Impact of perioperative blood transfusion on prognosis after nephrectomy in patients with renal cell carcinoma: A meta-analysis and systematic review.

BACKGROUND: Perioperative blood transfusion (PBT) has been associated with worse prognosis in several malignancies. For renal cell carcinoma (RCC), the effect of PBT is still debated. OBJECTIVE: To evaluate the impact of PBT on prognosis after nephrectomy in patients with RCC. METHODS: This study is A systematic review and meta-analysis of published article data (PRISMA protocol) for literature related to PBT and RCC through extensive search of EMBASE, Medline via PubMed, Web of Science and Cochrane Library, language limited to English, with no time constraint until May 20, 2022. We pooled the results of multivariable cox regression analyses from each study, with subgroup analyses by dose and timing of transfusion. All analyses were done using Stata14. RESULTS: A total of 12 studies involving 27,683 participants were included. Our meta-analysis pooled the results of multivariable cox regression analysis in each study, showing that PBT is associated with higher overall Mortality (OM; hazard ratio [HR] = 1.34, 1.23-1.44), cancer-specific mortality (CSM; HR = 1.35, 1.20-1.51), and disease recurrence (HR = 1.54, 1.18-1.89). when only patients with nonmetastatic RCC were included, PBT was still associated with higher OM (HR = 1.29, 1.11-1.47) and disease recurrence (HR = 1.58, 1.18-1.98), but the association with CSM (HR = 1.26, 0.99-1.52) was not statistically significant. In subgroup analysis by transfusion dose, small (1-2) units of PBT were not associated with CSM (HR = 1.84, 0.95-2.73), but large (≥3) units were associated with higher CSM (HR = 2.98, 1.74-4.22) and disease recurrence (HR = 1.99, 1.31-2.67). Each additional unit of PBT resulted in a higher CSM (HR = 1.07, 1.04-1.10). In subgroup analysis by transfusion timing, intraoperative transfusion was associated with higher CSM and disease recurrence, but postoperative transfusion was not. CONCLUSIONS: PBT is associated with higher OM, CSM and disease recurrence. This adverse effect seems to be particularly significant in high-dose intraoperative transfusion. It is necessary to limit the overuse of PBT, especially high-dose intraoperative transfusion, in order to improve the prognosis of patients undergoing nephrectomy for RCC.

Biologically produced and metal-organic framework delivered dual-cut CRISPR/Cas9 system for efficient gene editing and sensitized cancer therapy.

Manipulation of the lactate metabolism is an efficient way for cancer treatment given its involvement in cancer development, metastasis, and immune escape. However, most of the inhibitors of lactate transport carriers suffer from poor specificity. Herein, we use the CRISPR/Cas9 system to precisely downregulate the monocarboxylate carrier 1 (MCT1) expression. To avoid the self-repairing during the gene editing process, a dual-Cas9 ribonucleoproteins (duRNPs) system is generated using the biological fermentation method and delivered into cells by the zeolitic imidazolate framework-8 (ZIF-8) nanoparticles, enabling precise removal of a specific DNA fragment from the genome. For efficient cancer therapy, a specific glucose transporter 1 inhibitor (BAY-876) is co-delivered with the duRNPs, forming BAY/duRNPs@ZIF-8 nanoparticle. ZIF-8 nanoparticles can deliver the duRNPs into cells within 1 h, which efficiently downregulates the MCT1 expression, and prohibits lactate influx. Through simultaneous inhibition of the lactate and glucose influx, BAY/duRNPs@ZIF-8 prohibits ATP generation, arrests cell cycle, inhibits cell proliferation, and finally induces cellular apoptosis both in vitro and in vivo. Consequently, we demonstrate that the biologically produced duRNPs delivered into cells by the nonviral ZIF-8 carrier have expanded the CRISPR/Cas gene editing toolbox and elevated the gene editing efficiency, which will promote biological studies and clinical applications. STATEMENT OF SIGNIFICANCE: The CRISPR/Cas9 system, widely used as an efficient gene editing tool, faces a challenge due to cells' ability to self-repair. To address this issue, a strategy involving dual-cutting of the genome DNA has been designed and implemented. This strategy utilizes biologically produced dual-ribonucleoproteins delivered by a metal-organic framework. The effectiveness of this dual-cut CRISPR-Cas9 system has been demonstrated through a therapeutic approach targeting the simultaneous inhibition of lactate and glucose influx in cancer cells. The utilization of the dual-cut gene editing strategy has provided valuable insights into gene editing and expanded the toolbox of the CRISPR/Cas-based gene editing system. It has the potential to enable more efficient and precise manipulation of specific protein expression in the future.

Distinguishing high-metastasis-potential circulating tumor cells through fluidic shear stress in a bloodstream-like microfluidic circulatory system.

Circulating tumor cells (CTCs) play a critical role as initiators in tumor metastasis, which unlocks an irreversible process of cancer progression. Regarding the fluid environment of intravascular CTCs, a comprehensive understanding of the impact of hemodynamic shear stress on CTCs is of profound significance but remains vague. Here, we report a microfluidic circulatory system that can emulate the CTC microenvironment to research the responses of typical liver cancer cells to varying levels of fluid shear stress (FSS). We observe that HepG2 cells surviving FSS exhibit a marked overexpression of TLR4 and TPPP3, which are shown to be associated with the colony formation, migration, and anti-apoptosis abilities of HepG2. Furthermore, overexpression of these two genes in another liver cancer cell line with normally low TLR4 and TPPP3 expression, SK-Hep-1 cells, by lentivirus-mediated transfection also confirms the critical role of TLR4 and TPPP3 in improving colony formation, migration, and survival capability under a fluid environment. Interestingly, in vivo experiments show SK-Hep-1 cells, overexpressed with these genes, have enhanced metastatic potential to the liver and lungs in mouse models via tail vein injection. Mechanistically, TLR4 and TPPP3 upregulated by FSS may increase FSS-mediated cell survival and metastasis through the p53-Bax signaling pathway. Moreover, elevated levels of these genes correlate with poorer overall survival in liver cancer patients, suggesting that our findings could offer new therapeutic strategies for early cancer diagnosis and targeted treatment development.

Size and shape control of microgel-encapsulating tumor spheroid via a user-friendly solenoid valve-based sorter and its application on precise drug testing.

The precision of previous cancer research based on tumor spheroids, especially the microgel-encapsulating tumor spheroids, was limited by the high heterogeneity in the tumor spheroid size and shape. Here, we reported a user-friendly solenoid valve-based sorter to reduce this heterogeneity. The artificial intelligence algorithm was employed to detect and segmentate the tumor spheroids in real-time for the size and shape calculation. A simple off-chip solenoid valve-based sorting actuation module was proposed to sort out target tumor spheroids with the desired size and shape. Utilizing the developed sorter, we successfully uncovered the drug response variations on cisplatin of lung tumor spheroids in the same population but with different sizes and shapes. Moreover, with this sorter, the precision of drug testing on the spheroid population level was improved to a level comparable to the precise but complex single spheroid analysis. The developed sorter also exhibits significant potential for organoid morphology and sorting for precision medicine research.