TROPION-Lung07: Phase III study of Dato-DXd + pembrolizumab ± platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer.

For patients with advanced/metastatic non-small-cell lung cancer (NSCLC) without actionable genomic alterations and low (<50%) PD-L1 expression, pembrolizumab plus pemetrexed and platinum chemotherapy is a preferred first-line treatment. These patients have comparatively worse outcomes than those with higher PD-L1 expression, underscoring the need for new combination strategies. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has demonstrated encouraging antitumor activity and safety in this patient population. We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival.Clinical Trial Registration: NCT05555732 (ClinicalTrials.gov).

Most patients discover they have non-small-cell lung cancer (NSCLC) after it has already spread beyond the lungs (metastasized) making it more challenging to treat. If patients with NSCLC also lack specific genetic changes, called "actionable genomic alterations", or have low levels of a protein called PD-L1 (which cancer cells use to avoid attack from the immune system and continue to grow), current treatments may not fully help, or only help for a while. However, newer approaches are being investigated that may benefit these patients with fewer side effects than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is an investigational drug which combines an antibody with a chemotherapy agent to specifically target and kill cancer cells. The antibody in Dato-DXd attaches to a protein called TROP2, which is widely expressed in NSCLC tumors, and delivers chemotherapy directly into cancer cells to kill them. The TROPION-Lung07 study will assess the potential benefits and side effects of adding Dato-DXd to other drugs, including pembrolizumab (an immunotherapy which attaches to PD-1 on immune cells and triggers the death of cancer cells) and chemotherapy. Three treatment groups will be compared: pembrolizumab with chemotherapy; Dato-DXd with pembrolizumab; and Dato-DXd with pembrolizumab and chemotherapy. The study will help us to understand if adding Dato-DXd to other anticancer drugs allow patients to live longer without their disease getting worse.

The CACNA1A Mutant Disrupts Lysosome Calcium Homeostasis in Cerebellar Neurons and the Resulting Endo-Lysosomal Fusion Defect Can be Improved by Calcium Modulation.

Mutations in P/Q type voltage gated calcium channel (VGCC) lead severe human neurological diseases such as episodic ataxia 2, familial hemiplegic migraine 1, absence epilepsy, progressive ataxia and spinocerebellar ataxia 6. The pathogenesis of these diseases remains unclear. Mice with spontaneous mutation in the Cacna1a gene encoding the pore-forming subunit of P/Q type VGCC also exhibit ataxia, epilepsy and neurodegeneration. Based on the previous work showing that the P/Q type VGCC in neurons regulates lysosomal fusion through its calcium channel activity on lysosomes, we utilized CACNA1A mutant mice to further investigate the mechanism by which P/Q-type VGCCs regulate lysosomal function and neuronal homeostasis. We found CACNA1A mutant neurons have reduced lysosomal calcium storage without changing the resting calcium concentration in cytoplasm and the acidification of lysosomes. Immunohistochemistry and transmission electron microscopy reveal axonal degeneration due to lysosome dysfunction in the CACNA1A mutant cerebella. The calcium modulating drug thapsigargin, by depleting the ER calcium store, which locally increases the calcium concentration can alleviate the defective lysosomal fusion in mutant neurons. We propose a model that in cerebellar neurons, P/Q-type VGCC maintains the integrity of the nervous system by regulating lysosomal calcium homeostasis to affect lysosomal fusion, which in turn regulates multiple important cellular processes such as autophagy and endocytosis. This study helps us to better understand the pathogenesis of P/Q-type VGCC related neurodegenerative diseases and provides a feasible direction for future pharmacological treatment.

Propagation of Spin Waves in a 2D Vortex Network.

Efficient propagation of spin waves in a magnetically coupled vortex is crucial to the development of future magnonic devices. Thus far, only a double vortex can serve as spin-wave emitter or oscillator; the propagation of spin waves in the higher-order vortex is still lacking. Here, we experimentally realize a higher-order vortex (2D vortex network) by a designed nanostructure, containing four cross-type chiral substructures. We employ this vortex network as a waveguide to propagate short-wavelength spin waves (∼100 nm) and demonstrate the possibility of guiding spin waves from one vortex to the network. It is observed that the spin waves can propagate into the network through the nanochannels formed by the Bloch-Néel-type domain walls, with a propagation decay length of several micrometers. This technique paves the way for the development of low-energy, reprogrammable, and miniaturized magnonic devices.

A Randomized, Double-Blinded, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus (HSV) Type 2 Vaccine, HSV529, in Adults With or Without HSV Infection.

BACKGROUND: Herpes simplex virus 2 (HSV2) causes genital herpes in >400 million persons worldwide. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial of a replication-defective HSV2 vaccine, HSV529. Twenty adults were enrolled in each of 3 serogroups of individuals: those negative for both HSV1 and HSV2 (HSV1-/HSV2-), those positive or negative for HSV1 and positive for HSV2 (HSV1±/HSV2+), and those positive for HSV1 and negative for HSV2 (HSV1+/HSV2-). Sixty participants received vaccine or placebo at 0, 1, and 6 months. The primary end point was the frequency of solicited local and systemic reactions to vaccination. RESULTS: Eighty-nine percent of vaccinees experienced mild-to-moderate solicited injection site reactions, compared with 47% of placebo recipients (95% confidence interval [CI], 12.9%-67.6%; P = .006). Sixty-four percent of vaccinees experienced systemic reactions, compared with 53% of placebo recipients (95% CI, -17.9% to 40.2%; P = .44). Seventy-eight percent of HSV1-/HSV2- vaccine recipients had a ≥4-fold increase in neutralizing antibody titer after 3 doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36%, 46%, and 27% of HSV1-/HSV2-, HSV1±/HSV2+, and HSV1+/HSV2- participants, respectively, 1 month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants, respectively. CONCLUSIONS: HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV-seronegative vaccinees. CLINICAL TRIALS REGISTRATION: NCT01915212.

Activation of Kagome lattice-structured Cu3V2O7(OH)2·2H2O volborthite via hydrothermal crystallization for boosting visible light-driven water oxidation.

We report a feasible strategy via hydrothermal crystallization to activate Kagome lattice-structured Cu3V2O7(OH)2·2H2O volborthite mineral as a stable visible-light-driven photocatalyst. It was demonstrated to play a crucial role in stimulating absorption ability and photodegradation performance for the removal of methylene blue present in high concentration. In contrast, direct calcination was almost ineffective, whereas post-calcination was significantly detrimental. Moreover, the photocatalytic water oxidation activity of hydrothermally crystallizated volborthite was comparable to that of BiVO4, and it was clearly higher than those of WO3 and g-C3N4 from aqueous NaIO3 solution. By further in situ decoration with an optimum amount of CoOx cocatalysts (i.e., 2 wt%), the oxygen evolution rate of volborthite was greatly enhanced, and it was 1.6-fold, 1.8-fold and 2.9-fold higher than those of BiVO4, WO3 and g-C3N4, respectively. The importance of hydrothermal crystallization can be elucidated in terms of water-Kagome lattice structure interactions involving built-in intrinsic electric field and formation of single hydrogen bonds.

Enhancing Solar-Driven Water Purification by Multiscale Biomimetic Evaporators Featuring Lamellar MoS2/GO Heterojunctions.

Solar-powered steam generation holds a strong sustainability in facing the global water crisis, while the production efficiency and antifouling performance remain challenges. Inspired by river moss, a multiscale biomimetic evaporator is designed, where the key photothermal conversion film composed of lamellar MoS2/graphene oxides (GO) can significantly enhance the evaporation efficiency and solve the problem of fouling. First-level leaf-like MoS2/GO nanosheets, obtained by a modified hydrothermal synthesis with an assisted magnetic-field rotation stirring, are self-assembled into a second-level nanoporous film, which achieves an evaporation rate (ER) of 1.69 kg m-2 h-1 under 1 sun illumination and an excellent self-cleaning ability. The tertiary-bionic evaporator with a macroscopic crownlike shape further enhances the ER to 3.20 kg m-2 h-1, 189% above that of planar film, yielding 20.25 kg m2 of freshwater from seawater during a daytime exposure of 6 h. The exceptional outcomes originate from the macroscopic biomimetic design and the microscopic integration of heterojunction interfaces between the MoS2 and GO interlayers and the nanoporous surface. The biomimetic evaporator indicates a potential direction through surface/interface regulation of photothermal nanomaterials for water desalination.

Covalent bonding coating of quantum-sized TiO2 with polydopamine on catheter surface for synergistically enhanced antimicrobial and anticoagulant performances.

The catheters coating can be effective in reducing bloodstream infection and thrombosis, which are the major complications in blood contact catheters. However, the surface functional coating is difficult to be implemented due to the high surface stretching force from the minor-caliber. In this work, we propose a covalent bonding coating of polydopamine/titanium dioxide quantum dots (PDA/TiO2 QDs) on polyurethane (PU) catheters, which can fulfill a dual-function of antibacterial and antithrombosis. The PDA/TiO2 QDs layer was prepared by dip-coating, where the intermediate transition layer of PDA was reacted with the internal hydroxyls of PU surface by pre-oxidation and bonds with the external TiO2 QDs coating. The surface microstructures are analyzed by SEM, TEM and XPS methods, and the antimicrobial and anticoagulant performances are investigated by bacterial plate count and platelet adhesion tests. The oxidizing and hydrophilic effect of the top layer of TiO2 QDs were enhanced by the QD-sized particles. The antibacterial activities of the PDA/TiO2 QDs coating on PU catheters against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), especially to S. aureus, are evidenced by bacterial plate count test, reaching good bactericidal rates of 49.9 % against E. coli and 83.7 % against S. aureus, respectively. Platelet adhesion test and whole blood dynamic circulation modeling demonstrate that the PDA/TiO2 QDs coating effectively inhibits platelet adhesion due to an excellent hydrophilicity of TiO2 QDs surface, and thereafter reduce thrombus formation.

[Experimental study on therapeutic effect of Dabuyin Wan on true precocious puberty in female rats].

OBJECTIVE: To study the therapeutic effect of Dabuyin Wan on true precocious puberty of female rats and its possible mechanism. METHOD: Twenty-two-day-old female SD rats were subcutaneously injected with 40 mg x kg(-1) N-methyl-DL-aspartic acid (NMA) at 14:00 and 16:00 every day; meanwhile, the rats were given Dabuyin Wan for intervention. Visual inspection was conducted for the time of vaginal opening. The first estrus was observed by yaginal smear test. Their ovaries and uterus were weighed to calculate organ coefficients. Conventional pathological slices were made to observe morphological changes in ovaries and uterus and calculate the thickness of uterine walls and the number of corpus luteums. The level of E2 in serum was detected to assess the therapeutic effect of Dabuyin Wan on NMA precocious puberty in rats. expressions of GnRH, GPR54 and Kiss-1 mRNA in hypothalamus were measured by semi-quantitative RT-PCR to investigate the possible mechanism of Dabuyin Wan. RESULT: Dabuyin Wan at 3.24 g x kg(-1) and 1.62 g x kg(-1) significantly decreased the organ coefficients in rats with precocious puberty (P < 0.05), decrease the number of vaginal openings in rats (P < 0.01) and the thickness of uterine walls and the number of corpus luteums (P < 0.05), and notably down-regulated expressions of GnRH, GPR54 and Kiss-1 mRNA in hypothalamus (P < 0.05), without significant impact on E2 in serum. CONCLUSION: Dabuyin Wan may inhibit GnRH synthesis and release as well as startup of hypothalamic-pituitary-gonadal axis by down-regulating Kiss-1/GPR54 mRNA expression in hypothalamus, in order to realize the therapeutic effect on true precocious puberty.

Structured Benefit-Risk Assessment of a New Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) in Individuals Ages 12 Months and Older.

INTRODUCTION: A favorable benefit-risk balance is required to support licensure of biologics, in keeping with regulatory agencies' evolving recommendations, including the United States Food and Drugs Administration. We present a structured semi-quantitative benefit-risk analysis of MenACYW-TT, a quadrivalent meningococcal conjugate vaccine against Neisseria meningitidis serogroups, A, C, W and Y versus licensed comparators in individuals aged ≥ 12 months. METHODS: We used data from six MenACYW-TT clinical trials, stratified by age group, versus licensed vaccines: toddlers (12-23 months; Nimenrix® [MCV4-TT]), children (2-9 years; Menveo® [MCV4-CRM]), adolescents (10-17 years; MCV4-CRM or Menactra® [MCV4-DT]), adults (18-55 years; MCV4-DT) and older adults (≥ 56 years; Menomune®-A/C/Y/W-135 [MPSV4]). Eight benefit (seroresponse and seroprotection for A, C, W and Y) and five risk outcomes (any and grade 3 solicited injection site and systemic reactions, and serious adverse events) were measured at Day 30 after initial vaccination. Analyses were conducted by baseline vaccination status (meningococcal vaccine-naïve or vaccine-primed). RESULTS: MenACYW-TT showed favorable seroresponse and seroprotection among vaccine-naïve participants aged ≥ 2 years, against all serogroups, compared with MCV4-CRM, MCV4-DT and MPSV4. In vaccine-naïve toddlers, there was a favorable effect for serogroup C, but no difference between MenACYW-TT and MCV4-TT for serogroups A, Y and W. A favorable effect for MenACYW-TT against serogroup C was observed in all vaccine-naïve and combined vaccine-naïve and MenC conjugate vaccine-primed groups. For all risk criteria, there were no differences between MenACYW-TT and MCV4s in toddlers, children, adolescents and adults. Results for solicited injection site and systemic reactions favored MPSV4 in older adults. CONCLUSIONS: The benefit-risk profile for MenACYW-TT showed favorable seroresponse and seroprotection in individuals aged ≥ 2 years and no difference in risk criteria between MenACYW-TT and MCV4s. MenACYW-TT may provide an alternative to the standard-of-care for meningococcal disease prevention in those aged ≥ 12 months.

Aerobic glycolysis in colon cancer is repressed by naringin via the HIF1Α pathway. / 柚皮苷通过HIF1Aé€šè·¯æŠ‘åˆ¶ç»“è‚ ç™Œçš„æœ‰æ°§ç³–é µè§£.

Metabolic reprogramming is a common phenomenon in cancer, with aerobic glycolysis being one of its important characteristics. Hypoxia-inducible factor-1α (HIF1Α) is thought to play an important role in aerobic glycolysis. Meanwhile, naringin is a natural flavanone glycoside derived from grapefruits and many other citrus fruits. In this work, we identified glycolytic genes related to HIF1Α by analyzing the colon cancer database. The analysis of extracellular acidification rate and cell function verified the regulatory effects of HIF1Α overexpression on glycolysis, and the proliferation and migration of colon cancer cells. Moreover, naringin was used as an inhibitor of colon cancer cells to illustrate its effect on HIF1Α function. The results showed that the HIF1Α and enolase 2 (ENO2) levels in colon cancer tissues were highly correlated, and their high expression indicated a poor prognosis for colon cancer patients. Mechanistically, HIF1Α directly binds to the DNA promoter region and upregulates the transcription of ENO2; ectopic expression of ENO2 increased aerobic glycolysis in colon cancer cells. Most importantly, we found that the appropriate concentration of naringin inhibited the transcriptional activity of HIF1Α, which in turn decreased aerobic glycolysis in colon cancer cells. Generally, naringin reduces glycolysis in colon cancer cells by reducing the transcriptional activity of HIF1Α and the proliferation and invasion of colon cancer cells. This study helps to elucidate the relationship between colon cancer progression and glucose metabolism, and demonstrates the efficacy of naringin in the treatment of colon cancer.

Ultralow-iridium content NiIr alloy derivative nanochain arrays as bifunctional electrocatalysts for overall water splitting.

The development of low-cost and high-durability bifunctional electrocatalysts is of considerable importance for overall water splitting (OWS). This work reports the controlled synthesis of nickel-iridium alloy derivative nanochain array electrodes (NiIrx NCs) with fully exposed active sites that facilitated mass transfer for efficient OWS. The nanochains have a self-supported three-dimensional core-shell structure, composed of a metallic NiIrx core and a thin (5-10 nm) amorphous (hydr)oxide film as the shell (e.g., IrO2/NiIrx and Ni(OH)2/NiIrx). Interestingly, NiIrx NCs have bifunctional properties. Particularly, the oxygen evolution reaction (OER) current density (electrode geometrical area) of NiIr1 NCs is four times higher than that of IrO2 at 1.6 V vs. RHE. Meanwhile, its hydrogen evolution reaction (HER) overpotential at 10 mA cm-2 (η10 = 63 mV) is comparable to that of 10 wt% Pt/C. These performances may originate from the interfacial effect between the surface (hydr)oxide shell and metallic NiIrx core, which facilitates the charge transfer, along with the synergistic effect between Ni2+ and Ir4+ in the (hydr)oxide shell. Furthermore, NiIr1 NCs exhibits excellent OER durability (100 h @ 200 mA cm-2) and OWS durability (100 h @ 500 mA cm-2) with the nanochain array structure well preserved. This work provides a promising route for developing effective bifunctional electrocatalysts for OWS applications.

Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 Protein Vaccine.

Background: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. Methods: We conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged ≥18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 µg of ancestral (D614) and 5 µg of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 ≥14 days after the second injection (post-dose 2 [PD2]). Results: Between 19 Oct 2021 and 15 Feb 2022, 12,924 participants received ≥1 study injection. 75% of participants were SARS-CoV-2 non-naïve. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) ≥14 days PD2 with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naïve and 30.9% (95% CI -39.3; 66.7%) in naïve participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile. Conclusions: A bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naïve adults 18-59 years of age.

Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial.

BACKGROUND: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. This study aimed to describe the clinical efficacy and safety of a bivalent SARS-CoV-2 recombinant protein vaccine as a two-injection primary series during a period of circulation of the omicron (B.1.1.529) variant. METHODS: We conducted a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial in adults aged 18 years or older at 54 clinical research centres in eight countries (Colombia, Ghana, India, Kenya, Mexico, Nepal, Uganda, and Ukraine). Participants were recruited from the community and randomly assigned (1:1) by use of an interactive response technology system to receive two intramuscular 0·5 mL injections, 21 days apart, of the bivalent vaccine (5 µg of ancestral [D614] and 5 µg of beta [B.1.351] variant spike protein, with AS03 adjuvant) or placebo (0·9% normal saline). All participants, outcome assessors, and laboratory staff performing assays were masked to group assignments; those involved in the preparation and administration of the vaccines were unmasked. Participants were stratified by age (18-59 years and ≥60 years) and baseline SARS-CoV-2 rapid serodiagnostic test positivity. Symptomatic COVID-19 was defined as laboratory-confirmed (via nucleic acid amplification test or PCR test) COVID-19 with COVID-19-like illness symptoms. The primary efficacy endpoint was the clinical efficacy of the bivalent vaccine for prevention of symptomatic COVID-19 at least 14 days after the second injection (dose 2). Safety was assessed in all participants receiving at least one injection of the study vaccine or placebo. This trial is registered with ClinicalTrials.gov (NCT04904549) and is closed to recruitment. FINDINGS: Between Oct 19, 2021, and Feb 15, 2022, 13 002 participants were enrolled and randomly assigned to receive the first dose of the study vaccine (n=6512) or placebo (n=6490). 12 924 participants (6472 in the vaccine group and 6452 in the placebo group) received at least one study injection, of whom 7542 (58·4%) were male and 9693 (75·0%) were SARS-CoV-2 non-naive. Of these 12 924 participants, 11 543 (89·3%) received both study injections (5788 in the vaccine group and 5755 in the placebo group). The efficacy-evaluable population after dose 2 comprised 11 416 participants (5736 in the vaccine group and 5680 in the placebo group). The median duration of follow-up was 85 days (IQR 50-95) after dose 1 and 58 days (29-70) after dose 2. 121 symptomatic COVID-19 cases were reported at least 14 days after dose 2 (32 in the vaccine group and 89 in the placebo group), with an overall vaccine efficacy of 64·7% (95% CI 46·6 to 77·2). Vaccine efficacy against symptomatic COVID-19 was 75·1% (95% CI 56·3 to 86·6) in SARS-CoV-2 non-naive participants and 30·9% (-39·3 to 66·7) in SARS-CoV-2-naive participants. Viral genome sequencing identified the infecting strain in 68 (56·2%) of 121 cases (omicron [BA.1 and BA.2] in 63; delta in four; and both omicron and delta in one). Immediate unsolicited adverse events were reported by four (<0·1%) participants in the vaccine group and seven (0·1%) participants in the placebo group. Immediate unsolicited adverse reactions within 30 min after any injection were reported by four (<0·1%) participants in the vaccine group and six (<0·1%) participants in the placebo group. In the reactogenicity subset with available data, solicited reactions (solicited injection-site reactions and solicited systemic reactions) within 7 days after any injection occurred in 1398 (57·8%) of 2420 vaccine recipients and 983 (40·9%) of 2403 placebo recipients. Grade 3 solicited reactions were reported by 196 (8·1%; 95% CI 7·0 to 9·3) of 2420 vaccine recipients and 118 (4·9%; 4·1 to 5·9) of 2403 placebo recipients within 7 days after any injection, with comparable frequencies after dose 1 and dose 2 in the vaccine group. At least one serious adverse event occurred in 30 (0·5%) participants in the vaccine group and 26 (0·4%) in the placebo group. The proportion of adverse events of special interest and deaths was less than 0·1% in both study groups. No adverse event of special interest, serious adverse event, or death was deemed to be treatment related. There were no reported cases of thrombosis with thrombocytopenia syndrome, myocarditis, pericarditis, Bell's Palsy, or Guillain-Barré syndrome, or other immune-mediated diseases. INTERPRETATION: The bivalent variant vaccine conferred heterologous protection against symptomatic SARS-CoV-2 infection in the epidemiological context of the circulating contemporary omicron variant. These findings suggest that vaccines developed with an antigen from a non-predominant strain could confer cross-protection against newly emergent SARS-CoV-2 variants, although further investigation is warranted. FUNDING: Sanofi, US Biomedical Advanced Research and Development Authority, and the US National Institute of Allergy and Infectious Diseases.

Efficacy of a monovalent (D614) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, multi-country study.

Background: The literature on first generation COVID-19 vaccines show they were less effective against new SARS-CoV-2 variants of concern including Omicron (BA.1, BA.2, BA.4 and BA.5 subvariants). New vaccines developed against variant strains may provide cross-protection against emerging variants when used as boosters and facilitate vaccination across a range of countries, healthcare settings and populations. However, there are no data on such vaccines when used as a primary series. Methods: A global Phase 3, multi-stage efficacy study (NCT04904549) among adults (≥18 years) was conducted in 53 research centres in eight countries (United States, Honduras, Japan, Colombia, Kenya, India, Ghana, Nepal). Participants were randomized 1:1 to receive two intramuscular injections of a monovalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (10 µg of the spike (S) protein from the ancestral D614 strain) or placebo on Day 1 (D01) and Day 22 (D22). The primary efficacy endpoint was prevention of virologically confirmed SARS-CoV-2 infection with symptoms of COVID-19-like illness (CLI) ≥14 days after the second injection (post-dose 2 [PD2]) in participants who were SARS-CoV-2 naïve on D01 + D22. Safety and reactogenicity were also evaluated. Findings: Between May 26 and November 7, 2021, 10,114 participants received ≥1 study injection, and 9441 participants received both injections. 2108 (20.8%) participants were SARS-CoV-2 naïve at D01 and D22. The primary endpoint was analysed in a subset of the full analysis set (the modified full analysis set PD2 [mFAS-PD2], excluding participants who did not complete the vaccination schedule or received vaccination despite meeting one of the contraindication criteria, had onset of symptomatic COVID-19 between the first injection and before 14 days after the second injection, or participants who discontinued before 14 days after the second injection [n = 9377; vaccine, n = 4702; placebo, n = 4675]). Data were available for 2051 SARS-CoV-2 naïve and 7159 non-naïve participants. At the cut-off date (January 28, 2022), symptomatic COVID-19 was reported in 169 naïve participants (vaccine, n = 81; placebo, n = 88) ≥14 days PD2, with a vaccine efficacy (VE) of 15.3% (95% CI, -15.8; 38.2). VE regardless of D01/D22 serostatus was 32.9% (95% CI, 15.3; 47.0) and VE in non-naïve participants was 52.7% (95% CI, 31.2; 67.9). Viral genome sequencing was performed up to the data cut-off point and identified the infecting strain in 99/169 adjudicated cases in the PD2 naïve population (Delta [25], Omicron [72], other variants [3], one participant had infection with both Delta and Omicron variants and has been included in the totals for both Delta and Omicron). The vaccine was well-tolerated with an acceptable safety profile. Interpretation: In the context of changing circulating viral variants, it is challenging to induce protection in naïve individuals with a two-dose priming schedule based on the parental D614 strain. However, while the primary endpoint of this trial was not met, the results show that a monovalent D614 vaccine can still be of value in individuals previously exposed to SARS-CoV-2. Funding: This study was funded in whole or in part by Sanofi and by federal funds from the Biomedical Advanced Research and Development Authority, part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under contract number HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense under contract number W15QKN-16-9-1002. The views presented here are those of the authors and do not purport to represent those of the Department of the Army, the Department of Health and Human Services, or the U.S. government.

Reinforced Layered Double Hydroxide Oxygen-Evolution Electrocatalysts: A Polyoxometallic Acid Wet-Etching Approach and Synergistic Mechanism.

Nickel-iron-based layered double hydroxides (NiFe LDHs) have attracted tremendous research and industrial interests for oxygen evolution reaction (OER) electrocatalysis. However, methodologies on simultaneous regulation of performance-influencing factors remain scarce and their real synergistic effects are not clear enough. Herein, a versatile polyoxometallic acids (POMs) etching approach is reported to ingeniously reconstruct NiFe LDH, including 3D morphological nanotailoring, Fe3+ and α-Ni(OH)2 active species reconfiguration, creation of multiple Ni, Fe, and O vacancies, and intercalation of POM polyanionic clusters. The experimental and theoretical data collaboratively unveil that control of the key performance-influencing factors and their multiple synergistic mechanisms dominantly contribute to the step-like OER performance enhancement. The reinforced electrocatalyst is further produced with low cost and high performance up to Ф180 mm in diameter, showing its feasibility and advancement of the promising configuration of NiFe LDH-PMo12(+) II Ni@NiFe LDH(-) for alkaline anion-exchange-membrane electrode stack cells. Furthermore, to mathematically evaluate the evolution, a novel empirical formula is proposed for quantitative identification of structure-activity correlations, which offers an opportunity for first and fast reliability on materials screening.

Rare-earth single atoms decorated 2D-TiO2 nanosheets for the photodegradation of gaseous O-xylene.

In this work, rare-earth single atoms (La, Er) were decorated on the surface of 2D-TiO2 nanosheets by an impregnation-calcination strategy. The formation of rare-earth single atoms was certified by AC HAADF-STEM and XAS. TiO2 decorated with rare-earth single atoms (La1-TiO2 and Er1-TiO2) exhibited outstanding photocatalytic activity than pure 2D-TiO2 nanosheets (2D-TiO2) towards gas-phase degradation of O-xylene. Compared with 2D-TiO2, the rare-earth single atoms greatly improved the adsorption capacity of O-xylene without increasing their specific surface area. This is because rare-earth single atoms provide additional adsorption sites and reduce the adsorption energy of O-xylene. In addition, the hybrid orbital formed by the combination of rare-earth single atom and oxygen atom is beneficial to the rapid transmission and separation of photo-induced electrons, thereby improving the performance of photocatalytic degradation. In addition, in-situ DRIFTS and GC-MS were used to reveal the photocatalytic oxidation mechanism. Interestingly, the results showed that the La1-TiO2 and Er1-TiO2 samples can reduce the types of intermediates and simplify the reaction route, implying that the single atoms play an important role in the modulation and thorough mineralization of intermediate products. This work shows that the rare-earth single atom decorated 2D-TiO2 nanosheets have great potential in photocatalytic air pollution control.

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

BACKGROUND: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. METHODS: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. FINDINGS: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group. INTERPRETATION: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Microstructure Evolution and Mechanical Properties of Austenite Stainless Steel with Gradient Twinned Structure by Surface Mechanical Attrition Treatment.

Gradient structures in engineering materials produce an impressive synergy of strength and plasticity, thereafter, have recently attracted extensive attention in the material families. Gradient structured stainless steels (SS) were prepared by surface mechanical attrition treatment (SMAT) with different impacting velocities. The microstructures of the treated samples are characterized by gradient twin fraction and phase constituents. Quantitative relations of gradient microstructure with impacting time and mechanical properties are analyzed according to the observations of SEM, TEM, XRD, and tests of mechanical property. The processed SSs exhibited to be simultaneously stiff, strong, and ductile, which can be attributed to the co-operation of the different spatial distributions of multi-scaled structures. The formation of gradient twinned structure is resolved and the strengthening by gradient structure is explored.

Corrosion Behavior and Biocompatibility of Na2EDTA-Induced Nacre Coatings on AZ91D Alloys Prepared via Hydrothermal Treatment.

An effective method for controlling the corrosion rate of Mg-based implants must be urgently developed to meet the requirements of clinical applications. As a naturally occurring osteoid material, nacre offers a strategy to endow biomedical Mg alloys with excellent biocompatibility, and corrosion resistance. In this study, pearl powder and NaH2PO4 were used as precursors to deposit coatings on AZ91D alloy substrates hydrothermally based on Na2EDTA-assisted induction. Na2EDTA-induced nacre coatings were fabricated at various pH values, and its chemical composition and microstructure were analyzed via energy-dispersive X-ray, scanning electron microscopy, and X-ray diffraction spectroscopy. The corrosion-resistant performance and cytocompatibility of the samples were evaluated via electrochemical measurements and in vitro cell experiments. Results showed that the samples hydrothermally treated under faint acid conditions present excellent corrosion resistance, whereas the samples treated under slight alkaline conditions demonstrate improved biocompatibility due to high Ca and P content and large Ca/P atomic ratio. This study provides substantial evidence of the potential value of nacre coatings in expanding the biological applications of implanted biomaterials.

Enzymatic hydrolysis of Alaska pollack (Theragra chalcogramma) skin and antioxidant activity of the resulting hydrolysate.

BACKGROUND: Fish skin, a by-product of the food industry, contains a large amount of collagen. However, only a small proportion of fish skin is used in the production of leather materials and animal feedstuffs, most of it being discarded. The aims of this study were to prepare peptides from Alaska pollack (Theragra chalcogramma) skin by enzymatic hydrolysis and to evaluate the antioxidant activity of the resulting hydrolysate. RESULTS: Protamex was the most efficient enzyme for preparing antioxidant peptides from Alaska pollack skin. The optimal hydrolysis conditions were as follows: hydrolysis time 8 h; enzyme/substrate ratio 2:1000; skin/water ratio 1:6; temperature 55 degrees C; pH 6.0. Under these conditions the highest yield of peptides was 83.44%, with 85.95% of the hydrolysate being mainly composed of oligopeptides with molecular weights ranging from 180 to 1000 Da. The hydrolysate showed 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity, with an IC(50) value of 2.5 mg mL(-1), and its reducing power was 0.14 at 1 mg mL(-1), 53.8% of that of reduced glutathione at the same concentration. CONCLUSION: This study demonstrated that the hydrolysate of Alaska pollack skin was mainly composed of oligopeptides with two to eight amino acid residues and possessed antioxidant activity.