CHANGES IN HEIGHT AND BODY MASS AMONG TWINS OVER 18

CHANGES IN HEIGHT AND BODY MASS AMONG TWINS OVER 18 were studied in the context of their size and rate of development in earlier phases of ontogenesis. Several environmental factors contributing to adult body height among the twins were assessed

Muscle Atrophy: Counteracting Muscle Atrophy on Earth and in Space via Nanofluidics Delivery of Formoterol

Skeletal muscle atrophy is a critical health problem that affects quality of life and increases morbidity and mortality. At present, exercise training remains the only intervention and pharmaceutical treatments remain elusive. Formoterol (FMT), a β2‐adrenergic receptor agonist, has emerged as a potential therapeutic by triggering skeletal muscle anabolism with daily dosing. Here, the efficacy of sustained FMT release is investigated via a subcutaneously implanted nanofluidic delivery system (nF) to prevent muscle wasting. Pharmacokinetics of nF‐mediated sustained FMT delivery (nF‐FMT) in healthy mice is assessed for 56 days, which demonstrates an anabolic effect on skeletal muscles. Using a hind limb suspension unloading mouse model, it is shown that nF‐FMT treatment attenuates soleus mass loss in comparison to control mice. Further, the very first study of an implantable drug delivery device in microgravity in vivo is launched. The microgravity environment aboard the International Space Station is leveraged to assess the atrophy prevention capability of nF‐FMT in mice for 29 and 55 days. Muscle hypertrophy is observed in both ground control and spaceflight mice treated with nF‐FMT compared to their respective vehicle controls. Overall, the nF system is presented as a viable platform for sustained delivery of FMT for therapeutic intervention of skeletal muscle atrophy

Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy.In this study, we tested the efficacy of a novel mTOR catalytic inhibitor (here named Tool Compound 1 or TC1) previously reported to be more brain-penetrant compared with other mTOR inhibitors. Using a well-characterized hypomorphic Tsc2 mouse model, which displays a translationally relevant seizure phenotype, we tested the efficacy of TC1.Our results show that chronic treatment with this novel mTOR catalytic inhibitor (TC1), which affects both the mTORC1 and mTORC2 signaling complexes, reduces seizure burden, and extends the survival of Tsc2 hypomorphic mice, restoring species typical weight gain over development.Novel mTOR catalytic inhibitor TC1 exhibits a promising therapeutic option in the treatment of TSC

Discovery of an Acrylic Acid Based Tetrahydro­isoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

Tetrahydroisoquinoline <b>40</b> has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ <b>40</b> and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ <b>40</b> in a MCF-7 human breast cancer xenograft model

Discovery of an Acrylic Acid Based Tetrahydro­isoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

Tetrahydroisoquinoline <b>40</b> has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ <b>40</b> and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ <b>40</b> in a MCF-7 human breast cancer xenograft model

Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation

<div><p>Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. <i>In vivo</i> experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.</p></div

Englerin A selectivity against TRP family and non-TRP family ion channels.

<p>Englerin A selectivity against TRP family and non-TRP family ion channels.</p

Overexpression of TRPC5 can also confer sensitivity to englerin A.

<p>(<b>A</b>) Expression of TRPC4 and TRPC5 in the cell lines from the CLiP experiment. Each circle represents a single cell line and expression levels were measured by microarray (TRPC4 probe 220818_s_at, TRPC5 probe 220552_at). The circle representing the DMS-79 cell line is indicated. (<b>B</b>) The effect of englerin A on cell viability in HEK293T cells transiently transfected with a vector expressing TRPC5 (mean +/- standard deviation).</p

Englerin A affects proliferation of a subset of cancer cell lines across many cell lineages while englerin B is inactive.

<p>(<b>A</b>) Scatterplot of englerin A cell line profiling experiment. (<b>B</b>) Scatterplot of englerin B cell line profiling experiment. Each point represents effect of englerin A or B on growth of a single tumor cell line. Y-axis indicates maximal effect on growth and X-axis indicates potency. Tumor cell line lineage is indicated by color and the legend is in the figure. Englerin A sensitive (circles), englerin A refractory (squares) and englerin A intermediate (diamonds) cell line calls are indicated.</p

Englerin A agonizes the TRPC4/C5 ion channels and channel activation is needed for cell growth inhibition.

<p>(<b>A</b>) Calcium flux stimulated by englerin A in HEK293T cells overexpressing different TRPC proteins (mean +/- standard deviation): TRPC5 (closed diamonds), TRPC4beta (closed squares), TRPC4 (closed circles), TRPC6 (open squares), mock transfected cells (open circles). (<b>B</b>) Membrane depolarization stimulated by englerin A in HEK293T cells overexpressing different TRPC proteins (mean +/- standard deviation), markers as above. (<b>C</b>) TRPC4 current evoked by stimulation of 5 μM Englerin A, saline, or 5 μM Englerin A + 10 μM ML204 in 293T cells with Doxycyline-induced TRPC4. Currents were elicited by 200 ms voltage ramps from -100 to +100 mV, applied every 10 s from holding potential of 0 mV. (<b>D</b>) Summary of englerin A, englerin-B and ML-204 activity on membrane currents (mean +/- S.E.M.) (<b>E</b>) A-673 cell viability in the presence or absence of 50 nM englerin A and/or 50 μM ML204, a TRPC4/C5 channel blocker (mean +/- standard deviation).</p