Efficacy of Fu's Subcutaneous Needling on Myofascial Trigger Points for Lateral Epicondylalgia: A Randomized Control Trial.

Lateral epicondylalgia (LE), a common overuse syndrome of the extensor muscle and tendons on the lateral epicondyle, causes persistent severe musculoskeletal pain on the outer part of the elbow. Fu's subcutaneous needling (FSN), a newly invented subtype of acupuncture and dry needling, is a new trend and potential treatment of LE by targeting the myofascial trigger points (MTrPs). However, no scientific evidence is available to support this method. This study aims to evaluate the distal FSN treatment on the LE by measuring pain-related scales, such as visual analog scale (VAS), pressure pain threshold (PPT), muscle tissue hardness (TH), pain-free grip (PFG), and the functional outcome by a patient-rated tennis elbow evaluation (PRTEE) questionnaire study. A total of 60 LE patients were randomly divided into FSN (n = 30) and transcutaneous electrical nerve stimulation (TENS, n = 30) as the control group. Every subject was treated with three regimens and followed up for 15 days. Results showed that FSN has an immediate effect on VAS, PPT, TH, and PFG. Moreover, sustained effects on pain relief were followed up to 15 days. Pain remission was consistent with long-term PRTEE results. Overall, FSN is a safe and efficient therapy option for LE, significantly improving pain relief and activity difficulty with immediate, short-term, and long-term effectiveness. This trial is registered with ClinicalTrials.gov NCT03605563.

Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer.

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

Effect of aloin on viral neuraminidase and hemagglutinin-specific T cell immunity in acute influenza.

BACKGROUND: Millions of people are infected by the influenza virus worldwide every year. Current selections of anti-influenza agents are limited and their effectiveness and drug resistance are still of concern. PURPOSE: Investigation on in vitro and in vivo effect of aloin from Aloe vera leaves against influenza virus infection. METHODS: In vitro antiviral property of aloin was measured by plaque reduction assay in which MDCK cells were infected with oseltamivir-sensitive A(H1N1)pdm09, oseltamivir-resistant A(H1N1)pdm09, H1N1 or H3N2 influenza A or with influenza B viruses in the presence of aloin. In vivo activity was tested in H1N1 influenza virus infected mice. Aloin-mediated inhibition of influenza neuraminidase activity was tested by MUNANA assay. Aloin treatment-mediated modulation of anti-influenza immunity was tested by the study of hemagglutinin-specific T cells in vivo. RESULTS: Aloin significantly reduced in vitro infection by all the tested strains of influenza viruses, including oseltamivir-resistant A(H1N1)pdm09 influenza viruses, with an average IC50 value 91.83 ± 18.97 µM. In H1N1 influenza virus infected mice, aloin treatment (intraperitoneal, once daily for 5 days) reduced virus load in the lungs and attenuated body weight loss and mortality. Adjuvant aloin treatment also improved the outcome with delayed oseltamivir treatment. Aloin inhibited viral neuraminidase and impeded neuraminidase-mediated TGF-ß activation. Viral neuraminidase mediated immune suppression with TGF-ß was constrained and influenza hemagglutinin-specific T cell immunity was increased. There was more infiltration of hemagglutinin-specific CD4+ and CD8+ T cells in the lungs and their production of effector cytokines IFN-γ and TNF-α was boosted. CONCLUSION: Aloin from Aloe vera leaves is a potent anti-influenza compound that inhibits viral neuraminidase activity, even of the oseltamivir-resistant influenza virus. With suppression of this virus machinery, aloin boosts host immunity with augmented hemagglutinin-specific T cell response to the infection. In addition, in the context of compromised benefit with delayed oseltamivir treatment, adjuvant aloin treatment ameliorates the disease and improves survival. Taken together, aloin has the potential to be further evaluated for clinical applications in human influenza.

Near-Infrared Fluorescent Dye-Decorated Nanocages to Form Grenade-like Nanoparticles with Dual Control Release for Photothermal Theranostics and Chemotherapy.

Recently, nanoparticles (NPs) have been widely investigated for delivery of anticancer drugs. Here, a dual control drug-release modality was developed that uses naturally occurring protein apoferritin loaded with doxorubicin (DOX) and ADS-780 near-infrared (NIR) fluorescent dye-decorated NPs (ADNIR NPs). ADNIR NPs act as a grenade to detonate the targeted tumor site following laser irradiation (photothermal therapy, PTT) and explode into cluster warheads (apoferritin-loaded DOX nanocages, AF-DOX NCs) that further destroy the tumor cells (chemotherapy). Light was shown to disrupt the grenade-like structure of NPs to release AF-DOX NCs as well as DOX from NCs in low-pH intercellular environments. In vitro and in vivo studies showed that the structure of AF-DOX NCs was disassembled to release DOX, which then killed the cancer cells in organelles with acidic environments. In vivo studies showed that the ADNIR NP-decorated with NIR dye facilitated tracking of the accumulated NPs at the tumor site using an IVIS imaging system. Overall, targeted ADNIR NPs with dual-release mechanisms were developed for use in photothermal theranostic and chemotherapy. This modality has high potential for application in cancer treatment and clinical translation for drug delivery and imaging.

Immunochemotherapy benefits in gastric cancer patients stratified by programmed death-1 ligand-1.

BACKGROUND: Effectiveness of protein-bound polysaccharide K (PSK) during adjuvant chemotherapy in gastric cancer patients expressing programmed death-1 ligand 1 (PD-L1) has not been investigated. Investigating this might help in triaging candidates eligible to immunochemotherapy. MATERIALS AND METHODS: In total, 918 patients with stages II and III gastric cancer, undergoing curative gastrectomy, and receiving adjuvant chemotherapy were enrolled in a prospective database, and the patients were retrospectively reviewed. We classified those patients into four cohorts stratified by PD-L1 expression and PSK administration, namely PD-L1, PSK (-,+); PD-L1, PSK (-,-); PD-L1, PSK (+,+); and PD-L1, PSK (+,-). In addition, another independent cohort of 20 patients undergoing radical gastrectomy was prospectively recruited to check their immunological cells of sera before and 2 mo after PSK administration. RESULTS: PSK treatment was an independent prognostic factor for patient's overall survival (P = 0.020), whereas PD-L1 expression per se was not. Administration of PSK prolonged patient survival in stages IIIA and IIIB (P = 0.031) but not in stage II or stage IIIC. Patients with negative expression of PD-L1, treated with PSK had longer survival than those not treated with PSK (P = 0.033). PSK did not affect the survival of patients with positive expression of PD-L1, (P = 0.421). The percentages of natural killer and natural killer T (NKT) cells, but not Th1, Th17, Treg, or IFN-γ+/CD8+ T cells, were significantly increased in PD-L1 (-) patients treated with PSK. However, these findings were not evident in PD-L1 (+) patients. CONCLUSIONS: PSK treatment preferentially confers a survival gain for patients with stage IIIA/IIIB gastric cancer, especially in the PD-L1 (-) subpopulation.

Adjuvant therapy for hepatocellular carcinoma after curative treatment.

Hepatocellular carcinoma (HCC) is a common malignancy in the world. Although resection and various locoregional therapies can achieve eradication or complete ablation of small HCC, HCC recurrence after these therapies is still common. Although candidates for medical ablation usually exhibit compensated hepatic functional status, the frequent recurrence of HCC after successful ablation contributes to short survival. Therefore, attempts to prevent HCC recurrence are essential to prolong survival. Efforts in preventing HCC recurrence after curative therapies include prevention of early recurrence by improving liver immunity and eliminating microscopic tumor foci or micrometastases, and prevention of late recurrence by reducing the hepatitis activity and using antiviral therapies based on viral suppression/eradication. In HCC with vascular invasion, adjuvant transcatheter arterial chemoembolization should be considered to provide better control. Whether the adjuvant use of sorafenib may suppress microscopic tumor foci or micrometastases may be unveiled in the near future. This review article will update the algorithms, novel medication or study drugs in the prevention of HCC after curative therapies.

A simple cell patterning method using magnetic particle-containing photosensitive poly (ethylene glycol) hydrogel blocks: a technical note.

All human organs consist of multiple types of cells organized in a complex pattern to meet specific functional needs. One possible approach for reconstructing human organs in vitro is to generate cell sheets of a specific pattern and later stack them systematically by layer into a three-dimensional organoid. However, many commonly used cell patterning techniques suffer drawbacks such as dependence on sophisticated instruments and manipulation of cells under suboptimal growth conditions. Here, we describe a simple cell patterning method that may overcome these problems. This method is based on magnetic force and photoresponsive poly (ethylene glycol) diacrylate (PEG-DA) hydrogels. The PEG-DA hydrogel was magnetized by mixing with iron ferrous microparticles and then fabricated into blocks with a specific pattern by photolithography. The resolution of the hydrogel empty space pattern was approximately 150 µm and the generated hydrogel blocks can be remotely manipulated with a magnet. The magnetic PEG-DA blocks were used as a stencil to define the area for cell adhesion in the cell culture dish, and the second types of cells could be seeded after the magnetic block was removed to create heterotypic cell patterns. Cell viability assay has demonstrated that magnetic PEG-DA and the patterning process produced negligible effects on cell growth. Together, our results indicate that this magnetic hydrogel-based cell patterning method is simple to perform and is a useful tool for tissue surrogate assembly for disease mechanism study and drug screening.