Modular Synthesis of Anti-HER2 Dual-Drug Antibody-Drug Conjugates Demonstrating Improved Toxicity.

Antibodies have gained clinical success in the last two decades for the targeted delivery of highly toxic small molecule chemotherapeutics. Yet antibody-drug conjugates (ADCs) often fail in the clinic due to the development of resistance. The delivery of two mechanistically distinct small molecule drugs on one antibody is of increasing interest to overcome these challenges with single-drug ADCs.

Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer.

Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype.

Data-driven synapse classification reveals a logic of glutamate receptor diversity.

The rich diversity of synapses facilitates the capacity of neural circuits to transmit, process and store information. We used multiplex super-resolution proteometric imaging through array tomography to define features of single synapses in mouse neocortex. We find that glutamatergic synapses cluster into subclasses that parallel the distinct biochemical and functional categories of receptor subunits: GluA1/4, GluA2/3 and GluN1/GluN2B.

Aged neurons don't register energy need.

Neuronal activity and mitochondrial gene expression become decoupled in aged mice.

Trifold Flap for Total/Subtotal Nasal Reconstruction.

Reconstructing the nose is one of facial plastic surgery's most common reconstructive challenges. While the forehead flap is widely utilized in nasal reconstruction, the effectiveness of a single forehead flap for subtotal/total nasal reconstruction is limited. Building on previously described fold-over flap techniques, we introduce a unique trifold forehead flap method for total nasal reconstruction utilizing a single forehead flap.

Distinctive physiology of molecularly identified medium spiny neurons in the macaque putamen.

The distinctive physiology of striatal medium spiny neurons (MSNs) underlies their ability to integrate sensory and motor input. In rodents, MSNs have a hyperpolarized resting potential and low input resistance. When activated, they have a delayed onset of spiking and regular spike rate.

Health Disparities and the Influence of Culturally Competent Care in Overall Health and Healthcare Utilization among Hispanics in a Southeastern US Community.

This study sought to assess disparities in health/healthcare utilization for Hispanic immigrant community in Greenville County, SC. The study also assessed the role of culturally competent care perceptions on health/healthcare utilization within this growing community. Secondary administrative data collected by a large health care system in the county facilitated the assessment of health/healthcare utilization disparities using multivariate regression.

Exposure effects of synthetic glucocorticoid drugs on skeletal developmental and immune cell function in zebrafish.

Synthetic glucocorticoids (GCs) are used to treat a wide range of human health conditions and as such are frequently detected in the aquatic environment. This, together with the highly conserved nature of the glucocorticoid system across vertebrates means that the potential for biological effects of GCs in fish is relatively high. Here, we found that exposure of zebrafish (Danio rerio) to environmentally relevant concentrations of 4 of the most widely used synthetic GCs (beclomethasone dipropionate, budesonide, fluticasone propionate, and prednisolone), from 0 to 4 days post fertilisation (dpf), resulted in no effects on embryo-larval development or bone and cartilage formation.

Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits.

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos.

Areal specializations in the morpho-electric and transcriptomic properties of primate layer 5 extratelencephalic projection neurons.

Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas.

Creating "a Safe Place to Go": Yarning With Health Workers About Stroke Recovery Care for Aboriginal Stroke Survivors-A Qualitative Study.

Stroke affects Aboriginal people at disproportionate rates compared to other populations in Australia. Aboriginal peoples are less likely to receive a timely stroke diagnosis, or timely culturally responsive treatment, as there are very few stroke resources and recovery plans that have been developed by Aboriginal peoples for Aboriginal peoples. Understanding how to develop and implement culturally responsive stroke care requires research approaches that are informed by and with Aboriginal people.

A novel translational model of atherosclerosis, the ex vivo pump-perfused amputated human limb model.

The preclinical study of atherosclerosis has traditionally centred around the use of small animal models, translating to large animal models, prior to first-in-man studies. We propose to disrupt this paradigm by designing an ex vivo pump perfused human limb model. The novel model consists of taking a freshly amputated limb and incorporating it into an ex situ pump-perfused bypass system (akin to extracorporeal membrane oxygenation), circulating warmed, oxygenated blood.

Cutaneous hypersensitivity to chlorhexidine following facial fat grafting: a delayed intradermal response.

Chlorhexidine (CHD) is commonly included in surgical antiseptics and can be associated with adverse reactions ranging from contact dermatitis to anaphylaxis. A 32-year-old female presented to the OR for facial fat grafting. Surgical sites were prepped with CHD gluconate or topical iodine.

Surface-Available HER2 Levels Alone Are Not Indicative of Cell Response to HER2-Targeted Antibody-Drug Conjugate Therapies.

HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective in patients with elevated levels of HER2, questioning whether the amount of HER2 is sufficiently predictive of patient outcomes.

Sacituzumab Govitecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III EVOKE-01 Study.

Purpose: The open-label, phase III EVOKE-01 study evaluated sacituzumab govitecan (SG) versus standard-of-care docetaxel in metastatic non-small cell lung cancer (mNSCLC) with progression on/after platinum-based chemotherapy, anti-PD-(L)1, and targeted treatment for actionable genomic alterations (AGAs). Primary analysis is reported.

Methods: Patients were randomly assigned 1:1 (stratified by histology, best response to last anti-PD-(L)1-containing regimen, and AGA treatment received or not) to SG (one 10 mg/kg intravenous infusion on days 1 and 8) or docetaxel (one 75 mg/m intravenous infusion on day 1) in 21-day cycles.

Design of greener drugs: aligning parameters in pharmaceutical R&D and drivers for environmental impact.

Active pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients.

Forensic geoscience non-invasive detection and characterisation of underground clandestine complexes, bunkers, tunnels and firing ranges.

Recent events in conflict zones have emphasized that the successful detection and characterisation of buried clandestine complexes, bunkers and tunnels is vitally important for forensic investigators globally, to reduce or solve criminal activities, address national security threats and avoid potential terrorist attacks. However, this can often prove very difficult, particularly in urban areas, with potentially both below-ground non target items and above-ground infrastructures present, that can interfere with detecting target(s). Here we provide selected successful case studies where forensic geoscience techniques were used to detect and characterise buried clandestine complexes, bunkers and tunnels using different geophysical techniques.