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MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation., (Copyright © 2022 Mirati Therapeutics, Inc. Published by Elsevier Ltd.. All rights reserved.)

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP -deleted cancers. Here, we report the discovery of development candidate MRTX1719 . MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP -deleted cells compared to MTAP -wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP -deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2 H )-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719 .

Prepectoral breast reconstruction is increasingly popular. This study compares complications between 2 subpectoral and 1 prepectoral breast reconstruction technique., Methods: Between 2008 and 2015, 294 two-staged expander breast reconstructions in 213 patients were performed with 1 of 3 surgical techniques: (1) Prepectoral, (2) subpectoral with acellular dermal matrix (ADM) sling ("Classic"), or (3) subpectoral/subserratus expander placement without ADM ("No ADM"). Demographics, comorbidities, radiation therapy, and chemotherapy were assessed for correlation with Clavien IIIb score outcomes. Follow-up was a minimum of 6 months., Results: Surgical cohorts (n = 165 Prepectoral; n = 77 Classic; n = 52 No ADM) had comparable demographics except Classic had more cardiac disease ( P = 0.03), No ADM had higher body mass index (BMI) ( P = 0.01), and the Prepectoral group had more nipple-sparing mastectomies ( P < 0.001). Univariate analysis showed higher expander complications with BMI ≥ 40 ( P = 0.05), stage 4 breast cancer ( P = 0.01), and contralateral prophylactic mastectomy ( P = 0.1), whereas implant complications were associated with prior history of radiation ( P < 0.01). There was more skin necrosis ( P = 0.05) and overall expander complications ( P = 0.01) in the Classic cohort, whereas the No ADM group trended toward the lowest expander complications among the 3. Multivariate analysis showed no difference in overall expander complication rates between the 3 groups matching demographics, mastectomy surgery, risks, and surgical technique., Conclusions: Prepectoral and subpectoral Classic and No ADM breast reconstructions demonstrated comparable grade IIIb Clavien score complications. BMI > 40, stage 4 cancer, and contralateral prophylactic mastectomy were associated with adverse expander outcomes and a prior history of radiation therapy adversely impacted implant outcomes. Ninety-day follow-up for expander and implant complications may be a better National Surgical Quality Improvement Program measure., Competing Interests: Disclosure: None of the authors has a financial interest in any of the products or devices mentioned in this article. Dr. Daniel Jacobs is a co-founder for AirXpanders, Inc., not involved in this study. The Article Processing Charge was paid for by the authors.

Mid-winter limnological surveys of Lake Erie captured extremes in ice extent ranging from expansive ice cover in 2010 and 2011 to nearly ice-free waters in 2012. Consistent with a warming climate, ice cover on the Great Lakes is in decline, thus the ice-free condition encountered may foreshadow the lakes future winter state. Here, we show that pronounced changes in annual ice cover are accompanied by equally important shifts in phytoplankton and bacterial community structure. Expansive ice cover supported phytoplankton blooms of filamentous diatoms. By comparison, ice free conditions promoted the growth of smaller sized cells that attained lower total biomass. We propose that isothermal mixing and elevated turbidity in the absence of ice cover resulted in light limitation of the phytoplankton during winter. Additional insights into microbial community dynamics were gleaned from short 16S rRNA tag (Itag) Illumina sequencing. UniFrac analysis of Itag sequences showed clear separation of microbial communities related to presence or absence of ice cover. Whereas the ecological implications of the changing bacterial community are unclear at this time, it is likely that the observed shift from a phytoplankton community dominated by filamentous diatoms to smaller cells will have far reaching ecosystem effects including food web disruptions., (© 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.)

There is a myriad of research in the pharmacological manipulation of skin flap survival. However, skepticism exists as to whether any of these drugs is clinically useful. We evaluated the efficacy of five categories of agents in improving skin flap survival in five different rat flap models. Diltiazem, isoxsuprine hydrochloride, nitroglycerin, prazosin hydrochloride (two doses), and methyldopa were compared in a double-blind, randomized fashion. Their benefits were assessed in a musculocutaneous flap, axial flap, and three types of random flaps. The "best" drug was determined to be nitroglycerin. Its efficacy was verified in a primate model.