Benefit-Cost Analysis of the HHS COVID-19 Campaign: April 2021-March 2022.

INTRODUCTION: This study estimated the benefits and costs of the U.S. Department of Health and Human Services' We Can Do This COVID-19 public education campaign (the Campaign) and associated vaccination-related impacts. METHODS: Weekly media market and national Campaign expenditures were used to estimate weekly first-dose vaccinations that would not have occurred absent the Campaign, weekly Campaign-attributed complete vaccinations, and corresponding COVID-19 cases, hospitalizations, and deaths averted. Benefits were valued using estimated morbidity and mortality reductions and associated values of a statistical life and a statistical case. Costs were estimated using Campaign paid media expenditures and corresponding vaccination costs. The net Campaign and vaccination benefit and return on investment were calculated. Analyses were conducted from 2022 to 2024. RESULTS: Between April 2021 and March 2022, an estimated 55.9 million doses of COVID-19 vaccines would not have been administered absent the Campaign. Campaign-attributed vaccinations resulted in 2,576,133 fewer mild COVID-19 cases, 243,979 fewer nonfatal COVID-19 hospitalizations, and 51,675 lives saved from COVID-19. The total Campaign benefit was $740.2 billion, and Campaign and vaccination costs totaled $8.3 billion, with net benefits of approximately $732.0 billion. For every $1 spent, the Campaign and corresponding vaccination costs resulted in benefits of approximately $89.54. CONCLUSIONS: The We Can Do This COVID-19 public education campaign saved more than 50,000 lives and prevented hundreds of thousands of hospitalizations and millions of COVID-19 cases, representing hundreds of billions of dollars in benefits in less than one year. Findings suggest that public education campaigns are a cost-effective approach to reducing COVID-19 morbidity and mortality.

Evaluation of thoracic sympathetic ganglion block as a predictor for response to ketamine infusion therapy and spinal cord stimulation in patients with chronic upper extremity pain.

OBJECTIVE: To investigate the predictive value of thoracic sympathetic ganglion block (TSGB) in response to ketamine infusion therapy (KIT) and spinal-cord stimulation (SCS) in patients with chronic upper-extremity pain including complex regional pain syndrome (CRPS). DESIGN: Retrospective. SETTING: Tertiary hospital single-center. SUBJECTS: Patients who underwent TSGB receiving KIT or SCS within a 3-year window. METHODS: Positive TSGB outcomes were defined as ≥ 2 0-10 Numerical Rating Scale (NRS) score reduction at 2 weeks post-procedure. Positive KIT and SCS outcomes were determined by ≥ 2 NRS score reduction at 2-4 weeks post-KIT and ≥4 NRS score reduction at 2-4 weeks post-SCS implantation, respectively. RESULTS: Among 207 patients who underwent TSGB, 38 received KIT and 34 underwent SCS implantation within 3 years post-TSGB; 33 patients receiving KIT and 32 patients receiving SCS were included. Among 33 patients who received KIT, 60.6% (n = 20) reported a ≥ 2 0-10 NRS pain-score reduction. Positive response to TSGB occurred in 70.0% (n = 14) KIT responders, significantly higher than that in 30.8% (n = 4) KIT non-responders. Multivariable analysis revealed a positive association between positive responses to TSGB and KIT (OR 7.004, 95% CI 1.26-39.02). Among 32 patients who underwent SCS implantation, 68.8% (n = 22) experienced short-term effectiveness. Positive response to TSGB was significantly higher in SCS responders (45.5%, n = 10) than in non-responders (0.0%). However, there were no associations between pain reduction post-TSGB and that post-KIT or post-SCS. CONCLUSIONS: A positive response to TSGB is a potential predictor for positive KIT and SCS outcomes among patients with chronic upper-extremity pain, including CRPS.

Differences in social media use by COVID-19 vaccination status.

The near-ubiquitous use of social media in the United States (U.S.) highlights the utility of social media for encouraging vaccination. Vaccination campaigns have used social media to reach audiences, yet research linking the use of specific social media platforms and vaccination uptake is nascent. This descriptive study assesses differences in social media use by COVID-19 vaccination status among adults overall and those who reported baseline vaccine hesitancy. We used data from a nationally representative longitudinal survey of U.S. adults administered between January 2021-August 2022 (n = 2,908). Results indicated a positive association between frequent Instagram and/or Twitter use and vaccination status (p <.05). Among baseline vaccine hesitant adults, results indicated a positive association between frequent TikTok, Instagram, and/or Twitter use and vaccination status (p <.05). Findings have implications for research that examines the content of social media platforms and their environment on vaccine attitudes and uptake.

Trends in primary, booster, and updated COVID-19 vaccine readiness in the United States, January 2021-April 2023: Implications for 2023-2024 updated COVID-19 vaccines.

OBJECTIVE: COVID-19 vaccines have mitigated the severity of COVID-19 and its sequelae. The emergence of new SARS-CoV-2 variants and waning immunity conferred by COVID-19 vaccination have necessitated booster and updated COVID-19 vaccines. This study examined trends in vaccine readiness-a composite measure of intention and uptake-for the primary, booster, and 2022-2023 updated (bivalent) COVID-19 vaccines among U.S. adults. METHODS: Data from the nationally-representative U.S. Department of Health and Human Services' COVID-19 Monthly Outcome Survey from January 2021 to April 2023 were analyzed (N = 140,180). We conducted pairwise comparisons (weighted t-tests) to assess for significant between-month differences in the proportion of participants in each vaccine-readiness category (vaccine ready, wait and see, and no vaccine intention) for the following outcomes: (1) primary; (2) booster; and (3) updated COVID-19 vaccine readiness. RESULTS: From January 2021 to April 2023, significant increases in the primary vaccine ready group were accompanied by decreases in the wait and see and no vaccine intention groups (p < 0.001). From January to September 2022, the no booster intention group notably increased (p < 0.001), whereas the booster ready group decreased (p < 0.001), and the wait and see group remained stable (p = 0.116). From October 2022 to April 2023, the no updated vaccine intention group increased (p < 0.001), the wait and see group decreased (p < 0.01), and the updated vaccine ready group remained unchanged (p = 0.357). CONCLUSIONS: Findings show decreased vaccine readiness for the booster and 2022-2023 updated (bivalent) COVID-19 vaccines relative to the primary COVID-19 vaccines. Implications for the 2023-2024 updated COVID-19 vaccines are discussed.

Association between vaccination beliefs and COVID-19 vaccine uptake in a longitudinal panel survey of adults in the United States, 2021-2022.

COVID-19 vaccine hesitancy has been a major limiting factor to the widespread uptake of COVID-19 vaccination in the United States. A range of interventions, including mass media campaigns, have been implemented to encourage COVID-19 vaccine confidence and uptake. Such interventions are often guided by theories of behavior change, which posit that behavioral factors, including beliefs, influence behaviors such as vaccination. Although previous studies have examined relationships between vaccination beliefs and COVID-19 vaccination behavior, they come with limitations, such as the use of cross-sectional study designs and, for longitudinal studies, few survey waves. To account for these limitations, we examined associations between vaccination beliefs and COVID-19 vaccine uptake using data from six waves of a nationally representative, longitudinal survey of U.S. adults (N = 3,524) administered over a nearly 2-year period (January 2021-November 2022). Survey-weighted lagged logistic regression models were used to examine the association between lagged reports of vaccination belief change and COVID-19 vaccine uptake, using five belief scales: (1) importance of COVID-19 vaccines, (2) perceived benefits of COVID-19 vaccination, (3) COVID-19 vaccine concerns and risks, (4) normative beliefs about COVID-19 vaccination, and (5) perceptions of general vaccine safety and effectiveness. Analyses controlled for confounding factors and accounted for within-respondent dependence due to repeated measures. In individual models, all vaccination belief scales were significantly associated with increased COVID-19 vaccine uptake. In a combined model, all belief scales except the benefits of COVID-19 vaccination were significant predictors of vaccine uptake. Overall, belief scales indicating the importance of COVID-19 vaccines and normative beliefs about COVID-19 vaccination were the strongest predictors of COVID-19 vaccine uptake. Findings demonstrate that changes in vaccination beliefs influence subsequent COVID-19 vaccine uptake, with implications for the development of future interventions to increase COVID-19 vaccination.

Association Between the "We Can Do This" Campaign and COVID-19 Booster Uptake, U.S., 2021-2022.

Introduction: Monovalent COVID-19 boosters lower the risk of COVID-19 disease, infection, hospitalization, and death. This study examined associations between exposure to a booster public education campaign (the booster campaign) and the increases in booster uptake and reduced length of time until booster uptake among U.S. adults. Methods: Data included a national survey panel of U.S. adults and booster campaign paid media (i.e., digital impressions and TV gross rating points) from September 2021 to May 2022. Multilevel logistic regression models examined the association between exposure to the booster campaign and the likelihood of booster uptake. A Cox proportional hazard model evaluated the association between the booster campaign and booster uptake timing. Interaction terms between the booster campaign media variables and first-dose COVID-19 vaccine date examined differential effects of the booster campaign based on when individuals received their first dose. Results: Interactions between first-dose vaccination date and the booster campaign were statistically significant for cumulative digital impressions (ß=4.75e-08; 95% CIs=5.93e-09, 8.90e-08) and TV gross rating points (ß = 4.62e-05; 95% CIs=5.09e-06, 8.73e-05), suggesting that booster uptake was strongest among those who received their first-dose COVID-19 vaccine later. Booster campaign cumulative digital impressions and TV gross rating points were associated with accelerated booster uptake among those with later first-dose vaccination dates (digital: ß=9.98e-08; 95% CIs=2.70e-08, 1.73e-07; TV: ß=0.0001; 95% CIs=2.80e-05, 0.0002), relative to those with earlier first-dose vaccination dates. Conclusions: The booster campaign may have increased monovalent booster uptake and reduced how long individuals waited until getting their booster. Public education campaigns show promise in stemming the tide of pandemic fatigue and increasing booster confidence.

A Prospective Comparative Study of 18 F-FDOPA PET/CT Versus 123 I-MIBG Scintigraphy With SPECT/CT for the Diagnosis of Pheochromocytoma and Paraganglioma.

PURPOSE: This study aimed to compare the diagnostic performances of 18 F-FDOPA PET/CT and 123 I-MIBG scintigraphy with SPECT/CT for detection of pheochromocytoma and paraganglioma (PPGL). PATIENTS AND METHODS: We conducted a prospective, single-institution comparative study. Patients suspected of having PPGL or those showing recurrence and/or distant metastasis of PPGL were enrolled. The primary objective was to affirm the noninferiority of 18 F-FDOPA PET/CT for diagnostic sensitivity. Both 123 I-MIBG scintigraphy with SPECT/CT (at 4 and 24 hours) and 18 F-FDOPA PET/CT (at 5 and 60 minutes after radiotracer administration) were performed. The final diagnosis was established either pathologically or via clinical follow-up. Nuclear physicians, unaware of the clinical data, undertook image analysis. RESULTS: Thirty-two patients were evaluated: 14 of 21 with an initial diagnosis and 9 of 11 with recurrence/metastasis had PPGLs in their final diagnoses. In patient-based analyses, 18 F-FDOPA PET/CT (95.7%) exhibited noninferior sensitivity compared with 123 I-MIBG SPECT/CT (91.3%), within the predetermined noninferiority margin of -12% by a 95% confidence interval lower limit of -10%. Both modalities showed no significant difference in specificity (88.9% vs 88.9%). In the region-based analysis for the recurrence/metastasis group, 18 F-FDOPA PET/CT demonstrated significantly higher sensitivity compared with 123 I-MIBG SPECT/CT (86.2% vs 65.5%, P = 0.031) and superior interobserver agreement (κ = 0.94 vs 0.85). The inclusion of an early phase in dual-phase 18 F-FDOPA PET/CT slightly improved diagnostic performance, albeit not to a statistically significant degree. CONCLUSIONS: 18 F-FDOPA PET/CT demonstrated noninferior sensitivity and comparable specificity to 123 I-MIBG SPECT/CT in the diagnosing PPGL. Notably, in the assessment of PPGL recurrence and metastasis, 18 F-FDOPA PET/CT outperformed 123 I-MIBG SPECT/CT in terms of both sensitivity and interobserver agreement.

Association Between the United States Department of Health and Human Services' COVID-19 Public Education Campaign and Initial Adult COVID-19 Vaccination Uptake by Race and Ethnicity in the United States, 2020-2022.

Non-Hispanic Black (Black) and Hispanic/Latino (Latino) populations face an increased risk of COVID-19 infection, hospitalization, and death from COVID-19 relative to non-Hispanic White (White) populations. When COVID-19 vaccines became available in December 2020, Black and Latino adults were less likely than White adults to get vaccinated due to factors such as racial discrimination and structural barriers to uptake. In April 2021, the U.S. HHS COVID-19 public education campaign (the Campaign) was launched to promote vaccination through general and audience-tailored messaging. As of March 2022, Black and Latino adults had reached parity with White adults in COVID-19 vaccine uptake. This study evaluated the relationship between Campaign exposure and subsequent vaccine uptake among Black, Latino, and White adults in the United States and assessed whether participant race/ethnicity moderated the relationship between Campaign exposure and vaccine uptake. Campaign media delivery data was merged with survey data collected from a sample of U.S. adults (n = 2,923) over four waves from January 2021 to March 2022. Logistic regression analysis showed that cumulative Campaign digital impressions had a positive, statistically significant association with COVID-19 vaccine uptake, and that participant race/ethnicity moderated this association. Compared with White adults, the magnitude of the relationship between cumulative impressions and vaccination was greater among Black and Latino adults. Results from a simulation model suggested that the Campaign may have been responsible for closing 5.0% of the gap in COVID-19 vaccination by race/ethnicity from April to mid-September 2021. We discuss implications for future public education campaigns that aim to reduce health disparities.

Development of 3D Printable Calcium Phosphate Cement Scaffolds with Cockle Shell Powders.

Three-dimensional (3D) printed calcium phosphate cement (CPC) scaffolds are increasingly being used for bone tissue repair. Traditional materials used for CPC scaffolds, such as bovine and porcine bone, generally contain low amounts of calcium phosphate compounds, resulting in reduced production rates of CPC scaffolds. On the other hand, cockle shells contain more than 99% CaCO3 in the form of amorphous aragonite with excellent biocompatibility, which is expected to increase the CPC production rate. In this study, 3D-printed cockle shell powder-based CPC (CSP-CPC) scaffolds were developed by the material extrusion method. Lactic acid and hyaluronic acid were used to promote the printability. The characterization of CSP-CPC scaffolds was performed using Fourier transform infrared spectra, X-ray diffraction patterns, and scanning electron microscopy. The biocompatibility of CSP-CPC scaffolds was evaluated using cell viability, Live/Dead, and alkaline phosphatase assays. In addition, CSP-CPC scaffolds were implanted into the mouse calvarial defect model to confirm bone regeneration. This study provides an opportunity to create high value added in fishing villages by recycling natural products from marine waste.

Development of 18F-Labeled PET Tracer Candidates for Imaging of the Abelson Non-receptor Tyrosine Kinase in Parkinson's Disease.

Activated Abelson non-receptor tyrosine kinase (c-Abl) plays a harmful role in neurodegenerative conditions such as Parkinson's disease (PD). Inhibition of c-Abl is reported to have a neuroprotective effect and be a promising therapeutic strategy for PD. We have previously identified a series of benzo[d]thiazole derivatives as selective c-Abl inhibitors from which one compound showed high therapeutic potential. Herein, we report the development of a complementary positron emission tomography (PET) tracer. In total, three PET tracer candidates were developed and eventually radiolabeled with fluorine-18 for in vivo evaluation studies in mice. Candidate [18F]3 was identified as the most promising compound, since it showed sufficient brain uptake, good washout kinetics, and satisfactory metabolic stability. In conclusion, we believe this tracer provides a good starting point to further validate and explore c-Abl as a target for therapeutic strategies against PD supported by PET.

A clinical retrospective study of implant as a risk factor for medication-related osteonecrosis of the jaw: surgery vs loading?

BACKGROUND: Risk factors for developing medication-related osteonecrosis of the jaw (MRONJ) include the general condition of the patient, smoking habit, poor oral hygiene, and the type, duration, and administration route of the drug, dentoalveolar surgery, such as implant placement. This study aimed to discuss whether implants may induce osteonecrosis in older patients receiving long-term medication and to analyze the radiological pattern of the bone necrosis. METHODS: This study included 33 patients diagnosed with dental implant-associated medication-related osteonecrosis of the jaw. Data regarding the medical history, type of medication used, durations of administration, laboratory test results, onset of bone necrosis since implant placement, type of opposing teeth, and radiological pattern of the bone necrosis on cone-beam computed tomography were recorded in patients with and without implants. RESULTS: The most commonly used drug was bisphosphonate, with an average duration of use of 61.37 (± 53.72) months. The laboratory results showed average serum C-terminal cross-linking telopeptide (CTX) level of 0.23 ng/mL, vitamin D, 23.42 ng/mL, and osteocalcin, 4.92 ng/mL. Osteonecrosis occurred after an average of 51.03 (± 39.75) months following implant placement. Radiological evaluation revealed obvious sequestration in the implant-absent group, and the formation of a unit sequestration with an implant fixture (en bloc) was observed in the implant-present group. The patients underwent surgical treatment of sequestrectomy and explantation. CONCLUSION: Implant placement, especially loading, may be considered a potential risk factor for the development of osteonecrosis in patients undergoing antiresorptive treatment.

Evaluation of the "We Can Do This" Campaign Paid Media and COVID-19 Vaccination Uptake, United States, December 2020-January 2022.

Public education campaigns are promising methods for promoting vaccine uptake. In April 2021, the U.S. Department of Health and Human Services launched the We Can Do This COVID-19 public education campaign. This study is one of the first evaluations of this COVID-19 public education campaign. We tested associations between channel-specific campaign exposure (i.e. digital, TV, radio, print, and out-of-home advertising) and COVID-19 first-dose vaccinations among a nationally representative online sample of 3,278 adults. The study introduces novel ways to simultaneously evaluate short- and long-term cumulative media dose, filling an important gap in campaign evaluation literature. We observed a positive, statistically significant relationship between the short-term change in digital media dose and the likelihood of first-dose vaccination, and a positive, statistically significant relationship between long-term cumulative TV dose and the likelihood of first-dose vaccination. Results suggest that both digital and TV ads contributed to vaccination, such that digital media was associated with more immediate behavioral changes, whereas TV gradually shifted behaviors over time. As findings varied by media channel, this study suggests that public education campaigns should consider delivering campaign messages across multiple media channels to enhance campaign reach across audiences.

Clinical outcome of narrow diameter dental implants: a 3-year retrospective study.

BACKGROUND: This study aimed to analyze the clinical outcome and complications of narrow-diameter dental implants (NDIs) (diameter ≤3.5 mm). METHODS: The 274 NDIs that met the selection criteria from 2013 to 2018 were included in the retrospective study, and the survival rates (SVR) were compared. Mechanical complications included screw loosening and fractures of the implant components, such as the implant fixture, abutment, and prosthesis. In addition, marginal bone loss (MBL) was measured immediately after surgery and 1 year after loading. RESULTS: The 3-year cumulative SVR was 92.4%. Nineteen fixtures failed during the follow-up. The failure rate was significantly higher (OR=4.573, p<0.05) in smokers and was significantly higher in osteoporosis patients (OR=3.420, p<0.05). The vertical and horizontal values of MBL were 0.33±0.32 mm and 0.18±0.17 mm, respectively. Mechanical complications included screw loosening (5.5%) and porcelain fracture (2.2%), but no fractures of the fixture or components were observed. The choice of titanium and zirconium (TiZr) alloy implant was significantly more frequent in the posterior region. Bone graft was significantly more frequently done in the anterior region. CONCLUSIONS: According to the high SVR and stability of NDIs, the findings of the study suggest that NDIs may be a replacement for regular diameter dental implants (RDIs) and the use of TiZr alloy could extend the indication of NDIs. In the esthetic area, contour augmentation may be a reason for increasing the frequency of bone grafts.

Integration of blue light with near-infrared irradiation accelerates the osteogenic differentiation of human dental pulp stem cells.

Blue light is used less in photobiomodulation than red or near-infrared light because of concerns about its high energy. However, some reports have suggested that blue light releases NO from nitrosated proteins, affects cell signal regulation, and promotes stem cell differentiation. Because blue and red lights could have different mechanisms of action, their combination is expected to have new consequences. In this study, human dental pulp stem cells (hDPSCs) were sequentially exposed to blue and near-infrared light to study their effects on proliferation, osteogenic differentiation, and immunomodulation. We found that NIR irradiation applied after blue light can reduce blue light toxicity improving the cell viabiltiy. Delayed luminescence and transmission electron microscopy studies showed that this combination excited hDPSCs and activated mitochondrial biogenesis. Those modulations accelerated hDPSC differentiation, as shown by an increase of about 1.3-fold in alkaline phosphatase activity in vitro and an about 1.5-fold increase in the osteocalcin-positive regions in cells implanted in nude mice compared with mice exposed to near-infrared alone.

Selection of iPSCs without mtDNA deletion for autologous cell therapy in a patient with Pearson syndrome.

Screening for genetic defects in the cells should be examined for clinical application. The Pearson syndrome (PS) patient harbored nuclear mutations in the POLG and SSBP1 genes, which could induce systemic large-scale mitochondrial genome (mtDNA) deletion. We investigated iPSCs with mtDNA deletions in PS patient and whether deletion levels could be maintained during differentiation. The iPSC clones derived from skin fibroblasts (9% deletion) and blood mononuclear cells (24% deletion) were measured for mtDNA deletion levels. Of the 13 skin-derived iPSC clones, only 3 were found to be free of mtDNA deletions, whereas all blood-derived iPSC clones were found to be free of deletions. The iPSC clones with (27%) and without mtDNA deletion (0%) were selected and performed in vitro and in vivo differentiation, such as embryonic body (EB) and teratoma formation. After differentiation, the level of deletion was retained or increased in EBs (24%) or teratoma (45%) from deletion iPSC clone, while, the absence of deletions showed in all EBs and teratomas from deletion-free iPSC clones. These results demonstrated that non-deletion in iPSCs was maintained during in vitro and in vivo differentiation, even in the presence of nuclear mutations, suggesting that deletion-free iPSC clones could be candidates for autologous cell therapy in patients. [BMB Reports 2023; 56(8): 463-468].

SMO-CRISPR-mediated apoptosis in CD133-targeted cancer stem cells and tumor growth inhibition.

Cancer stem cells (CSCs) possess the ability to indefinitely proliferate and resist therapy, leading to cancer relapse and metastasis. To address this, we aimed to develop a CSC-inclusive therapy that targets both CSCs and non-CSC glioblastoma (GBM) cells. We accomplished this by using a smoothened (SMO) CRISPR/Cas9 plasmid to suppress the hedgehog pathway in CSCs, in combination with inhibiting the serine hydroxymethyl transferase 1 (SHMT1)-driven thymidylate biosynthesis pathway in non-CSC GBM cells using SHMT1 siRNA (siSHMT1). We targeted CSCs using a CD133 peptide attached to an osmotically active vitamin B6-coupled polydixylitol vector (VPX-CD133) by a photoactivatable heterobifunctional linker. VPX-CD133 nanocomplexes in comparison to VPX complexes remarkably targeted and transfected CSCs both in vitro and in subcutaneous tumor. The VPX-CD133-mediated targeted delivery of SMO CRISPR in CSCs led to SMO suppression that negatively affected its growth. Next, we performed comprehensive therapy in xenograft mice using VPX-CD133, which delivered SMO-CRISPR to CSCs, and VPX, which delivered siSHMT1 to non-CSC GBM cells. The combined treatment induced apoptosis in a large number of cells, reduced tumor volume by up to 81%, and improved the health of treated mice significantly. By eliminating CSCs together with the non-CSC GBM cells, the combined study paves the way for developing CSC-inclusive therapies for GBM.

Development of a Scaffold-on-a-Chip Platform to Evaluate Cell Infiltration and Osteogenesis on the 3D-Printed Scaffold for Bone Regeneration.

Developing a scaffold for efficient and functional bone regeneration remains challenging. To accomplish this goal, a "scaffold-on-a-chip" device was developed as a platform to aid with the evaluation process. The device mimics a microenvironment experienced by a transplanted bone scaffold. The device contains a circular space at the center for scaffold insert and microfluidic channel that encloses the space. Such a design allows for monitoring of cell behavior at the blood-scaffold interphase. MC3T3-E1 cells were cultured with three different types of scaffold inserts to test its capability as an evaluation platform. Cellular behaviors, including migration, morphology, and osteogenesis with each scaffold, were analyzed through fluorescence images of live/dead assay and immunocytochemistry. Cellular behaviors, such as migration, morphology, and osteogenesis, were evaluated. The results revealed that our platform could effectively evaluate the osteoconductivity and osteoinductivity of scaffolds with various properties. In conclusion, our proposed platform is expected to replace current in vivo animal models as a highly relevant in vitro platform and can contribute to the fundamental study of bone regeneration.

Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial.

BACKGROUND AND AIM: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). METHODS: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells ("SMT-NK") on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. RESULTS: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. CONCLUSIONS: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.

SHMT1 siRNA-Loaded hyperosmotic nanochains for blood-brain/tumor barrier post-transmigration therapy.

The near-perivascular accumulation in solid tumors and short-lived span in circulation, derails even the most competent nanoparticles (NPs) from achieving their maximum therapeutic potential. Moreover, delivering them across the blood brain/tumor barrier (BBB/BTB) is further challenging to sought anticancer effect. To address these key challenges, we designed a linearly aligned nucleic acid-complexed polydixylitol-based polymeric nanochains (X-NCs), with inherent hyperosmotic properties enabling transmigration of the BBB/BTB and navigation through deeper regions of the brain tumor. The high aspect ratio adds shape-dependent functional aspects to parent particles by providing effective payload increment and nuclear factor of activated T cells-5 (NFAT5)-mediated cellular uptake. Therefore, serine hydroxymethyltransferase 1 (SHMT1) siRNA-loaded nanochains not only demonstrated to transmigrate the BTB, but also resulted in remarkably reducing the tumor size to 97% in the glioblastoma xenograft brain tumor mouse models. Our study illustrates how the hyperosmotic nanochains with high aspect ratio and aligned structure can accelerate a therapeutic effect in aggressive brain tumors post-transmigration of the BBB/BTB by utilizing an NFAT5 mode of uptake mechanism.