Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12- (quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC₅₀ and in vivo human IC₅₀ values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden.

Annelies Wouters, Jan-Pieter Ploem, Sabine A. S. Langie, Tom Artois, Aziz Aboobaker, and Karen Smeets

Pluripotent stem cells hold great potential for regenerative medicine. Increased replication and division, such is the case during regeneration, concomitantly increases the risk of adverse outcomes through the acquisition of mutations. Seeking for driving mechanisms of such outcomes, we challenged a pluripotent stem cell system during the tightly controlled regeneration process in the planarian Schmidtea mediterranea. Exposure to the genotoxic compound methyl methanesulfonate (MMS) revealed that despite a similar DNA-damaging effect along the anteroposterior axis of intact animals, responses differed between anterior and posterior fragments after amputation. Stem cell proliferation and differentiation proceeded successfully in the amputated heads, leading to regeneration of missing tissues. Stem cells in the amputated tails showed decreased proliferation and differentiation capacity. As a result, tails could not regenerate. Interference with the body-axis-associated component β-catenin-1 increased regenerative success in tail fragments by stimulating proliferation at an early time point. Our results suggest that differences in the Wnt signalling gradient along the body axis modulate stem cell responses to MMS.

Kristi McElmurry, Jessica E. Stone, Donghan Ma, Phillip Lamoureux, Yueyun Zhang, Michelle Steidemann, Lucas Fix, Fang Huang, Kyle E. Miller, and Daniel M. Suter

Previously, we have shown that bulk microtubule (MT) movement correlates with neurite elongation, and blocking either dynein activity or MT assembly inhibits both processes. However, whether the contributions of MT dynamics and dynein activity to neurite elongation are separate or interdependent is unclear. Here, we investigated the underlying mechanism by testing the roles of dynein and MT assembly in neurite elongation of Aplysia and chick neurites using time-lapse imaging, fluorescent speckle microscopy, super-resolution imaging and biophysical analysis. Pharmacologically inhibiting either dynein activity or MT assembly reduced neurite elongation rates as well as bulk and individual MT anterograde translocation. Simultaneously suppressing both processes did not have additive effects, suggesting a shared mechanism of action. Single-molecule switching nanoscopy revealed that inhibition of MT assembly decreased the association of dynein with MTs. Finally, inhibiting MT assembly prevented the rise in tension induced by dynein inhibition. Taken together, our results suggest that MT assembly is required for dynein-driven MT translocation and neurite outgrowth.

Sriram Sudarsanam, Shiri Yaniv, Hagar Meltzer, and Oren Schuldiner

The mechanisms that control intrinsic axon growth potential, and thus axon regeneration following injury, are not well understood. Developmental axon regrowth of Drosophila mushroom body -neurons during neuronal remodeling offers a unique opportunity to study the molecular mechanisms controlling intrinsic growth potential. Motivated by the recently uncovered developmental expression atlas of -neurons, we here focus on the role of the actin-severing protein cofilin during axon regrowth. We show that Twinstar (Tsr), the fly cofilin, is a crucial regulator of both axon growth and branching during developmental remodeling of -neurons. tsr mutant axons demonstrate growth defects both in vivo and in vitro, and also exhibit actin-rich filopodial-like structures at failed branch points in vivo. Our data is inconsistent with Tsr being important for increasing G-actin availability. Furthermore, analysis of microtubule localization suggests that Tsr is required for microtubule infiltration into the axon tips and branch points. Taken together, we show that Tsr promotes axon growth and branching, likely by clearing F-actin to facilitate protrusion of microtubules.

Human bone marrow stromal cells (BMSC) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key stromal cell functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key stromal cell regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSC, down-regulated upon culture, and low in non-colony-forming CD45^neg stromal cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSC. Overexpression of EGR1 in stromal cells induced potent hematopoietic stroma support as indicated by an increased production of transplantable CD34⁺CD90⁺ hematopoietic stem cells in expansion co-cultures. The improvement in bone marrow stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. Furthermore, EGR1 overexpression markedly decreased stromal cell proliferation whereas EGR1 knockdown caused the opposite effects. These findings thus show that EGR1 is a key stromal transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to co-ordinate the specific functions of BMSC in their different biological contexts.

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07–1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer.Significance:The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.

A new global simulation model offers the first long-term look at how urbanization -- the growth of cities and towns -- will unfold in the coming decades. The research team projects the total amount of urban areas on Earth can grow anywhere from 1.8 to 5.9-fold by 2100, building approximately 618,000 square miles.

Follow our live coronavirus updates here Coronavirus: the symptoms

John Lewis sales have plunged, despite a surge in online orders, after it was forced to shut stores in face of coronavirus.

Directives from the Centre have to be executed at the state level. So, there are many things that are not in Modi’s hands, says Raamdeo Agrawal.

India has inflation and it reflects the fundamental growth, Christopher Wood, equity strategist, CLSA, said at ET Now Mkt Summit-2010.

HAIR loss treatment: The quest for magic cure to help halt the process of hair loss produces numerous searches and theories. Taking this essential mineral helps strengthen hair follicles which stimulate hair growth.

Australia's electricity grid operator wants the authority to remotely switch off new rooftop solar systems in SA in order to manage their "invisible and uncontrolled" growth.

Aiming to enable a “nirvana” experience for travelers has driven CellPoint towards block-chain powered, biometric-enabled identification.

Keep on reading: Growth Players: CellPoint Mobile’s CEO Kristian Gjerding

Investors in Regeneron could afford a rare smile in these difficult times, as the company’s first quarter…

COVID-19 is having varying effects on different markets within healthcare, with drug delivery systems…

Thirteen individuals, including five doctors, one pharmacist and one chiropractor, were charged today for their participation in the illegal distribution of pain killers, steroids and human growth hormones through “pill mills” operating in Broward, Palm Beach and Martin Counties in Florida, and through the internet, respectively.

We recognize the Committee’s interest in this matter. We share that interest and are conducting a thorough and complete investigation and analysis of the allegations of targeting by the IRS. While I know you are frustrated by the fact that I cannot at this time disclose any specifics about the investigation, I do pledge to you that when our investigation is completed, we will provide Congress with detailed information about the facts we uncovered and the conclusions we reached in this matter

Alkemist Labs is pleased to announce a move to a new facility with over four times more space to expand capacity and accommodate continued growth.

Media registration is open for the APEC Concluding Senior Officials’ Meeting to take place on 7 December 2019 at the APEC Secretariat in Singapore.

Structural reforms can counter slower economic growth in the Asia-Pacific region, says a new report by the APEC Policy Support Unit.

Members of the Asia-Pacific Economic Cooperation (APEC) will continue to work together towards more inclusive and sustainable growth, pledged APEC Senior Officials at the concluding event for Chile’s host year of APEC.

Chinese Taipei has voluntarily contributed USD 550,000 in funding to support APEC initiatives that advance regional economic integration and inclusive sustainable growth across the Asia-Pacific.

LetsVenture Plus will allow Indian investors access to investments across growth-stage private companies and global funds.

The post Indian angel investor LetsVenture launches growth-stage platform to tap domestic capital appeared first on DealStreetAsia.

npj Microgravity, Published online: 08 April 2020; doi:10.1038/s41526-020-0101-4

Mouse studies suggest inhibiting PGF could help treat hypertension.

Tumor cell and mouse studies suggest tetravalent antibodies that target four different antigens could help treat cancers resistant to HER-targeted therapies.

Daniel Ricciardo says he and Red Bull enter the Australian Grand Prix with far greater confidence than last year despite a rather indifferent winter testing campaign

At a time when 95 percent of Americans, and much of the world, is in lockdown, the often invisible and underappreciated work that women do all the time—at home, caring for children and families, caring for others (women make up three-quarters of health care workers), and in the classroom (women are the majority of teachers)—is…

Around the world, household final consumption expenditure rose by $18.2 trillion in 2011 PPP terms between 2010 and 2020, from $46.5 trillion to $64.8 trillion. This growth, averaging about 3.3 percent per year, was the same as the average growth over the previous forty years—a bit better than growth in the first decade of this…

At a time when 95 percent of Americans, and much of the world, is in lockdown, the often invisible and underappreciated work that women do all the time—at home, caring for children and families, caring for others (women make up three-quarters of health care workers), and in the classroom (women are the majority of teachers)—is…

At a time when 95 percent of Americans, and much of the world, is in lockdown, the often invisible and underappreciated work that women do all the time—at home, caring for children and families, caring for others (women make up three-quarters of health care workers), and in the classroom (women are the majority of teachers)—is…

This week in Class Notes: Both Senator Warren's wealth tax and a popular alternative – a Swiss-style tax on household wealth – would have miniscule effects on income inequality. The ACA Medicaid expansion substantially increased insurance coverage and improved access to health care among unemployed workers. An increased tendency for men and women to remain single may have contributed…

Loose financial conditions that increase GDP growth in the near-term may come with a tradeoff for higher risks to future economic growth, according to a new paper from Brookings Senior Fellow Nellie Liang, and Tobias Adrian, Federico Grinberg, and Sheheryar Malik from the International Monetary Fund.  The authors study 11 advanced economies to develop a…