A Dual-Responsive Magnetoactive and Electro-Ionic Soft Actuator Derived from a Nickel-Based Metal-Organic Framework.

There is growing demand for multiresponsive soft actuators for the realization of natural, safe, and complex motions in robotic interactions. In particular, soft actuators simultaneously stimulated by electrical and magnetic fields are always under development owing to their simple controllability and reliability during operation. Herein, magnetically and electrically driven dual-responsive soft actuators (MESAs) derived from novel nickel-based metal-organic frameworks (Ni-MOFs-700C), are reported. Nanoscale Ni-MOFs-700C has excellent electrochemical and magnetic properties that allow it to be used as a multifunctional material under both magnetoactive and electro-ionic actuations. The dual-responsive MESA exhibits a bending displacement of 30 mm and an ultrafast rising time of 1.5 s under a very low input voltage of 1 V and also exerts a bending deflection of 12.5 mm at 50 mT under a high excitation frequency of 5 Hz. By utilizing a dual-responsive MESA, the hovering motion of a hummingbird robot is demonstrated under magnetic and electrical stimuli.

Identification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program.

PURPOSE: Tumor-only genomic testing can uncover somatic and germline pathogenic variants [pathogenic/likely pathogenic (P/LP)] in cancer predisposition genes. We describe the prevalence of P/LPs in BRCA1/2 and PALB2 (B1B2P2) across malignancies and the frequency of clinical germline testing (CGT) in patients with P/LPs in B1B2P2 identified on tumor-only testing. EXPERIMENTAL DESIGN: Among 7,575 patients with cancer tested between 2016 and 2018 with the OncoPanel tumor-only sequencing assay, we characterized P/LP frequencies by tumor type, receipt of CGT prior to or within 12 months after OncoPanel, and factors associated with CGT. RESULTS: 272 (3.6%) patients had OncoPanel-detected P/LPs in B1B2P2: 37.5% of P/LPs were in BRCA-related cancers; the remainder were in non-BRCA tumors. P/LPs were detected in ≥5% of breast, pancreatic, prostate, ovarian, nonmelanoma skin, endometrial, small cell lung, and colorectal cancers. 37.9% of patients with P/LPs received CGT prior to OncoPanel; an additional 10.7% underwent CGT within 12 months of OncoPanel. Among 132 with CGT, 88.6% had ≥1 clinical factor for CGT compared with 47.1% who did not undergo CGT. Patients with BRCA tumors were more likely to have CGT compared with those without (81.4% vs. 29.0%, P < 0.0001). Among patients with CGT, 70.5% (93/132) of P/LPs were germline. CONCLUSIONS: Tumor-only genomic testing identified P/LPs in B1B2P2 in 3.6% of patients. 52.9% of patients with tumor-detected P/LPs and without CGT did not meet personal or family history criteria for CGT. In addition, some patients with tumor-detected P/LPs were not referred for CGT, especially those with non-BRCA tumors. Given implications for treatment selection and familial cancer risk, processes to reliably trigger CGT from tumor-genomic findings are needed.

Cancer control in Latin America and the Caribbean: recent advances and opportunities to move forward.

The increasing burden of cancer represents a substantial problem for Latin America and the Caribbean. Two Lancet Oncology Commissions in 2013 and 2015 highlighted potential interventions that could advance cancer care in the region by overcoming existing challenges. Areas requiring improvement included insufficient investment in cancer control, non-universal health coverage, fragmented health systems, inequitable concentration of cancer services, inadequate registries, delays in diagnosis or treatment initiation, and insufficient palliative services. Progress has been made in key areas but remains uneven across the region. An unforeseen challenge, the COVID-19 pandemic, strained all resources, and its negative effect on cancer control is expected to continue for years. In this Series paper, we summarise progress in several aspects of cancer control since 2015, and identify persistent barriers requiring commitment of additional resources to reduce the cancer burden in Latin America and the Caribbean.

Adenylyl Cyclase and Protein Kinase A Play Redundant and Distinct Roles in Growth, Differentiation, Antifungal Drug Resistance, and Pathogenicity of Candida auris.

Candida auris is a globally emerging multidrug-resistant fungal pathogen. Its pathogenicity-related signaling networks are largely unknown. Here, we characterized the pathobiological functions of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris. We focused on adenylyl cyclase (CYR1), the PKA regulatory subunit (BCY1), and the PKA catalytic subunits (TPK1 and TPK2). We concluded that PKA acts both dependently and independently of Cyr1 in C. auris. Tpk1 and Tpk2 have major and minor roles, respectively, in PKA activity and functions. Both Cyr1 and PKA promote growth, thermotolerance, filamentous growth, and resistance to stress and antifungal drugs by regulating expression of multiple effector genes. In addition, Cyr1 and PKA subunits were involved in disinfectant resistance of C. auris. However, deletion of both TPK1 and TPK2 generally resulted in more severe defects than CYR1 deletion, indicating that Cyr1 and PKA play redundant and distinct roles. Notably, Tpk1 and Tpk2 have redundant but Cyr1-independent roles in haploid-to-diploid cell transition, which increases virulence of C. auris. However, Tpk1 and Tpk2 often play opposing roles in formation of biofilms and the cell wall components chitin and chitosan. Surprisingly, deletion of CYR1 or TPK1/TPK2, which resulted in severe in vitro growth defects at 37°C, did not attenuate virulence, and BCY1 deletion reduced virulence of C. auris in a systemic murine infection model. In conclusion, this study provides comprehensive insights into the role of the cAMP/PKA pathway in drug resistance and pathogenicity of C. auris and suggests a potential therapeutic option for treatment of C. auris-mediated candidemia. IMPORTANCE Despite the recently growing concern of pan-resistant Candida auris infection, the pathogenicity of this ascomycetous fungal pathogen and the signaling circuitries governing its resistance to antifungal drugs are largely unknown. Therefore, we analyzed the pathobiological functions of cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris, which plays conserved roles in the growth and virulence of fungal pathogens. We show that adenylyl cyclase Cyr1 and PKA have pleiotropic roles in growth, morphogenesis, stress responses, antifungal drug and disinfectant resistance, and ploidy shifts of C. auris. Notably, however, we observed that the tpk1Δ tpk2Δ mutant generally exhibited more disrupted phenotypes than the cyr1Δ mutant, and we suggest Tpk1 and Tpk2 have both cAMP-dependent and -independent roles in this pathogen. Most surprisingly, we observed that hyperactivation, not inhibition, of the cAMP/PKA pathway reduced virulence of C. auris. Based on our results, we suggest and discuss potential therapeutic strategies for candidiasis caused by C. auris.

Validation of Dual Energy X-Ray Absorptiometry and Nuclear Magnetic Resonance in the Analysis of Body Composition in Mice.

BACKGROUND: As an instrument for measuring body composition in experimental animals, dual energy X-ray absorptiometry (DXA) is ideal for accuracy, cost, and measurement efficiency. However, there is too little insight into the effectiveness of the various aspects of applying DXA to experimental animals. We investigated whether to compare and verify the precision and accuracy of DXA and nuclear magnetic resonance (NMR) animal body composition analyzers. METHODS: We used 30 Institution of Cancer Research mice in the study. First, in order to evaluate the reproducibility of DXA and NMR, we did repeated measurements by repositioning each mouse in anesthesia and euthanasia states. Subsequently, the accuracy of each device was evaluated by comparing the weight measured before the experiment, the weight of the tissue extracted from the mice after the experiment, and the measured DXA and NMR. In addition, when measuring the body composition of animals, we compared the time and the measurable body composition parameters and summarized the advantages and disadvantages of the 2 devices. RESULTS: Compared to NMR, DXA had the advantage of a fast measurement of bone composition and rapid image analysis. In addition, DXA showed a higher correlation (>95%) with fat mass, lean mass baseline than did NMR (>85%). CONCLUSIONS: In conclusion, DXA was confirmed to have higher precision and measurement accuracy than did NMR. Therefore, DXA is an effective method for evaluating the body composition of experimental animals.

Microneedles with dual release pattern for improved immunological efficacy of Hepatitis B vaccine.

In this study, dissolving microneedles (DMNs) with dual-release pattern, capable of both bolus release and slow release, were prepared. These DMNs were used with a hepatitis B vaccine that requires multiple shots to achieve immunological efficacy comparable to that obtained when two separate shots are administered. Dissolving microneedles with HBsAg in PLA tips and CMC coating formulation together (HBsAg-PLA/CMC-DMNs) consist of polylactic acid (PLA) tips for slow release, a carboxy-methyl cellulose (CMC) coating formulation for bolus release, and a dissolving base of polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) for dissolution in the skin. The in vitro release pattern of HBsAg from the CMC coating formulation and PLA tips was observed. Through an in vivo test, 1) the delivery efficiency of HBsAg-PLA/CMC-DMNs was observed, and 2) the immunological efficacy of this method was compared with the efficacy of two shots delivered by conventional intramuscular (IM) administration and two shots delivered by HBsAg-coated microneedle (CMNs) administration. HBsAg-PLA/CMC-DMNs punctured the skin successfully. The PVA/PVP base was completely dissolved within 10 min of insertion, resulting in the delivery of all microneedle tips into the skin. In the in vitro release experiment, all of the HBsAg in the CMC coating formulation was released within 20 min, and the HBsAg present in the PLA tips was gradually released over more than 55 days. The antibody titer of one shot of HBsAg-PLA/CMC-DMNs was the same as or higher than two shots delivered by conventional IM and CMN methods. DMNs with dual-release pattern can deliver two formulations simultaneously with a single shot, resulting in improved immunological efficacy of HBsAg that requires multiple doses. In addition, this dual-release MN system can be used for the delivery of other drugs that require multiple administrations.

Effects of lifelong spontaneous exercise on the M1/M2 macrophage polarization ratio and gene expression in adipose tissue of super-aged mice.

In the adipose tissue (AT), an increase in the M1 macrophage (M1Ø)/M2 macrophage (M2Ø) polarization ratio can be a risk factor enhancing the inflammatory response during aging, as well as increasing the risk of chronic disease, thereby reducing lifespan, or at least reducing "healthy" lifespan. The purpose of this study was to analyze and compare the AT M1Ø/M2Ø polarization ratio at the final lifespan stage in aged and control animals performing lifelong spontaneous wheel running. Based on flow cytometric analysis, the AT ratio of macrophages revealed M2Ø polarization following lifelong spontaneous exercise (LSE) regardless of age. However, for Icam1 and Tnf, the qPCR analysis showed no difference in gene expressions in young mice; Arg1 expression was higher in Young-EXE (exercising) than in Young-CON (control) mice (p < .0001). In Old-EXE, Icam1 (p < .0001) and Tnf (p < .0001) expression were lower than in Old-CON; for Arg1, gene expression in Old-EXE was higher than in Old-CON (p < .0001). LSE prevents deterioration of physical fitness owing to aging, maintaining high M2Ø polarization levels in the AT. Additionally, LSE does not downregulate Icam1 and Tnf in the AT but appears to suppress the increased M1Ø polarization ratio attributed to aging by upregulating Arg1.

Neural maturation enhanced by exercise-induced extracellular derivatives.

Physical activity has profound effects on neuronal progenitor cell growth, differentiation, and integration, but the mechanism for these effects is still ambiguous. Using a mouse model, we investigated the effects of two weeks of treadmill running on the dynamics of the size distribution and miRNA profiles of serum extracellular derivatives (EDs) using particle-sizing analysis and small RNA sequencing. We found that an increased average diameter of EDs in the running group compared with the sedentary group (p < 0.05), and 16 miRNAs were significantly altered (p < 0.05) in the running group. Furthermore, functional annotation analysis of differentially expressed miRNA-predicted target genes showed that many of these target genes are involved in the PI3K-Akt pathway. Exercise-induced serum EDs increased Neuro2A cell viability and Akt phosphorylation. We also found that expression levels of neuronal maturation markers such as Microtubule-Associated Protein 2 (MAP2ab) and Neuronal nuclei (NeuN) were increased (p < 0.05, respectively), and that inhibition of the PI3K-Akt pathway by LY294002 pre-treatment ameliorated their expression in Neuro2A cells. Finally, the administration of exercise-induced EDs for 3 days increased the Histone 3 phosphorylation and ß-III tubulin expression in Ink/Arf null neural stem cells and progenitors (NSPCs) under each proliferation and differentiation condition. These results suggest that exercise-induced circulating EDs may mediate neuronal maturation during exercise.

Neuropeptides Profile and Increased Innervation in Becker's Nevus.

BACKGROUND: Melanocytes are derived from neural crest, and various pigmentary disorders may accompany abnormalities in nerve system or develop following dermatome, suggesting that melanocyte and pigmentation may be closely related to neural factors. There are reports of Becker's nevus (BN) showing linear and segmental configuration, suggesting the association of BN with nerve system. However, there are no studies regarding the expression of neuropeptides in BN. OBJECTIVE: We investigated the expression of neuropeptides and innervation in BN. METHODS: Polymerase chain reaction (PCR) array of 84 genes related to neuronal process was done. Among the genes with 10-fold or more increase in lesional, real-time PCR was performed for neuropeptide Y (NPY), galanin, neurotensin (NTS) and their receptors skin compared to normal skin. IHC stain was done to look for the expression of NPY, galanin, NTS and their receptors and the distribution of protein gene products (PGP) 9.5 immunoreactive nerve fibers. RESULTS: PCR array revealed that 16 out of 84 genes related to neuronal process were increased by 10-fold or more in lesional skin. In real-time PCR of NPY, galanin, NTS and their receptors, statistically significant increase of NPY1R (p<0.05) and marginally significant increase of NPY2R, GAL2R, and NTS2R (p<0.1) was verified in lesional skin. In immunohistochemistry, NPY, NPY1R NPY2R, and NTS2R were highly expressed in lesional skin and increased PGP 9.5 immunoreactive linear nerve fibers were found in the epidermis of BN. CONCLUSION: NPY, galanin, NTS and their receptors and increased innervation may play a role in the pathogenesis of BN.

Protective Effect of Topical Vitamin D3 against Photocarcinogenesis in a Murine Model.

BACKGROUND: Although the incidence of non-melanoma skin cancer is increasing, there are no effective practical preventive measures other than avoiding sun exposure. OBJECTIVE: To elucidate the protective effect of topical application of biologically active vitamin D3 (calcitriol) on skin cancer development caused by exposure to ultraviolet (UV). METHODS: Groups of hairless mice were topically treated with either calcitriol or vehicle immediately after exposure to UVB and UVA three times weekly for the initial 20 weeks, and without UV exposure in the following 6 weeks. Tumor number was counted and biopsies were done for histopathologic analysis. The changes of cyclobutane pyrimidine dimer (CPD) were evaluated 1 hour and 11 hours after short term of UV exposure and application of calcitriol. For safety evaluation, blood test and body weights were evaluated at 23rd and 25th week. RESULTS: Total tumor count and number of tumors less than 3 mm in size tended to be fewer in calcitriol group, and tumors more than 3 mm in size showed significantly lower tumor formation rate in calcitriol group. Single application of calcitriol reduced CPD at 1 hour and 11 hours after UV exposure. Histopathologic analysis showed tumors with lower grade malignancy in calcitriol group which suggested a delay in tumor progression. However, serum levels of calcium and phosphate in calcitriol group were above normal range, and weight loss was found. CONCLUSION: Topical calcitriol may suppress the formation and progression of UV-induced non-melanoma skin cancer by enhancing the repair mechanism of UV damage.

Concurrent Drug-Induced Linear Immunoglobulin A Dermatosis and Immunoglobulin A Nephropathy.

Diseases associated with immunoglobulin A (IgA) antibody include linear IgA dermatosis, IgA nephropathy, Celiac disease, Henoch-Schönlein purpura, etc. Although usually idiopathic, IgA antibody is occasionally induced by drugs (e.g., vancomycin, carbamazepine, ceftriaxone, and cyclosporine), malignancies, infections, and other causes. So far, only a few cases of IgA bullous dermatosis coexisting with IgA nephropathy have been reported. A 64-year-old female receiving intravenous ceftriaxone and metronidazole for liver abscess had purpuric macules and papules on her extremities. One week later, she had generalized edema and skin rash with bullae and was diagnosed with concurrent linear IgA dermatosis and IgA nephropathy. After steroid treatment, the skin lesion subsided within two weeks, and kidney function slowly returned to normal. As both diseases occurred after a common possible cause, we predict their pathogeneses are associated.

Co-infection of Scedosporium apiospermum and Mycobacterium chelonae in an immunocompetent host.

A 75-year-old man presented with multiple, scaly, erythematous, grouped papules, nodules and plaques with tenderness ranging from the right forearm to hand dorsum and the right lower leg for 2-3 months. Five months prior to presentation, the patient had received an antibiotic skin test on his right forearm. Lesions appeared approximately 2-3 months after the antibiotic skin test, slowly progressing without clinical improvement. Culture for fungus on the right forearm revealed growth of Scedosporium apiospermum. The tissue acid-fast bacilli (AFB) culture for the right forearm and right leg revealed growth of non-tuberculous mycobacteria which was Mycobacterium chelonae, and subsequent tissue polymerase chain reaction of both sites reported positive signs of M. chelonae. On diastase periodic acid-Schiff stain of the biopsy specimen of the right forearm, fungal hyphae were found while rod-shaped bacilli could be seen in AFB stain for the biopsy specimen of the right leg. The patient was treated with oral clarithromycin and ciprofloxacin along with an oral antifungal agent for 13 weeks. After the treatment, the lesions subsided and left a scar. We report a rare case of co-infection of S. apiospermum and M. chelonae in an immunocompetent host.