Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine

Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo. The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo. Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t 1/2 = 9.7 h) relative to vincristine (t 1/2 = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine. These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A Great Promise and a Great Threat : Milwaukee Children in the Great Depression

I am a high school boy ... my father earns a salary that keeps us living, but does not allow for extras, a boy named Art explained in 1937. He wrote the Milwaukee Journal protesting the new fees the city had placed on recreational facilities to make up for budget cuts. The new tax slammed on tennis courts and swimming pools takes away from me the two sports I enjoy most .... Last summer I was frequently (almost daily) in the habit of swimming in the afternoon and playing tennis in the evening, or vise versa. Art argued that the city recreation facilities were established to keep people out of mischief and off the streets, but the new fees would prevent him and other children from using the pools and tennis courts. Art wondered what he would do with his extra free time. This summer I will probably have to lounge about street corners, pool halls or stroll through the parks trying to \u27pick up\u27 girlfriends. It does not sound pretty, but forced idleness is not pleasant. \u27..

A great promise and a great threat : Milwaukee children in the Great Depression

In the first decades of the twentieth century child advocates defined the ideal childhood. They argued that each child needed a stable home life, a quality education, and to be protected from the exploitation of work. Adults additionally, asserted that children needed the proper guidance to help them transition from childhood to maturity. Between 1900 and 1929, adults created laws, policies, and institutions to ensure boys and girls had proper childhood. The Great Depression robbed many children of this model life, causing reformers grave alarm. They turned to the federal government for assistance and used New Deal programs to aid the poorest children, end most forms of child labor, provide many jobless youth employment, and improve the education system. Adults saw the New Deal as a vital component in returning the model childhood to the nation\u27s youngest citizens. While these efforts helped they were not enough. By the mid-1930s idle children were committing crimes in record numbers, forcing juvenile justice officials to devise a low-cost crime-fighting strategy. They passed resolutions protecting girls and boys from bad influences such as salacious movies. They also used federal money to create the Toy Loan Project, which lent poor children toys to keep them out of trouble. The Great Depression also turned many children into activists. Needy children worked to change school culture so it was more accommodating to underprivileged students and sculpted the New Deal to meet their needs. Middle class youngsters contributed to charities that aided the poor and led the peace movement. As the Great Depression came to a close, adults believed that children had become radicals and criminals. In response, adults redefined citizenship so it emphasized American ideals and loyalty. While educators taught this new concept of citizenship, government officials began preparing youth to defend the nation. By the late 1930s, as the threat of fascism grew, children turned away from the anti-war movement to embrace the new patriotism. The approaching war also revitalized the economy and reformers saw the ideal childhood return to many children

Identification of Intracellular Calcium Oxalate Crystals in Chamelaucium Uncinatum (Myrtaceae)

Intracellular inclusions in the pedicel and calyx-tube tissues of Chamelaucium uncinatum Schauer (Myrtaceae) flowers are irregular in shape. They were shown, by polarised light and scanning electron microscopy, to be birefringent 8.9–29.5 μm druse (i.e. aggregate) crystals. Energy-dispersive X-ray spectroscopy showed that these crystals were predominantly composed of calcium. Histochemical and acid-solubility tests indicated that the crystals were calcium oxalate. Raman microprobe spectroscopy was used to confirm this chemical identity. The calcium oxalate crystals were located in xylem-vessel lumens and also in parenchyma cells adjacent to vascular tissues. Thus, the crystals may function to regulate soluble calcium concentrations in C. uncinatum tissues near sites where calcium is unloaded from the xylem

Peptide identifications of the features detected with 3DID and varying minimum voxel intensities 3DID, and the identified features from TFD/E, and MaxQuant.

Peptide identifications of the features detected with 3DID and varying minimum voxel intensities 3DID, and the identified features from TFD/E, and MaxQuant.</p

Feature attributes used for identifiability classifier inputs.

Feature attributes used for identifiability classifier inputs.</p

A raw data MS1 full-frame view at an instant of retention time.

The inset shows an enlarged region of the frame with three candidate features visible; (A) a charge 2+ feature, (B) and (C) charge 4+ features.</p