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Among 173 consecutive open lung biopsies, nine gave a histopathological diagnosis of bronchiolitis. Seven of these patients had some connective tissue disorder (CTD), six of whom are presented in this report; two had classical and one possible rheumatoid arthritis (RA), one ankylosing spondylitis, one scleroderma, and one developed classical RA four years after biopsy. Four of the patients were smokers, most suffered from breathlessness and cough. In terms of lung function three patients had obstruction, one both restriction and obstruction and three a decreased diffusion capacity. For control purposes peripheral lung tissue was studied histologically from 24 consecutive smoking patients without CTD who underwent a lobectomy for cancer. Intraluminal plugs and mucosal lymphoplasmocytic infiltration of the bronchiolar walls were more prevalent and abundant in the CTD patients than in the controls (p less than 0.02 and p less than 0.001 respectively). Two CTD patients also showed some obliterative bronchiolitis. Corticosteroids were effective in one out of four patients treated. One patient improved and the others did not show any progression during the follow up. The results suggest that smoking alone does not explain the lesions of the small airways found in CTD patients, and that bronchiolitis may be specifically associated with the basic disorder in such cases. [ABSTRACT FROM PUBLISHER]

Triple-negative breast cancer (TNBC) is still the most aggressive cancer in women. Combination chemotherapy holds great potential for cancer therapy; however, the off-target and side effects of free chemotherapy administration remain a major challenge. In this study, we developed a photo/thermo-responsive nanoplatform that can be used for TNBC treatment via photothermic therapy in combination with multidrug therapy. By conjugating the chemotherapy drug PTX prodrug on the surface of mesoporous silica-coated gold nanorod nanoparticles and then loading another chemotherapy drug, CPT, the Au@MSN-PTX@CPT nanoparticles exhibited great photothermal response, redox response drug release and cancer cell inhibition abilities. Otherwise, we further coated the Au@MSN-PTX@CPT nanoparticle with a temperature-sensitive polymer poly(N-isopropylacrylamide-co-methacrylic acid) (p(NIPAM-co-MAAc)), and the polymer-coated Au@MSN-PTX@TPT@polymer nanoparticles showed perfect near-infrared (NIR) light controlled drug release. Finally, the Au@MSN-PTX@CPT@polymer nanoparticles were injected into the 4T1 breast cancer mouse model. The Au@MSN-PTX@CPT@polymer nanoparticles preferably accumulated at the tumor site and had reduced chemotherapy injuries and great antitumor activity when combined with 650 nm laser treatment. In summary, our developed Au@MSN-PTX@CPT@polymer nanoparticles served as a good method for controlled chemodrug delivery and provided a good choice for TNBC combination therapy., Competing Interests: The authors declare no conflict of interest. Hongbo Zhang is a member of the Smart Medicine editorial board., (© 2022 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Ribonucleoprotein (RNP) based CRISPR/Cas9 gene-editing system shows great potential in biomedical applications. However, due to the large size, charged surface and high biological sensitivity of RNP, its efficient delivery with precise control remains highly challenging. Herein, a microfluidic-assisted metal-organic framework (MOF) based biomineralization strategy is designed and utilized for the efficient delivery and remote regulation of CRISPR/Cas9 RNP gene editing. The strategy is realized by biomimetic growing of thermo-responsive EuMOFs onto photothermal template Prussian blue (PB). The RNP is loaded during MOFs crystallization in microfluidic channels. By adjusting different microfluidic parameters, well-defined and comparable RNP encapsulated nanocarrier (PB@RNP-EuMOFs) are obtained with high loading efficiency (60%), remarkable RNP protection and NIR-stimulated release capacity. Upon laser exposure, the nanocarrier induces effective endosomal escape (4 h) and precise gene knockout of green fluorescent protein by 40% over 2 days. Moreover, the gene-editing activity can be programmed by tuning exposure times (42% for three times and 47% for four times), proving more controllable and inducible editing modality compared to control group without laser irradiation. This novel microfluidic-assisted MOFs biomineralization strategy thus offers an attractive route to optimize delivery systems and reduce off-target side effects by NIR-triggered remote control of CRISPR/Cas9 RNP, improving the potential for its highly efficient and precise therapeutic application.

Appropriate tuning of robust artificial coatings can not only enhance intracellular delivery but also preserve the biological functions of genetic molecules in gene based therapies. Here, we report a strategy to synthesize controllable nanostructures in situ by encapsulating CRISPR/Cas9 plasmids into metal-organic frameworks (MOFs) via biomimetic mineralization. The structure-functionality relationship studies indicate that MOF-coated nanostructures dramatically impact the biological features of the contained plasmids through different embedding structures. The plasmids are homogeneously distributed within the heterogeneous nanoarchitecture and protected from enzymatic degradation. In addition, the plasmid-MOF structure exhibits excellent loading capability, pH-responsive release, and affinity for plasmid binding. Through in vitro assays it was found that the superior MOF vector can greatly enhance cellular endocytosis and endo/lysosomal escape of sheltered plasmids, resulting in successful knock-in of GFP-tagged paxillin genomic sequences in cancer cell lines with high transfection potency compared to our previous studies. Thus, the development of new cost-effective approaches for MOF-based intracellular delivery systems offers an attractive option for overcoming the physiological barriers to CRISPR/Cas9 delivery, which shows great potential for investigating paxillin-associated focal adhesions and signal regulation.

CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9) is a potent technology for gene-editing. Owing to its high specificity and efficiency, CRISPR/Cas9 is extensity used for human diseases treatment, especially for cancer, which involves multiple genetic alterations. Different concepts of cancer treatment by CRISPR/Cas9 are established. However, significant challenges remain for its clinical applications. The greatest challenge for CRISPR/Cas9 therapy is how to safely and efficiently deliver it to target sites in vivo. Nanotechnology has greatly contributed to cancer drug delivery. Here, we present the action mechanisms of CRISPR/Cas9, its application in cancer therapy and especially focus on the nanotechnology-based delivery of CRISPR/Cas9 for cancer gene editing and immunotherapy to pave the way for its clinical translation. We detail the difficult barriers for CRISIR/Cas9 delivery in vivo and discuss the relative solutions for encapsulation, target delivery, controlled release, cellular internalization, and endosomal escape., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The biologically active form of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), modulates innate and adaptive immunity via genes regulated by the transcription factor vitamin D receptor (VDR). In order to identify the key vitamin D target genes involved in these processes, transcriptome-wide datasets were compared, which were obtained from a human monocytic cell line (THP-1) and peripheral blood mononuclear cells (PBMCs) treated in vitro by 1,25(OH) 2 D 3 , filtered using different approaches, as well as from PBMCs of individuals supplemented with a vitamin D 3 bolus. The led to the genes ACVRL1 , CAMP , CD14 , CD93 , CEBPB , FN1 , MAPK13 , NINJ1 , LILRB4 , LRRC25 , SEMA6B , SRGN , THBD , THEMIS2 and TREM1 . Public epigenome- and transcriptome-wide data from THP-1 cells were used to characterize these genes based on the level of their VDR-driven enhancers as well as the level of the dynamics of their mRNA production. Both types of datasets allowed the categorization of the vitamin D target genes into three groups according to their role in (i) acute response to infection, (ii) infection in general and (iii) autoimmunity. In conclusion, 15 genes were identified as major mediators of the action of vitamin D in innate and adaptive immunity and their individual functions are explained based on different gene regulatory scenarios.

Objective: To examine the severity of rheumatoid arthritis (RA), as defined by the American Rheumatism Association (ARA) 1987 revised criteria, at the population level., Methods: The level of functional disability of the 103 patients with RA who represented practically all subjects with RA in a rural community of 13,000 adult inhabitants was assessed by the ARA Functional Classification and the Health Assessment Questionnaire (HAQ)., Results: Only one of the 103 patients was bedridden (ARA Class IV). According to the HAQ Functional Disability Index (FDI) two thirds of the patients had mild or at most moderate disability. Overall, less than 10% of the patients in the community were severely disabled., Conclusion: The level of disability in our series is lower than that reported earlier in populations with RA. These patients were treated aggressively with a median interval of one year from the first joint symptoms to the start of disease modifying antirheumatic drugs and had a median number of 2 orthopedic operations. How these interventions influenced the result cannot be accurately assessed on the basis of our cross sectional study protocol. However, high grade impairment due to destruction of large joints of lower limbs was in most instances compensated by total joint replacement surgery, performed in 20% of the cases in the series. This may partly explain the low prevalence of totally disabled patients with severe restriction in mobility in this population.

To acquire more information on the controversial question of a possible association between rheumatoid arthritis (RA) and insulin dependent diabetes mellitus we searched for insulin dependent diabetes mellitus among patients hospitalized due to RA in 2 rheumatism hospitals in Finland. Nine subjects with insulin dependent diabetes mellitus were found among an annual number of 1460 patients admitted to one of the hospitals due to RA. These figures give a frequency of insulin dependent diabetes mellitus in patients with RA of 0.6% (95% confidence interval 0.2-1.0%), which does not exceed the prevalence of insulin dependent diabetes mellitus among the middle aged population of Finland in general (0.5-0.6%). Accordingly, no overrepresentation of homozygosity for HLA-DR4 was found among the total number of 25 patients with RA as well as insulin dependent diabetes mellitus, though the opposite might be expected as these diseases have a common DR4 association--RA with DR4 and DR1 and insulin dependent diabetes mellitus with DR4 and DR3. Instead, an increased frequency of DR1 (p less than 0.0002) and the antigen combination DR1/4 (p less than 0.01) was found in the subjects with both RA and insulin dependent diabetes mellitus compared with the subjects with insulin dependent diabetes mellitus alone.