LTC settings; mainstream societal; and individuals’ ethno-cultures. This research explores these cultures as reflected in focus group discussions conducted with residents and family-of-residents in two LTC homes: one exclusively Chinese (EC); one multicultural (MC). Method: Fourteen residents and 13 family members participated in the four focus groups. Discussions were audio-recorded, transcribed, and themes were extracted and compared. Results: Four themes characterized residents’ discussions: 1-Variations in Range/Type of ACP Discussions/Actions; 2-Care of Family; 3-Reliance on Staff; and 4-Quality-of-Life at End-of-Life. Exclusively Chinese residents expressed reluctance to speak about ACP, were more likely to state “family would handle it,” less likely to call upon staff, and more acquiescent concerning death. Multicultural residents were more likely to pejoratively mention pull or absence of family and reliance upon staff; also, wanting personal awareness and control at end-of-life. Family themes were 1-Timing/Focus of ACP Discussions, 2-Communication with Family, 3-Care Home and Staff Influences, and 4-Cultural and Religious Issues. Exclusively Chinese families spoke of need to involve family in ACP discussions inclusive of residents and of Chinese cultural influences on ACP. Multicultural families reported being “taken by surprise” and feeling “overwhelmed” by requests to engage in ACP and document completion on behalf of residents. Conclusion: Findings provide evidence of multiple cultural influences on ACP in LTC but existing institutional policies and practices offer little direction and support on how to balance/prioritize them. Our analyses may provide a starting point

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms.

Background: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness. Objective: The present study examined the longitudinal relationship between sleep disturbance and PTSD symptomatology in a cohort of Marines and Navy Corpsmen deployed to Iraq and Afghanistan (n = 2,404) assessed prior to deployment, as well as at -3 and 6 months post-deployment. Additionally, we aimed to investigate the extent to which these relationships are moderated by combat-stress severity, and to what extent these findings are replicated in a second, separate cohort of Marines and Navy corpsmen (n = 938) assessed with identical measures prior to deployment and within 3 months of return. Method: The present study employed latent variable path models to examine the relationships between pre-deployment sleep disturbance and post-deployment re-experiencing symptoms. Initial cross-lagged path models were conducted on discovery and replication samples to validate the hypothesized predictive relationships. Follow up moderation path models were then conducted to include the effect of combat-stress severity on these relationships. Results: Initial cross-lagged models supported a significant relationship between pre-deployment sleep disturbance and future re-experiencing PTSD symptoms at all time points. Initial moderation models showed a small moderator effect of combat-stress severity, though the main predictive relationship between pre-deployment sleep disturbance and PTSD symptoms remained significant. The moderator effect was not significant in the replication sample. Conclusions: The results of this study support pre-deployment sleep disturbance as a risk factor for development of post-deployment PTSD symptoms. Interventions aimed at normalizing sleep may be important in preventive measures for PTSD