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目的：以WHO 2020身體活動指引觀點來探究肌力與平衡能力對於高齡者之重要性。方法：綜整WHO 2020身體活動指引與高齡者有關之重要資訊及肌力、平衡能力對於高齡者身體表現影響之國內、外文獻，使讀者了解身體活動的重要性。結果：高齡者任何持續時間的身體活動都與改善健康有關，平衡和功能性訓練可以降低跌倒率，而進行一系列不同類型的身體活動有助於改善各種身體機能。結論：高齡者除了可在日常生活透過簡易的步行或在安全前提下進行高強度間歇訓練，提高身體活動量外，每週應進行3天或更多天的多變、多組成身體活動，特別是強調功能性平衡及中等或更高強度的肌力訓練，以增強功能性能力並防止跌倒。 Purposes: Exploring the importance of muscle strength and balance to the elderly from the perspective of the WHO 2020 guideline on physical activity. Methods: A narrative review of important information related to the elderly in the new edition of the WHO 2020 physical activity guidelines and collects domestic and foreign literature on the effects of muscle strength and balance on the physical performance of the elderly that readers can understand the importance of physical activity. Results: Older adults should do physical activity of any bout duration is associated with improved health outcomes. Balance and functional exercises reduce the rate of falls and that engaging in a range of different types of physical activity can help to improve a wide range of elements of physical function. Conclusions: In addition to improving the amount of physical activity through walking or high-intensity interval training under safe conditions in daily life, elderly people should perform variable and varied physical activities for 3 or more days a week, especially emphasizing functional balance and moderate or higher-intensity muscle training for benefit enhance functional ability and prevent falls. &nbsp

Supplementary Figures S1-S6 and Tables S1-S3

The potency of tumor-specific antigen (TSA) vaccines, such as neoantigen (neoAg)-based cancer vaccines, can be compromised by host immune checkpoint inhibitory mechanisms, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), that attenuate neoAg presentation on dendritic cells (DC) and hinder T cell–mediated cytotoxicity. To overcome PD-1/PD-L1 inhibition in DCs, we developed a novel adeno-associated virus (meAAV) neoAg vaccine, modified with TLR9 inhibitory fragments, PD-1 trap, and PD-L1 miRNA, which extend the persistence of meAAV and activate neoAg-specific T-cell responses in immune-competent colorectal and breast cancer murine models. Moreover, we found that in combination with radiotherapy, the meAAV-based neoAg cancer vaccine not only elicited higher antigen presentation ability, but also maintained neoAg-specific cytotoxic T lymphocyte (CTL) responses. These functional PD-1 traps and PD-L1 miRNAs overcome host PD-1/PD-L1 inhibitory mechanisms and boost the therapeutic efficacy of radiotherapy. More importantly, combined radiotherapy and meAAV neoAg cancer vaccines significantly enhanced neoAg-specific CTL responses, increased CTL infiltration in tumor microenvironment, and decreased tumor-associated immunosuppression. This process led to the complete elimination of colorectal cancer and delayed tumor growth of breast cancer in tumor-bearing mice. Taken together, our results demonstrated a novel strategy that combines neoAg cancer vaccine and radiotherapy to increase the therapeutic efficacy against colorectal and breast cancers.

Graft copolymers with diblock side-chains in a selective solvent can self-assemble into atypical vesicles with monolayered and multilayered nonlamellar structures, subject to the same copolymer concentration.

Background: Percutaneous central venous catheters (PCVCs) are used commonly and widely in the neonatal intensive care unit (NICU). Malposition of PCVCs may cause life-threatening complications and prolong hospitalization. In Taiwan, conventional chest-abdomen radiography (CXR) has been used widely and routinely for assessing tip location of PCVCs. Compared to ultrasonography (US), CXR cannot provide real-time assessment, and patients are exposed to radiation. Therefore, this study aimed to analyze the role of US in detecting PCVC tip location in the lower extremities. Methods: Neonates who received PCVC insertion in the lower extremities in NICU from March 2019 to April 2020 were enrolled in this prospective cohort study. PCVC tip location was confirmed finally by conventional CXR after US examination and patients were included in the sono group; those not assessed by US formed the non-sono group. In addition, PCVCs inserted in 2018 for which tip location was evaluated only by CXR, were reviewed retrospectively and these cases were included in the non-sono group. Withdrawal rates between the two groups were analyzed using Chi-square test. Results: The sono group included 166 neonates with PCVCs and 141 were in the non-sono group. Median gestational age at date of PCVC insertion was 33.21 and 32.71 weeks in sono and non-sono groups, respectively (p = 0.37). Withdrawal rates were 10.84% and 65.95% (p

AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.

It is known that the adhesive property and mechanical strength of an apolar polymer can be improved by grafting with polar side chains, whereas the underlying mechanism is still elusive. In this work, the equilibrium structure and mechanical moduli of the melt of graft copolymers have been explored by dissipative particle dynamics. Due to the strong immiscibility of the non-polar backbone and polar side chains, nano-clusters of side chains formed and acted as physical crosslinkers. Moreover, non-affinity adsorption of polar side chains in the melt to the wall was observed, revealing an improvement in the adhesion property. Subjecting graft copolymers to cyclic deformation, the storage and loss moduli were acquired, and they grew with increasing grafting density. The melt strength in terms of the crossover frequency ascended with more side chains on the backbone. Our findings reveal that the strengthening of the mechanical properties of graft copolymers can be attributed to the formation of weakly cross-linked structures, thus offering an insight into the molecular design to aid the development of stronger graft copolymers.

Hybrid membranes of lipids and AxByAz triblock copolymers can possess better biocompatibility and mechanical stability. In this work, triblock copolymer conformations and stability of asymmetric me...

The potency of tumor-specific antigen (TSA) vaccines, such as neoantigen (neoAg)-based cancer vaccines, can be compromised by host immune checkpoint inhibitory mechanisms, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), that attenuate neoAg presentation on dendritic cells (DC) and hinder T cell–mediated cytotoxicity. To overcome PD-1/PD-L1 inhibition in DCs, we developed a novel adeno-associated virus (meAAV) neoAg vaccine, modified with TLR9 inhibitory fragments, PD-1 trap, and PD-L1 miRNA, which extend the persistence of meAAV and activate neoAg-specific T-cell responses in immune-competent colorectal and breast cancer murine models. Moreover, we found that in combination with radiotherapy, the meAAV-based neoAg cancer vaccine not only elicited higher antigen presentation ability, but also maintained neoAg-specific cytotoxic T lymphocyte (CTL) responses. These functional PD-1 traps and PD-L1 miRNAs overcome host PD-1/PD-L1 inhibitory mechanisms and boost the therapeutic efficacy of radiotherapy. More importantly, combined radiotherapy and meAAV neoAg cancer vaccines significantly enhanced neoAg-specific CTL responses, increased CTL infiltration in tumor microenvironment, and decreased tumor-associated immunosuppression. This process led to the complete elimination of colorectal cancer and delayed tumor growth of breast cancer in tumor-bearing mice. Taken together, our results demonstrated a novel strategy that combines neoAg cancer vaccine and radiotherapy to increase the therapeutic efficacy against colorectal and breast cancers.

Idiopathic pulmonary fibrosis (IPF) is characterized by a profound remodeling of the collagen in the extracellular matrix (ECM), where the fibers become both denser and more highly aligned. However, it is unknown how this reconfiguration of the collagen matrix affects disease progression. Here, we investigate the role of specific alterations in collagen fiber organization on cell migration dynamics by using biomimetic image-based collagen scaffolds representing normal and fibrotic lung, where the designs are derived directly from high-resolution second harmonic generation microscopy images. The scaffolds are fabricated by multiphoton-excited (MPE) polymerization, where the process is akin to three-dimensional printing, except that it is performed at much greater resolution (∼0.5 microns) and with collagen and collagen analogs. These scaffolds were seeded with early passaged primary human normal and IPF fibroblasts to enable the decoupling of the effect of cell-intrinsic characteristics (normal vs. IPF) versus ECM structure (normal vs. IPF) on migration dynamics. We found that the highly aligned IPF collagen structure promoted enhanced cell elongation and F-actin alignment along with increased cell migration speed and straightness relative to the normal tissues. Collectively, the data are consistent with an enhanced contact guidance mechanism on the aligned IPF matrix. Although cell intrinsic effects were observed, the aligned collagen matrix morphology had a larger effect on these metrics. Importantly, these biomimetic models of the lung cannot be synthesized by conventional fabrication methods. We suggest that the MPE image-based fabrication method will enable additional hypothesis-based testing studies of cell-matrix interactions in the context of tissue fibrosis.

Background/aim Casticin, one of the active components of Vitex rotundifolia L., presents biological and pharmacological activities including inhibition of migration, invasion and induction of apoptosis in numerous human cancer cells in vitro. This study aimed to assess the effects of casticin on tumor growth in a human oral cancer SCC-4 cell xenograft mouse model in vivo. Materials and methods Twenty-four nude mice were injected subcutaneously with SCC-4 cells and when palpable tumors reached a volume of 100-120 mm3 the mice were randomly divided into three groups. The control (0.1% dimethyl sulfoxide), casticin (0.2 mg/kg), and casticin (0.4 mg/kg) groups were intraperitoneally injected every two days for 18 days. Tumor volume and body weights were measured every two days. Results Casticin significantly decreased tumor volume and weight in SCC-4 cell xenograft mice but there was no statistically significant difference between the body weights of control mice and mice treated with 0.2 mg/kg or 0.4 mg/kg casticin. Therefore, the growth of SCC-4 cells in athymic nude mice can be inhibited by casticin in vivo. Conclusion These findings support further investigations in the potential use of casticin as an oral anti-cancer drug in the future.

The therapeutic efficacy of methoxypolyethylene glycol (mPEG)-coated nanomedicines in solid tumor treatment is hindered by tumor-associated fibroblasts (TAFs), which promote tumor progression and form physical barriers. We developed an anti-HER2/anti-FAP/anti-mPEG tri-specific antibody (TsAb) for one-step conversion of mPEG-coated liposomal doxorubicin (Lipo-Dox) to immunoliposomes, which simultaneously target HER2+ breast cancer cells and FAP+ TAFs. The non-covalent modification did not adversely alter the physical characteristics and stability of Lipo-Dox. The TsAb-Lipo-Dox exhibited specific targeting and enhanced cytotoxicity against mono- and co-cultured HER2+ breast cancer cells and FAP+ TAFs, compared to bi-specific antibody (BsAb) modified or unmodified Lipo-Dox. An in vivo model of human breast tumor containing TAFs also revealed the improved tumor accumulation and therapeutic efficacy of TsAb-modified mPEGylated liposomes without signs of toxicity. Our data indicate that arming clinical mPEGylated nanomedicines with the TsAb is a feasible and applicable approach for overcoming the difficulties caused by TAFs in solid tumor treatment.

Geometric and chemical defects are frequently found or created on smooth graphene for applications of nanofluidics. In this work, imbibition dynamics and steady flows of water in graphene nanochannels with sparse defects are explored by molecular dynamics. The water contact angle is raised slightly by geometric defects (hole and protrusion) but lowered significantly by chemical defects (hydroxyl and epoxide groups). In steady flows, the mean velocity and slip length are always reduced by sparse defects and the effect of chemical defects is more significant than that of geometric defects. Moreover, it is interesting to find that the velocity profile is plug-like for geometric defects but becomes parabolic for chemical defects, regardless of the slip length. Sparse defects on graphene nanoslits also affect the imbibition dynamics remarkably, which generally follows Washburn's equation with the slip length. For chemical defects, surface friction (slip length) dominates over the driving force associated with surface wettability (contact angle). Nonetheless, for protrusion defects, the stick-slip behavior caused by contact line pinning and thermal fluctuations can be observed. Our new and novel findings indicate that the defect nature is crucial in nanoscale flows and imbibition processes, which the conventional hydrodynamic theory fails to depict.

Simple Summary This study aims to evaluate the induction of immunogenic cell death (ICD) for anticancer immunity by the novel topoisomerase I inhibitor lipotecan. These results show that lipotecan can remarkably elicit ICD and increase tumor immunogenicity, which promotes the therapeutic efficacy of radiotherapy compared to conventional chemoradiotherapy in vivo. These results provide potential therapeutic strategies to improve the efficacy of chemoradiotherapy in colorectal cancer (CRC), which may increase the local control rate and decrease tumor relapse in locally advanced rectal cancer (LARC) patients who receive preoperative chemoradiotherapy. Abstract Rectal cancer accounts for 30–40% of colorectal cancer (CRC) and is the most common cancer-related death worldwide. The preoperative neoadjuvant chemoradiotherapy (neoCRT) regimen is the main therapeutic strategy for patients with locally advanced rectal cancer (LARC) to control tumor growth and reduce distant metastasis. However, 30–40% of patients achieve a partial response to neoCRT and suffer from unnecessary drug toxicity side effects and a risk of distant metastasis. In our study, we found that the novel topoisomerase I inhibitor lipotecan (TLC388) can elicit immunogenic cell death (ICD) to release damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT exposure. Lipotecan thereby increases cancer immunogenicity and triggers an antitumor immune response to attract immune cell infiltration within the tumor microenvironment (TME) in vitro and in vivo. Taken together, these results show that lipotecan can remodel the tumor microenvironment to provoke anticancer immune responses, which can provide potential clinical benefits to the therapeutic efficacy of neoCRT in LARC patients.

The InterPro database (https://www.ebi.ac.uk/interpro/) provides an integrative classification of protein sequences into families, and identifies functionally important domains and conserved sites. InterProScan is the underlying software that allows protein and nucleic acid sequences to be searched against InterPro's signatures. Signatures are predictive models which describe protein families, domains or sites, and are provided by multiple databases. InterPro combines signatures representing equivalent families, domains or sites, and provides additional information such as descriptions, literature references and Gene Ontology (GO) terms, to produce a comprehensive resource for protein classification. Founded in 1999, InterPro has become one of the most widely used resources for protein family annotation. Here, we report the status of InterPro (version 81.0) in its 20th year of operation, and its associated software, including updates to database content, the release of a new website and REST API, and performance improvements in InterProScan.

Radiotherapy can boost the therapeutic response to immune checkpoint inhibitors (ICIs) by recruiting T lymphocytes and upregulating PD-L1 expression within the tumor microenvironment (TME). However, in some cases, tumor PD-L1 expression cannot be induced, even in the presence of abundant T lymphocytes, in locally advanced colorectal cancer patients who receive preoperative neoadjuvant concurrent chemoradiotherapy (CCRT). In this study, we found that PD-L1 promoter methylation is negatively correlated with tumor PD-L1 expression and is an independent biomarker for locally advanced colorectal cancer patients. PD-L1 methylation (mCD274) was significantly associated with shorter disease-free survival (cg15837913 loci, p = .0124). By multivariate Cox proportional hazards analyses including influent factors, mCD274 was classified as an independent prognostic factor for poor 5-year DFS [cg15837913, hazard ratio: HR = 4.06, 95% CI = 1.407–11.716, p = .01]. We found that the immunomodulatory agent DNA methyltransferase inhibitor (DNMTi) led to demethylation of the PD-L1 promoter and increased radiotherapy-induced PD-L1 upregulation via interferon β (IFNβ). DNMTi not only induced tumor PD-L1 expression but increased the expression of immune-related genes as well as intratumoral T cell infiltration in vivo. Furthermore, DNMTi strongly enhanced the response to combined treatment with radiotherapy and anti-PD-L1 inhibitors, and prolonged survival in microsatellite stability (MSS) colorectal model. Therefore, DNMTi remodeled the tumor microenvironment to improve the effect of radiotherapy and anti-PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger immune responses, which may provide potential clinical benefits to colorectal cancer patients in the future.

Background/Aim: Casticin, one of the active components of Vitex rotundifolia L., presents biological and pharmacological activities including inhibition of migration, invasion and induction of apoptosis in numerous human cancer cells in vitro. This study aimed to assess the effects of casticin on tumor growth in a human oral cancer SCC-4 cell xenograft mouse model in vivo. Materials and Methods: Twenty-four nude mice were injected subcutaneously with SCC-4 cells and when palpable tumors reached a volume of 100-120 mm(3) the mice were randomly divided into three groups. The control (0.1% dimethyl sulfoxide), casticin (0.2 mg/kg), and casticin (0.4 mg/kg) groups were intraperitoneally injected every two days for 18 days. Tumor volume and body weights were measured every two days. Results: Casticin significantly decreased tumor volume and weight in SCC-4 cell xenograft mice but there was no statistically significant difference between the body weights of control mice and mice treated with 0.2 mg/kg or 0.4 mg/kg casticin. Therefore, the growth of SCC-4 cells in athymic nude mice can be inhibited by casticin in vivo. Conclusion: These findings support further investigations in the potential use of casticin as an oral anti-cancer drug in the future.

A series of naturally occurring cardenolides that exhibit potent anti-transmissible gastroenteritis virus (TGEV) activity in swine testicular (ST) cells has been identified. In an immunofluorescence assay, these cardenolides were found to diminish the expressions of TGEV nucleocapsid and spike protein, which was used as an indication for viral replication; block TGEV infection induced apoptosis and cytopathic effects; and impart the same trend of inhibitory activity against Na+/K+-ATPase as for anti-TGEV activity. The viral titer inhibition was found to take place in a dose-dependent manner. Knocking down expression of Na+/K+-ATPase, the cellular receptor of cardenolides, in ST cells was found to significantly impair the susceptibility of ST cells to TGEV infectivity. Thus, we have identified Na+/K+-ATPase as an anti-viral drug target and its antagonists, cardenolides, a novel class of anti- TGEV agents.

Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.

Interruption of the Warburg effect - the observation that un-stimulated macrophages reprogram their core metabolism from oxidative phosphorylation toward aerobic glycolysis to become pro-inflammatory M1 macrophages upon stimulation - is an emerging strategy for the treatment of cancer and anti-inflammatory diseases such as rheumatoid arthritis. We studied this process with view to the discovery of novel therapeutics, and found that tylophorine-based compounds targeted a ribonucleoprotein complex containing caprin-1 and mRNAs of c-Myc and HIF-1α in LPS/IFN-γ stimulated Raw264.7 cells, diminished the protein levels of c-Myc and HIF-1α, and consequently downregulated their targeted genes that are associated with the Warburg effect, as well as the pro-inflammatory iNOS and COX2. The tylophorine-based compound DBQ 33b significantly meliorated the severity and incidence of type II collagen-monoclonal antibody-induced rheumatoid arthritis and diminished gene expressions of c-Myc, HIF-1α, iNOS, COX2, TNFα, and IL-17A in vivo. Moreover, pharmacological inhibition of either c-Myc or HIF-1α exhibited similar effects as the tylophorine-based compound DBQ 33b, even though inhibition of c-Myc reversed the induction of iNOS and COX2 in LPS/IFN-γ stimulated Raw264.7 cells to a lesser degree. Therefore, simultaneous inhibition of both c-Myc and HIF-1α is efficacious for anti-inflammation in vitro and in vivo and merits further study.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis with short lifespan following diagnosis as patients have limited effective treatment options. A fundamental limitation is a lack of knowledge of the underlying collagen alterations in the disease, as this could lead to better diagnostics, prognostics, and measures of treatment efficacy. While the fibroses is the primary presentation of the disease, the collagen architecture has not been well studied beyond standard histology. Here, we used several metrics based on second harmonic generation (SHG) microscopy and optical scattering measurements to characterize the subresolution collagen assembly in human IPF and normal lung tissues. Using SHG directional analysis, we found that while collagen synthesis is increased in IPF, the resulting average fibril architecture is more disordered than in normal tissue. Wavelength-dependent optical scattering measurements lead to the same conclusion, and both optical approaches are consistent with ultrastructural analysis. SHG circular dichroism revealed significant differences in the net chirality between the fibrotic and normal collagen, where the former has a more randomized helical structure. Collectively, the measurements reveal significant changes in the collagen macro/supramolecular structure in the abnormal fibrotic collagen, and we suggest these alterations can serve as biomarkers for IPF diagnosis and progression.