Dermatologic manifestations of hematologic disorders.

Distinguishing key morphologic features and understanding the pathophysiology of common cutaneous manifestations of hematologic disorders is essential to ensure prompt and appropriate treatment. In fact, classic cutaneous signs may provide the first clue to the diagnosis of an underlying hematologic disease. Disorders of coagulation, vascular abnormalities, or cutaneous infiltration and deposition are responsible for the underlying pathophysiology of cutaneous manifestations in the majority of cases. Hematologists often feel ill-equipped in identifying morphologic changes in the skin. Thus, the purpose of this review is to provide a comprehensive overview of classic cutaneous manifestations and diagnostic considerations of the associated hematologic conditions. Though there is a specific focus on non-malignant disorders, those straddling the spectrum of malignancy are also discussed. In many disease states, the skin may serve as an important marker of an emerging hematologic disorder, so close collaboration and multidisciplinary input remain essential to provide optimal and timely care for these patients.

Predicting Serious Bacterial Infections Among Hypothermic Infants in the Emergency Department.

BACKGROUND: There is insufficient evidence to guide the initial evaluation of hypothermic infants. We aimed to evaluate risk factors for serious bacterial infections (SBI) among hypothermic infants presenting to the emergency department (ED). METHODS: We conducted a multicenter case-control study among hypothermic (rectal temperature <36.5°C) infants ≤90 days presenting to the ED who had a blood culture collected. Our outcome was SBI (bacteremia, bacterial meningitis, and/or urinary tract infection). We performed 1:2 matching. Historical, physical examination and laboratory covariables were determined based on the literature review from febrile and hypothermic infants and used logistic regression to identify candidate risk factors. RESULTS: Among 934 included infants, 57 (6.1%) had an SBI. In univariable analyses, the following were associated with SBI: age > 21 days, fever at home or in the ED, leukocytosis, elevated absolute neutrophil count, thrombocytosis, and abnormal urinalysis. Prematurity, respiratory distress, and hypothermia at home were negatively associated with SBI. The full multivariable model exhibited a c-index of 0.91 (95% confidence interval: 0.88-0.94). One variable (abnormal urinalysis) was selected for a reduced model, which had a c-index of 0.82 (95% confidence interval: 0.75-0.89). In a sensitivity analysis among hypothermic infants without fever (n = 22 with SBI among 116 infants), leukocytosis, absolute neutrophil count, and abnormal urinalysis were associated with SBI. CONCLUSIONS: Historical, examination, and laboratory data show potential as variables for risk stratification of hypothermic infants with concern for SBI. Larger studies are needed to definitively risk stratify this cohort, particularly for invasive bacterial infections.

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques.

The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.

AZD5582 plus SIV-specific antibodies reduce lymph node viral reservoirs in antiretroviral therapy-suppressed macaques.

The main barrier to HIV cure is a persistent reservoir of latently infected CD4+ T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir. In this study, we investigated the effects of AZD5582 in combination with four SIV Env-specific Rhesus monoclonal antibodies (RhmAbs) ± N-803 (an IL-15 superagonist) in SIV-infected, ART-suppressed rhesus macaques. Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4+ T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure.

Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques.

TLR agonists are a promising class of immune system stimulants investigated for immunomodulatory applications in cancer immunotherapy and viral diseases. In this study, we sought to characterize the safety and immune activation achieved by different TLR agonists in rhesus macaques (Macaca mulatta), a useful preclinical model of complex immune interactions. Macaques received one of three TLR agonists, followed by plasma cytokine, immune cell subset representation, and blood cell activation measurements. The TLR4 agonist LPS administered i.v. induced very transient immune activation, including TNF-α expression and monocyte activation. The TLR7/8 agonist 2BXy elicited more persistent cytokine expression, including type I IFN, IL-1RA, and the proinflammatory IL-6, along with T cell and monocyte activation. Delivery of 2BXy i.v. and i.m. achieved comparable immune activation, which increased with escalating dose. Finally, i.v. bacillus Calmette-Guérin (BCG) vaccination (which activates multiple TLRs, especially TLR2/4) elicited the most pronounced and persistent innate and adaptive immune response, including strong induction of IFN-γ, IL-6, and IL-1RA. Strikingly, monocyte, T cell, and NK cell expression of the proliferation marker Ki67 increased dramatically following BCG vaccination. This aligned with a large increase in total and BCG-specific cells measured in the lung. Principal component analysis of the combined cytokine expression and cellular activation responses separated animals by treatment group, indicating distinct immune activation profiles induced by each agent. In sum, we report safe, effective doses and routes of administration for three TLR agonists that exhibit discrete immunomodulatory properties in primates and may be leveraged in future immunotherapeutic strategies.

An Investigation into the Surface Integrity of Micro-Machined High-Speed Steel and Tungsten Carbide Cutting Tools.

The performance and lifespan of cutting tools are significantly influenced by their surface quality. The present report highlights recent advances in enhancing the surface characteristics of tungsten carbide and high-speed steel cutting tools using a novel micro-machining technique for polishing and edge-honing. Notably, the main aim was to reduce the surface roughness while maintaining the hardness of the materials at an optimal level. By conducting a thorough analysis of surfaces obtained using different techniques, it was found that the micro-machining method effectively decreased the surface roughness of the cutting tools the most effectively out of the techniques investigated. Significantly, the surface roughness was reduced from an initial measurement of 400 nm to an impressive value of 60 nm. No significant change in hardness was observed, which guarantees the maintenance of the mechanical properties of the cutting tools. This analysis enhances the comprehension of surface enhancement methodologies for cutting tools through the presentation of these findings. The observed decrease in surface roughness, along with the consistent hardness, exhibits potential for improving tool performance. These enhancements possess the capacity to optimise manufacturing processes, increase tool reliability, and minimise waste generation.

The role of community healthcare professionals in discussing sexual assault experiences during obstetrics and gynecological healthcare appointments.

BACKGROUND: Nearly half of adult women in the US report experiencing sexual assault, with almost one-fifth reporting rape. For many sexual assault survivors, healthcare professionals are the first point of contact and disclosure. This study aimed to understand how healthcare professionals working in community settings perceived their role in discussing sexual violence experiences with women during obstetrical and gynecological healthcare appointments. The secondary purpose was to compare healthcare professionals' perspectives with the patients' to determine how sexual violence conversations should occur in these environments. METHODS: Data were collected in two phases. Phase 1 consisted of 6 focus groups (Sept-Dec, 2019) with women aged 18-45 (n = 22) living in Indiana who sought community-based or private healthcare for women's reproductive healthcare needs. Phase 2 included 20 key-informant interviews with non-physician healthcare professionals (i.e., NP, RN, CNM, doula, pharmacist, chiropractor) living in Indiana (September 2019-May 2020) who provided community-based women's reproductive healthcare. Focus groups and interviews were audio-recorded, transcribed, and analyzed using thematic analyses. HyperRESEARCH assisted in data management and organization. RESULTS: There were three resulting themes: (1) healthcare professionals' approaches to screening for a history of sexual violence varied depending on how they ask, what setting they work in, and type of professional asking; (2) healthcare experiences can compound traumatic experiences and create distrust with survivors; and (3) sexual violence impacts patient healthcare experiences through what services they seek, how professionals may interact with them, and what professionals they are willing to utilize. CONCLUSIONS: Findings offered insight into actionable and practical strategies for enhancing sexual violence screening and discussions in community-based women's reproductive health settings. The findings offer strategies to address barriers and facilitators among community healthcare professionals and the people they serve. Incorporating healthcare professional and patient experiences and preferences for violence-related discussions during obstetrical and gynecological healthcare appointments can assist in violence prevention efforts, improve patient-professional rapport, and yield better health outcomes.

Anesthesia and analgesia for experimental craniotomy in mice and rats: a systematic scoping review comparing the years 2009 and 2019.

Experimental craniotomies are a common surgical procedure in neuroscience. Because inadequate analgesia appears to be a problem in animal-based research, we conducted this review and collected information on management of craniotomy-associated pain in laboratory mice and rats. A comprehensive search and screening resulted in the identification of 2235 studies, published in 2009 and 2019, describing craniotomy in mice and/or rats. While key features were extracted from all studies, detailed information was extracted from a random subset of 100 studies/year. Reporting of perioperative analgesia increased from 2009 to 2019. However, the majority of studies from both years did not report pharmacologic pain management. Moreover, reporting of multimodal treatments remained at a low level, and monotherapeutic approaches were more common. Among drug groups, reporting of pre- and postoperative administration of non-steroidal anti-inflammatory drugs, opioids, and local anesthetics in 2019 exceeded that of 2009. In summary, these results suggest that inadequate analgesia and oligoanalgesia are persistent issues associated with experimental intracranial surgery. This underscores the need for intensified training of those working with laboratory rodents subjected to craniotomies. Systematic review registration: https://osf.io/7d4qe.

Convalescent human IgG, but not IgM, from COVID-19 survivors confers dose-dependent protection against SARS-CoV-2 replication and disease in hamsters.

Introduction: Antibody therapeutic strategies have served an important role during the COVID-19 pandemic, even as their effectiveness has waned with the emergence of escape variants. Here we sought to determine the concentration of convalescent immunoglobulin required to protect against disease from SARS-CoV-2 in a Syrian golden hamster model. Methods: Total IgG and IgM were isolated from plasma of SARS-CoV-2 convalescent donors. Dose titrations of IgG and IgM were infused into hamsters 1 day prior to challenge with SARS-CoV-2 Wuhan-1. Results: The IgM preparation was found to have ~25-fold greater neutralization potency than IgG. IgG infusion protected hamsters from disease in a dose-dependent manner, with detectable serum neutralizing titers correlating with protection. Despite a higher in vitro neutralizing potency, IgM failed to protect against disease when transferred into hamsters. Discussion: This study adds to the growing body of literature that demonstrates neutralizing IgG antibodies are important for protection from SARS-CoV-2 disease, and confirms that polyclonal IgG in sera can be an effective preventative strategy if the neutralizing titers are sufficiently high. In the context of new variants, against which existing vaccines or monoclonal antibodies have reduced efficacy, sera from individuals who have recovered from infection with the emerging variant may potentially remain an efficacious tool.

The peroxidase response of Alternanthera philoxeroides (Alligator Weed) and Nasturtium officinale (Watercress) to heavy metal exposure.

We examined the effects of copper and lead on the antioxidant enzyme response of Alternanthera philoxeroides and Nasturtium officinale using a benchtop luminometer. Alternanthera philoxeroides is a nonnative invasive plant species that has spread throughout the wetland ecosystem in the southern part of the USA. Its invasion is facilitated by its ability to thrive in a wide range of abiotic conditions. Nasturtium officinale is an aquatic plant that is sensitive to relatively low amounts of pollution and is most commonly found in springs and shallow bodies of water. While A. philoxeroides tolerates organic pollution and heavy metals, N. officinale exhibits stress at low levels of pollution. Alternanthera philoxeroides antioxidant enzyme production was unaffected by increasing concentrations of both copper and lead. The antioxidant enzyme response of N. officinale showed a significant increase when plants were exposed to 10 and 25 ppm lead. Endogenous peroxidase concentrations of the control plants were also compared showing that A. philoxeroides possessed a significantly higher concentration of peroxidases than N. officinale. We hypothesize that a higher endogenous peroxidase concentration may be a mechanism that hyperaccumulator plants use to tolerate inhospitable concentrations of copper and lead.

Short-range multispectral imaging is an inexpensive, fast, and accurate approach to estimate biodiversity in a temperate calcareous grassland.

Image sensing technologies are rapidly increasing the cost-effectiveness of biodiversity monitoring efforts. Species differences in the reflectance of electromagnetic radiation can be used as a surrogate estimate plant biodiversity using multispectral image data. However, these efforts are often hampered by logistical difficulties in broad-scale implementation. Here, we investigate the utility of multispectral imaging technology from commercially available unmanned aerial vehicles (UAVs, or drones) in estimating biodiversity metrics at a fine spatial resolution (0.1-0.5 cm pixel resolution) in a temperate calcareous grassland in Oxfordshire, UK. We calculate a suite of moments (coefficient of variation, standard deviation, skewness, and kurtosis) for the distribution of radiance from multispectral images at five wavelength bands (Blue 450 ± 16 nm; Green 560 ± 16 nm; Red 650 ± 16 nm; Red Edge 730 ± 16 nm; Near Infrared 840 ± 16 nm) and test their effectiveness at estimating ground-truthed biodiversity metrics from in situ botanical surveys for 37-1 × 1 m quadrats. We find positive associations between the average coefficient of variation in spectral radiance and both the Shannon-Weiner and Simpson's biodiversity indices. Furthermore, the average coefficient of variation in spectral radiance is consistent and highly repeatable across sampling days and recording heights. Positive associations with biodiversity indices hold irrespective of the image recording height (2-8 m), but we report reductions in estimates of spectral diversity with increases to UAV recording height. UAV imaging reduced sampling time by a factor of 16 relative to in situ botanical surveys. We demonstrate the utility of multispectral radiance moments as an indicator of biodiversity in this temperate calcareous grassland at a fine spatial resolution using a widely available UAV monitoring system with a coarse spectral resolution. The use of UAV technology with multispectral sensors has far-reaching potential to provide cost-effective and high-resolution monitoring of biodiversity.

Grimace scale, burrowing, and nest building for the assessment of post-surgical pain in mice and rats-A systematic review.

Several studies suggested an informative value of behavioral and grimace scale parameters for the detection of pain. However, the robustness and reliability of the parameters as well as the current extent of implementation are still largely unknown. In this study, we aimed to systematically analyze the current evidence-base of grimace scale, burrowing, and nest building for the assessment of post-surgical pain in mice and rats. The following platforms were searched for relevant articles: PubMed, Embase via Ovid, and Web of Science. Only full peer-reviewed studies that describe the grimace scale, burrowing, and/or nest building as pain parameters in the post-surgical phase in mice and/or rats were included. Information about the study design, animal characteristics, intervention characteristics, and outcome measures was extracted from identified publications. In total, 74 papers were included in this review. The majority of studies have been conducted in young adult C57BL/6J mice and Sprague Dawley and Wistar rats. While there is an apparent lack of information about young animals, some studies that analyzed the grimace scale in aged rats were identified. The majority of studies focused on laparotomy-associated pain. Only limited information is available about other types of surgical interventions. While an impact of surgery and an influence of analgesia were rather consistently reported in studies focusing on grimace scales, the number of studies that assessed respective effects was rather low for nest building and burrowing. Moreover, controversial findings were evident for the impact of analgesics on post-surgical nest building activity. Regarding analgesia, a monotherapeutic approach was identified in the vast majority of studies with non-steroidal anti-inflammatory (NSAID) drugs and opioids being most commonly used. In conclusion, most evidence exists for grimace scales, which were more frequently used to assess post-surgical pain in rodents than the other behavioral parameters. However, our findings also point to relevant knowledge gaps concerning the post-surgical application in different strains, age levels, and following different surgical procedures. Future efforts are also necessary to directly compare the sensitivity and robustness of different readout parameters applied for the assessment of nest building and burrowing activities.

Difficult to hear but easy to see: Audio-visual perception of the /r/-/w/ contrast in Anglo-English.

This paper investigates the influence of visual cues in the perception of the /r/-/w/ contrast in Anglo-English. Audio-visual perception of Anglo-English /r/ warrants attention because productions are increasingly non-lingual, labiodental (e.g., [ʋ]), possibly involving visual prominence of the lips for the post-alveolar approximant [ɹ]. Forty native speakers identified [ɹ] and [w] stimuli in four presentation modalities: auditory-only, visual-only, congruous audio-visual, and incongruous audio-visual. Auditory stimuli were presented in noise. The results indicate that native Anglo-English speakers can identify [ɹ] and [w] from visual information alone with almost perfect accuracy. Furthermore, visual cues dominate the perception of the /r/-/w/ contrast when auditory and visual cues are mismatched. However, auditory perception is ambiguous because participants tend to perceive both [ɹ] and [w] as /r/. Auditory ambiguity is related to Anglo-English listeners' exposure to acoustic variation for /r/, especially to [ʋ], which is often confused with [w]. It is suggested that a specific labial configuration for Anglo-English /r/ encodes the contrast with /w/ visually, compensating for the ambiguous auditory contrast. An audio-visual enhancement hypothesis is proposed, and the findings are discussed with regard to sound change.

Hormonal Male Contraception: Formative Research to Develop and Test Communication Messaging.

Male-controlled contraception is limited, yet a promising hormonal male contraceptive (HMC) development in may increase options for men to share in the work of pregnancy prevention. This study examined college-aged (18-26 years) men's and women's perceptions of influential marketing strategy for an experimental novel HMC method, a transdermal gel. Six focus groups (n = 29) were conducted to glean insights for ad prototype creation. Ad prototypes were designed and then tested in semi-structured interviews (n = 20) to understand whether the messages were adequately representing the attributes intended while also allowing participants to contribute insights on improving appeal. A constant comparative approach was used for data contextualization and theme identification. Results provided a foundation for the creation of HMC message prototypes, aimed at increasing knowledge and uptake of a novel family planning method for men. Representation of a relatable character, or drawing on authentic experiences, aligned best with participant values. Focus groups illuminated salient concepts for HMC marketing, including humor, destigmatization, information, and credibility. Interview message testing yielded an understanding of elements participants responded most strongly to, including (1) ad sentiment and (2) trustworthiness. Findings provide a basis for understanding the placement of a potential marketing campaign to effectively frame HMC uptake as easy to use, safe, and popular while building on peer norms and group acceptability among a college-aged demographic. Healthcare providers and other practitioners can utilize these findings while engaging in family planning conversations, interventions, and message development.

Broad coverage of neutralization-resistant SIV strains by second-generation SIV-specific antibodies targeting the region involved in binding CD4.

Both SIV and SHIV are powerful tools for evaluating antibody-mediated prevention and treatment of HIV-1. However, owing to a lack of rhesus-derived SIV broadly neutralizing antibodies (bnAbs), testing of bnAbs for HIV-1 prevention or treatment has thus far been performed exclusively in the SHIV NHP model using bnAbs from HIV-1-infected individuals. Here we describe the isolation and characterization of multiple rhesus-derived SIV bnAbs capable of neutralizing most isolates of SIV. Eight antibodies belonging to two clonal families, ITS102 and ITS103, which target unique epitopes in the CD4 binding site (CD4bs) region, were found to be broadly neutralizing and together neutralized all SIV strains tested. A rare feature of these bnAbs and two additional antibody families, ITS92 and ITS101, which mediate strain-specific neutralizing activity against SIV from sooty mangabeys (SIVsm), was their ability to achieve near complete (i.e. 100%) neutralization of moderately and highly neutralization-resistant SIV. Overall, these newly identified SIV bnAbs highlight the potential for evaluating HIV-1 prophylactic and therapeutic interventions using fully simian, rhesus-derived bnAbs in the SIV NHP model, thereby circumventing issues related to rapid antibody clearance of human-derived antibodies, Fc mismatch and limited genetic diversity of SHIV compared to SIV.

A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine Is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model.

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery that will improve vaccination compliance and demonstrate efficacy against emerging variants. Here, we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprising stabilized, pre-fusion spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction in lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.

Dimers of isatin derived α-methylene-γ-butyrolactone as potent anti-cancer agents.

The IKK-NFκB complex is a key signaling node that facilitates activation of gene expression in response to extracellular signals. The kinase IKKß and the transcription factor RELA have been targeted by covalent modifiers that bind to surface exposed cysteine residues. A common feature in well characterized covalent modifiers of RELA and IKKß is the Michael acceptor containing α-methylene-γ-butyrolactone functionality. Through synthesis and evaluation of a focused set of α-methylene-γ-butyrolactone containing spirocyclic dimers (SpiDs) we identified SpiD3 as an anticancer agent with low nanomolar potency. Using cell-free and cell-based studies we show that SpiD3 is a covalent modifier that generates stable RELA containing high molecular weight complexes. SpiD3 inhibits TNFα-induced IκBα phosphorylation resulting in the blockade of RELA nuclear translocation. SpiD3 induces apoptosis, inhibits colony formation and migration of cancer cells. The NCI-60 cell line screen revealed that SpiD3 potently inhibits growth of leukemia cell lines, making it a suitable pre-therapeutic lead for hematological malignancies.

Small-molecule IKKß activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth.

Activation of inhibitor of nuclear factor NF-κB kinase subunit-ß (IKKß), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKß knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKß and its activation in cancer. We also conducted a hit-to-lead optimization study that led to the identification of 39-100 as a selective mitogen-activated protein kinase kinase kinase (MAP3K) 1 inhibitor. We show that IKKß is not required for growth of Kras mutant pancreatic cancer (PC) cells but is critical for PC tumor growth in mice. We also observed elevated basal levels of activated IKKß in PC cell lines, PC patient-derived tumors, and liver metastases, implicating it in disease onset and progression. Optimization of an ATP noncompetitive IKKß inhibitor resulted in the identification of 39-100, an orally bioavailable inhibitor with improved potency and pharmacokinetic properties. The compound 39-100 did not inhibit IKKß but inhibited the IKKß kinase MAP3K1 with low-micromolar potency. MAP3K1-mediated IKKß phosphorylation was inhibited by 39-100, thus we termed it IKKß activation modulator (IKAM) 1. In PC models, IKAM-1 reduced activated IKKß levels, inhibited tumor growth, and reduced metastasis. Our findings suggests that MAP3K1-mediated IKKß activation contributes to KRAS mutation-associated PC growth and IKAM-1 is a viable pretherapeutic lead that targets this pathway.

Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques.

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Postpyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage fluid. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage fluid following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that postpyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques. IMPORTANCE SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution, and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however, no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here, we report that oral administration of live SARS-CoV-2 in nonhuman primates may offer prophylactic benefits, but the formulation and route of administration will require further optimization.

A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 µg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses.