Engineered Platelet for In Situ Natural Killer Cell Activation to Inhibit Tumor Recurrence.

Natural killer (NK) cells offer profound advantages against tumor recurrence due to their unique immunological behavior. NK cell therapies associated with the antibody-dependent cell-mediated cytotoxicity (ADCC) effect have made remarkable progress while being limited by insufficient antibody binding and the exhausted state of NK cells in the postsurgical immunosuppressive microenvironment. Leveraging the adherence of PLT to tumor cells, we developed an exogenously implanted platelet (PLT)-based NK cell-driven system (PLT-IgG-IL15) to improve the identifiability of residual tumors with IgG antibody labeling for NK cells catching and engaging, which consequently restored the ADCC effect and promoted the recovery of their killing function. Furthermore, interleukin-15 (IL-15) participated in the augmentation of NK cell function. Collectively, PLT-IgG-IL15 served as an NK cell tumor cell engager as well as an NK cell charger, achieving a <40% recurrence rate in mouse tumor models.

Design of a novel multi-epitope vaccine candidate against endometrial cancer using immunoinformatics and bioinformatics approaches.

Endometrial cancer (EC) is one of the most common cancers of the female reproductive system. Multi-epitope vaccine may be a promising and effective strategy against EC. In this study, we designed a novel multi-epitope vaccine based on the antigenic proteins PRAME and TMPRSS4 using immunoinformatics and bioinformatics approaches. After a rigorous selection process, 14 cytotoxic T lymphocyte (CTL) epitopes, 6 helper T lymphocyte (HTL) epitopes, and 8 B cell epitopes (BCEs) were finally selected for vaccine construction. To enhance the immunogenicity of the vaccine candidate, the pan HLA DR-binding epitope was included in the vaccine design as an adjuvant. The final vaccine construct had 455 amino acids and a molecular weight of 49.8 kDa, and was predicted to cover 95.03% of the total world population. Docking analysis showed that there were 10 hydrogen bonds and 19 hydrogen bonds in the vaccine-HLA-A*02:01 and vaccine-HLA-DRB1*01:01 complexes, respectively, indicating that the vaccine has a good affinity to MHC molecules. This was further supported by molecular dynamics (MD) simulation. Immune simulation showed that the designed vaccine was able to induce higher levels of immune cell activity, with the secretion of numerous cytokines. The codon adaptation index (CAI) value and GC content of the optimised codon sequences of the vaccine were 0.986 and 54.43%, respectively, indicating that the vaccine has the potential to be highly expressed. The in silico analysis suggested that the designed vaccine may provide a novel therapeutic option for the individualised treatment of EC patients in the future.Communicated by Ramaswamy H. Sarma.

Redox modulation with a perfluorocarbon nanoparticle to reverse Treg-mediated immunosuppression and enhance anti-tumor immunity.

Tumor hypoxia and high glutathione (GSH) expression promote regulatory T cell (Treg) infiltration and maintain its immunosuppressive function, which significantly reduces the response rate of cancer immunotherapy. Here, we developed an immunomodulatory nano-formulation (FEM@PFC) to reverse Treg-mediated immunosuppression by redox regulation in the tumor microenvironment (TME). Oxygen carried in perfluorocarbon (PFC) was delivered to the TME, thus relieving the hypoxic condition and inhibiting Treg infiltration. More importantly, GSH depletion by the prodrug efficiently restricted the Foxp3 expression and immunosuppressive function of Tregs, thus breaking the shackles of tumor immunosuppression. Additionally, the supplement of oxygen cooperated with the consumption of GSH to enhance the irradiation-induced immunogenic cell death and subsequent dendritic cell (DC) maturation, thereby efficiently promoting the activation of effector T cells and restricting the immunosuppression of Tregs. Collectively, the FEM@PFC nano-formulation reverses Treg-mediated immunosuppression and regulates the redox balance in the TME to boost anti-tumor immunity and prolong the survival of tumor-bearing mice, which provides a new immunoregulatory strategy from the perspective of redox modulation.

Associations between weight-adjusted waist index and fractures: a population-based study.

INTRODUCTION: The weight-adjusted waist circumference index (WWI) is a novel obesity evaluation indicator that appears to be superior to body mass index (BMI) and waist circumference (WC) in evaluating muscle and fat mass. The purpose of this study was to investigate the association between WWI and fractures among adults. METHODS: In this cross-sectional study, multivariate logistic regression and smoothed curve fitting were used to investigate linear and nonlinear associations between WWI and fractures, based on data from 28,679 adult participants in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. RESULTS: After adjusting for all covariates, the prevalence of hip/wrist/spine fractures among all participants was 1.09%, 8.87%, and 1.97%, respectively. A 1-unit increase in WWI was associated with a 5% increase in the odds of hip fractures [1.05 (1.01, 1.10)], and a 9% increase in the odds of spine fractures [1.09 (1.06, 1.13)], but not with the prevalence of wrist fractures [0.97 (0.94, 1.06)]. CONCLUSIONS: Higher WWI was associated with an increased prevalence of hip fracture and spine fracture, but not wrist fracture.

Site-Specific Polyplex on CCR7 Down-Regulation and T Cell Elevation for Lymphatic Metastasis Blocking on Breast Cancer.

Tumor metastasis contributes to high cancer mortality. Tumor cells in lymph nodes (LNs) are difficult to eliminate but underlie uncontrollable systemic metastasis. The CC chemokine receptor 7 (CCR7) is overexpressed in tumor cells and interacts with CC chemokine ligand 21 (CCL21) secreted from LNs, potentiating their lymphatic migration. Here, a site-specific polyplex is developed to block the CCR7-CCL21 signal and kill tumor cells toward LNs, greatly limiting their lymphatic infiltration. A CCR7-targeting small interfering RNA (siCCR7) is condensed by mPEG-poly-(lysine) with chlorin e6 (Ce6) modification (PPLC) to form PPLC/siCCR7. The knockdown of CCR7 by siCCR7 in tumor cells significantly reduced their response on CCL21 and LN tropism. Additionally, photodynamic therapy-mediated immune activation precisely targets and kills tumor cells released from the primary foci before they reaches the LNs, reducing the number of tumor cells entering the LNs. Consequently, the PPLC/siCCR7 polyplexes inhibited up to 92% of lung metastasis in 4T1 tumor bearing mice and reduced tumor cell migration to LNs by up to 80%. This site-specific strategy optimized anti-metastasis efficacy and promotes the clinical translational development of anti-metastatic therapy.

Endoscopically Assisted, Minimally Invasive Reconstruction for Chronic Achilles Tendon Rupture With a Double-Bundle Flexor Hallucis Longus.

BACKGROUND: High morbidity has been reported regarding Achilles tendon (AT) injuries, and the upward trend has accelerated since the mid-1990s. A chronic Achilles tendon rupture usually results from a neglected or misdiagnosed acute rupture, and about one-fifth of acute AT ruptures are missed and lead to chronic AT rupture. Although many techniques have been described, there is no gold standard in the treatment of chronic AT ruptures. HYPOTHESIS: Endoscopically assisted, minimally invasive reconstruction for chronic AT rupture using a double-bundle flexor hallucis longus (FHL) tendon would result in improvement of the overall function, with a low rate of wound complications. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between May 2015 and November 2016, a total of 19 consecutive patients were enrolled and treated using endoscopically assisted, minimally invasive reconstruction for chronic AT rupture using a double-bundle FHL. The operative assessment comprised the Achilles Tendon Total Rupture Score, the American Orthopaedic Foot & Ankle Society score, the Victorian Institute of Sports Assessment-Achilles score, and a postoperative questionnaire. All postoperative complications were recorded. RESULTS: The mean follow-up time for all patients was 31 months (range, 20-42 months). According to the postoperative questionnaire, the result of surgery was excellent in 8 (42%) of 19 patients, good in 10 (53%), and fair in 1 (5%). All clinical outcome scores (mean ± SD) improved significantly after surgery: Achilles Tendon Total Rupture Score, 23.3 ± 10.3 vs 98.3 ± 9.2 (postoperatively vs preoperatively); American Orthopaedic Foot & Ankle Society, 52.1 ± 12.4 vs 97.5 ± 18.9; and Victorian Institute of Sports Assessment-Achilles, 23.4 ± 11.2 vs 95.7 ± 17.1 (P < .05). No complications with regard to wound healing or infection were noted. Twelve relatively young patients returned to preinjury activity levels, such as playing basketball or badminton, and the older patients were able to meet their daily needs, such as walking up stairs and jogging. CONCLUSION: Chronic AT ruptures were successfully treated via minimally invasive reconstruction using a double-bundle FHL, which provided excellent functional improvement. It is best suited for patients with complex requirements who are at high risk for wound complications.

Development and Biocompatibility Analysis of NBD Peptide Sustained- Release Microsphere Scaffold Nanoparticle SP-Sr-CaS/NBD.

BACKGROUND: In clinical treatment, it is difficult to carry out effective bone tissue transplantation and anti-inflammatory treatment at the same time due to bone defects and osteomyelitis where the tissue is contaminated or infected. As a downstream target of TNF-α, NF-κB has an inhibition effect on the proliferation and differentiation of cells surrounding the lesion. As a negative effect, it leads to a reduction in bone growth and development. METHODS: In this study, the small molecule NBD polypeptide and bone conduction matrix Sr-CaS are microspheres, formed to prepare Sr-CaS, NBD drug-loaded sustained-release microspheres in order to achieve a Sr-CaS/NBD peptide drug-loaded sustained release microsphere scaffold material (SP-Sr-CaS/NBD). We prepared the microspheres and optimized the production process to obtain particles with stable morphological properties and sustained release properties. RESULT: In vitro experiments demonstrated that SP-Sr-CaS/NBD could reduce TNF-α-induced cell growth inhibition, caspase-3 activity and NF-κB transcriptional activation as the function of continuous NBD peptide dosing regimen. CONCLUSION: Also, the introduction of the Sr-CaS matrix potentiates microspheres to promote cell proliferation and provides a basis to become a promising 3D bone scaffold material in the future.

A retrospective analysis of 140 patients with giant cell tumor in the extremity: a multicenter study based on four hospitals in South China.

BACKGROUND: Update reports are rarely available regarding the bone giant cell tumors (GCTs) in the extremity in Chinese people. The aim of this study was to review the epidemiological characteristics of bone GCT in the extremity based on the clinical data from four hospitals in South China. METHODS: We searched medical electronic records from January 2001 to December 2011 in four hospitals in South China to identify patients with definite diagnosis of extremity GCT. Epidemiological data including gender, tumor site, age at the time of first diagnosis, local recurrence and pulmonary metastasis were collected and analyzed statistically. Differences between-genders were particularly analyzed regarding first diagnosis age, tumor site, local recurrence and pulmonary metastasis. T-test and Chi-square test were used for continuous and dichotomous variables, respectively. RESULTS: A total of 140 GCT patients (87 males and 53 females) were identified. The gender ratio was 1.64 for a male predominance. GCTs were mostly located around the knee (67 cases). 92 patients were in their 20s to 40s upon first diagnosis. The average age at the time of first diagnosis for all was 30.49 years, 30.76 years for males and 30.06 years for females (P = 0.757). GCT recurred locally in 50 patients (26 males and 24 females) with no gender difference (P = 0.065). The average interval from first surgery to local recurrence was 21.42 months. Pulmonary metastasis was found in 11 patients (8 males and 3 females) also with no gender difference (P = 0.667). The average interval from first diagnosis to metastasis was 36.45 months. CONCLUSIONS: Extremity GCT may have a male predominance in Chinese population and mostly occur at 20-40 years of age and around the knee. Follow-ups for GCT patients should be carried on for at least 3 years after primary surgery according to the average intervals for possible local recurrence and pulmonary metastasis.