Search

MicroRNA-124 (miR-124) is the most abundant miRNA in the brain. Biogenesis of miR-124 displays specific temporal and spatial profiles in various cell and tissue types and affects a broad spectrum of biological functions in the central nervous system (CNS). Recently, the link between dysregulation of miR-124 and CNS disorders, such as neurodegeneration, CNS stress, neuroimmune disorders, stroke, and brain tumors, has become evident. Here, we provide an overview of the specific molecular function of miR-124 in the CNS and a revealing insight for the therapeutic potential of miR-124 in the treatment of human CNS diseases.

Iron cyanide compounds are among the oldest known synthetic coordination compounds, dating back to the early 18 th century. By contrast, iron complexes of the cyaphide ion (C≡P - )─a heavy valence isoelectronic analog of the cyanide ion─are unknown. Herein we report the synthesis of highly stable mono- and bis-cyaphide complexes of iron(II), namely Fe(depe) 2 (Cl)(CP) and Fe(depe) 2 (CP) 2 (depe = 1,2-bis(diethylphosphino)ethane). These iron(II) cyaphide complexes are capable of further coordination to iron(I) in a hitherto unknown linear coordination geometry, affording the conjugated multimetallic mixed-valence complexes [{Fe(depe) 2 } 2 (μ-CP)(N 2 )][BAr F 4 ] 2 and [{Fe(depe) 2 } 3 (μ-CP) 2 ][OTf] 2 .

Despite effective countermeasures, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists worldwide because of its ability to diversify and evade human immunity. This evasion stems from amino acid substitutions, particularly in the receptor binding domain (RBD) of the spike protein that confers resistance to vaccine-induced antibodies and antibody therapeutics. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different RBD sites into multispecific antibodies. Here, we describe multispecific antibodies, including a trivalent trispecific antibody that potently neutralized diverse SARS-CoV-2 variants and prevented virus escape more effectively than single antibodies or mixtures of the parental antibodies. Despite being generated before the appearance of Omicron, this trispecific antibody neutralized all major Omicron variants through BA.4/BA.5 at nanomolar concentrations. Negative stain electron microscopy suggested that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated binding across more than one spike protein. Moreover, a tetravalent trispecific antibody containing the same variable regions as the trivalent trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2, and BA.5 challenge, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. These results demonstrated that multispecific antibodies have the potential to provide broad SARS-CoV-2 coverage, decrease the likelihood of escape, simplify treatment, and provide a strategy for antibody therapies that could help eliminate pandemic spread for this and other pathogens.

Despite their potential relevance as molecular models for industrial and biological catalysis, well-defined mononuclear iron carbide complexes are unknown, in part due to the limited number of appropriate C 1 synthons. Here, we show the ability of the cyaphide anion (C≡P - ) to serve as a C 1 source. The high spin ( S = 2) cyaphide complex PhB( t BuIm) 3 Fe-C≡P (PhB( t BuIm) 3 - = phenyl(tris(3- tert -butylimidazol-2-ylidene)borate) is readily accessed using the new cyaphide transfer reagent [Mg( Dipp NacNac)(CP)] 2 ( Dipp NacNac = CH{C(CH 3 )N(Dipp)} 2 and Dipp = 2,6-di(iso-propyl)phenyl). Phosphorus atom abstraction is effected by the three-coordinate Mo(III) complex Mo(N t BuAr) 3 (Ar = 3,5-Me 2 C 6 H 3 ), which produces the known phosphide ( t BuArN) 3 Mo≡P along with a transient iron carbide complex PhB( t BuIm) 3 Fe≡C. Electronic structure calculations reveal that PhB( t BuIm) 3 Fe≡C adopts a doublet ground state with nonzero spin density on the carbide ligand. While isolation of this complex is thwarted by rapid dimerization to afford the corresponding diiron ethynediyl complex, the carbide can be intercepted by styrene to provide an iron alkylidene.

The Valsalva maneuver (VM), commonly used to assess cardiovascular and autonomic nervous system functions, can induce changes in hemodynamic function that may affect cerebral vascular functionality, such as arterial elasticity. This study aimed to investigate the effects of low-pressure VM on cerebral arterial stiffness and cerebral vascular dynamics. Thirty-one healthy young participants (average age 21.58±1.72 years) were recruited for this study. These participants were instructed to maintain an expiratory pressure of 30-35 mmHg for 15 seconds. We measured the vasoconstriction and vasodilation diameters (VCD and VDD) of the common carotid artery (CCA), as well as systolic and diastolic blood pressures (SBP and DBP), before and after VM (PRE&#95;VM and POST&#95;VM). Additionally, we assessed mean arterial pressure (MAP), pulse pressure (PP), pulse wave velocity (PWV), and arterial stiffness. Our findings revealed significant increases in both the VCD and VDD of the CCA (2.15%, p = 0.039 and 4.55%, p<0.001, respectively), MAP (1.67%, p = 0.049), and DBP (1.10%, p = 0.029) following low-pressure VM. SBP showed an increasing trend, but this was not statistically significant (p = 0.108). Interestingly, we observed significant decreases in arterial stiffness and PWV in POST&#95;VM when comparing with PRE&#95;VM (p<0.001 and p<0.001, respectively). In conclusion, our study demonstrated the effectiveness of low-pressure VM in reducing the PWV and stiffness of the CCA. This suggests that low-pressure VM can be a simple and cost-effective method to reduce cerebrovascular stiffness in a brief interval, without the need for specific environmental conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: An excessive and abrupt increase in cerebral blood flow may cause blood vessel damage, leading to stroke. Therefore, appropriate methods to immediately regulate blood flow velocity are important. Through an analysis of 31 healthy adults, we therefore investigated whether stimulating the common carotid artery (CCA) using transcutaneous electrical nerve stimulation (TENS) could modulate blood flow velocity in the CCA., Methods: Three stimulation intensities (below-threshold, threshold, and above-threshold) were applied in a random order. Blood velocity changes were examined by the measurement of peak systolic velocity (PSV) with Doppler ultrasound before, during, and after TENS stimulation. To evaluate arterial stiffness, pulse wave velocity (PWV) was calculated using CCA diameter, and blood pressure was measured before and after stimulation., Results: PSV changes in the below-threshold level were significant ( p = 0.028). The PSV after below-threshold stimulation was significantly decreased by 2.23% compared to that before stimulation ( p = 0.031). PWV showed no significant differences; however, a nonsignificant increase was observed immediately after stimulation only in the above-threshold condition. Above-threshold stimulation can increase vascular tone by activating the sympathetic nerve, possibly triggering vasoconstriction., Conclusions: A decrease in blood flow velocity may not be expected upon the above-threshold stimulation. In contrast, the below-threshold stimulation immediately reduces blood flow velocity, without significantly affecting hemodynamic function, such as arterial flexibility. Therefore, this short-term and low electrical stimulation technique can help to lower vascular resistance and prevent vascular damage from rapid blood flow velocity.

Purpose: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with biliary tract cancer (BTC) with ERBB2/3 amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab are reported., Methods: Eligible patients had advanced BTC, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with ERBB2/3 alterations, and a lack of standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16+ weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety., Results: Twenty-nine patients were enrolled from February 2017 to January 2022, and all had advanced BTC with an ERBB2/3 alteration. One patient was not evaluable for efficacy. One complete response, eight partial responses, and two SD16+ were observed for DC and OR rates of 40% (90% CI, 27 to 100) and 32% (95% CI, 16 to 52), respectively. The null hypothesis of 15% DC rate was rejected ( P = .0015). Four patients had at least one grade 3 adverse event (AE) or serious AE at least possibly related to treatment: anemia, diarrhea, infusion-related reaction, and fatigue., Conclusion: Pertuzumab plus trastuzumab met prespecified criteria to declare a signal of activity in patients with BTC and ERBB2/3 amplification, overexpression, or mutation.

Reaction of a nucleophilic germylene Ge[CH(SiMe 3 ) 2 ] 2 with the phosphanyl phosphaketene [{(H 2 C)(NDipp)} 2 P]PCO induces decarbonylation to form a phosphanyl phosphagermene [{(H 2 C)(NDipp)} 2 P]P=Ge[CH(SiMe 3 ) 2 ] 2 (1; Dipp=2,6-diisopropyl-phenyl). Addition of CO 2 or MeCN to 1 results in [3+2]-cycloaddition reactions to afford five-membered heterocycles. This mode of reactivity is reminiscent of that observed for frustrated Lewis pairs, with the pendant phosphanyl group acting as a base and the germanium center as a Lewis acid. Contrastingly, 1,2-addition across the P=Ge bond was observed when using ammonia, small primary amines (NH 2 n P), or metal complexes (e. g. Au(PPh 3 )Cl and ZnEt 2 ). These latter reactions allow for the one-step synthesis of metal phosphide complexes., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Ribonucleotide Reductase (RNR) is a rate-limiting enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro. We also evaluated the selective RRM2 subunit inhibitor, 3-AP, as a radiosensitizer to treat pNET metastases in vivo. Knockdown of RNR subunits demonstrated that RRM1 and RRM2 subunits, but not p53R3, play significant roles in cell proliferation. RRM2 inhibition activated DDR pathways through phosphorylation of ATM and DNA-PK protein kinases but not ATR. RRM2 inhibition also induced Chk1 and Chk2 phosphorylation, resulting in G1/S phase cell cycle arrest. RRM2 inhibition sensitized pNET cells to radiotherapy and induced apoptosis in vitro. In vivo, we utilized pNET subcutaneous and lung metastasis models to examine the rationale for RNR-targeted therapy and 3-AP as a radiosensitizer in treating pNETs. Combination treatment significantly increased apoptosis of BON (human pNET) xenografts and significantly reduced the burden of lung metastases. Together, our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo. Therefore, treatment with the selective RRM2 inhibitor, 3-AP, is a promising radiosensitizer in the therapeutic armamentarium for metastatic pNETs., Competing Interests: Declaration of Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean IC 80 s of 0.314 and 0.033 µg mL -1 , respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To determine the feasibility and utility of conebeam CT-guided stereotactic radiotherapy for locally recurrent, previously irradiated head and neck cancer (HNC) patients on the Halcyon, a ring delivery system (RDS). This research aims to quantify plan quality, treatment delivery accuracy, and overall efficacy by comparing against novel clinical TrueBeam HyperArc method. Ten recurrent HNC patients who were treated at our institution on TrueBeam (6MV-FFF) for 30 to 40 Gy in 3 to 5 fractions with noncoplanar HyperArc plans were re-planned on Halcyon (6MV-FFF). These plans were re-planned with the same Acuros-based dose engine. Additionally, we used site-specific full/partial coplanar VMAT arcs. PTV coverage, mean dose to GTV, maximum dose to organs-at-risk (OAR), beam-on time (BOT), and quality assurance (QA) results were investigated and compared. Halcyon provided highly conformal HNC SRT plans with slightly superior mean PTVD99 coverage (96.7% vs 95.5%, p = 0.071), and slightly lower mean GTV dose (37.8 Gy vs 38.2 Gy, p = 0.241) when compared to the HyperArc plans. Differences in plan conformality and maximum dose to OARs were statistically insignificant. Due to Halcyon's coplanar geometry, D2cm was significantly higher (p = 0.001) but Halcyon did result in a reduced normal brain dose by 1 Gy on average and up to 5.2 Gy in some cases. Halcyon provided similar patient-specific QA pass rates with a 2%/2mm gamma criteria (98.2% vs 98.5%) and independent in-house Monte Carlo second check results (97.7% vs 98.2%), suggesting identical treatment delivery accuracy. Halcyon plans resulted in slightly longer beam-on time (3.16 vs 2.30 minutes, p = 0.010), however door-to-door patient time is expected to be <10 minutes. Compared to clinical TrueBeam HyperArc, Halcyon SRT plans provided similar plan quality and treatment delivery accuracy with a potentially faster overall treatment using fully automated patient setup and verification. Rapid delivery of recurrent HNC SRT may reduce intrafraction motion errors while also improving patient compliance and comfort. To provide high-quality of HNC SRT similar to HyperArc, we recommend Halcyon users consider commissioning this novel method. This method will be useful for remote and underserved patient cohorts including Halcyon-only clinics as well., (Copyright © 2023 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Development of assays to reliably identify and characterize anti-drug antibodies (ADAs) depends on positive control anti-idiotype (anti-id) reagents, which are used to demonstrate that the standards recommended by regulatory authorities are met. This work employs a set of therapeutic antibodies under clinical development and their corresponding anti-ids to investigate how different positive control reagent properties impact ADA assay development. Positive controls exhibited different response profiles and apparent assay analytical sensitivity values depending on assay format. Neither anti-id affinity for drug, nor sensitivity in direct immunoassays related to sensitivity in ADA assays. Anti-ids were differentially able to detect damage to drug conjugates used in bridging assays and were differentially drug tolerant. These parameters also failed to relate to assay sensitivity, further complicating selection of anti-ids for use in ADA assay development based on functional characteristics. Given this variability among anti-ids, alternative controls that could be employed across multiple antibody drugs were investigated as a more uniform means to define ADA detection sensitivity across drug products and assay protocols, which could help better relate assay results to clinical risks of ADA responses. Overall, this study highlights the importance of positive control selection to reliable detection and clinical interpretation of the presence and magnitude of ADA responses., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Osimertinib, a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively targets the EGFR T790M mutant in non-small cell lung cancer (NSCLC). However, the newly identified EGFR C797S mutation confers resistance to osimertinib. In this study, we explored the role of pyruvate dehydrogenase kinase 1 (PDK1) in osimertinib resistance. Patients exhibiting osimertinib resistance initially displayed elevated PDK1 expression. Osimertinib-resistant cell lines with the EGFR C797S mutation were established using A549, NCI-H292, PC-9, and NCI-H1975 NSCLC cells for both in vitro and in vivo investigations. These EGFR C797S mutant cells exhibited heightened phosphorylation of EGFR, leading to the activation of downstream oncogenic pathways. The EGFR C797S mutation appeared to increase PDK1-driven glycolysis through the EGFR/AKT/HIF-1α axis. Combining osimertinib with the PDK1 inhibitor leelamine helped successfully overcome osimertinib resistance in allograft models. CRISPR-mediated PDK1 knockout effectively inhibited tumor formation in xenograft models. Our study established a clear link between the EGFR C797S mutation and elevated PDK1 expression, opening new avenues for the discovery of targeted therapies and improving our understanding of the roles of EGFR mutations in cancer progression., (© 2024. The Author(s).)

Purpose: This study aimed to provide a novel noninvasive method to quantify abscopal immune activation and predict combinational treatment response using [ 68 Ga]-NOTA-GZP positron emission tomography (PET) imaging., Methods and Materials: 4T1 breast cancer cells were implanted bilaterally in the mammary fat pad of Balb/c mice and Lewis's lung cancer cells (LLC) were implanted bilaterally on the shoulders of C57/Bl6 mice. One of the tumors received a single fraction of 12 Gy irradiation followed by combination of concurrent PD-1 and CTLA-4 inhibitors or controls. Tumor growth of the irradiated and nonirradiated tumors was measured and compared with 12 Gy irradiation only, checkpoint inhibitor only, and no treatment control group. Changes in granzyme B activity were assessed with [ 68 Ga]-NOTA-GZP PET imaging from baseline and every 3 days until day 9., Results: In the 4T1 model, concurrent treatment with dual checkpoint inhibitors and radiation resulted in reduction of the irradiated tumor volume at day 30. At this same time point, the nonirradiated tumor volume for combination treatment decreased significantly, consistent with abscopal immune activation. Similarly, in the LLC model, concurrent treatment inhibited tumor growth on the nonirradiated tumor at day 15. On day 9, granzyme B PET signal in both 4T1 and LLC models was significantly higher in the nonirradiated tumors that responded to concurrent treatment compared with subsequent nonresponding tumors. A similar lack of granzyme B signal was observed in the nonirradiated tumors from mice that received radiation or checkpoint inhibitors only and control tumors. Receiver operating characteristic analysis identified a PET threshold of 1.505 and 1.233 on day 9 that predicted treatment response in 4T1 and LLC models, respectively., Conclusions: [ 68 Ga]-NOTA-GZP PET imaging was able to noninvasively predict abscopal immune activation before subsequent tumor volume changes after combination treatment. It provides a potential translational paradigm for investigating distal immune activation postradiation in a clinical setting., (Copyright © 2024. Published by Elsevier Inc.)

We introduce the arsenido ligand onto the Ti IV ion, yielding a remarkably covalent Ti≡As bond and the parent arsinidene Ti═AsH moiety. An anionic arsenido ligand is assembled via reductive decarbonylation involving the discrete Ti II salt [K(cryptand)][(PN) 2 TiCl] ( 1 ) (cryptand = 222-Kryptofix) and Na(OCAs)(dioxane) 1.5 in thf/toluene to produce the mixed alkali ate-complex [(PN) 2 Ti(As)] 2 (μ 2 -KNa(thf) 2 ) ( 2 ) and the discrete salt [K(cryptand)][(PN) 2 Ti≡As] ( 3 ) featuring a terminal Ti≡As ligand. Protonation of 2 or 3 with various weak acids cleanly forms the parent arsinidene [(PN) 2 Ti═AsH] ( 4 ), which upon deprotonation with KCH 2 Ph in thf generates the more symmetric anionic arsenido [(PN) 2 Ti(As){μ 2 -K(thf) 2 }] 2 ( 5 ). Experimental and computational studies suggest the p K a of 4 to be ∼23, and the bond orders in 2 , 3 , and 5 are all in the range of a Ti≡As triple bond, with decreasing bond order in 4 .

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Targeted therapy against the epidermal growth factor receptor (EGFR) is a promising treatment approach for NSCLC. However, resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major challenge in its clinical management. EGFR mutation elevates the expression of hypoxia-inducible factor-1 alpha to upregulate the production of glycolytic enzymes, increasing glycolysis and tumor resistance. The inhibition of glycolysis can be a potential strategy for overcoming EGFR-TKI resistance and enhancing the effectiveness of EGFR-TKIs. In this review, we specifically explored the effectiveness of pyruvate dehydrogenase kinase inhibitors and lactate dehydrogenase A inhibitors in combating EGFR-TKI resistance. The aim was to summarize the effects of these natural products in preclinical NSCLC models to provide a comprehensive understanding of the potential therapeutic effects. The study findings suggest that natural products can be promising inhibitors of glycolytic enzymes for the treatment of EGFR-TKI-resistant NSCLC. Further investigations through preclinical and clinical studies are required to validate the efficacy of natural product-based glycolytic inhibitors as innovative therapeutic modalities for NSCLC.

Photoredox catalysis has flourished in recent years, but due to its widespread utility applications have grown faster than mechanistic understanding. In this report we help to address this deficit by isolating and characterising one of the intermediates of the iconic photocatalyst [Ru(bipy) 3 ] 2+ , and testing its initial photoreactivity towards common substrates.

We describe the facile synthesis of [(Me 3 Si) 2 CH] 2 E=PMes* (E=Ge, Sn) from the reaction of the tetrylenes with the phospha-Wittig reagent, Me 3 P-PMes*. Their reactivity towards a range of substrates with protic and hydridic E-H bonds (E=N, O, Si) is described. In addition to hydroelementation reactions of the E=P bonds, we show that these compounds, particularly [(Me 3 Si) 2 CH] 2 Sn=PMes*, also act as base-stabilized phosphinidenes, allowing phosphinidene transfer to other nucleophiles., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T., Patients and Methods: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing., Results: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response., Conclusions: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy., Competing Interests: Disclosure KJ: Consultant/Advisory Board: Novartis, AstraZeneca, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, AbbVie, Eisai, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Gilead, Olema Pharmaceuticals, Sun Pharma Advanced Research Company Ltd., Menarini/Stemline, and Scorpion Therapeutics. Research Funding: Novartis, Genentech/Roche, AstraZeneca, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals/Loxo Oncology, Zymeworks, Gilead, Puma Biotechnology, Merck Pharmaceuticals, and Scorpion Therapeutics. HW: His institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Daiichi Sankyo, Gilead, Lilly, Augustine Therapeutics, AstraZeneca, Immutep Pty, MSD, and Roche. He received travel support from Gilead, Daiichi Sankyo, and Pfizer. SAH: Contracted research paid to institution +/- editorial support for authorship: Ambrx, Arvinas, AstraZeneca, Bayer, Celcuity, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, Greenwich Life Sciences Inc., GSK, Immunomedics, Eli Lilly, Loxo, Macrogenics, Novartis, OBI Pharma, Orinove, Orum, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Sanofi, Seattle Genetics/Seagen, and Zymeworks. Speaking: Daiichi Sankyo (2021). AG-Z: Advisory/Consultancy: AstraZeneca, Novartis, MSD, Pierre-Fabre, and Exact Science. Speaker Bureau/Expert testimony: Roche, AstraZeneca, Novartis, MSD, Pfizer, Lilly, and Pierre-Fabre. Research grant/Funding (institution): Pfizer. Travel/Accommodation/Expenses: Roche, Novartis, and Pfizer. NU: Consultant/Advisory Board: Novartis, Eli Lilly, BioTheranostics, Gilead. AB: Consultant: AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma, Myriad, and Gilead; research support: Agendia and AstraZeneca. HP: Research grants to institution: Adlai Nortye USA, Ambrx, Aprea Therapeutics AB, Array BioPharma, AstraZeneca, BJ Bioscience, Bristol-Myers Squibb, Daiichi Pharmaceutical, Elicio Therapeutics, Exelixis, Fate Therapeutics, Genentech, GlaxoSmithKline, Gossamer Bio, Hutchison MediPharma, ImmuneOncia Therapeutics, ImmunoGen, Mabspace Biosciences, MacroGenics, Merck, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, PsiOxus Therapeutics, RePare Therapeutics, Seattle Genetics, Synermore Biologics, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Xencor. ESY: Research funding: Puma Biotechnology; Advisory boards: Bayer, Clovis; Consultant: AstraZeneca. IS: Institutional Research Funding: Roche/Genentech, Puma Biotechnology, MSD, Merck, AstraZeneca, Incyte, Orion, Genmab, Bristol-Myers Squibb, Bayer/Loxo Oncology, Lilly Pharmaceuticals/Loxo Oncology, Novartis, Pfizer, Amgen, Repare Therapeutics. Honoraria: AstraZeneca. Support for travel and meeting attendance: Roche, Novartis, Merck/Pfizer, Incyte, and AstraZeneca. SR: Consultant/Advisory board: Novartis, AstraZeneca, Gilead, and Daiichi Sankyo. MBh: Consulting/Advisory Board: Daiichi Sankyo, Merck, Pfizer, and AstraZeneca. SV: Funding from Pfizer directly to institution for conducting clinical trial. MA: Consulting or advisory role: Pfizer, AstraZeneca, Menarini, Novartis, Daiichi Sankyo, and Gilead. Speaker’s bureau: Pfizer, Novartis, and Gilead. Research funding: AstraZeneca. F-CB: Consulting or advisory role: Pfizer; AstraZeneca; Lilly; Novartis; Menarini; Sanofi; GSK; Rain Oncology; Caris Life Sciences; GE Healthcare; Exact Sciences; Gilead. Speaker's bureau: Pfizer; Novartis; AstraZeneca; Roche; Lilly; Rain Oncology; Daiichi Sankyo; and Menarini-Stemline. Research Funding: Novartis; Pfizer; Menarini Silicon Biosystems; Prolynx; Merck KGaA; and GE Healthcare. SL: Receives research funding to her institution from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnology, Inc., Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb. JC: Has taken part in advisory boards for Puma Biotechnology. His unit is the recipient of a peer-reviewed grant from Science Foundation Ireland (an Irish government organization) which is part-funded by Puma Biotechnology Inc. Neither he nor his spouse own Puma Biotechnology stock. MEB: Medical advisory board of Strata Oncology; Research funding from AbbVie, Arcus, Apollomics, Elevation Oncology, Endeavor, Genetech, Puma, Loxo Oncology, and Seagen. SAP-P: Clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immorna Biotherapeutics, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, ZielBio, Inc., NCI/NIH, P30CA016672—Core Grant (CCSG Shared Resources); and consulting fees from CRC Oncology. JMS: Research grant support: AstraZeneca and Strata Oncology. SC: Advisory/Consultancy: Novartis, F. Hoffmann-La Roche, Pfizer, Eli Lilly, AstraZeneca, Amgen, Gilead, Merck, and Exact Sciences. Research funding to the institution: Novartis, F. Hoffmann-La Roche, Pfizer, Genomic Health/Exact Sciences, AstraZeneca, Genentech, Celgene, Amgen, BMS, Merck, Sanofi, Puma, and Gilead. CS: Consulting, advisory role or travel grants from: AstraZeneca, AX'Consulting, Byondis B.V, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd., Lilly, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre-Fabre, PintPharma, Puma Biotechnology, Seagen, and Zymeworks. JAG-S: Consulting or advisory role: Novartis Pharmaceuticals Corporation, AstraZeneca, Lilly, Seagen, Daiichi Sankyo, Gilead Sciences, Exact Sciences, and Stemline Menarini; speakers bureau: Novartis Pharmaceuticals Corporation, Lilly, AstraZeneca, and Stemline Menarini; travel, accommodations, expenses: Daiichi Sankyo, Gilead Sciences, and Exact Sciences. VG: Advisory Board: Boehringer. Research Funding: Bayer, Boehringer, Roche. Institutional Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, and MSD. ENG-Y: Honoraria from Novartis, Pfizer, Eli Lilly, MSD, and AstraZeneca. CM: Has received research grants from Puma Biotechnology and Pfizer. She received consulting fees from AstraZeneca, Olaris, Novartis, and Sanofi. ABH: Reports stock and other ownership interests in Pfizer (immediate family member) and research funding from Takeda. JWG: has received institutional research funding from Puma Biotechnology Inc. RB: Receives research grant from Puma; has performed consulting for Genentech. JSKB: Employee (and stockholder) of Tempus Labs. LDE, DD, AF, and AW: Employees and stockholders of Puma Biotechnology. CLA: Has received research grants from Pfizer, Lilly, and Takeda. He serves or has served as scientific advisor to Novartis, Lilly, AstraZeneca, Daiichi Sankyo, Merck, Immunomedics, OrigiMed, Sanofi, TAIHO Oncology, and Puma Biotechnology. DBS: Has served as a consultant for/received honorarium from Pfizer, Vividion Therapeutics, Scorpion Therapeutics, FORE Therapeutics, Fog Pharma, Elsie Biotechnologies, Fog Pharma, Rain Oncology, Function Oncology, and BridgeBio. All other authors have declared no conflicts of interest. Data Sharing The authors declare that the data supporting the findings of this study are available within the article. Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several examples of the cyaphide-azide 1,3-dipolar cycloaddition reaction to afford metallo-triazaphospholes are reported. The gold(I) triazaphospholes Au(IDipp)(CPN 3 R) (IDipp=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; R= t Bu, Ad, Dipp), magnesium(II) triazaphospholes, {Mg( Dipp NacNac)(CPN 3 R)} 2 ( Dipp NacNac=CH{C(CH 3 )N(Dipp)} 2 , Dipp=2,6-diisopropylphenyl; R= t Bu, Bn), and germanium(II) triazaphosphole Ge( Dipp NacNac)-(CPN 3 t Bu) can be prepared straightforwardly, under mild conditions and in good yields, in a manner reminiscent of the classic alkyne-azide click reaction (albeit without a catalyst). This reactivity can be extended to compounds with two azide functional groups such as 1,3-diazidobenzene. It is shown that the resulting metallo-triazaphospholes can be used as precursors to carbon-functionalized species, including protio- and iodo-triazaphospholes., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Purpose: Stereotactic body radiation therapy (SBRT) is increasingly used as a definitive treatment option for patients with prostate adenocarcinoma. The aim of this study was to assess the late toxicity, patient-reported quality of life outcomes, and biochemical recurrence rates after prostate SBRT with simultaneous integrated boost (SIB) targeting lesions defined by magnetic resonance imaging (MRI)., Methods and Materials: Patients were eligible if they had biopsy-proven low- or intermediate-risk prostate adenocarcinoma, one or more focal lesions on MRI, and an MRI-defined total prostate volume of <120 mL. All patients received SBRT delivered to the entire prostate to a dose of 36.25 Gy in 5 fractions with an SIB to the lesions seen on MRI to 40 Gy in 5 fractions. Late toxicity was defined as any possible treatment-related adverse event occurring after 3 months from the completion of SBRT. Patient-reported quality of life was ascertained using standardized patient surveys., Results: A total of 26 patients were enrolled. Six patients (23.1%) had low-risk disease and 20 patients had intermediate-risk disease (76.9%). Seven patients (26.9%) received androgen deprivation therapy. Median follow-up was 59.5 months. No biochemical failures were observed. Three patients (11.5%) experienced late grade 2 genitourinary (GU) toxicity requiring cystoscopy, and 7 patients (26.9%) had late grade 2 GU toxicity requiring oral medications. Three patients (11.5%) had late grade 2 gastrointestinal toxicity characterized by hematochezia requiring colonoscopy and steroids per rectum. There were no grade 3 or higher toxicity events observed. The patient-reported quality-of-life metrics at the time of last follow-up were not significantly different than the pre-treatment baseline., Conclusions: The results of this study support that SBRT to the entire prostate to a dose of 36.25 Gy in 5 fractions with focal SIB to 40 Gy in 5 fractions has excellent biochemical control and is not associated with undue late gastrointestinal or GU toxicity or long-term quality of life decrement. Focal dose escalation with an SIB planning approach may be an opportunity to improve biochemical control while limiting dose to nearby organs at risk., Competing Interests: Disclosures Eddy S. Yang reports research grants from Eli Lilly, AstraZeneca, Clovis, NIH, and ASCO unrelated to the present study; consulting fees from AstraZeneca and Bayer unrelated to the present study; and being Chair of Research Advisory Board (unpaid) and a steering committee member of ASCO TAPUR (unpaid). Rex A. Cardan reports grants, royalties, consulting fees, and honoraria from Varian Medical Systems unrelated to the present study. Richard Popple reports contracts with institution and honoraria from Varian Medical Systems unrelated to the present study, and UAB Research Foundation and Varian Medical Systems patent and royalties unrelated to the present study. Soroush Rais-Bahrami reports Genomic Health Inc and Blue Earth Diagnostics research funding unrelated to the present study, and MDxHealth, Intuitive Surgical, Bayer Healthcare, Progenics/Lantheus, Exact Sciences, Boston Scientific, and UroViu Corp consulting fees unrelated to the present study. John B. Fiveash reports grants from Varian Medical Systems unrelated to the present study. Andrew M. McDonald reports grants from Varian Medical Systems unrelated to the present study., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

New vaccine delivery technologies, such as mRNA, have played a critical role in the rapid and efficient control of SARS-CoV-2, helping to end the COVID-19 pandemic. Enveloped virus-like particles (eVLPs) are often more immunogenic than protein subunit immunogens and could be an effective vaccine platform. Here, we investigated whether the genetic delivery of eVLPs could achieve strong immune responses in mice as previously reported with the immunization of in vitro purified eVLPs. We utilized Newcastle disease virus-like particles (NDVLPs) to display SARS-CoV-2 prefusion-stabilized spikes from the WA-1 or Beta variant (S-2P or S-2Pᵦ, respectively) and evaluated neutralizing murine immune responses achieved by a single-gene-transcript DNA construct for the WA-1 or Beta variant (which we named S-2P-NDVLP-1T and S-2Pᵦ-NDVLP-1T, respectively), by multiple-gene-transcript DNA constructs for the Beta variant (S-2Pᵦ-NDVLP-3T), and by a protein subunit-DNA construct for the WA-1 or Beta variant (S-2P-TM or S-2Pᵦ-TM, respectively). The genetic delivery of S-2P-NDVLP-1T or S-2Pᵦ-NDVLP-1T yielded modest neutralizing responses after a single immunization and high neutralizing responses after a second immunization, comparable to previously reported results in mice immunized with in vitro purified S-2P-NDVLPs. Notably, genetic delivery of S-2Pᵦ-NDVLP-3T yielded significantly higher neutralizing responses in mice after a second immunization than S-2Pᵦ-NDVLP-1T or S-2Pᵦ-TM. Genetic delivery also elicited high spike-specific T-cell responses. Collectively, these results indicate that genetic delivery can provide an effective means to immunize eVLPs and that a multiple-gene transcript eVLP platform may be especially efficacious and inform the design of improved vaccines.

While several COVID-19 vaccines have been in use, more effective and durable vaccines are needed to combat the ongoing COVID-19 pandemic. Here, we report highly immunogenic self-assembling SARS-CoV-2 spike-HBsAg nanoparticles displaying a six-proline-stabilized WA1 (wild type, WT) spike S6P on a HBsAg core. These S6P-HBsAgs bound diverse domain-specific SARS-CoV-2 monoclonal antibodies. In mice with and without a HBV pre-vaccination, DNA immunization with S6P-HBsAgs elicited significantly more potent and durable neutralizing antibody (nAb) responses against diverse SARS-CoV-2 strains than that of soluble S2P or S6P, or full-length S2P with its coding sequence matching mRNA-1273. The nAb responses elicited by S6P-HBsAgs persisted substantially longer than by soluble S2P or S6P and appeared to be enhanced by HBsAg pre-exposure. These data show that genetic delivery of SARS-CoV-2 S6P-HBsAg nanoparticles can elicit greater and more durable nAb responses than non-nanoparticle forms of stabilized spike. Our findings highlight the potential of S6P-HBsAgs as next generation genetic vaccine candidates against SARS-CoV-2., (© 2023. Springer Nature Limited.)

We review the known chemistry of the cyaphide ion, (C≡P) - . This remarkable diatomic anion has been the subject of study since the late nineteenth century, however its isolation and characterization eluded chemists for almost a hundred years. In this mini-review, we explore the pioneering synthetic experiments that first allowed for its isolation, as well as more recent developments demonstrating that cyaphide transfer is viable in well-established salt-metathesis protocols. The physical properties of the cyaphide ion are also explored in depth, allowing us to compare and contrast the chemistry of this ion with that of its lighter congener cyanide (an archetypal strong field ligand and important organic functional group). Recent studies show that the cyaphide ion has the potential to be used as a versatile chemical regent for the synthesis of novel molecules and materials, hinting at many interesting future avenues of investigation., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, we report the crystal structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) in complex with MAb WRAIR-2063, a moderate-potency neutralizing antibody with exceptional sarbecovirus breadth, that targets the highly conserved cryptic class V epitope. This epitope overlaps substantially with the spike protein N-terminal domain (NTD) -interacting region and is exposed only when the spike is in the open conformation, with one or more RBDs accessible. WRAIR-2063 binds the RBD of SARS-CoV-2 WA-1, all variants of concern (VoCs), and clade 1 to 4 sarbecoviruses with high affinity, demonstrating the conservation of this epitope and potential resiliency against variation. We compare structural features of additional class V antibodies with their reported neutralization capacity to further explore the utility of the class V epitope as a pan-sarbecovirus vaccine and therapeutic target. IMPORTANCE Characterization of MAbs against SARS-CoV-2, elicited through vaccination or natural infection, has provided vital immunotherapeutic options for curbing the COVID-19 pandemic and has supplied critical insights into SARS-CoV-2 escape, transmissibility, and mechanisms of viral inactivation. Neutralizing MAbs that target the RBD but do not block ACE2 binding are of particular interest because the epitopes are well conserved within sarbecoviruses and MAbs targeting this area demonstrate cross-reactivity. The class V RBD-targeted MAbs localize to an invariant site of vulnerability, provide a range of neutralization potency, and exhibit considerable breadth against divergent sarbecoviruses, with implications for vaccine and therapeutic development., Competing Interests: The authors declare a conflict of interest. Patent application number PCT/US 63/140,763, PCT WO 2022/159839 A1 was filed containing the mAbs described in this publication for authors S.J.K., K.M., V.D., and N.L.M. M.G.J. and K.M. are named as inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on international patent application WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion coronavirus spike proteins and their use.” The other authors declare no competing interests.

Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment., Significance: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown., (© 2023 The Authors; Published by the American Association for Cancer Research.)

HER2-targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2-targeted therapies, have demonstrated sensitivity to poly-(ADP-ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2- breast cancer cells. Further, we evaluated the utility of 3'-Deoxy-3'-[ 18 F]-fluorothymidine positron emission tomography ([ 18 F]FLT-PET) imaging for early response assessment in a HER2+ patient derived xenograft (PDX) model of breast cancer. In vitro, we observed decreased cell viability. In vivo, we observed decreased inhibition in tumor growth in combination therapies, compared to vehicle and monotherapy-treated cohorts. Early assessment of cellular proliferation corresponds to endpoint cell viability. Standard summary statistics of [ 18 F]FLT uptake from PET were insensitive to early proliferative changes. Meanwhile, histogram analysis of [ 18 F]FLT uptake indicated the potential translatability of imaging proliferation biomarkers. This study highlights the potential of combined trastuzumab and PARP inhibition in HER2+ breast cancer, while demonstrating a need for optimization of [ 18 F]FLT-PET quantification in heterogeneous models of HER2+ breast cancer.

Background: There is a deficiency of palliative care education in surgical residency programs and a lack of research on palliative care education in rural surgery residency programs. Because rural palliative care presents unique challenges due to fewer specialists and resources, we investigated potential areas of improvement in palliative care education in a rural general surgery residency program., Methods: An anonymous survey was sent to all residents of a rural general surgery residency program. The survey assessed prior hospice/palliative care education in medical school, prior volunteering experience in palliative care, comfort with having "goals of care" discussions and delivering serious news, and perceived indications for palliative care consultation. A follow-up survey assessed attitudes and interest related to palliative care education integration in a rural surgical residency program., Results: Of 17 residents, 14 (82.4%) responded to the initial survey. Four respondents (28.6%) had over a half day of palliative care education in medical school. Eight of fourteen respondents (57.1%) feel comfortable having "goals of care" discussions: 0/4 interns (0%) compared to 8/10 junior and senior residents (80%). Half of respondents feel comfortable delivering serious news: 1/4 interns (25%) compared to 6/10 junior and senior residents (60%). All respondents agreed that palliative care education is necessary. Four themes were identified in content analysis of perceived indications for palliative care consultation: future planning, deferring to the expert, patient/family education, and surgeon/trainee discomfort. The follow-up survey revealed perceived limitations in palliative care resources available in a rural surgery setting., Conclusions: These results highlight the need for formal palliative care education in a rural surgery residency program. Throughout training, residents appear to develop more comfort with "goals of care" discussions than delivering serious news. In response, we are instituting palliative care discussions during educational conference, including interactive simulations to improve communication skills, and a palliative care telemedicine elective.

Alphaviruses are RNA viruses that represent emerging public health threats. To identify protective antibodies, we immunized macaques with a mixture of western, eastern, and Venezuelan equine encephalitis virus-like particles (VLPs), a regimen that protects against aerosol challenge with all three viruses. Single- and triple-virus-specific antibodies were isolated, and we identified 21 unique binding groups. Cryo-EM structures revealed that broad VLP binding inversely correlated with sequence and conformational variability. One triple-specific antibody, SKT05, bound proximal to the fusion peptide and neutralized all three Env-pseudotyped encephalitic alphaviruses by using different symmetry elements for recognition across VLPs. Neutralization in other assays (e.g., chimeric Sindbis virus) yielded variable results. SKT05 bound backbone atoms of sequence-diverse residues, enabling broad recognition despite sequence variability; accordingly, SKT05 protected mice against Venezuelan equine encephalitis virus, chikungunya virus, and Ross River virus challenges. Thus, a single vaccine-elicited antibody can protect in vivo against a broad range of alphaviruses., Competing Interests: Declaration of interests NIH has submitted a provisional patent application for select antibodies described in this manuscript on which M.S.S., S.K., R.V., P.D.K., and M.R. are co-inventors., (Published by Elsevier Inc.)

Enterovirus D68 (EV-D68) causes severe respiratory illness in children and can result in a debilitating paralytic disease known as acute flaccid myelitis. No treatment or vaccine for EV-D68 infection is available. Here, we demonstrate that virus-like particle (VLP) vaccines elicit a protective neutralizing antibody against homologous and heterologous EV-D68 subclades. VLP based on a B1 subclade 2014 outbreak strain elicited comparable B1 EV-D68 neutralizing activity as an inactivated viral particle vaccine in mice. Both immunogens elicited weaker cross-neutralization against heterologous viruses. A B3 VLP vaccine elicited more robust neutralization of B3 subclade viruses with improved cross-neutralization. A balanced CD4 + T helper response was achieved using a carbomer-based adjuvant, Adjuplex. Nonhuman primates immunized with this B3 VLP Adjuplex formulation generated robust neutralizing antibodies against homologous and heterologous subclade viruses. Our results suggest that both vaccine strain and adjuvant selection are critical elements for improving the breadth of protective immunity against EV-D68.

The synthesis of group 9 pyridine-diimine complexes M( Dipp PDI)X and [M( Dipp PDI)L] + (M = Co, Rh; Dipp PDI = 1,1'-(pyridine-2,6-diyl)bis( N -(2,6-diisopropylphenyl)ethan-1-imine); X = CP - , CCH - ; L = CO, t BuNC) bearing a series of strong-field ligands, including the cyaphide ion (C[triple bond, length as m-dash]P - ), is reported. A combined experimental and computational comparative study of the group 9 PDI cyaphide complexes Co( Dipp PDI)(CP) and Rh( Dipp PDI)(CP), as well as the N-heterocyclic carbene (NHC) gold(i) cyaphide complex Au(IDipp)(CP) (IDipp = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), reveals the σ donor and π acceptor properties of the κ C -cyaphido ligand, and allow us to suggest a position for this ion in the spectrochemical series., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: In nonmetastatic hormone receptor-positive and Her2-negative breast cancer, preoperative endocrine therapies can yield outcomes similar with chemotherapy. We evaluated the tolerability and preliminary antitumor activity of preoperative letrozole, everolimus, and carotuximab, a monoclonal antibody targeting endoglin, in nonmetastatic breast cancer., Methods: Eligible patients had newly diagnosed, stage 2 or 3, hormone receptor-positive and Her2/neu-negative breast cancer. Patients received escalating doses of everolimus; the dose of letrozole and carotuximab were fixed at 2.5 mg PO daily and 15 mg/kg intravenously every 2 weeks, respectively. The primary objective was to determine the safety and tolerability of the combination. Secondary objectives included pharmacokinetic and pharmacodynamic studies and assessments of antitumor activity., Results: Fifteen patients enrolled. The recommended phase 2 dose of everolimus in combination with letrozole and carotuximab was 10 mg PO daily. The most frequent adverse events were headache (67%), fatigue (47%), facial flushing and swelling (47%), gingival hemorrhage (40%), epistaxis (33%), nausea and vomiting (27%). Headache constituted a dose-limiting toxicity. At least two signs of mucocutaneous telangiectasia developed in 92% of patients. Carotuximab accumulated in the extravascular space and accelerated the biodistribution and clearance of everolimus. All patients had residual disease. Gene expression analyses were consistent with downregulation of genes involved in proliferation and DNA repair. Among 6 patients with luminal B breast cancer, 5 converted to luminal A after one cycle of therapy., Conclusion: Letrozole, everolimus, and carotuximab were tolerated in combination at their single-agent doses. Pharmacokinetic studies revealed an interaction between everolimus and carotuximab., Trial Registration: This trial is registered with ClinicalTrials.gov (Identifier: NCT02520063), first posted on August 11, 2015, and is active, not recruiting., (© 2023. The Author(s).)

Purpose: Cancer trial participants do not reflect the racial and ethnic diversity in the population of people with cancer in the United States. As a result of multiple system-, patient-, and provider-level factors, including implicit bias, cancer clinical trials are not consistently offered to all potentially eligible patients., Materials and Methods: ASCO and ACCC evaluated the utility (pre- and post-test knowledge changes) and feasibility (completion rates, curriculum satisfaction metrics, survey questions, and interviews) of a customized online training program combined with facilitated peer-to-peer discussion designed to help research teams identify their own implicit biases and develop strategies to mitigate them. Discussion focused on (1) specific elements of the training modules; (2) how to apply lessons learned; and (3) key considerations for developing a facilitation guide to support peer-to-peer discussions in cancer clinical research settings. We evaluated discussion via a qualitative assessment., Results: Participant completion rate was high: 49 of 50 participating cancer programs completed training; 126 of 129 participating individuals completed the training (98% response rate); and 119 completed the training and evaluations (92% response rate). Training increased the mean percentage change in knowledge scores by 19%-45% across key concepts (eg, causes of health disparities) and increased the mean percentage change in knowledge scores by 10%-31% about strategies/actions to address implicit bias and diversity concerns in cancer clinical trials. Knowledge increases were sustained at 6 weeks. Qualitative evaluation validated the utility and feasibility of facilitated peer-to-peer discussion., Conclusion: The pilot implementation of the training program demonstrated excellent utility and feasibility. Our evaluation affirms that an online training designed to raise awareness about implicit bias and develop strategies to mitigate biases among cancer research teams is feasible and can be readily implemented in cancer research settings.

Metabolic disorder is a major characteristic of cancer cells, and controlling genes involved in metabolic shifts can be an effective strategy for cancer treatment. Andrographolide (AG), a diterpenoid lactone, is widely recognized as a natural anticancer drug due to its ability to inhibit cancer growth. The present study aimed to investigate the mechanism underlying the mitochondrial‑mediated anticancer effect of AG by inhibiting pyruvate dehydrogenase kinase 1 (PDK1) expression in lung cancer cells. Cells were treated with AG and PDK1 mRNA and protein expression was determined using reverse transcription‑quantitative PCR and western blotting, respectively. As a result, AG significantly inhibited the viability of human lung cancer cells and suppressed aerobic glycolysis by decreasing lactate generation. AG further decreased the PDK1 protein and mRNA levels in a dose‑dependent manner. AG‑induced cell death was assessed by flow cytometry and fluorescence microscopy. AG induced apoptotic cell death that was associated with the cleavage of poly (ADP ribose) polymerase, activation of caspase‑3, and mitochondrial damage, which was associated with an increase in reactive oxygen species and loss of mitochondrial membrane potential. AG‑induced cell death was partially suppressed via PDK1 overexpression in lung cancer cells. Therefore, the anticancer effects of AG on human lung cancer cells may negatively regulate the expression of PDK1.

The cyaphide anion, CP - , is shown to undergo three distinct oligomerization reactions in the coordination sphere of metals. Reductive coupling of Au(IDipp)(CP) (IDipp=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) by Sm(Cp*) 2 (OEt 2 ) (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl), was found to afford a tetra-metallic complex containing a 2,3-diphosphabutadiene-1,1,4,4-tetraide fragment. By contrast, non-reductive dimerization of Ni(SIDipp)(Cp)(CP) (SIDipp=1,3-bis(2,6-diisopropylphenyl)-imidazolidin-2-ylidene; Cp=cyclopentadienyl), gives rise to an asymmetric bimetallic complex containing a 1,3-diphosphacyclobutadiene-2,4-diide moiety. Spontaneous trimerization of Sc(Cp*) 2 (CP) results in the formation of a trimetallic complex containing a 1,3,5-triphosphabenzene-2,4,6-triide fragment. These transformations show that while cyaphido transition metal complexes can be readily accessed using metathesis reactions, many such species are unstable to further oligomerization processes., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Purpose: To validate the association between body composition and mortality in men treated with radiation for localized prostate cancer (PCa). Secondarily, to integrate body composition as a factor to classify patients by risk of all-cause mortality., Materials and Methods: Participants of NRG/Radiation Therapy Oncology Group (RTOG) 9406 and NRG/RTOG 0126 with archived computed tomography were included. Muscle mass and muscle density were estimated by measuring the area and attenuation of the psoas muscles on a single slice at L4-L5. Bone density was estimated by measuring the attenuation of the vertebral body at mid-L5. Survival analyses, including Cox proportional hazards models, assessed the relationship between body composition and mortality. Recursive partitioning analysis (RPA) was used to create a classification tree to classify participants by risk of death., Results: Data from 2066 men were included in this study. In the final multivariable model, psoas area, comorbidity score, baseline prostate serum antigen, and age were significantly associated with survival. The RPA yielded a classification tree with four prognostic groups determined by age, comorbidity, and psoas area. Notably, the classification among older (≥70 years) men into prognostic groups was determined by psoas area., Conclusions: This study strongly supports that body composition is related to mortality in men with localized PCa. The inclusion of psoas area in the RPA classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. More research is needed to determine the clinical impact of body composition on prognostic models in men with PCa., (© 2022 American Cancer Society.)

Background: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction., Methods: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients., Results: Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low., Conclusions: The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications., (© 2023. The Author(s).)

Purpose: The TAPUR Study is a phase II basket trial that aims to evaluate activity of approved targeted agents in patients with advanced cancers with potentially actionable genomic variants. Data from a cohort of patients with metastatic castrate-resistant prostate cancer (mCRPC) and BRCA1 / 2 mutations treated with olaparib are reported., Methods: Eligible patients with measurable mCRPC were matched to treatment according to protocol-specified genomic matching rules. Patients had no remaining standard treatment options, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Simon's two-stage design was used with a primary end point of disease control, defined as objective response or stable disease of at least 16-week duration. Secondary end points include radiographic progression-free survival, overall survival, duration of response, duration of stable disease, and safety., Results: Thirty patients with mCRPC with BRCA1 / 2 mutations were treated with olaparib. The disease control rate was 69% (95% CI, 51 to 81), and the objective response rate was 58% (95% CI, 37 to 77). The median radiographic progression-free survival and the median overall survival were 38.4 (95% CI, 16.3 to 52.1) weeks and 76.4 (95% CI, 49.3 to 106.0) weeks, respectively. Six of 30 (20%) patients experienced grade 3-4 adverse or serious adverse events including anemia, aspiration, decreased WBC count, and fatigue., Conclusion: Olaparib has antitumor activity in patients with mCRPC with BRCA1 / 2 mutations and warrants further study to determine how to best integrate it into the standard treatment of patients with BRCA1 / 2 -mutated prostate cancer.

Purpose: To assess trans-regional differences, reproducibility across different MRI scanners, and interobserver agreement of liver surface nodularity (LSN) score from routine liver MRI and to evaluate the correlation between LSN score and liver stiffness (LS) value on MR elastography., Materials and Methods: Ninety patients who underwent gadoxetic acid-enhanced liver MRI twice using different MRI scanners within a year were evaluated. On axial hepatobiliary phase images, right anterior (LSN RT&#95;ANT ), right posterior (LSN RT&#95;POST ), and left anterior hepatic surface (LSN LT ) were chosen for the quantification of LSN score. Repeated-measures ANOVA, paired t test, Pearson's correlation coefficient analysis, and intraclass correlation coefficient (ICC) were used for statistical analysis., Results: LSN scores from high to low were LSN RT&#95;POST , LSN RT&#95;ANT , and LSN LT , representing trans-regional differences (p < 0.001). Reproducibility of LSN measurement across different MRI scanners was high to excellent (ICC = 0.838-0.921). The mean difference between first and second examinations in LSN RT&#95;ANT , LSN RT&#95;POST , and LSN LT were 0.032 (p = 0.013), 0.002 (p = 0.910), and 0.010 (p = 0.285) for reader 1 and 0.051 (p = 0.004), 0.061 (p = 0.002), and 0.023 (p = 0.005) for reader 2. The first and second examinations were highly correlated in all hepatic regions (r = 0.712-0.839, p < 0.001). There was a low to moderate correlation between LSN score and LS value (r = 0.364-0.592, p ≤ 0.001), which was higher in the chronic hepatitis B (CHB) group than in the non-CHB group in all hepatic regions., Conclusions: In our study, LSN measurement on liver MRI showed trans-regional differences and excellent reproducibility across different MRI scanners. To use LSN score more widely, standardization of quantification software and selected hepatic regions is needed., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The reaction of TaMe 3 Cl 2 with the rigid acridane-derived trisamine H 3 NNN yields the tantalum(V) complex [TaCl 2 (NNN cat )]. Subsequent reaction with dioxygen results in the full four-electron reduction of O 2 yielding the oxido-bridged bimetallic complex [{TaCl 2 (NNN sq )} 2 O]. This dinuclear complex features an open-shell ground state due to partial ligand oxidation and was comprehensively characterized by single crystal X-ray diffraction, LIFDI mass spectrometry, NMR, EPR, IR and UV/VIS/NIR spectroscopy. The mechanism of O 2 activation was investigated by DFT calculations revealing initial binding of O 2 to the tantalum(V) center followed by complete O 2 scission to produce a terminal oxido-complex., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Purpose: To identify the safety of niraparib, a PARP inhibitor, in combination with Radium-223 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations., Patients and Methods: Men with progressive mCPRC following ≥1 line of androgen receptor (AR)-targeted therapy and bone metastases but no documented BRCA-1 or BRCA-2 alterations or bulky visceral disease were included. Niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The highest dose level with a DLT probability <20% was defined as MTD. Secondary endpoints included PSA change and progression-free survival. Exploratory analyses included assessing DNA mutations found in ctDNA as well as gene expression changes assessed in whole blood samples., Results: Thirty patients were treated with niraparib and radium-223: 13 patients received 100 mg, 12 received 200 mg, and 5 patients received 300 mg of niraparib. There were six DLT events: two (13%) for neutropenia, two (13%) for thrombocytopenia, whereas fatigue and nausea each occurred once (3%). Anemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events. For patients with prior chemotherapy exposure, the MTD was 100 mg, whereas the MTD for chemotherapy naïve patients was 200 mg. Whole blood gene expression of PAX5 and CD19 was higher in responders and ARG-1, IL2R, and FLT3 expression was higher in nonresponders., Conclusions: Combining niraparib with Radium-223 in patients with mCRPC was safe; however, further studies incorporating biomarkers will better elucidate the role of combinations of PARP inhibitors with DNA damaging and other agents., (©2022 American Association for Cancer Research.)

Antibody CAP256-VRC26.25 targets the second hypervariable region (V2) at the apex of the HIV envelope (Env) trimer with extraordinary neutralization potency, although less than optimal breadth. To improve breadth, we linked the light chain of CAP256V2LS, an optimized version of CAP256-VRC26.25 currently under clinical evaluation, to the llama nanobody J3, which has broad CD4-binding site-directed neutralization. The J3-linked bispecific antibody exhibited improved breadth and potency over both J3 and CAP256V2LS, indicative of synergistic neutralization. The cryo-EM structure of the bispecific antibody in complex with a prefusion-closed Env trimer revealed simultaneous binding of J3 and CAP256V2LS. We further optimized the pharmacokinetics of the bispecific antibody by reducing the net positive charge of J3. The optimized bispecific antibody, which we named CAP256.J3LS, had a half-life similar to CAP256V2LS in human FcRn knock-in mice and exhibited suitable auto-reactivity, manufacturability, and biophysical risk. CAP256.J3LS neutralized over 97% of a multiclade 208-strain panel (geometric mean concentration for 80% inhibition (IC 80 ) 0.079 μg/ml) and 100% of a 100-virus clade C panel (geometric mean IC 80 of 0.05 μg/ml), suggesting its anti-HIV utility especially in regions where clade C dominates.

Background/aim: A feline inductive odontogenic tumor (FIOT) is a rare type of tumor that is unique to young cats., Case Report: Herein, we report on three cats (aged 6 months to 2.5 years) that had a bulging mass on the maxilla. On diagnostic imaging, cases 1 and 3 had bone expansion in the affected area, and all three cats were diagnosed with FIOT by histological examination. Maxillectomy and/or incisivectomy techniques were performed according to the tumor site with an intended surgical margin of 5 mm. To increase both precision and safety, a piezoelectric surgical instrument was used. The local advancement flaps were used to repair the surgical sites. The surgical outcomes were excellent, and there were no major complications related to the surgery or tumor recurrences during long-term follow-up (3-5 years) for any of the cats., Conclusion: The results from this study were excellent, which may have been due in part to the choice of the surgical instrument that allowed for the implementation of precise and accurate surgical excision and the tension-free flap method for preventing dehiscence of the surgical site., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)