Stoneatkins1347

-39.7%; TCG BDC Inc, -48.8%; TCG BDC II, -48.8%) of the DPEGs examined in November 2020 even after receiving a $10 million forgivable Small Business Administration Paycheck Protection Program loan in May 2020. After pharmaceutical companies announced effective COVID-19 vaccine candidates in November 2020, there was a modest and significant improvement in debt valuations (2.3%; 95% CI, 0.2%-0.4%; P = .03); however, they remained discounted. Only PhyNet Dermatology's debt instruments improved to a premium valuation by August 2021.

Debt valuations of some DPEGs found in this cross-sectional study suggest a lower probability that their loans will be repaid in full. This could be a signal that some DPEGs are not performing well financially.

Debt valuations of some DPEGs found in this cross-sectional study suggest a lower probability that their loans will be repaid in full. This could be a signal that some DPEGs are not performing well financially.

Biologics are new treatment alternatives in Takayasu arteritis (TA), although data in childhood is limited. The aim of this study was to share our experience in seven childhood-onset TA patients who received a TNF-α inhibitor (adalimumab) or the IL-6 receptor inhibitor (tocilizumab) and the effect of switching therapy.

We retrospectively evaluated the medical treatment records of seven patients with TA, followed between August 2005 and January 2021 at the Pediatric Rheumatology Department of Hacettepe University Faculty of Medicine.

The median age of patients was 14 (11-15) years, and six were female. All of the patients had severe disease and high acute-phase reactants. The patients initially received only steroids or steroids+CYC. Prednisone was decreased, and biological agents were started once the acute phase reactants decreased, and the Indian Takayasu Activity Score (ITAS) returned to normal. Initially, four patients received tocilizumab (TCZ) [median 25.5 (11-52) months], and three patients received adalimumab (ADA) [median 13 (10-41) months]. However, due to the progression of MR angiography findings or persistent elevation in acute-phase reactants, the biological agents were switched from TCZ to ADA in four patients and from ADA to TCZ in three patients. The patients' median follow-up time after changing was 50 (12-89) months, and median ITAS was evaluated as "0" after 2 (1-5) months.

In conclusion, both TNF-α and IL-6 inhibitors are effective alternatives in treating patients with childhood-onset TA. However, prospective randomized controlled trials are needed for the comparison of their effectiveness.

In conclusion, both TNF-α and IL-6 inhibitors are effective alternatives in treating patients with childhood-onset TA. However, prospective randomized controlled trials are needed for the comparison of their effectiveness.Neurons are highly polarized cells forming an intricate network of dendrites and axons. They are shaped by the dynamic reorganization of cytoskeleton components and cellular organelles. Axon branching allows the formation of new paths and increases circuit complexity. However, our understanding of branch formation is sparse due to the lack of direct in-depth observations. Using in situ cellular cryo-electron tomography on primary mouse neurons, we directly visualized the remodeling of organelles and cytoskeleton structures at axon branches. Strikingly, branched areas functioned as hotspots concentrating organelles to support dynamic activities. Unaligned actin filaments assembled at the base of premature branches accompanied by filopodia-like protrusions. Microtubules and ER comigrated into preformed branches to support outgrowth together with accumulating compact, ∼500-nm mitochondria and locally clustered ribosomes. We obtained a roadmap of events supporting the hypothesis of local protein synthesis selectively taking place at axon branches, allowing them to serve as unique control hubs for axon development and downstream neural network formation.The mitochondrial outer membrane (MOM) harbors proteins that traverse the membrane via several helical segments and are called multi-span proteins. To obtain new insights into the biogenesis of these proteins, we utilized yeast mitochondria and the multi-span protein Om14. Testing different truncation variants, we show that while only the full-length protein contains all the information that assures perfect targeting specificity, shorter variants are targeted to mitochondria with compromised fidelity. Employing a specific insertion assay and various deletion strains, we show that proteins exposed to the cytosol do not contribute significantly to the biogenesis process. We further demonstrate that Mim1 and Porin support optimal membrane integration of Om14 but none of them are absolutely required. Unfolding of newly synthesized Om14, its optimal hydrophobicity, and higher fluidity of the membrane enhanced the import capacity of Om14. Collectively, these findings suggest that MOM multi-span proteins follow different biogenesis pathways in which proteinaceous elements and membrane behavior contribute to a variable extent to the combined efficiency.KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.How to specifically target oncogenic KRAS-driven cancers while sparing normal tissues remains an unmet need in cancer therapy. In this issue of JEM, Jiang et al. (2022. J. Exp. Med.https//doi.org/10.1084/jem.20210739) leveraged KRAS-induced iron addiction in cancer cells to design a clever drug delivery approach to enable selective inhibition of KRAS signaling in mutant KRAS tumors but not in normal tissues, offering a new strategy for treating this largely incurable disease.Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.

De-escalation of dual-antiplatelet therapy through dose reduction of prasugrel improved net adverse clinical events after acute coronary syndrome (ACS), mainly through the reduction of bleeding without an increase in ischemic outcomes. However, whether such benefits are similarly observed in those receiving complex procedures is unknown.

To investigate whether the benefits of prasugrel dose de-escalation therapy are maintained in the complex percutaneous coronary intervention (PCI) subgroup.

This was a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial, a randomized, open-label, adjudicator-blinded, multicenter trial performed at 35 hospitals in South Korea. Study participants included patients with ACS who were receiving PCI. Nesuparib ic50 Data were collected from September 30, 2014, to December 18, 2015, and analyzed from September 17, 2020, to June 15, 2021.

Patients were randomized to a prasugrel dose de-escalation (5 mg daily) at 1 month post-PCI group or a conventional (10 mg daily) group. Complex PCI wa PCI; P for interaction = .84) but decreased BARC class 2 or higher bleeding events (HR, 0.25; 95% CI, 0.10-0.61; P = .002 in complex PCI; HR, 0.62; 95% CI, 0.38-1.00; P = .05 in noncomplex PCI; P for interaction = .08), albeit with wide 95% CIs.

In this post hoc analysis of patients with ACS, prasugrel dose de-escalation compared with conventional therapy was not associated with an increased risk of ischemic outcomes but may reduce the risk of minor bleeding events at 1 year, irrespective of PCI complexity.

ClinicalTrials.gov Identifier NCT02193971.

ClinicalTrials.gov Identifier NCT02193971.

Ovarian cancer has the highest mortality rate among gynecologic malignant tumors. Data are lacking on the survival benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with ovarian cancer who underwent primary or interval cytoreductive surgery.

To assess the clinical benefit of HIPEC after primary or interval maximal cytoreductive surgery in women with stage III or IV primary advanced ovarian cancer.

In this single-blind randomized clinical trial performed at 2 institutions in South Korea from March 2, 2010, to January 22, 2016, a total of 184 patients with stage III or IV ovarian cancer with residual tumor size less than 1 cm were randomized (11) to a HIPEC (41.5 °C, 75 mg/m2 of cisplatin, 90 minutes) or control group. The primary end point was progression-free survival. Overall survival and adverse events were key secondary end points. The date of the last follow-up was January 10, 2020, and the data were locked on February 17, 2020.

Hyperthermic intraperitoneal chemotherapy after cn overall survival was 48.2 months (IQR, 33.8-61.3 months) in the control group and 61.8 months (IQR, 46.7 months to not reported) in the HIPEC group (hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). In the subgroup of primary cytoreductive surgery, median progression-free survival was 29.7 (IQR, 17.2-90.1 months) in the control group and 23.9 months (IQR, 12.3-71.5 months) in the HIPEC group, and the median overall survival was not reached in the control group and 71.3 months (IQR, 45.6 months to not reported) in the HIPEC group.

The addition of HIPEC to cytoreductive surgery did not improve progression-free and overall survival in patients with advanced epithelial ovarian cancer. Although the results are from a subgroup analysis, the addition of HIPEC to interval cytoreductive surgery provided an improvement of progression-free and overall survival.

ClinicalTrials.gov Identifier NCT01091636.

ClinicalTrials.gov Identifier NCT01091636.