A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer.

In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency.

Physical, Chemical, and Biological Properties of Chitosan-Coated Alginate Microparticles Loaded with Porcine Interleukin-1ß: A Potential Protein Adjuvant Delivery System.

We previously developed chicken interleukin-1ß (IL-1ß) mutants as single-dose adjuvants that induce protective immunity when co-administered with an avian vaccine. However, livestock such as pigs may require a vaccine adjuvant delivery system that provides long-lasting protection to reduce the need for successive booster doses. Therefore, we developed chitosan-coated alginate microparticles as a carrier for bovine serum albumin (BSA) or porcine IL-1ß (pIL-1ß) and assessed their physical, chemical, and biological properties. Electrospraying of the BSA-loaded alginate microparticles (BSA/ALG MPs) resulted in an encapsulation efficiency of 50%, and those MPs were then coated with chitosan (BSA/ALG/CHI MPs). Optical and scanning electron microscopy, zeta potential analysis, and Fourier transform infrared spectroscopy were used to characterize these MPs. The BSA encapsulation parameters were applied to ALG/CHI MPs loaded with pIL-1ß, which were not cytotoxic to porcine fibroblasts but had enhanced bio-activity over unencapsulated pIL-1ß. The chitosan layer of the BSA/ALG/CHI MPs prevented burst release and facilitated sustained release of pIL-1ß for at least 28 days. In conclusion, BSA/ALG/CHI MPs prepared as a carrier for pIL-1ß may be used as an adjuvant for the formulation of pig vaccines.

Evaluation of greenhouse gas emission and reduction potential of high-food-waste-content municipal solid waste landfills: A case study of a landfill in the east of China.

This study proposes a comprehensive evaluation method based on a two-stage model to assess greenhouse gas (GHG) emissions and reductions in high-food-waste-content (HFWC) municipal solid waste (MSW) landfills. The proposed method considers typical processes such as fugitive landfill gas (LFG), LFG collection, flaring, power generation, and leachate treatment. A case study of an HFWC MSW landfill in eastern China is considered to illustrate the evaluation. The findings revealed that the GHG emissions equivalent of the case landfill amounted to 21.23 million tons from 2007 to 2022, averaging 1.03 tons CO2-eq per ton of MSW. There was a potential underestimation of LFG generation at the landfill site during the initial stages, which led to delayed LFG collection and substantial fugitive LFG emissions. Additionally, the time distribution of GHG emissions from HFWC MSW was significantly different from that of low-food-waste-content (LFWC) MSW landfills, with peak emissions occurring much earlier. Owing to the rapid degradation characteristics of HFWC MSW, the cumulative LFG production of the landfill by 2022 (2 years after the final cover) was projected to reach 77 % of the total LFG potential. In contrast, it would take until 2030 for LFWC MSW landfills to reach this level. Furthermore, various scenarios were analyzed, in which if the rapid LFG generation characteristics of HFWC MSW are known in advance, and relevant facilities are constructed ahead of time, the collection efficiency can be improved from 31 % to over 78 %, resulting in less GHG emissions.

Research progress and clinical evaluation of histotripsy: a narrative review.

Background and Objective: As a soft-tissue noninvasive ablation technology, high-intensity focused ultrasound (HIFU) has been widely used to treat many clinical diseases. However, traditional HIFU, based on thermal effects, has a high local working temperature, which may cause thermal damage to surrounding tissues and reduce the therapeutic effect. Based on the cavitation effect of HIFU, histotripsy can mechanically destroy the cells in the target lesion. This paper aims to explain the mechanism of histotripsy, summarize the research progress of animal models for clinical evaluation and clinical application, and analyze the advantages and limitations of histotripsy. Methods: Literature published from January 2006 to March 2022 was retrieved from the PubMed database. We reviewed these articles to examine histotripsy from the aspects of the mechanism, animal experiments, clinical trials, advantages, disadvantages, and optimization. Key Content and Findings: Histotripsy is a noninvasive, nonionizing, nonthermal ablation technique. The clinical application of histotripsy has made significant progress in the treatment of liver tumors, benign prostatic hyperplasia, and aortic valve calcification stenosis. Phase I clinical trials have demonstrated the safety and efficacy of histotripsy in the treatment of these diseases. More research is needed to evaluate and optimize its efficacy and safety and to fully explore its mechanism of action, pathological and immunological effects, and the short-term and long-term reactions of the body after treatment. Conclusions: Histotripsy has broad application prospects in ablation therapy and will benefit patients after more clinical trials are conducted in the future.

Interspecific competition between the bloom-causing dinoflagellates Hetrocapsa bohaiensis and the local species Chlorella pyrenoidosa.

Harmful algal blooms caused by Heterocapsa bohaiensis have broken out in aquaculture areas near Liaodong Bay, China, since 2012, resulting in mass mortality of Eriocheir sinensis larvae and substantial economic loss. Chlorella pyrenoidosa is a local phytoplankton species that is found in aquaculture ponds. However, the reason why H. bohaiensis dominated and proliferated in the phytoplankton community remains unknown. Previous studies have revealed the toxicity and hemolytic activity of H. bohaiensis. It is suspected that the out-competition of H. bohaiensis to C. pyrenoidosa was associated with toxicity. Filtrate and bi-algal cultures were investigated to determine the interspecific competition between H. bohaiensis and C. pyrenoidosa in this study. Filtrate experiments revealed that H. bohaiensis showed no toxin allelopathy in C. pyrenoidosa. However, the C. pyrenoidosa filtrates had significant allelopathic effects on the growth of H. bohaiensis. The bi-algal culture experiments and the simulation showed that the dominant species were dependent on the initial cell density ratios of the species and nutrient ratios. Therefore, H. bohaiensis achieved competitive advantage through exploitation competition but not allelopathy. The results contribute to the reasons for the occurrence of H. bohaiensis blooms in a further study.

Pressure-Activatable Liquid Metal Composites Flexible Sensor with Antifouling and Drag Reduction Functional Surface.

Flexible sensors produced through three-dimensional (3D) printing have exhibited promising results in the context of underwater sensing detection (for applications in navigational vehicles and human activities). However, underwater vehicles and activities such as swimming and diving are highly susceptible to drag, which can cause negative impacts such as reduced speed and increased energy consumption. Additionally, microbial adhesion can shorten the service life of these vehicles. However, natural organisms are able to circumvent such problems, with shark skin offering excellent barrier properties and ruffled papillae providing effective protection against fouling. Here, we show that a sandwich system consisting of a spraying layer, conductive elastomer composite, and encapsulation layer can be printed for multifunctional integrated underwater sensors. The modulated viscoelastic properties of liquid metal form the foundation for printing features, while its pressure-activated properties offer the potential for switchable sensors. An integrated drag reduction and antifouling layer were created by combining the shark skin surface shield scale structure with the lotus leaf surface papillae structure. A 3D-printed flexible sensor was designed using our approach to monitor attitude changes and strain in underwater environments, showcasing its capabilities. Our printed sensors can reduce biological attachment density by more than 50% and reduce underwater drag by 8.6-10.3%.

Predicting the recurrence-free survival of phyllodes tumor of the breast: a nomogram based on clinicopathology features, treatment, and surgical margin.

Background: Grading based on histopathologic indicators cannot accurately assess the prognosis of phyllodes tumor (PT) of the breast. This article aimed to investigate the correlation between PT prognosis and clinicopathological features, treatment, and surgical margin. Methods: The clinicopathological data of patients with pathologically confirmed PT at our institution were retrospectively collected. Univariate and multivariate Cox proportional risk models were employed to test the effects of different variables on the prognosis of PT. A nomogram to predict the 1-, 3-, 5-, and 10-year recurrence-free survival (RFS) of PT was proposed, and its discriminative ability and calibration were tested using the concordance index (C-index), area under the curve (AUC), and calibration plots. All statistical analyses were performed using R. Results: A total of 342 PT patients were included, including 242 benign (70.8%), 75 borderline (21.9%) and 25 malignant (7.3%) cases. The median follow-up period was 64.5 months (range, 3-179 months), 66 PT patients had local recurrence (LR), and four patients had distant metastasis. The 1-, 3-, 5-, and 10-year RFS of the PT patients were 90.8%, 81.8%, 78%, and 76.7%, respectively. Age, fibroadenoma (FA) surgery history, treatment, mitotic activity, and surgical margin were selected as the independent factors for PT prognosis. The nomogram showed good discriminative ability and calibration, as indicated by the C-index [0.78, 95% confidence interval (CI): 0.75-0.11]. Conclusions: Independent predictors related to PT prognosis were selected to establish a nomogram for predicting the RFS of PT. This nomogram was able to objectively stratify PT patients into prognostic groups and performed well in the internal validation.

Contralateral prophylactic mastectomy for unilateral breast cancer in Chinese female population: a retrospective cohort study.

Background: Due to differences in socioeconomic and cultural backgrounds, the characteristics and prognosis of Asian female patients choosing contralateral prophylactic mastectomy (CPM) are likely to be different from Western patients. To fill the research gap of CPM in Asian populations, this study aims to explore the application trend, survival benefits, decision-making factors, and satisfaction of CPM based on the Chinese patients undergoing CPM. Methods: The 0-III stage unilateral breast cancer (UBC) patients who received breast surgery in the Chinese PLA General Hospital from 2005 to 2017 were selected. The surgical procedures included simple mastectomy (SM), nipple-sparing mastectomy (NSM), breast conserving surgery (BCS), and CPM. Cox proportional regression analyses and Kaplan-Meier (KM) curve were performed to compare the overall survival (OS) and disease-free survival (DFS) rates between CPM group and unilateral mastectomy (UM) group. Proportional propensity score matching (PSM) with a 1:1 ratio was used to match the two groups and secondary survival analysis was performed. Logistic regression models were used to test predictive factors related to patients' CPM surgical decision-making. Results: Four thousand two hundred and seventy-six patients were included in the study, with 73 patients receiving CPM, 3,567 receiving SM, 151 receiving NSM, and 485 receiving BCS. CPM surgery was first used in 2007, with a peak application rate of 3.02% in 2016. Three thousand seven hundred and ninety-one patients were included in the survival analysis, with a median follow-up time of 66.60 months. Compared to UM patients, neither the KM survival curve nor Cox regression hazard analyses of CPM showed better OS (P=0.963; P=0.834). After PSM, CPM also did not exhibit significant survival benefits in OS (P=0.335) and DFS (P=0.409). The logistic regression analyses showed that NSM surgery and lower tumor-node-metastasis (TNM) stage were independent factors to promote the CPM decision-making of patients. The CPM group showed high overall satisfaction (84.9%) and relatively low appearance satisfaction (69.9%). Conclusions: CPM was practiced for the first time since 2007 in our hospital. CPM does not provide any OS and DFS benefits compared to UM and the appearance satisfaction procedure was relatively low. Therefore, clinicians should fully communicate with patients before surgery and be more cautious in giving CPM recommendations.

A background parenchymal enhancement quantification framework of breast magnetic resonance imaging.

Background: Background parenchymal enhancement (BPE) is defined as the enhanced proportion of normal fibroglandular tissue on enhanced magnetic resonance imaging. BPE shows promise as a quantitative imaging biomarker (QIB). However, the lack of consensus among radiologists in their semi-quantitative grading of BPE limits its clinical utility. Methods: The main objective of this study was to develop a BPE quantification model according to clinical expertise, with the BPE integral being used as a QIB to incorporate both the volume and intensity of the enhancement metrics. The model was applied to 2,786 cases to compare our quantitative results with radiologists' semi-quantitative BPE grading to evaluate the effectiveness of using the BPE integral as a QIB for analyzing BPE. Comparisons between multiple groups of nonnormally distributed BPE integrals were performed using the Kruskal-Wallis test. Results: Our study found a considerable degree of concordance between our BPE quantitative integral and radiologists' semi-quantitative assessments. Specifically, our research results revealed significant variability in BPE integral attained through the BPE quantification framework among all semi-quantitative BPE grading groups labeled by experienced radiologists, including mild-moderate (P<0.001), mild-marked (P<0.001), and moderate-marked (P<0.001). Furthermore, there was an apparent correlation between BPE integral and BPE grades, with marked BPE displaying the highest BPE integral, followed by moderate BPE, with mild BPE exhibiting the lowest BPE integral value. Conclusions: The study developed and implemented a BPE quantification framework, which incorporated both the volume and intensity of enhancement and which could serve as a QIB for BPE.

Surgical management in phyllodes tumors of the breast: a systematic review and meta-analysis.

Background: Information is still controversial in the studies regarding the current optimal surgical management of phyllodes tumors (PTs) of the breast. Local recurrence (LR) may occur with an upgraded in the pathological grade, influencing the prognosis of patients with PT. This systematic review and meta-analysis aimed to investigate the association of LR risk with margin status and margin width which could have significant implications on the surgical management of PT. Methods: Independent and comprehensive searches were performed by two authors through five databases including PubMed, Medline, Embase, ScienceDirect and Cochrane Library from January 1990 to October 2021. Studies investigating the association between margin width, margin status and LR rates were considered for inclusion. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS). Meta-analysis was performed using RevMan5.3 software, and statistical heterogeneity was assessed using the Chi-square test and quantified using the I2 statistic. Visual inspection of funnel plots was used to judge publication bias. Results: A total of 34 articles were included in this article, all of which with NOS scores above 5. Regardless of the PT grade, positive margin significantly increased the risk of LR [odds ratio (OR) 3.64, 95% confidence interval (CI): 2.60-5.12]. No significant difference was found in the risk of LR between the margins <1 and ≥1 cm (OR 1.39, 95% CI: 0.67-2.92). For benign and borderline PTs, there were no significant differences of the LR risk between breast-conserving surgery (BCS) and mastectomy (benign OR 0.68, 95% CI: 0.12-3.78; borderline OR 1.14, 95% CI: 0.29-4.51). While the LR risk was significantly increased by BCS for malignant PT (OR 2.77, 95% CI: 1.33-5.74). Discussion: Different surgical management strategies should be considered for different PT grades. BCS was a feasible option and margins <1 cm was not significantly associated with LR risk for all grade of PT. After BCS, benign PT with positive margin could adopt the "wait and watch" strategy with regular follow-up, while borderline and malignant PTs were expected to underwent re-excision to ensure negative margins. More studies are still needed to clarify and update the existing conclusions and improve the prognosis of PT patients.