Metal-organic framework based on hinged cube tessellation as transformable mechanical metamaterial

Mechanical metamaterials exhibit unusual properties, such as negative Poisson???s ratio, which are difficult to achieve in conventional materials. Rational design of mechanical metamaterials at the microscale is becoming popular partly because of the advance in three-dimensional printing technologies. However, incorporating movable building blocks inside solids, thereby enabling us to manipulate mechanical movement at the molecular scale, has been a difficult task. Here, we report a metal-organic framework, self-assembled from a porphyrin linker and a new type of Zn-based secondary building unit, serving as a joint in a hinged cube tessellation. Detailed structural analysis and theoretical calculation show that this material is a mechanical metamaterial exhibiting auxetic behavior. This work demonstrates that the topology of the framework and flexible hinges inside the structure are intimately related to the mechanical properties of the material, providing a guideline for the rational design of mechanically responsive metal-organic frameworks

Precision genome engineering with programmable DNA-nicking enzymes

Zinc finger nucleases (ZFNs) are powerful tools of genome engineering but are limited by their inevitable reliance on error-prone nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs), which gives rise to randomly generated, unwanted small insertions or deletions (indels) at both on-target and off-target sites. Here, we present programmable DNA-nicking enzymes (nickases) that produce single-strand breaks (SSBs) or nicks, instead of DSBs, which are repaired by error-free homologous recombination (HR) rather than mutagenic NHEJ. Unlike their corresponding nucleases, zinc finger nickases allow site-specific genome modifications only at the on-target site, without the induction of unwanted indels. We propose that programmable nickases will be of broad utility in research, medicine, and biotechnology, enabling precision genome engineering in any cell or organism.

Directed evolution of CRISPR-Cas9 to increase its specificity

The use of CRISPR-Cas9 as a therapeutic reagent is hampered by its off-target effects. Although rationally designed S. pyogenes Cas9 (SpCas9) variants that display higher specificities than the wild-type SpCas9 protein are available, these attenuated Cas9 variants are often poorly efficient in human cells. Here, we develop a directed evolution approach in E. coli to obtain Sniper-Cas9, which shows high specificities without killing on-target activities in human cells. Unlike other engineered Cas9 variants, Sniper-Cas9 shows WT-level on-target activities with extended or truncated sgRNAs with further reduced off-target activities and works well in a preassembled ribonucleoprotein (RNP) format to allow DNA-free genome editing.

In vivo genome editing with a small Cas9 orthologue derived from Campylobacter jejuni

Several CRISPR-Cas9 orthologues have been used for genome editing. Here, we present the smallest Cas9 orthologue characterized to date, derived from Campylobacter jejuni (CjCas9), for efficient genome editing in vivo. After determining protospacer-adjacent motif (PAM) sequences and optimizing single-guide RNA (sgRNA) length, we package the CjCas9 gene, its sgRNA sequence, and a marker gene in an all-in-one adeno-associated virus (AAV) vector and produce the resulting virus at a high titer. CjCas9 is highly specific, cleaving only a limited number of sites in the human or mouse genome. CjCas9, delivered via AAV, induces targeted mutations at high frequencies in mouse muscle cells or retinal pigment epithelium (RPE) cells. Furthermore, CjCas9 targeted to the Vegfa or Hif1a gene in RPE cells reduces the size of laser-induced choroidal neovascularization, suggesting that in vivo genome editing with CjCas9 is a new option for the treatment of age-related macular degeneration.

Treatment outcomes of stereotactic body radiation therapy for pulmonary metastasis from sarcoma: a multicenter, retrospective study

Purpose The aim of this study was to evaluate the treatment outcomes and potential dose-response relationship of stereotactic body radiation therapy (SBRT) for pulmonary metastasis of sarcoma. Materials and methods A retrospective review of 39 patients and 71 lesions treated with SBRT from two institutions was performed. The patients had oligometastatic or oligoprogressive disease, or were receiving palliation. Doses of 20–60Gy were delivered in 1–5 fractions. The local control per tumor (LCpT) was evaluated according to the biologically effective dose with an α/β ratio of 10 (BED10) of the prescribed dose (BED10 ≥ 100Gy vs. BED10 < 100Gy). Clinical outcomes per patient, including local control per patient (LCpP), pulmonary progression-free rate (PPFR), any progression-free rate (APFR), and overall survival (OS) were investigated. Results The median follow-up period was 27.2 months. The 1-, 2-, and 3-year LCpT rates for the entire cohort were 100.0%, 88.3%, and 73.6%, respectively. There was no observed difference in LCpT between the two BED10 groups (p = 0.180). The 3-year LCpP, PPFR, APFR, and OS rates were 78.1%, 22.7%, 12.9%, and 83.7%, respectively. Five (12.8%) patients with oligometastasis had long-term disease-free intervals, with a median survival period of 40.7 months. Factors that were associated with a worse prognosis were oligoprogression (vs. oligometastasis), multiple pulmonary metastases, and simultaneous extrathoracic metastasis. Conclusion SBRT for pulmonary metastasis of sarcoma is effective. Some selected patients may achieve durable response. Considerations of SBRT indication and disease extent may be needed as they may influence the prognosis.This work was supported by the National Research Foundation of Korea grant funded by the Korean Government (2022R1A2C1092928)

Nanozyme Based on Porphyrinic Metal-Organic Framework for Electrocatalytic CO2 Reduction

Mimicry of natural enzyme systems is an important approach for catalyst design. To create an enzyme-inspired catalyst, it is essential to mimic both the active center and the second coordination sphere. Metal-organic frameworks (MOFs), an emerging class of porous materials, are ideal candidates for heterogeneous catalysts because their versatile building blocks confer a high level of structural tunability, and the chemical environment surrounding the active center can be controlled at the molecular level. Herein, a new 2D porphyrinic MOF, PPF-100, constructed from a nonplanar saddle-distorted porphyrin linker and a Cu paddle-wheel metal node is reported. The strategic introduction of ethyl substituents allows not only to mimic the active center and second coordination sphere but also to increase the catalytic selectivity while completely inhibiting H-2 generation in the CO2 reduction reaction

Stereotactic body radiotherapy for hepatocellular carcinoma: meta-analysis and International Stereotactic Radiosurgery Society practice guidelines

PURPOSE This systematic review and meta-analysis reports on outcomes and hepatic toxicity rates following stereotactic body radiotherapy (SBRT) for liver confined hepatocellular carcinoma (HCC), and presents consensus guidelines regarding appropriate patient management. METHODS AND MATERIALS Using the Preferred Reporting Items for Systemic Review and Meta-analyses guidelines, a systematic review was performed from articles reporting outcomes at ≥5 years published prior to October 2022 from the Embase, MEDLINE, Cochrane, and Scopus databases using the key words terms ("Stereotactic body radiotherapy" OR "SBRT" OR "SABR" OR "Stereotactic ablative radiotherapy") AND ("Hepatocellular carcinoma" OR "HCC"). An aggregated data (AD) meta-analysis was conducted to assess overall survival (OS) and local control (LC) using weighted random effects models. In addition, an individual patient data (IPD) analysis incorporating data from 6 institutions was conducted as its own subgroup analyses. RESULTS Seventeen observational studies, comprising 1889 HCC patients treated with ≤9 SBRT fractions, between 2003 and 2019, were included in the AD meta-analysis. The 3- and 5- year OS rates after SBRT were 57% (95% confidence interval [CI], 47-66%) and 40% (95% CI, 29-51%). The 3- and 5- year LC rates after SBRT were 84% (95% CI, 77-90%) and 82% (95% CI, 74-88%), respectively. Tumor size was the only prognostic factor for LC. Tumor size and region were significantly associated with OS. Five-year LC and OS rates of 79% (95% CI, 0.74-0.84) and 25% (95% CI, 0.20-0.30), respectively, were observed in the IPD analyses. Factors prognostic for improved OS were tumor size <3 cm, eastern region, Child-Pugh score ≤B7, and the Barcelona Clinic Liver Cancer stage of 0 and A. The incidence of severe hepatic toxicity varied according to the criteria applied. CONCLUSIONS SBRT is an effective treatment modality for HCC patients with mature follow up. Clinical practice guidelines were developed on behalf of the XXXX