Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers.

In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan et al. (Oncogenesis 2020) and Wang et al. (Cancer Cell Int 2022) demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib. The studies also identified hyaluronic acid synthase -3 (HAS3) as a bonafide target of Sorafenib in RCC cells. The studies demonstrate that an over-the-counter drug Hymecromone (4-methylumbelliferone) blocks inactivation of Sorafenib in RCC cells and improves its efficacy against mRCC through the inhibition of HAS3 expression and HA signaling. In the broader context, improving the efficacy of "old and failed drugs" that have favorable safety profiles should increase the availability of effective treatments for patients with advanced cancers.

An inhibitory acetylcholine receptor gates context dependent mechanosensory processing in C. elegans.

An animal's current behavior influences its response to sensory stimuli, but the molecular and circuit-level mechanisms of this context-dependent decision-making is not well understood. In the nematode C. elegans, inhibitory feedback from turning associated neurons alter downstream mechanosensory processing to gate the animal's response to stimuli depending on whether the animal is turning or moving forward [1-3]. Until now, the specific neurons and receptors that mediate this inhibitory feedback were not known. We use genetic manipulations, single-cell rescue experiments and high-throughput closed-loop optogenetic perturbations during behavior to reveal the specific neuron and receptor responsible for receiving inhibition and altering sensorimotor processing. An inhibitory acetylcholine gated chloride channel comprised of lgc-47 and acc-1 expressed in neuron RIM receives inhibitory signals from turning neurons and performs the gating that disrupts the worm's mechanosensory evoked reversal response.

Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention.

The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, and became moribund. Lung tissues from these mice and bronchoalveolar lavage and lung tissues from patients with COVID-19 showed elevated levels of hyaluronic acid (HA), HA-family members, an inflammatory signature, and immune cell infiltration. 4-methylumbelliferone (4-MU), an oral drug for biliary-spasm treatment, inhibits HA-synthesis. At the human equivalent dose, 4-MU prevented/inhibited COVID-19-like pathologies and long-term morbidity; 4-MU and metabolites accumulated in mice lungs. Therefore, these versatile SARS-COV-2 ribo-oligonucleotide oropharyngeal models recapitulate COVID-19 pathology, with HA as its critical mediator and 4-MU as a potential therapeutic for COVID-19.

Light evokes stereotyped global brain dynamics in Caenorhabditis elegans.

Stereotyped oscillations in population neural activity recordings from immobilized Caenorhabditis elegans have garnered interest for their striking low dimensionality and their evocative state-space trajectories or manifolds. Previously these oscillations have been interpreted as intrinsically driven global motor commands. Here we test whether these oscillations are intrinsic. We show that similar oscillations are evoked by high-intensity blue light commonly used for calcium imaging. Oscillations are reduced or absent and have a lower frequency when a longer imaging wavelength is used. Under the original blue light illumination, oscillations are reduced or have a lower frequency in animals that lack GUR-3, an endogenous light- and hydrogen-peroxide-sensitive gustatory receptor. Additional experiments with hydrogen peroxide are consistent with GUR-3's involvement. We therefore propose that blue light evokes global oscillations in part through the creation of reactive oxygen species that activate the hydrogen-peroxide-sensing receptor GUR-3.

A bis-quinoline ruthenium(II) arene complex with submicromolar cytotoxicity in castration-resistant prostate cancer cells.

A new Ru(II) arene chlorido organometallic complex [(η6-p-cymene)(L)RuCl]PF6 (named as pCYRuL) using 2-bis(quinolin-2-ylmethylene) hydrazine (L) was developed that exhibits potent anticancer activity against castration-resistant prostate cancer (CRPC) (IC50 = 0.71 µM), and it is 45 times more effective than the standard drug cisplatin (IC50 = 31.3 µM) in a castration-resistant human prostatic adenocarcinoma cell line (PC-3) but non-toxic in normal human kidney cells (HK2) as well as normal breast cells (MCF10A) and found that pCYRuL exerted anticancer activity via apoptosis induction and cell cycle arrest in the G2/M phase of PC-3 cells.