Suppression of NBS1 Upregulates CyclinB to Induce Olaparib Sensitivity in Ovarian Cancer.

Background: Deficiencies in DNA damage repair responses promote chemotherapy sensitivity of tumor cells. The Nibrin homolog encoding gene Nijmegen Breakage Syndrome 1 (NBS1) is a crucial component of the MRE11-RAD50-NBN complex (MRN complex) and is involved in the response to DNA double-strand breaks (DSBs) repair that has emerged as an attractive strategy to overcome tumor drug resistance, but the functional relationship between NBS1 regulated DNA damage repair and cell cycle checkpoints has not been fully elucidated. Methods: In this study, lentivirus-mediated RNAi was used to construct NBS1-downregulated cells. Flow cytometry, qPCR, and immunohistochemistry were used to explore the regulatory relationship between NBS1 and CyclinB in vivo and in vitro. Results: Our findings suggest that NBS1 deficiency leads to defective homologous recombination repair. Inhibition of NBS1 expression activates CHK1 and CyclinB signaling pathways leading to cell cycle arrest and sensitizes ovarian cancer cells to Olaparib treatment in vitro and in vivo. NBS1-deficient ovarian cancer cells tend to maintain sensitivity to chemotherapeutic drugs through activation of cell cycle checkpoints. Conclusions: NBS1 may be a potential therapeutic target for epithelial ovarian cancer as it plays a role in the regulation of the DNA damage response and cell cycle checkpoints. Suppression of NBS1 upregulates CyclinB to induce Olaparib sensitivity in ovarian cancer.

Sequential high-intensity focused ultrasound treatment combined with chemotherapy for inoperable pancreatic cancer: a retrospective analysis for prognostic factors and survival outcomes.

OBJECTIVE: To evaluate the effect of HIFU (High-Intensity Focused Ultrasound) therapy on the survival and prognosis of patients with inoperable pancreatic cancer, and the clinical application of serological prognostic indicators. METHODS: We retrospectively analyzed the clinicopathological features, laboratory tests and follow-ups of 192 patients. Among the patients, 57 were treated with HIFU prior to chemotherapy (HIFU-priority), and 135 patients received chemotherapy followed by HIFU (HIFU-second). Univariate and multivariate Cox regression analysis was used to determine the prognostic value of tumor inflammation-related serological markers. A nomogram model was established based on the identified prognostic factors. RESULTS: Univariate analysis showed that receiving the treatment regimen in HIFU-priority was a significant protective factor for overall survival (OS, p < 0.001). Tumor stage, high C-reactive protein (CRP), high gamma-glutamyl transferase(γGT) high carbohydrate antigen 125 (CA125), high neutrophil-to-lymphocyte ratio (NLR), high lymphocyte-to-monocyte ratio (LMR) and liver metastasis were significant risk factors for poor prognosis (p < 0.05). CRP combined with normal tumor marker CA125 (CRP + CA125) was associated with longer OS (p = 0.005). Multivariate analysis shows that HIFU-priority is a protective factor for OS (Hazard Ratio, HR: 0.38; 95% confidence interval(CI): 0.25-0.57), tumor stage (HR: 1.61; 95% CI: 1.12-2.31), CRP + CA125 (HR: 1.46; 95% CI: 1.02-2.08) and γGT (HR: 1.44; 95% CI: 1.04-1.98) are risk factors for OS and serve as independent prognostic factors in the nomogram. CONCLUSION: Early application of HIFU treatment improves the OS of patients with inoperable pancreatic cancer. CRP + CA125 and γGT are independent prognostic factors.

Lung Transplantation for Pulmonary Arterial Hypertension: Optimized Referral and Listing Based on an Evolving Disease Concept.

Pulmonary hypertension (PH) was once a devastating and fatal disease entity, the outlook of which has been significantly improved by the continued progress of medical treatment algorithms. However, some patients still ultimately fail to achieve an adequate clinical response despite receiving maximal medical treatment. Historically, lung transplantation (LTx) has been the only effective therapeutic option that could lead to satisfactory outcomes and save these advanced patients' lives. However, patients with PH tend to have the highest mortality rates on the transplant waiting list; especially after comprehensive medical treatment, they continue to deteriorate very rapidly, eventually missing optimal transplantation windows. Balancing optimized medical treatment with the appropriate timing of referral and listing has been highly controversial in LTx for patients with PH. The 2021 consensus document for the selection of lung transplant candidates from the International Society for Heart and Lung Transplantation (ISHLT) updated the specific recommendations for the LTx referral and listing time for patients with PH based on objective risk stratification. Herein, we review the evolving PH-related concepts and highlight the optimization of LTx referral and listing for patients with PH, as well as their management on the waiting list.

A New Type of Endometrial Cancer Models in Mice Revealing the Functional Roles of Genetic Drivers and Exploring their Susceptibilities.

Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing-based strategy to generate primary, orthotopic, and driver-defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid-initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high-throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.

Risk factors of aspiration occurrence with different feeding patterns in elderly intensive care unit patients: a cross-sectional study.

Background: Elderly intensive care unit (ICU) patients represent a high-risk group of aspiration. Different feeding patterns will lead to different incidences of aspiration. However, there are few studies on the risk factors of aspiration in elderly ICU patients under different feeding patterns. The aim of this study was to analyze the effects of different eating styles on the occurrence of overt and silent aspiration in elderly ICU patients and to compare the independent risk factors, in order to provide a basis for targeted aspiration prevention. Methods: We retrospectively analyzed the incidence of aspiration in elderly patients admitted to the ICU from April 2019 to April 2022, a total of 348 cases. The patients were divided into the oral feeding group, gastric tube feeding group, and post-pyloric feeding group according to their feeding method. Multi-factor logistic regression was used to analyze the independent risk factors for overt and silent aspiration caused by the different eating patterns of patients. Results: Among the 348 elderly ICU patients included, the overall incidence of aspiration was 72%, with a 22% rate of overt aspiration and a 49% rate of silent aspiration. The overt aspiration rates were 16%, 30%, and 21% in the oral, the gastric tube and the post-pyloric feeding group, respectively; while the silent aspiration rates were 52%, 55%, and 40% in the three groups, respectively. Multiple logistic regression analysis showed that the independent risk factors for both overt and silent aspiration were history of aspiration [odds ratio (OR) =0.075, P=0.004; OR =0.205, P=0.042] and gastrointestinal tumor (OR =0.100, P=0.028; OR =0.063, P=0.003) in the oral feeding group. In the gastric tube feeding group, the independent risk factor for both overt and silent aspiration was the history of aspiration (OR =4.038, P=0.040; OR =4.658, P=0.012). In the post-pyloric feeding group, the independent risk factors for both overt and silent aspiration were mechanical ventilation (OR =0.211, P=0.019; OR =0.336, P=0.037) and intra-abdominal hypertension (OR =0.225, P=0.020; OR =0.329, P=0.032). Conclusions: There were significant differences in the influencing factors and characteristics of aspiration among the elderly patients in the ICU with different feeding patterns. Personalized precautions should be implemented early, so as to reduce the possibility of aspiration.

Gap design to enable functionalities into nested antiresonant nodeless fiber based systems.

By modifying the interconnection design between standard single-mode fiber (SSMF) and nested antiresonant nodeless type hollow-core fiber (NANF), we create an air gap between SSMF and NANF. This air gap enables the insertion of optical elements, thus providing additional functions. We show low-loss coupling using various graded-index multimode fibers acting as mode-field adapters resulting in different air-gap distances. Finally, we test the gap functionality by inserting a thin glass sheet in the air gap, which forms a Fabry-Perot interferometer and works as a filter with an overall insertion loss of only 0.31 dB.

KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition.

KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX-5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition.

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment.

For coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 15-30% of patients are likely to develop COVID-19-related acute respiratory distress syndrome (ARDS). There are still few effective and well-understood therapies available. Novel variants and short-lasting immunity are posing challenges to vaccine efficacy, so finding antiviral and antiinflammatory treatments remains crucial. Here, tripterin (TP), a traditional Chinese medicine, was encapsulated into liposome (TP lipo) to investigate its antiviral and antiinflammatory effects in severe COVID-19. By using two severe COVID-19 models in human ACE2-transgenic (hACE2) mice, an analysis of TP lipo's effects on pulmonary immune responses was conducted. Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment. TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice, two crucial events in severe COVID-19 pathophysiology, it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.

Dissecting the genetic and microenvironmental factors of gastric tumorigenesis in mice.

Gastric cancer (GC) is one of the most frequent and lethal malignancies in the world. However, our understanding of the mechanisms underlying its initiation and progression is limited. Here, we generate a series of primary GC models in mice with genome-edited gastric organoids, which elucidate the genetic drivers for sequential transformation from dysplasia to well-differentiated and poorly differentiated GC. Further, we find that the orthotopic GC, but not the subcutaneous GC even with the same genetic drivers, display remote metastasis, suggesting critical roles of the microenvironment in GC metastasis. Through single-cell RNA-seq analyses and functional studies, we show that the interaction between fibronectin 1 on stomach-specific macrophages and integrin a6ß4 on GC cells promotes remote metastases. Taken together, our studies propose a strategy to model GC and dissect the genetic and microenvironmental factors driving the full-range gastric tumorigenesis.

Low loss and broadband low back-reflection interconnection between a hollow-core and standard single-mode fiber.

We report simultaneous low coupling loss (below 0.2 dB at 1550 nm) and low back-reflection (below -60 dB in the 1200-1600 nm range) between a hollow core fiber and standard single mode optical fiber obtained through the combination of an angled interface and an anti-reflective coating. We perform experimental optimization of the interface angle to achieve the best combination of performance in terms of the coupling loss and back-reflection suppression. Furthermore, we examine parasitic cross-coupling to the higher-order modes and show that it does not degrade compared to the case of a flat interface, keeping it below -30 dB and below -20 dB for LP11 and LP02 modes, respectively.

COPS5 Conferred the Platinum Resistance in Epithelial Ovarian Cancer.

Development of platinum resistance is one of the major causes of epithelial ovarian cancer (EOC) treatment failure. COP9 signalosome subunit 5 (COPS5) was found to take part in the progression of EOC in our previous study. Herein, we aim to uncover the potential utility of COPS5 in EOC chemoresistance. COPS5 levels were analyzed to define clinic pathologic correlates using a matched tissue microarray and online datasets. The effect of COPS5 inhibition by the lentivirus-mediated short hairpin RNA on cell viability, proliferation and migration was accessed in vitro and in vivo. Results showed that COPS5 was upregulated in patients after platinum resistance. Kaplan-Meier survival curves revealed that COPS5 overexpression was correlated with shorter PFS and OS. COPS5 downregulation inhibited the cell proliferation, migration, and reduced the sensitivity of EOC to platinum. Overall, our data indicated that COPS5 inhibition might represent a new therapeutic strategy for overcoming platinum resistance in patients with EOC.

Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.

Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.

Fabrication of alkali lignin-based emulsion electrospun nanofibers for the nanoencapsulation of beta-carotene and the enhanced antioxidant property.

For the greater utilization of ß-carotene in antioxidant material, ß-carotene-loaded emulsion stabilized by alkali lignin (AL) was successfully electrospinning with poly (vinyl alcohol) (PVA) (PVA/AL/ß-carotene nanofiber). Transmission electron microscopy demonstrated the core-shell structure of nanofiber with the average diameter being 356.31 nm, and 85.7 % of ß-carotene was effectively encapsulated into the core section. Fourier transform infrared spectra and differential scanning calorimetry revealed the good compatibility and decreased crystallinity of ß-carotene, favoring its stability and solubility, respectively. As expected, the PVA/AL/ß-carotene nanofiber exhibited higher antioxidant activity than free ß-carotene due to the protection of AL matrix and the special structure of nanofiber, as the DPPH free radical scavenging rate being 90.7 % at 7th day. The sustained release behavior of ß-carotene and AL from fiber followed Fickian diffusion model, contributing to the greater protection for fish oil than that of emulsion. Thus, this study provides an approach to develop hydrophobic compounds-loaded emulsion electrospun antioxidant material with controlled release property and enhanced activity.

Care Bundles plus Detailed Nursing on Mortality and Nursing Satisfaction of Patients with Septic Shock in ICU.

Objective: To evaluate the effect of care bundles combined with detailed nursing on the mortality and nursing satisfaction of patients with septic shock in the intensive care unit (ICU). Methods: Ninety patients with septic shock in the ICU admitted to our hospital from April 2019 to April 2020 were recruited and assigned to an experimental group and a control group via the random table method, with 45 cases in each group. The control group adopted conventional nursing, and the experimental group received care bundles combined with detailed nursing. The nursing effect, satisfaction, and mortality of the two groups were compared. The "Glasgow Coma Scale" (GCS) was used to evaluate the coma of the patients, the "Coma Recovery Scale" (CRS-R) was used to assess the state of consciousness of the patients, and the "Hospital Anxiety and Depression" (HAD) scale was used to evaluate the patient's emotional status before and after the intervention. Results: The experimental group showed a significantly higher nursing efficiency and better nursing satisfaction than the control group (P < 0.05). Lower mortality was found in the experimental group in contrast to the control group (P < 0.05). The experimental group had higher GCS scores and CRS-R scores and lower HAD scores than the control group (P < 0.05). Conclusion: Care bundles plus detailed nursing for patients with septic shock in the ICU improve the nursing effect and nursing satisfaction, reduce the mortality rate, and mitigate the clinical symptoms of patients, which shows great potential in clinical application and promotion.

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.

Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.

Identifying a confused cell identity for esophageal squamous cell carcinoma.

The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer. Here, we report that esophageal squamous cell carcinoma (ESCC) cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells, which we term as confused cell identity (CCI). CCI is an independent prognostic marker associated with poor prognosis in ESCC. Further, we identify tropomyosin 4 (TPM4) as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo. And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway. Thus, our study suggests an unrecognized feature of ESCC cells, which might be of value for clinic prognosis and potential interference.

Production, purification and characterization of a novel antithrombotic and anticoagulant serine protease from food grade microorganism Neurospora crassa.

A novel thrombolytic enzyme was produced by food grade microorganism Neurospora crassa using agro-industrial by-products as substrates. Process parameters were optimized using Plackett-Berman and Box-Benhken design. Under the optimized fermentation conditions, high fibrinolytic activity of 403.59 U/mL was obtained. It was purified with a specific activity of 3572.4 U/mg by ammonium sulfate precipitation and SP Sepharose chromatography. The molecular weight of the enzyme was approximately 32 kDa. It exhibited maximum activity at 40 °C and pH 7.4. Its activity was enhanced by Cu2+, Na+, Zn2+, and completely inhibited by phenylmethanesulfonyl fluoride, soybean trypsin inhibitor, aprotinin, which indicates it could be a serine protease. The enzyme could degrade fibrin clot directly without the need of plasminogen activator, and effectively cleaved Aα, Bß, γ chains of fibrinogen. It could inhibit the formation of blood clots in vitro and acts as an anticoagulant. Compared to heparin the purified enzyme showed extended anticoagulant activity. Blood clots were dissolved effectively and dissolution rate was increased with time. Based on these results, this novel enzyme has the potential to be developed as a thrombolytic agent.

A combined strategy of TK1, HE4 and CA125 shows better diagnostic performance than risk of ovarian malignancy algorithm (ROMA) in ovarian carcinoma.

BACKGROUND: The dual marker algorithm Risk of Ovarian Malignancy Algorithm (ROMA) has been widely used in the clinic for the identification of equivocal pelvic masses in ovarian carcinoma. To obtain higher diagnostic efficiency, we created a new diagnostic index, Risk of Ovarian Malignancy Index (ROMI), by combing thymidine kinase 1 (TK1), HE4 and CA125. METHODS: 335 patients with pelvic masses on imaging and 46 healthy controls were enrolled. Serum TK1 was analyzed before further study. ROMI and ROMA were evaluated for diagnostic efficiency. RESULTS: The level of TK1 was elevated in malignant ovarian tumors compared to benign masses (p < 0.001) and healthy controls (p < 0.001). TK1 expression was positively correlated with stage, intrapelvic metastasis, lymphatic metastasis and distant metastasis (all p values < 0.001). The area under the receiver operating characteristic curve (AUC) of ROMI was higher than that of ROMA for both pre- and postmenopausal women. ROMI had better sensitivity, specificity, accuracy, and positive and negative predictive values than ROMA in diagnosis of all-stage or stage I + II ovarian carcinoma for both pre- and postmenopausal women. CONCLUSIONS: TK1 is a potential biomarker in detection of ovarian carcinoma. ROMI shows better diagnostic performance than ROMA in distinguishing malignant ovarian tumors from benign masses.

SRT1720 inhibits the growth of bladder cancer in organoids and murine models through the SIRT1-HIF axis.

There are unmet clinical needs for novel therapeutic targets and drugs for bladder cancer. Majority of previous work relied on limited bladder cancer cell lines, which could not well represent the tumor heterogeneity and pathology of this disease. Recently, it has been shown that cancer organoids can recapitulate pathological and molecular properties of bladder cancer. Here, we report, by our knowledge, the first bladder cancer organoid-based small molecule screening for epigenetic drugs. We found that SRT1720, a Sirtuin 1 (SIRT1) activator, significantly inhibits the growth of both mouse and human bladder cancer organoids. And it also restrains the development of mouse in situ bladder cancer and human PDX bladder cancer. Mutation of Sirt1 promotes the growth of cancer organoids and decreases their sensitivity to SRT1720, which validate Sirt1 as the target of SRT1720 in bladder cancer. Mechanistically, SRT1720 treatment represses the hypoxia pathway through deacetylating HIF1α by activating Sirt1. Genetic or pharmaceutic inhibitions of HIF mimic the anti-tumor effect of SRT1720. Furthermore, the SIRT1-repressed gene signature is associated with the hypoxia target gene signature and poor prognosis in human bladder cancers. Thus, our study demonstrates the power of cancer organoid-based drug discovery and, in principle, identifies SRT1720 as a new treatment for bladder cancer.

Low loss and high performance interconnection between standard single-mode fiber and antiresonant hollow-core fiber.

We demonstrate halving the record-low loss of interconnection between a nested antiresonant nodeless type hollow-core fiber (NANF) and standard single-mode fiber (SMF). The achieved interconnection loss of 0.15 dB is only 0.07 dB above the theoretically-expected minimum loss. We also optimized the interconnection in terms of unwanted cross-coupling into the higher-order modes of the NANF. We achieved cross-coupling as low as -35 dB into the LP[Formula: see text] mode (the lowest-loss higher-order mode and thus the most important to eliminate). With the help of simulations, we show that the measured LP[Formula: see text] mode coupling is most likely limited by the slightly imperfect symmetry of the manufactured NANF. The coupling cross-talk into the highly-lossy LP[Formula: see text] mode ([Formula: see text] dB/km in our fiber) was measured to be below -22 dB. Furthermore, we show experimentally that the anti-reflective coating applied to the interconnect interface reduces the insertion loss by 0.15 dB while simultaneously reducing the back-reflection below -40 dB over a 60 nm bandwidth. Finally, we also demonstrated an alternative mode-field adapter to adapt the mode-field size between SMF and NANF, based on thermally-expanded core fibers. This approach enabled us to achieve an interconnection loss of 0.21 dB and cross-coupling of -35 dB into the LP[Formula: see text] mode.