Nonreciprocity and Circulation in a Passive Josephson-Junction Ring.

Building large-scale superconducting quantum circuits will require miniaturization and integration of supporting devices including microwave circulators, which are currently bulky, stand-alone components. Here, we report the measurement of microwave scattering from a ring of Josephson junctions, with dc-only control fields. We detect the effect of quasiparticle tunneling, and dynamically classify the system at its operating design point into different quasiparticle sectors. We optimize the device within one of the quasiparticle sectors, where we observe an unambiguous signature of nonreciprocal 3-port scattering within that sector. This enables operation as a circulator, and at the optimal circulation point, we observe on-resonance insertion loss of 2 dB, isolation of 14 dB, power reflectance of -11 dB, and a bandwidth of 200 MHz, averaged over the 3 input ports.

Passive Superconducting Circulator on a Chip.

An on-chip microwave circulator that is compatible with superconducting devices is a key element for scale up of superconducting circuits. Previous approaches to integrating circulators on chip involve either external driving that requires extra microwave lines or a strong magnetic field that would compromise superconductivity. Here we report the first proof-of-principle realization of a passive on-chip circulator that is made from a superconducting loop interrupted by three notionally identical Josephson junctions and is tuned with only dc control fields. Our experimental results show evidence for nonreciprocal scattering, and excellent agreement with theoretical simulations. We also present a detailed analysis of quasiparticle tunneling in our device using a hidden Markov model. By reducing the junction asymmetry and utilizing the known methods of protection from quasiparticles, we anticipate that Josephson-loop circulator will become ubiquitous in superconducting circuits.

Origin and Evolution of the Human Bcl2-Associated Athanogene-1 (BAG-1).

Molecular chaperones, particularly the 70-kDa heat shock proteins (Hsp70s), are key orchestrators of the cellular stress response. To perform their critical functions, Hsp70s require the presence of specific co-chaperones, which include nucleotide exchange factors containing the BCL2-associated athanogene (BAG) domain. BAG-1 is one of these proteins that function in a wide range of cellular processes, including apoptosis, protein refolding, and degradation, as well as tumorigenesis. However, the origin of BAG-1 proteins and their evolution between and within species are mostly uncharacterized. This report investigated the macro- and micro-evolution of BAG-1 using orthologous sequences and single nucleotide polymorphisms (SNPs) to elucidate the evolution and understand how natural variation affects the cellular stress response. We first collected and analyzed several BAG-1 sequences across animals, plants, and fungi; mapped intron positions and phases; reconstructed phylogeny; and analyzed protein characteristics. These data indicated that BAG-1 originated before the animals, plants, and fungi split, yet most extant fungal species have lost BAG-1. Furthermore, although BAG-1's structure has remained relatively conserved, kingdom-specific conserved differences exist at sites of known function, suggesting functional specialization within each kingdom. We then analyzed SNPs from the 1000 genomes database to determine the evolutionary patterns within humans. These analyses revealed that the SNP density is unequally distributed within the BAG1 gene, and the ratio of non-synonymous/synonymous SNPs is significantly higher than 1 in the BAG domain region, which is an indication of positive selection. To further explore this notion, we performed several biochemical assays and found that only one out of five mutations tested altered the major co-chaperone properties of BAG-1. These data collectively suggest that although the co-chaperone functions of BAG-1 are highly conserved and can probably tolerate several radical mutations, BAG-1 might have acquired specialized and potentially unexplored functions during the evolutionary process.

Selpercatinib for adult patients with locally advanced or metastatic RET-altered solid tumors.

INTRODUCTION: The rearranged during transfection (RET) mutation is an oncogene driver for the development of cancer. Selpercatinib is a highly selective RET inhibitor that has demonstrated anti-tumor activity in RET-mutated cancers. Selpercatinib is approved for use in RET fusion-positive non-small-cell lung cancer (NSCLC), RET-mutated medullary thyroid cancer, RET fusion-positive thyroid cancer, and RET fusion-positive solid tumors. AREAS COVERED: This review summarizes the pharmacology, efficacy, safety, and resistance mechanism of selpercatinib. EXPERT OPINION: Selpercatinib has demonstrated durable responses with a favorable safety profile making it an excellent treatment option for RET-mutated cancers. Clinical trials are currently underway to determine the optimal sequencing of selpercatinib in RET fusion-positive lung and RET-mutated medullary thyroid cancer in the first-line setting compared to the current standard of care. Selpercatinib has shown promising anti-tumor activity in various RET-altered solid tumors opening a new treatment option for these patients.

Changing Landscape of Systemic Therapy in Biliary Tract Cancer.

Biliary tract cancers (BTC) are often diagnosed at advanced stages and have a grave outcome due to limited systemic options. Gemcitabine and cisplatin combination (GC) has been the first-line standard for more than a decade. Second-line chemotherapy (CT) options are limited. Targeted therapy or TT (fibroblast growth factor 2 inhibitors or FGFR2, isocitrate dehydrogenase 1 or IDH-1, and neurotrophic tyrosine receptor kinase or NTRK gene fusions inhibitors) have had reasonable success, but <5% of total BTC patients are eligible for them. The use of immune checkpoint inhibitors (ICI) such as pembrolizumab is restricted to microsatellite instability high (MSI-H) patients in the first line. The success of the TOPAZ-1 trial (GC plus durvalumab) is promising, with numerous trials underway that might soon bring targeted therapy (pemigatinib and infrigatinib) and ICI combinations (with CT or TT in microsatellite stable cancers) in the first line. Newer targets and newer agents for established targets are being investigated, and this may change the BTC management landscape in the coming years from traditional CT to individualized therapy (TT) or ICI-centered combinations. The latter group may occupy major space in BTC management due to the paucity of targetable mutations and a greater toxicity profile.

Impact of Dose Intensity on Pathologic Complete Response Rate in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Docetaxel, Carboplatin, Trastuzumab and Pertuzumab (TCHP).

BACKGROUND: Neoadjuvant chemotherapy is the cornerstone treatment for locally advanced breast cancer. Balancing toxicity and efficacy are a common concern of patients treated with chemotherapy. OBJECTIVE: The objective of this study was to determine the impact of dose intensity on pathologic complete response (pCR) at the time of surgery in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. PATIENTS AND METHODS: A retrospective, single-center review was conducted on patients with HER2+ breast cancer who received neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCHP) followed by definitive surgery. RESULTS: A total of 159 patients were included in the analysis; pCR was obtained in 66 patients (42%). There was no statistically significant difference between the mean dose intensity of each of the individual agents in TCHP and pCR rates. The mean overall dose intensity of docetaxel, carboplatin, trastuzumab and pertuzumab was 90.5%, 90.9%, 97.5%, and 93.9%, respectively. Although higher chemotherapy dose intensity (> 85%) was associated with higher pCR rates, no statistically significant difference was found compared with chemotherapy dose intensity < 85%. The TCHP regimen was difficult to tolerate; 104 patients (65%) required a dose reduction or dose delay during treatment due to toxicity. CONCLUSION: The TCHP regimen, which combines chemotherapy and HER2-directed therapy is effective at obtaining pCR in patients with locally advanced HER2+ breast cancer. These results suggest that the dose intensity of the individual agents did not have a significant impact on pCR rates. Given these findings, providers may be more comfortable allowing dose reductions for greater patient tolerability without sacrificing efficacy.

The first years of liver transplantation: experiences at a single center.

Background: The aim of this study was to analyze the first stages of progress in liver transplantation (LT) at a single center in Vietnam. Methods: This study analyzed data from patients and donors who participated in the LT program between August 2018 and December 2021 at University Medical Center, Ho Chi Minh City. Study measures included any difficulties encountered, as well as the post-LT outcomes for living donor LT (LDLT) and deceased donor LT (DDLT). The chi-square test and Kaplan Meier survival analysis were used to test the factors that influenced the outcomes. Results: A total of 18 adult recipients with LT (LDLT, n=16; DDLT, n=2) were included (mean age, 55.2±2.6 years; male, 88.9%). The most common post-LT complications were middle hepatic venous stenosis (20%) and graft rejection (22.2%). These complications were observed in LDLT patients. For DDLT, graft rejection (50%) was the only complication recorded. The survival rates for recipients at 3 months, 6 months, and 1 year were 100%, 88.9%, and 88.9%, respectively. The LDs had their right livers without the middle hepatic veins harvested, and biliary leakage (6.25%) was the only complication observed. There were no deaths among recipients or LDs during the operations or hospital stays. Conclusions: This study provides key details about the process of LT, and these positive outcomes support LT as an important therapy for end-stage liver disease and early hepatocellular carcinomas.

Cost-Effectiveness of Population-Based Tobacco Control Interventions on the Health Burden of Cardiovascular Diseases in Vietnam.

This study sought to assess the cost-effectiveness of population-based tobacco control interventions, which included health promotion and education, smoke-free models, cessation programs, warning on package, marketing bans, and raising tax. Standardized activity-based costing ingredient approach was applied with the provider perspective to calculate interventions cost from 2013 to 2017. The potential health impacts of the aforementioned interventions were calculated through a Microsoft Excel-based modeling adapted from Higashi et al and Ngalesoni et al. All six population-based tobacco control interventions were highly cost-effective with ranges from 1405 VND (Vietnamese Dong) to 135 560 VND per DALY (disability-adjusted life year) averted. It was identified that raising cigarette taxes and applying health warnings on tobacco packages are the most favorable, cost-effective interventions. The results from this study provide a robust message that calls for increased attention and efforts in developing an appropriate policy agenda, which jointly integrates both political and community-based interventions, to maximize intervention impact on tobacco use.

Concurrent action of purifying selection and gene conversion results in extreme conservation of the major stress-inducible Hsp70 genes in mammals.

Several evolutionary mechanisms alter the fate of mutations and genes within populations based on their exhibited functional effects. To understand the underlying mechanisms involved in the evolution of the cellular stress response, a very conserved mechanism in the course of organismal evolution, we studied the patterns of natural genetic variation and functional consequences of polymorphisms of two stress-inducible Hsp70 genes. These genes, HSPA1A and HSPA1B, are major orchestrators of the cellular stress response and are associated with several human diseases. Our phylogenetic analyses revealed that the duplication of HSPA1A and HSPA1B originated in a lineage proceeding to placental mammals, and henceforth they remained in conserved synteny. Additionally, analyses of synonymous and non-synonymous changes suggest that purifying selection shaped the HSPA1 gene diversification, while gene conversion resulted in high sequence conservation within species. In the human HSPA1-cluster, the vast majority of mutations are synonymous and specific genic regions are devoid of mutations. Furthermore, functional characterization of several human polymorphisms revealed subtle differences in HSPA1A stability and intracellular localization. Collectively, the observable patterns of HSPA1A-1B variation describe an evolutionary pattern, in which purifying selection and gene conversion act simultaneously and conserve a major orchestrator of the cellular stress response.

A photoaffinity, non-steroidal, ecdysone agonist, bisacylhydrazine compound, RH-131039: characterization of binding and functional activity.

In this paper we describe the synthesis, ligand-binding and functional activity characteristics of the photoaffinity, non-steroidal, ecdysone agonist, bisacylhydrazine compound, 3-benzoyl-benzoic acid N-tert-butyl-N'-(2-ethyl-3-methoxy-benzoyl)-hydrazide (RH-131039). Tritiated RH-131039 is the first non-steroidal photoaffinity compound that was shown to bind specifically to ecdysone receptors (EcRs) from insects belonging to the orders Diptera and Lepidoptera. The spruce budworm (Choristoneura fumiferana) ecdysone receptor (CfEcR) bound with high affinity (K(d)=2.23+/-0.27 nM) to this compound. When irradiated with UV light (lambda=350 nm) under equilibrium ligand-binding conditions, RH-131039 attached specifically and covalently to the CfEcR ligand-binding domain (LBD). RH-131039 also bound to cloned ecdysone receptor proteins from three dipteran insects, Drosophila melanogaster, Aedes aegypti and Chironomous tentans. This paper also describes and invokes caution in interpretation of ligand-binding results obtained using crude cellular extracts containing target receptors, as illustrated with the use of Drosophila Kc cells that have functional EcR and L57 cells (derivatives of Kc cells in which EcR-B isoforms have been knocked out by "parahomologous" recombination). Tritiated RH-131039 is a useful tool to dissect ligand-binding and functional differences for EcRs from different arthropod species.

Triterpene saponins from the sea cucumber Stichopus chloronotus.

Sea cucumbers have been used as a dietary delicacy and important ingredient in Asian traditional medicine and functional foods over many centuries. Using combined chromatographic methods, six triterpene saponins (1-6), including a new compound, stichloroside F (1), were isolated from a methanol extract of the sea cucumber Stichopus chloronotus Brandt. Their structures were determined on the basis of spectroscopic (1H and 13C NMR, HSQC, HMBC, 1H-1lH COSY, ROESY) and FTICR-MS data and by comparison with literature values.