Targeted protein degradation directly engaging lysosomes or proteasomes.

Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and clinical contexts. The unique TPD mode-of-action has allowed previously undruggable proteins to become feasible targets, expanding the landscape of "druggable" properties and "privileged" target proteins. As TPD continues to evolve, a range of innovative strategies, which do not depend on recruiting E3 ubiquitin ligases as in proteolysis-targeting chimeras (PROTACs), have emerged. Here, we present an overview of direct lysosome- and proteasome-engaging modalities and discuss their perspectives, advantages, and limitations. We outline the chemical composition, biochemical activity, and pharmaceutical characteristics of each degrader. These alternative TPD approaches not only complement the first generation of PROTACs for intracellular protein degradation but also offer unique strategies for targeting pathologic proteins located on the cell membrane and in the extracellular space.

Treatment-related cardiovascular events in patients with non-small cell lung cancer: Evidence from real-world data with a competing risks approach.

BACKGROUND: Understanding cancer treatment-related cardiovascular (CV) events is important for cancer care; however, comprehensive evaluation of CV events in patients with lung cancer is limited. This study aimed to assess the cumulative incidence and associated risks of various CV event types in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 7868 individuals aged 40 years and older, recently diagnosed with NSCLC (2007-2018), were assessed with data obtained from the National Cancer Center, Korea. This study included nine types of CV events. A 2-year cumulative incidence function (CIF) of CV events was estimated, with death as a competing event. The associated risks were assessed by subdistribution hazard ratio (sHR) in the Fine-Gray competing risks model. RESULTS: CV events were observed in 7.8% of patients with NSCLC, with the most frequently observed types being atrial fibrillation and flutter (AF) (2.7%), venous thromboembolic disease (2.0%), and cerebrovascular disease (CeVD) (1.5%). Overall, all CV events were highest in the group treated with systemic therapy (CIF, 10.6%; 95% confidence interval [CI], 9.5%-11.8%), followed by those treated with surgery (CIF, 10.0%; 95% CI, 8.6%-11.6%); the incidence of AF (CIF, 5.7%; 95% CI, 4.6%-7.0%) was highest in patients treated with surgery. Individuals treated with systemic therapy were found to exhibit a higher CeVD risk than those treated with surgery (sHR, 4.12; 95% CI, 1.66-10.23). Among the patients who underwent surgery, those with lobectomy and pneumonectomy had a higher AF risk (vs. wedge resection/segmentectomy; sHR, 7.79; 95% CI, 1.87-32.42; sHR, 8.10; 95% CI, 1.60-40.89). CONCLUSIONS: These findings revealed treatment-related CV event risks in patients with NSCLC, which suggests that the risk of AF in surgery and CeVD in systemic therapy should be paid more attention to achieve a better prognosis and improve cancer survivorship outcomes. PLAIN LANGUAGE SUMMARY: Atrial fibrillation and flutter (AF) is the most common cardiovascular event, particularly at a high risk in patients with non-small cell lung cancer (NSCLC) undergoing surgery. Patients receiving surgery with poor performance status, diagnosed with regional stage, and undergoing lobectomy or pneumonectomy are at a high risk of AF. Systemic/radiotherapy is associated with cerebrovascular and ischemic heart disease in patients with NSCLC.

A predictive model using MRI and clinicopathologic features for breast cancer recurrence in young women treated with upfront surgery.

OBJECTIVES: To identify preoperative breast MR imaging and clinicopathological variables related to recurrence and develop a risk prediction model for recurrence in young women with breast cancer treated with upfront surgery. METHODS: This retrospective study analyzed 438 consecutive women with breast cancer aged 35 years or younger between January 2007 and December 2016. Breast MR images before surgery were independently reviewed by breast radiologists blinded to patient outcomes. The clinicopathological data including patient demographics, clinical features, and tumor characteristics were reviewed. Univariate and multivariate logistic regression analyses were used to identify the independent factors associated with recurrence. The risk prediction model for recurrence was developed, and the discrimination and calibration abilities were assessed. RESULTS: Of 438 patients, 95 (21.7%) developed recurrence after a median follow-up of 65 months. Tumor size at MR imaging (HR = 1.158, p = 0.006), multifocal or multicentric disease (HR = 1.676, p = 0.017), and peritumoral edema on T2WI (HR = 2.166, p = 0.001) were identified as independent predictors of recurrence, while adjuvant endocrine therapy (HR = 0.624, p = 0.035) was inversely associated with recurrence. The prediction model showed good discrimination ability in predicting 5-year recurrence (C index, 0.707 in the development cohort; 0.686 in the validation cohort) and overall recurrence (C index, 0.699 in the development cohort; 0.678 in the validation cohort). The calibration plot demonstrated an excellent correlation (concordance correlation coefficient, 0.903). CONCLUSION: A prediction model based on breast MR imaging and clinicopathological features showed good discrimination to predict recurrence in young women with breast cancer treated with upfront surgery, which could contribute to individualized risk stratification. CLINICAL RELEVANCE STATEMENT: Our prediction model, incorporating preoperative breast MR imaging and clinicopathological features, predicts recurrence in young women with breast cancer undergoing upfront surgery, facilitating personalized risk stratification and informing tailored management strategies. KEY POINTS: Younger women with breast cancer have worse outcomes than those diagnosed at more typical ages. The described prediction model showed good discrimination performance in predicting 5-year and overall recurrence. Incorporating better risk stratification tools in this population may help improve outcomes.

Use of a commercial artificial intelligence-based mammography analysis software for improving breast ultrasound interpretations.

OBJECTIVES: To evaluate the use of a commercial artificial intelligence (AI)-based mammography analysis software for improving the interpretations of breast ultrasound (US)-detected lesions. METHODS: A retrospective analysis was performed on 1109 breasts that underwent both mammography and US-guided breast biopsy. The AI software processed mammograms and provided an AI score ranging from 0 to 100 for each breast, indicating the likelihood of malignancy. The performance of the AI score in differentiating mammograms with benign outcomes from those revealing cancers following US-guided breast biopsy was evaluated. In addition, prediction models for benign outcomes were constructed based on clinical and imaging characteristics with and without AI scores, using logistic regression analysis. RESULTS: The AI software had an area under the receiver operating characteristics curve (AUROC) of 0.79 (95% CI, 0.79-0.82) in differentiating between benign and cancer cases. The prediction models that did not include AI scores (non-AI model), only used AI scores (AI-only model), and included AI scores (integrated model) had AUROCs of 0.79 (95% CI, 0.75-0.83), 0.78 (95% CI, 0.74-0.82), and 0.85 (95% CI, 0.81-0.88) in the development cohort, and 0.75 (95% CI, 0.68-0.81), 0.82 (95% CI, 0.76-0.88), and 0.84 (95% CI, 0.79-0.90) in the validation cohort, respectively. The integrated model outperformed the non-AI model in the development and validation cohorts (p < 0.001 for both). CONCLUSION: The commercial AI-based mammography analysis software could be a valuable adjunct to clinical decision-making for managing US-detected breast lesions. CLINICAL RELEVANCE STATEMENT: The commercial AI-based mammography analysis software could potentially reduce unnecessary biopsies and improve patient outcomes. KEY POINTS: • Breast US has high rates of false-positive interpretations. • A commercial AI-based mammography analysis software could distinguish mammograms having benign outcomes from those revealing cancers after US-guided breast biopsy. • A commercial AI-based mammography analysis software may improve interpretations for breast US-detected lesions.

Mammographic density assessment: comparison of radiologists, automated volumetric measurement, and artificial intelligence-based computer-assisted diagnosis.

BACKGROUND: Artificial intelligence-based computer-assisted diagnosis (AI-CAD) is increasingly used for mammographic exams, and its role in mammographic density assessment should be evaluated. PURPOSE: To assess the inter-modality agreement between radiologists, automated volumetric density measurement program (Volpara), and AI-CAD system in breast density categorization using the Breast Imaging-Reporting and Data System (BI-RADS) density categories. MATERIAL AND METHODS: A retrospective review was conducted on 1015 screening digital mammograms that were performed in Asian female patients (mean age = 56 years ± 10 years) in our health examination center between December 2022 and January 2023. Four radiologists with two different levels of experience (expert and general radiologists) performed density assessments. Agreement between the radiologists, Volpara, and AI-CAD (Lunit INSIGHT MMG) was evaluated using weighted kappa statistics and matched rates. RESULTS: Inter-reader agreement between expert and general radiologists was substantial (k = 0.65) with a matched rate of 72.8%. The agreement was substantial between expert or general radiologists and Volpara (k = 0.64-0.67) with a matched rate of 72.0% but moderate between expert or general radiologists and AI-CAD (k = 0.45-0.58) with matched rates of 56.7%-67.0%. The agreement between Volpara and AI-CAD was moderate (k = 0.53) with a matched rate of 60.8%. CONCLUSION: The agreement in breast density categorization between radiologists and automated volumetric density measurement program (Volpara) was higher than the agreement between radiologists and AI-CAD (Lunit INSIGHT MMG).

Impact of sagittal and coronal pelvic tilt on hip subluxation in non-ambulatory flaccid neuromuscular scoliosis patients following spinal correction.

PURPOSE: To evaluate the actual change in clinical hip pain and hip migration after operation for non-ambulatory flaccid neuromuscular (NM) scoliosis and investigate whether there is an association between hip migration and coronal/sagittal pelvic tilt (CO-PT/SA-PT). PATIENTS AND METHODS: This retrospective, single-center, observational study evaluated a total of 134 patients with non-ambulatory flaccid neuromuscular scoliosis who underwent surgery performed by a single surgeon between 2003 and 2020, with at least 2 years of follow-up period. Operation procedures were conducted in two stages, beginning with L5-S1 anterior release followed by posterior fixation. Radiologic parameters were measured at preoperative, immediate postoperative, and last follow-up periods with clinical hip pain and clinical hip dislocation events. RESULTS: The significant improvements occurred in various parameters after correction surgery for NM scoliosis, containing Cobb's angle of major curve and CO-PT. However, Reimer's hip migration percentage (RMP) was increased on both side of hip (High side, 0.23 ± 0.16 to 0.28 ± 0.21; Low side, 0.20 ± 0.14 to 0.23 ± 0.18). Hip pain and dislocation events were also increased (Visual analog scale score, 2.5 ± 2.3 to 3.6 ± 2.6, P value < 0.05; dislocation, 6-12). Logistic regression analysis of the interactions between ΔRMP(High) and the change of sagittal pelvic tilt (ΔSA-PT) after correction reveals a significant negative association. (95% CI 1.003-1.045, P value = 0.0226). CONCLUSIONS: In cases of non-ambulatory flaccid NM scoliosis, clinical hip pain, and subluxation continued to deteriorate even after correction of CO-PT. There was a relationship between the decrease in SA-PT, and an increase in hip migration percentage on high side, indicating the aggravation of hip subluxation.

Effect of saline irrigation temperature difference on postoperative acute pain and hypothermia during biportal endoscopic spine surgery.

BACKGROUND: Recently, enhanced recovery after surgery (ERAS) protocols have attracted attention; they emphasize on avoiding intraoperative hypothermia while performing lumbar fusion surgery. However, none of the studies have reported the protocol for determining the temperature of saline irrigation during biportal endoscopic spine surgery (BESS) procedure. This study evaluated the effectiveness of warm saline irrigation during BESS in acute postoperative pain and inflammatory reactions. MATERIALS AND METHODS: Fifty-five patients who underwent BESS procedure were retrospectively analyzed for the incidence of perioperative hypothermia (< 36oC), postoperative inflammatory factors (white blood cells (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), serum amyloid A (SAA)), and clinical outcomes (back visual analog scale (VAS) score, postoperative shivering). The patients were divided into the warm and cold saline irrigation groups. RESULTS: Hemoglobin, WBC, ESR, creatine kinase, and creatine kinase-muscle brain levels did not significantly differ between the warm and cold saline groups. The mean CRP, IL-6, and SAA levels were significantly higher in the cold saline group than in the warm saline group (p = 0.0058, 0.0028, and 0.0246, respectively); back VAS scores were also higher with a statistically significant difference until two days postoperatively (p < 0.001). During the entire procedure, the body temperature was significantly lower in the cold saline irrigation group, but the hypothermia incidence rate significantly differed 30 min after the operation was started. CONCLUSIONS: Using warm saline irrigation during BESS is beneficial for early recovery after surgery, as it is associated with reduced postoperative pain and complication rates.

The 3'tsRNAs are aminoacylated: Implications for their biogenesis.

Emerging evidence indicates that tRNA-derived small RNAs (tsRNAs) are involved in fine-tuning gene expression and become dysregulated in various cancers. We recently showed that the 22nt LeuCAG3´tsRNA from the 3´ end of tRNALeu is required for efficient translation of a ribosomal protein mRNA and ribosome biogenesis. Inactivation of this 3´tsRNA induced apoptosis in rapidly dividing cells and suppressed the growth of a patient-derived orthotopic hepatocellular carcinoma in mice. The mechanism involved in the generation of the 3´tsRNAs remains elusive and it is unclear if the 3´-ends of 3´tsRNAs are aminoacylated. Here we report an enzymatic method utilizing exonuclease T to determine the 3´charging status of tRNAs and tsRNAs. Our results showed that the LeuCAG3´tsRNA, and two other 3´tsRNAs are fully aminoacylated. When the leucyl-tRNA synthetase (LARS1) was inhibited, there was no change in the total tRNALeu concentration but a reduction in both the charged tRNALeu and LeuCAG3´tsRNA, suggesting the 3´tsRNAs are fully charged and originated solely from the charged mature tRNA. Altering LARS1 expression or the expression of various tRNALeu mutants were also shown to affect the generation of the LeuCAG3´tsRNA further suggesting they are created in a highly regulated process. The fact that the 3´tsRNAs are aminoacylated and their production is regulated provides additional insights into their importance in post-transcriptional gene regulation that includes coordinating the production of the protein synthetic machinery.

A polyyne toxin produced by an antagonistic bacterium blinds and lyses a Chlamydomonad alga.

Algae are key contributors to global carbon fixation and form the basis of many food webs. In nature, their growth is often supported or suppressed by microorganisms. The bacterium Pseudomonas protegens Pf-5 arrests the growth of the green unicellular alga Chlamydomonas reinhardtii, deflagellates the alga by the cyclic lipopeptide orfamide A, and alters its morphology [P. Aiyar et al., Nat. Commun. 8, 1756 (2017)]. Using a combination of Raman microspectroscopy, genome mining, and mutational analysis, we discovered a polyyne toxin, protegencin, which is secreted by P. protegens, penetrates the algal cells, and causes destruction of the carotenoids of their primitive visual system, the eyespot. Together with secreted orfamide A, protegencin thus prevents the phototactic behavior of C. reinhardtii A mutant of P. protegens deficient in protegencin production does not affect growth or eyespot carotenoids of C. reinhardtii Protegencin acts in a direct and destructive way by lysing and killing the algal cells. The toxic effect of protegencin is also observed in an eyeless mutant and with the colony-forming Chlorophyte alga Gonium pectorale These data reveal a two-pronged molecular strategy involving a cyclic lipopeptide and a conjugated tetrayne used by bacteria to attack select Chlamydomonad algae. In conjunction with the bloom-forming activity of several chlorophytes and the presence of the protegencin gene cluster in over 50 different Pseudomonas genomes [A. J. Mullins et al., bioRxiv [Preprint] (2021). https://www.biorxiv.org/content/10.1101/2021.03.05.433886v1 (Accessed 17 April 2021)], these data are highly relevant to ecological interactions between Chlorophyte algae and Pseudomonadales bacteria.

Percutaneous distal chevron osteotomy is associated with lower immediate postoperative pain and a greater range of motion than the open technique: A prospective randomized study.

PURPOSE: The results of past studies comparing percutaneous techniques with traditional open techniques for hallux valgus are controversial. Therefore, this study aimed to compare the radiologic and clinical outcomes of percutaneous and open distal chevron osteotomies. METHODS: Seventy-one patients with mild to severe hallux valgus deformity were randomized to undergo percutaneous distal chevron osteotomy (percutaneous group, n = 36) or open distal chevron osteotomy (open group, n = 35) between October 2019 and September 2020. Radiological and clinical outcomes were assessed preoperatively and postoperatively. Outcome measures included the foot and ankle outcome score, foot functional index, visual analogue scale (VAS) scores for pain, range of motion (ROM) of the first metatarsophalangeal (MTP) joint, hallux valgus angle, intermetatarsal angle, and first metatarsal shortening. Additionally, the first metatarsal declination angle was measured to evaluate sagittal malunion. RESULTS: The mean first metatarsal declination angle decreased significantly at 12 months postoperatively in both groups (p = 0.021 and p < 0.001 in the percutaneous and open groups, respectively), and the decrement was significantly greater in the open group (p = 0.033). The mean VAS score for pain on postoperative day one was 4.2 ± 1.9 and 5.3 ± 1.7 in the percutaneous and open groups, respectively (p = 0.019). The mean ROM of the first MTP joint did not change significantly after surgery, from 72.5 ± 7.5 preoperatively to 71.0 ± 9.5 at 12 months postoperatively in the percutaneous group (p = 0.215); however, it decreased significantly from 70.6 ± 7.3 preoperatively to 63.4 ± 10.4 at 12 months postoperatively in the open group (p < 0.001). There were no significant differences between the groups regarding other clinical outcomes. CONCLUSION: The percutaneous group showed a lower immediate pain level at postoperative day 1 and better ROM of the first MTP joint at 12 months postoperatively.

Hair Growth Promoting Effects of 15-Hydroxyprostaglandin Dehydrogenase Inhibitor in Human Follicle Dermal Papilla Cells.

Prostaglandin E2 (PGE2) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE2 levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema®, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.

Synthesis of S-Carbamidomethyl Cysteine and Its Use for Quantification of Cysteinyl Peptides by Targeted Proteomics.

Proteomics has played a central role in the identification of reliable disease biomarkers, which are the basis of precision medicine, a promising approach for tackling recalcitrant diseases such as cancer, that elude conventional treatments. Among proteomic methodologies, targeted proteomics employing stable isotope-labeled (SIL) internal standards is particularly suited for the clinical translation of biomarker information owing to its high throughput and accuracy in the quantitative analysis of patient-derived proteomes. Using SIL internal standards ensures the utmost level of confidence in detection and precision in targeted MS experiments. For successfully establishing assays based on targeted proteomics, it is crucial to secure broad coverage when selecting the SIL standard peptide panel. However, cysteinyl peptides have often been excluded because of cysteine's high chemical reactivity. To address this limitation, a new cysteine building block was developed by incorporating a sulfhydryl group configured with an S-carbamidomethyl group, which is commonly used in proteome sampling. This compound was found to be chemically stable and applicable to a variety of solid-phase peptide synthesis (SPPS) campaigns. Furthermore, a direct comparison of the synthesized SIL peptides and tryptic endogenous peptides demonstrated the potential utility of an SPPS flow based on the new cysteine building block for improving the success of targeted proteomic applications.

A conformation-selective protein binder for a KRAS mutant inhibits the interaction between RAS and RAF.

Small GTPases are key signaling nodes that regulate the cellular processes and subcellular events, and their abnormal activities and dysregulations are closely linked with diverse cancers. Here, we report the development of conformation-selective protein binders for a KRAS mutant. The conformation-specific protein binders were selected from a repebody scaffold composed of LRR (Leucine-rich repeat) modules through phage display and modular engineering against constitute active conformation of KRAS. Epitope of the selected binders was mapped to be located close to switch I of KRAS. The conformation-selective protein binders were shown to effectively block the interaction between active KRAS and RAS-binding domain of BRAF, suppressing the KRAS-mediated downstream signaling.

Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506).

PURPOSE: To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4. METHODS: The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3 year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL). We calculated that 252 pts were needed in each treatment group to enable the detection of non-inferiority (non-inferiority margin of 10%). RESULTS: In terms of ITT analysis, 248 pts were finally enrolled. The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm. With a median follow up of 64.1 months, the 3Y DFS was comparable between the two arms (75.8% in FEC3-D3 vs. 75.6% in AC4-D4). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44). CONCLUSION: Six cycles of FEC3-D3 could be an alternative to eight of AC4-D4. Trial registration ClinicalTrials.gov NCT02001506. Registered December 5,2013. https://clinicaltrials.gov/ct2/show/NCT02001506.

Effects of Preoperative Breast MRI on Breast Cancer Survival Outcomes in Women Aged 35 Years and Younger.

Background The impact of preoperative breast MRI on the long-term outcomes in patients with breast cancer who are 35 years and younger has not been established. Purpose To evaluate the impact of preoperative breast MRI on recurrence-free survival (RFS) and overall survival (OS) in women with breast cancer who are 35 years and younger by using propensity score matching. Materials and Methods A total of 708 women who were 35 years and younger (mean age, 32 years ± 3 [SD]) and diagnosed with breast cancer from 2007 to 2016 were retrospectively identified. Patients who underwent preoperative MRI (MRI group) were matched with those who did not (no MRI group) according to 23 patient and tumor characteristics. RFS and OS were compared using the Kaplan-Meier method. Cox proportional hazards regression analysis was used to estimate the hazard ratios (HRs). Results Of 708 women, 125 patient pairs were matched. In the MRI group versus the no MRI group, the mean follow-up time was 82 months ± 32 versus 106 months ± 42, and the rates of total recurrence and death were 22% (104 of 478 patients) versus 29% (66 of 230 patients) and 5% (25 of 478 patients) versus 12% (28 of 230 patients), respectively. The time to recurrence was 44 months ± 33 in the MRI group and 56 months ± 42 in the no MRI group. After propensity score matching, the MRI and no MRI groups did not show significant differences in total recurrence (HR, 1.0; P = .99), local-regional recurrence (HR, 1.3; P = .42), contralateral breast recurrence (HR, 0.7; P = .39), or distant recurrence (HR, 0.9; P = .79). The MRI group showed a tendency toward better OS, but this was not statistically significant (HR, 0.47; P = .07). In the entire unmatched cohort, MRI was not an independent significant factor for predicting RFS or OS. Conclusion Preoperative breast MRI was not a significant prognostic factor for recurrence-free survival in women 35 years and younger with breast cancer. A tendency toward better overall survival was observed in the MRI group, but this was not significant. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kim and Moy in this issue.

Construction and Functionalization of a Clathrin Assembly for a Targeted Protein Delivery.

Protein assemblies have drawn much attention as platforms for biomedical applications, including gene/drug delivery and vaccine, due to biocompatibility and functional diversity. Here, the construction and functionalization of a protein assembly composed of human clathrin heavy chain and light chain for a targeted protein delivery, is presented. The clathrin heavy and light chains are redesigned and associated with each other, and the resulting triskelion unit further self-assembled into a clathrin assembly with the size of about 28 nm in diameter. The clathrin assembly is dual-functionalized with a protein cargo and a targeting moiety using two different orthogonal protein-ligand pairs through one-pot reaction. The functionalized clathrin assembly exhibits about a 900-fold decreased KD value for a cell-surface target due to avidity compared to a native targeting moiety. The utility of the clathrin assembly is demonstrated by an efficient delivery of a protein cargo into tumor cells in a target-specific manner, resulting in a strong cytotoxic effect. The present approach can be used in the creation of protein assemblies with multimodality.

Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways.

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage-repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.

Marigold Flower-Shaped Metal-Organic Framework Supported Manganese Vanadium Oxide Electrocatalyst for Efficient Oxygen Evolution Reactions in an Alkaline Medium.

The electrochemical oxygen evolution reaction (OER) is a key process in many renewable energy systems. The development of low-cost, long-lasting alternatives to precious-metal catalysts, particularly functional electrocatalysts with high activity for OER processes, is crucial for reducing the operating expense and complexity of renewable energy generating systems. This work describes a concise method for generating marigold flower-like metal-organic frameworks (MOFs) aided manganese vanadium oxide via a hydrothermal procedure for increased OER activity. As synthesized MOF MnV oxide has a higher surface area due to the 3D flower-like structure, which is reinvented with enhanced electrocatalytic active sites. These distinctive structural features result in remarkable catalytic activity for MOF MnV oxide microflowers towards OER with a low overpotential of 310 mV at 50 mA cm-2 and a Tafel slope with only 51.4 mV dec-1 in alkaline conditions. This study provides a concise method for developing an optimized catalytic material with greater morphology and beneficial features for potential energy and environmental applications.

Improving mammography interpretation for both novice and experienced readers: a comparative study of two commercial artificial intelligence software.

OBJECTIVES: To evaluate the improvement of mammography interpretation for novice and experienced radiologists assisted by two commercial AI software. METHODS: We compared the performance of two AI software (AI-1 and AI-2) in two experienced and two novice readers for 200 mammographic examinations (80 cancer cases). Two reading sessions were conducted within 4 weeks. The readers rated the likelihood of malignancy (range, 1-7) and the percentage probability of malignancy (range, 0-100%), with and without AI assistance. Differences in AUROC, sensitivity, and specificity were analyzed. RESULTS: Mean AUROC increased in both novice (0.86 to 0.90 with AI-1 [p = 0.005]; 0.91 with AI-2 [p < 0.001]) and experienced readers (0.87 to 0.92 with AI-1 [p < 0.001]; 0.90 with AI-2 [p = 0.004]). Sensitivities increased from 81.3 to 88.8% with AI-1 (p = 0.027) and to 91.3% with AI-2 (p = 0.005) in novice readers, and from 81.9 to 90.6% with AI-1 (p = 0.001) and to 87.5% with AI-2 (p = 0.016) in experienced readers. Specificity did not decrease significantly in both novice (p > 0.999, both) and experienced readers (p > 0.999 with AI-1 and 0.282 with AI-2). There was no significant difference in the performance change depending on the type of AI software (p > 0.999). CONCLUSION: Commercial AI software improved the diagnostic performance of both novice and experienced readers. The type of AI software used did not significantly impact performance changes. Further validation with a larger number of cases and readers is needed. CLINICAL RELEVANCE STATEMENT: Commercial AI software effectively aided mammography interpretation irrespective of the experience level of human readers. KEY POINTS: • Mammography interpretation remains challenging and is subject to a wide range of interobserver variability. • In this multi-reader study, two commercial AI software improved the sensitivity of mammography interpretation by both novice and experienced readers. The type of AI software used did not significantly impact performance changes. • Commercial AI software may effectively support mammography interpretation irrespective of the experience level of human readers.

Bleeding Risk With Cold Snare Polypectomy of ≤10 mm Pedunculated Colon Polyps.

OBJECTIVES: Pedunculated polyps (PPs) in the colon are usually resected with hot snare polypectomy to prevent immediate postpolypectomy bleeding (IPPB). This study aimed to evaluate the safety of CSP of <10 mm PPs. MATERIALS AND METHODS: Patients undergoing colonoscopy from February 18, 2019, to April 24, 2020, and were found to have at least 1 ≤10 mm PP resected with CSP were included prospectively in a continuous quality improvement project to assess the risk of IPPB and delayed postpolypectomy bleeding. Polyp location, size, and pathology, as well as the method of resection, were recorded. In addition, we assessed the occurrence and severity of IPPB and the need for intervention. RESULTS: We found 239 eligible polyps in 182 patients. The mean (SD) age was 58.8 (8.3) years, and 61% were males. IPPB occurred in 72 of 239 polyps, corresponding to a per-polyp bleeding percentage of 30.1% and in 65 of 182 patients, equating to a per-patient bleeding rate of 35.7%. We successfully treated bleeding by endoscopic hemostasis in 57%; the remaining 31 polyps (43%) did not require endoscopic intervention. There was no association between IPPB with age, gender, or use of aspirin or antithrombotic agents. In the bivariate model, polyp size and pathology were not associated with the risk of IPPB. Right-sided polyps were associated with a reduced risk of IPPB in the bivariate model by 61% (odds ratio=0.39; 95% confidence interval, 0.21-0.74; P =0.0057). In the multivariate model, choking the polyp base decreased the likelihood of IPPB by 97% (odds ratio=0.03; 95% confidence interval, 0.00-0.86; P =0.0459). There were no instances of delayed bleeding, perforation, or postpolypectomy syndrome. CONCLUSIONS: CSP can be used for resection of ≤10 mm PPs. It is associated with a lower risk of immediate bleeding than the common perception among gastroenterologists.