Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics.

Telomere is a protective structure located at the end of chromosomes of eukaryotes, involved in maintaining the integrity and stability of the genome. Telomeres play an essential role in cancer progression; accordingly, targeting telomere dynamics emerges as an effective approach for the development of cancer therapeutics. Targeting telomere dynamics may work through multifaceted molecular mechanisms; those include the activation of anti-telomerase immune responses, shortening of telomere lengths, induction of telomere dysfunction and constitution of telomerase-responsive drug release systems. In this review, we summarize a wide variety of telomere dynamics-targeted agents in preclinical studies and clinical trials, and reveal their promising therapeutic potential in cancer therapy. As shown, telomere dynamics-active agents are effective as anti-cancer chemotherapeutics and immunotherapeutics. Notably, these agents may display efficacy against cancer stem cells, reducing cancer stem levels. Furthermore, these agents can be integrated with the capability of tumor-specific drug delivery by the constitution of related nanoparticles, antibody drug conjugates and HSA-based drugs.

Recycling drinking water treatment sludge in construction and building materials: A review.

Drinking water treatment sludge (DWTS) is a by-product of water treatment, and it is difficult to recycle to high value and poses potential environmental risks. Recycling DWTS into cement-based materials is an effective measure to achieve its high-volume utilization and reduce its environmental load. DWTS is rich in silica-alumina phases and has potential pozzolanic activity after drying, grinding and calcination, giving it similar properties to traditional supplementary cementitious materials. Adjusting the sludge production process and coagulant type will change its physical and chemical properties. Adding a small amount of DWTS can generate additional hydration products and refine the pore structure of the cement sample, thus improving the mechanical properties and durability of the sample. However, adding high-volume DWTS to concrete causes microstructural deterioration, but it is feasible to use high-volume DWTS to produce artificial aggregates, lightweight concrete, and sintered bricks. Meanwhile, calcined DWTS has similar compositions to clay, which makes it a potential raw material for cement clinker production. Cement-based materials can effectively solidify heavy metal ions in DWTS, and alkali-activated binders, magnesium-based cement, and carbon curing technology can further reduce the risk of heavy metal leaching. This review provides support for the high-value utilization of DWTS in cement-based materials and the reduction of its potential environmental risks.

Upcycling textile sludge into magnesium oxychloride cement: Physical properties, microstructure, and leaching behavior.

Textile sludge is a by-product produced during the wastewater treatment process in the textile printing and dyeing industry. Textile sludge is rich in heavy metal elements, which makes it a potential risk to the surrounding environment. This study designs a magnesium oxychloride cement (MOC) components to solidify harmful substances in textile sludge and studies the influence of textile sludge ash (TSA) on the mechanical properties and microstructure of MOC samples. The results indicated that adding 5 %-20 % TSA is beneficial for increasing the compressive strength of air-cured MOC paste and improving its water resistance. Meanwhile, the MOC sample shows volume expansion in 168 h, which is related to the further hydration of residual MgO. Incorporating 10 %-20 % TSA substantially increased the volume expansion ratio of the mixture compared to plain MOC sample. In addition, the porosity of TSA-modified MOC after water curing did not change significantly compared to the sample before water curing, while the pore structure of plain MOC after water curing significantly coarsened. This is mainly because TSA reacts with MOC and generates Mg-Al-Cl-Si-H and Mg-Cl-Si-H gels, consequently improving the water stability of MOC sample. At the nanoscale, the 3/5-phase crystal and unreacted MgO content in the 15 % TSA-modified MOC sample is relatively reduced by 7.79 % and 25 %, respectively, compared to the plain sample, but the 13 % gel phase is detected. In addition, the MOC component can effectively solidify heavy metal elements in textile sludge. For the leachate of 20 % TSA-modified MOC paste, the Ni element is not detected, and its solidifying effect on heavy elements such as Zn and Mn exceeded 99 %.

Cost-effectiveness of first-line immunotherapy for advanced non-small cell lung cancer with different PD-L1 expression levels: A comprehensive overview.

BACKGROUND: Immunotherapies can substantially improve treatment efficacy, despite their high cost. A comprehensive overview of the cost-effectiveness analysis (CEA) of immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer based on different tumor proportion scores (TPSs) was conducted. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and NHS Economic Evaluation databases were searched from their inception until August 24, 2022. Data relevant to the CEA results were recorded, and quality assessments conducted based on the Quality of Health Economic Studies (QHES) process. FINDINGS: Fifty-one original studies from seven countries were included. The mean QHES score was 77.0 (range: 53-95). Twenty-seven studies were classified as high-quality, and the rest as fair quality. Pembrolizumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, cemiplimab, sintilimab, tislelizumab, and durvalumab were identified using three TPS categories. While nivolumab plus ipilimumab and pembrolizumab plus chemotherapy were unlikely to be cost-effective in China, the results for the US were uncertain. Atezolizumab combinations were not cost-effective in China or the US, and tislelizumab and sintilimab were cost-effective in China. For TPSs ≥ 50%, the pembrolizumab monotherapy could be cost-effective in some developed countries. Cemiplimab was more cost-effective than chemotherapy, pembrolizumab, and atezolizumab in the US. For TPSs ≥ 1%, the cost-effectiveness of pembrolizumab was controversial due to the different willingness-to-pay thresholds. CONCLUSIONS: None of the atezolizumab combination regimens were found to be cost-effective in any perspective of evaluations. Camrelizumab, tislelizumab, and sintilimab have lower ICERs compared to atezolizumab, pembrolizumab, and nivolumab in China. Cemiplimab may be a more affordable alternative to pembrolizumab or atezolizumab. However, it remains unclear which ICIs are the best choices for each country. Future CEAs are required to select comprehensive regimens alongside randomized trials and real-world studies to help verify the economics of ICIs in specific decision-making settings.

A Two-part Transformer Network for Controllable Motion Synthesis.

Although part-based motion synthesis networks have been investigated to reduce the complexity of modeling heterogeneous human motions, their computational cost remains prohibitive in interactive applications. To this end, we propose a novel two-part transformer network that aims to achieve high-quality, controllable motion synthesis results in real-time. Our network separates the skeleton into the upper and lower body parts, reducing the expensive cross-part fusion operations, and models the motions of each part separately through two streams of auto-regressive modules formed by multi-head attention layers. However, such a design might not sufficiently capture the correlations between the parts. We thus intentionally let the two parts share the features of the root joint and design a consistency loss to penalize the difference in the estimated root features and motions by these two auto-regressive modules, significantly improving the quality of synthesized motions. After training on our motion dataset, our network can synthesize a wide range of heterogeneous motions, like cartwheels and twists. Experimental and user study results demonstrate that our network is superior to state-of-the-art human motion synthesis networks in the quality of generated motions.

Cost-effectiveness of first-line immunotherapy combinations with or without chemotherapy for advanced non-small cell lung cancer: a modelling approach.

BACKGROUND: Many studies have explored the cost-effectiveness of immunotherapy versus chemotherapy alone. However, there is paucity of evidence on direct pharmacoeconomic studies related to immunotherapy combinations. Thus, we aimed at assessing the economic outcomes of first-line immunotherapy combinations in the treatment of advanced non-small cell lung cancer (NSCLC) from the Chinese health care perspective. METHODS: The mutual hazard ratios (HRs) of ten immunotherapy combinations and one chemotherapy regimen for the overall survival (OS) and progression-free survival (PFS) were obtained from a network meta-analysis. Based on proportional hazard (PH) assumption, adjusted OS and PFS curves were established to make the effects comparable. With the parameters of cost and utility, and of scale and shape from the fit of adjusted OS and PFS curves obtained from previous studies, a partitioned survival model was designed to estimate the cost-effectiveness of immunotherapy combinations versus chemotherapy alone. Parameter uncertainty in model inputs was assessed using one-way deterministic and probabilistic sensitivity analyses. RESULTS: The incremental cost of camrelizumab plus chemotherapy versus chemotherapy alone was $13,180.65, the lowest among all the other immunotherapy combinations. Furthermore, sintilimab plus chemotherapy (sint-chemo) provided the highest quality-adjusted life-year (QALY) benefit versus chemotherapy alone (incremental QALYs = 0.45). Sint-chemo yielded the best incremental cost-effectiveness ratio (ICER) versus chemotherapy alone (ICER = $34,912.09/QALY), at the current price. The cost-effectiveness probabilities were 32.01% and 93.91% for pembrolizumab plus chemotherapy, and atezolizumab plus bevacizumab plus chemotherapy, respectively (if the original price of the pembrolizumab, atezolizumab, and bevacizumab were decreased by 90%). CONCLUSIONS: Based on the fact that there is fierce competition in the PD-1/PD-L1 market, pharmaceutical enterprises should strive for greater efficacy, and optimal pricing strategy for therapies.

Advances in aptamer-mediated targeted delivery system for cancer treatment.

Aptamers with high affinity and specificity for certain targets have rapidly become a novel class of targeted ligands applicated in drug delivery. Based on the excellent characteristics of aptamers, different aptamer-mediated drug delivery systems have been developed, including aptamer-drug conjugate (ApDC), aptamer-siRNA, and aptamer-functionalized nanoparticle systems for the effective treatment of cancer, which can reduce potential toxicity and improve therapeutic efficacy. In this review, we summarize the recent progress of aptamer-mediated delivery systems in cancer therapy, and discuss the application prospects and existing problems of innovative approaches based on aptamer therapy. Overall, this review aims to better understand the current aptamer-based targeted delivery applications through in-depth analysis to improve efficacy and develop new therapeutic methods which can ultimately improve treatment outcomes for cancer patients.

Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation.

OBJECTIVE: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy. METHODS: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3∼AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed. RESULTS: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3∼AE displayed highly potent cytotoxicity to cancer cells with IC50 at 0.1 nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3∼AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-ß in athymic mice. CONCLUSION: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.

A recombinant scFv antibody-based fusion protein that targets EGFR associated with IMPDH2 downregulation and its drug conjugate show therapeutic efficacy against esophageal cancer.

The present study aimed to evaluate the anti-tumor efficacy of the epidermal growth factor receptor (EGFR)-targeting recombinant fusion protein Fv-LDP-D3 and its antibody-drug conjugate Fv-LDP-D3-AE against esophageal cancer. Fv-LDP-D3, consisting of the fragment variable (Fv) of an anti-EGFR antibody, the apoprotein of lidamycin (LDP), and the third domain of human serum albumin (D3), exhibited a high binding affinity for EGFR-overexpressing esophageal cancer cells, inhibited EGFR phosphorylation and down-regulated inosine monophosphate dehydrogenase type II (IMPDH2) expression. Fv-LDP-D3 was taken up by cancer cells through intensive macropinocytosis; it inhibited the proliferation and induced the apoptosis of esophageal cancer cells. In vivo imaging revealed that Fv-LDP-D3 displayed specific tumor-site accumulation and a long-lasting retention over a 26-day period. Furthermore, Fv-LDP-D3-AE, a pertinent antibody-drug conjugate prepared by integrating the enediyne chromophore of lidamycin into the Fv-LDP-D3 molecule, displayed highly potent cytotoxicity, inhibited migration and invasion, induced apoptosis and DNA damage, arrested cells at G2/M phase, and caused mitochondrial damage in esophageal cancer cells. More importantly, both of Fv-LDP-D3 and Fv-LDP-D3-AE markedly inhibited the growth of esophageal cancer xenografts in athymic mice at well tolerated doses. The present results indicate that Fv-LDP-D3, and Fv-LDP-D3-AE exert prominent antitumor efficacy associated with targeting EGFR, suggesting their potential as promising candidates for targeted therapy against esophageal cancer.

The development of human serum albumin-based drugs and relevant fusion proteins for cancer therapy.

Human serum albumin (HSA)-based therapeutics have attracted tremendous attention in the development of anticancer agents. The versatile properties of HSA make HSA-based therapeutics possess improved pharmacokinetics, extended circulation half-life, enhanced efficacy, reduced toxicity, etc. Generally, the HSA-based therapeutics systems can be divided into four categories, i.e. HSA-drug nanoparticles, HSA-drug conjugates, HSA-binding prodrugs, and HSA-based recombinant fusion proteins: the latter mainly include antibody (domain)- and cytokine- fusion proteins. Advances in this area revealed the advantages of HSA-based systems in the development of tumor site-oriented therapeutics, partly referring to the enhanced penetration and retention (EPR) effect and the intensive macropinocytosis. Accordingly, a variety of technical platforms for the design and preparation of HSA-based therapeutics have been reported. Major strategies and directions for the drug development were discussed; those include (1) Tumor-site oriented drug delivery and enhanced drug retention, (2) Tumor-site prodrug release and activation, (3) Cancer cell bound intensive drug internalization, and (4) Tumor microenvironment (TME) directed immunomodulation. Notably, the multimodal HSA-based approach is promising for the development of tumor-oriented therapeutics for cancer therapy.

Low-Intensity Focused Ultrasound-Augmented Multifunctional Nanoparticles for Integrating Ultrasound Imaging and Synergistic Therapy of Metastatic Breast Cancer.

The metastasis of breast cancer is believed to have a negative effect on its prognosis. Benefiting from the remarkable deep-penetrating and noninvasive characteristics, sonodynamic therapy (SDT) demonstrates a whole series of potential leading to cancer treatment. To relieve the limitation of monotherapy, a multifunctional nanoplatform has been explored to realize the synergistic treatment efficiency. Herein, we establish a novel multifunctional nano-system which encapsulates chlorin e6 (Ce6, for SDT), perfluoropentane (PFP, for ultrasound imaging), and docetaxel (DTX, for chemotherapy) in a well-designed PLGA core-shell structure. The synergistic Ce6/PFP/DTX/PLGA nanoparticles (CPDP NPs) featured with excellent biocompatibility and stability primarily enable its further application. Upon low-intensity focused ultrasound (LIFU) irradiation, the enhanced ultrasound imaging could be revealed both in vitro and in vivo. More importantly, combined with LIFU, the nanoparticles exhibit intriguing antitumor capability through Ce6-induced cytotoxic reactive oxygen species as well as DTX releasing to generate a concerted therapeutic efficiency. Furthermore, this treating strategy actives a strong anti-metastasis capability by which lung metastatic nodules have been significantly reduced. The results indicate that the SDT-oriented nanoplatform combined with chemotherapy could be provided as a promising approach in elevating effective synergistic therapy and suppressing lung metastasis of breast cancer.

Exosomes-Coated miR-34a Displays Potent Antitumor Activity in Pancreatic Cancer Both in vitro and in vivo.

PURPOSE: MiR-34a, which acts as an important tumor suppressor gene, plays an important role in pancreatic cancer. However, the therapeutic application of miR-34a is limited by the lack of an effective delivery system. In the present study, we synthesize exosomes-coated miR-34a (exomiR-34a), and the anticancer effect of exomiR-34a was evaluated in pancreatic cancer. MATERIALS AND METHODS: An ultrasound approach was used to synthesize exomiR-34a, and its transfection efficiency was examined by confocal microscopy and flow cytometry. The level of miR-34a and its targeted gene Bcl-2 was detected by real-time quantitative PCR (qRT-PCR). MTT analysis was performed to determine the effect of exomiR-34a on the growth of pancreatic cancer cells. Annexin-V/PI double staining and Western blot analysis were carried out to determine the apoptosis of the pancreatic cancer cells. The xenograft nude mice model bearing human pancreatic cancer Panc28 cells was used to determine the antitumor effect of exomiR-34a in vivo. RESULTS: The exomiR-34a could cross the cell membrane efficiently, and downregulated the expression of the targeted gene Bcl-2. Treatment with exomiR-34a inhibited the growth of the pancreatic cancer cells significantly and the nanoparticles also induced apoptosis in cancer cells via affecting the expression of apoptotic-related genes. In vivo study using xenograft nude mice bearing Panc28 cancer cells revealed that exomiR-34a suppressed the growth of tumors significantly. CONCLUSION: ExomiR-34a can inhibit the growth of pancreatic cancer both in vitro and in vivo. Targeting miR-34a is a promising strategy for the treatment of pancreatic cancer. ExomiR-34a has the potential to be developed as a novel anticancer agent for the treatment of human pancreatic malignancy.

Vital and Distinct Roles of H2A.Z Isoforms in Hepatocellular Carcinoma.

PURPOSE: H2A.Z is an oncogenic histone variant that is overexpressed in cancers. Two isoforms of H2A.Z, H2AFZ and H2AFV, are identical except for a three-amino acid difference. However, their isoform-specific functions remain unclear in cancer development. Thereby, this study aimed to investigate whether the two isoforms play distinct functions in hepatocarcinogenesis. MATERIALS AND METHODS: Expressions of H2A.Z isoforms in 116 paired hepatocellular cancerous and para-cancerous tissues were detected by employing qPCR. GEO and TCGA databases were used to probe expressions and prognostic value of the two H2A.Z isoforms. A comprehensive meta-analysis was conducted. Furthermore, co-expressed analysis of H2AFZ and H2AFV was performed by using cBioPortal database. H2A.Z binding genes from Chip-seq were intersected with H2A.Z isoforms co-expressed genes to perform functional annotations. Cell proliferation experiments from H2AFZ knockout HepG2 and BEL-7402 cells were implemented. Finally, RNA-seq was applied to analyse alternative splicing in H2AFZ knockout and wild-type cells. RESULTS: H2AFZ and H2AFV were both significantly upregulated (P < 0.01) in hepatocellular carcinoma and related to poor prognosis (P < 0.01). The two H2A.Z isoforms played vital roles in cell proliferation. It is also predicted that unique functions of H2AFV contain spindle midzone and microtubule, while H2AFZ is especially associated with RNA export and spliceosome. Further, devoid H2AFZ may restrain liver cancer cell proliferation and cause many alternative splicing events. CONCLUSION: Both H2A.Z isoforms play vital and distinct roles in the occurrence and progression of liver cancer, which may pave a way for novel therapeutic applications for cancers in the future.

Exosomes-coated bcl-2 siRNA inhibits the growth of digestive system tumors both in vitro and in vivo.

BACKGROUND: The therapeutic application of small interfering RNA is limited by the lack of an effective delivery system to tumors. In the present study, an efficient approach to deliver siRNA to cancer cells using exosome system was developed. MATERIALS & METHODS: Exosomes were isolated from bovine milk and exosomes-coated bcl-2 siRNA (exosiBcl-2) was synthesized using ultrasonic approach. The anticancer effect of exsosiBcl-2 was studied by Confocal microscopy, flow cytometry, scratch wound healing and Transwell experiments, RT-qPCR and Western blot approaches, etc. Xenograft nude mice tumor model was performed to check the antitumor activity of exosiBcl-2 in vivo. RESULTS: ExosiBcl-2 can cross the cell membrane efficiently and inhibit the growth of cancer cells. ExosiBcl-2 treatment led to apoptosis and dramatic inhibition of migration and invasion of cancer cells via downregulating metastatic related genes. In vivo study revealed that exosiBcl-2 inhibited the tumor growth significantly in nude mice. CONCLUSION: ExosiBcl-2 has potential to be developed as a novel anticancer agent.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years.

BACKGROUND: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. OBJECTIVE: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. METHODS: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. RESULTS: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.