Azeliragon inhibits PAK1 and enhances the therapeutic efficacy of AKT inhibitors in pancreatic cancer.

Pancreatic cancer is a lethal malignancy for which there is currently no effective treatment strategy. We previously reported that p21-activated kinase 1 (PAK1) is aberrantly expressed in pancreatic cancer patients and that targeted inhibition of PAK1 significantly suppressed pancreatic cancer progression in vitro and in vivo. In this study, we identified the drug azeliragon as a novel inhibitor of PAK1. Cell experiments revealed that azeliragon abolished PAK1 activation and promoted apoptosis in pancreatic cancer cells. Azeliragon was also found to significantly inhibit tumor growth in a pancreatic cancer xenograft model; when combined with afuresertib, an oral pan-AKT kinase inhibitor, azeliragon exhibited a strong synergistic effect against pancreatic cancer cells. Interestingly, afuresertib enhanced the antitumor efficacy of azeliragon in a xenograft mouse model. Collectively, our findings revealed previously unreported aspects of the drug azeliragon, and identified a novel combination strategy for the treatment of pancreatic cancer patients.

Effect of high-flow nasal cannula oxygen therapy in combination with non-invasive ventilation on critically ill patients with acute respiratory failure: a retrospective study.

Background: Acute respiratory failure (ARF) is a respiratory disease in which ventilation dysfunction of the lungs occurs at rest due to various factors, resulting in oxygen deprivation and carbon dioxide (CO2) retention. In recent years, high-flow nasal cannula (HFNC), as a new type of oxygen therapy, has attracted increasing attention. Compared with traditional oxygen therapy, HFNC adopts nasal catheter to make it more in line with the physiological and respiratory characteristics of the human body, and thus can provide a higher and more constant inhalation of oxygen. This retrospective study was conducted to explore the clinical effect of HFNC combined with non-invasive ventilation (NIV) in the treatment of critically ill patients with ARF. Methods: A total of 532 critically ill patients with ARF treated in our hospital from January 2019 to December 2020 were screened for the suitability for being included in the study. Of these, 261 patients in this study received NIV. In total, 151 patients were included after applying the inclusion and exclusion criteria. NIV was generally given intermittently, and the daily duration of application was determined according to the patient's condition. The NIV-treated patients were assigned into two groups according to the oxygen inhalation mode during intermittent NIV: (I) standard group: normal oxygen inhalation was applied at the NIV interval; and (II) research group: patients treated with HFNC at the NIV interval. The respective basic data and outcome observation indices were collected. Results: In terms of the clinical outcome, the number of NIV treatment days in the research group was lower (P<0.05). At 30 min, 1 h, and 24 h after treatment, the partial pressure of arterial oxygen (PaO2), arterial oxygen saturation (SaO2), oxygenation index (P/F) indices in the research group were higher, while the CO2 partial pressure (PaCO2) was lower (P<0.05). Finally, the 28- and 90-day survival rates were compared between the groups and the results indicated no significant difference in the 28-day survival rates, but the 90-day survival rates of the research group were considerably higher (P<0.05). Conclusions: The use of HFNC combined with NIV to treat ARF in critically ill patients can effectively improve the ARF-related respiratory indicators in critically ill patients.

Natural Compound Shikonin Is a Novel PAK1 Inhibitor and Enhances Efficacy of Chemotherapy against Pancreatic Cancer Cells.

Shikonin is the main component of root extracts from the Chinese herbal medicine Lithospermum erythrorhizon, which is commonly used for the treatment of various diseases including cancer. Previous research showed that shikonin suppressed pancreatic cancer growth; nevertheless, its molecular targets and mechanisms have not been elucidated. This study aimed to investigate the interaction and regulatory mechanisms of shikonin on its potential target p21-activated kinase 1 (PAK1). Through a labchip-based screening method, shikonin was identified as a potential bioactive PAK1 inhibitor. Molecular docking technology was used to detect the interaction sites of shikonin and PAK1 kinase. Western blot was performed to validate the mechanism. MTT and flow cytometry were practiced to investigate the effect of shikonin against pancreatic cancer cells. The results show that shikonin significantly inhibited the activity of PAK1 kinase with IC50 value of 7.252 ± 0.054 µM. Molecular docking studies showed that shikonin binds to the ATP-binding pocket of the PAK1 kinase domain. Moreover, shikonin inhibited PAK1 activation and its downstream signaling pathway proteins, while reducing proliferation and inducing apoptosis of pancreatic cancer cells. Further studies showed that the treatment of shikonin sensitized pancreatic cancer cells to chemotherapeutic drugs. These results suggest that shikonin, a potential natural inhibitor targeting PAK1 kinase, has promising potent applications in the treatment of pancreatic cancer and chemotherapy sensitization.

Preliminary study of the effect of outpatient oxygen therapy on patients with chronic respiratory insufficiency receiving home oxygen therapy.

BACKGROUND: Chronic respiratory insufficiency is mainly the result of ventilatory dysfunction due to various causes, which results in decreased respiratory function. The most important cause of chronic respiratory insufficiency is chronic obstructive pulmonary disease, which has a high incidence and places a great burden on families and society. Therefore, it is important to find an effective treatment for this disease. METHODS: This study was a retrospective self-controlled study. Thirty-eight patients receiving home oxygen therapy who visited the outpatient oxygen therapy clinic from November 2020 to August 2021 were selected. After a comprehensive and systematic diagnosis and treatment, home oxygen therapy as standardized, and 38 patients were followed up for 6 months. Oxygen therapy compliance, the average daily oxygen therapy duration, arterial blood gas analysis, activities of daily living (ADL), and modified Medical Research Council Dyspnea Scale (mMRC) scores before and 6 months after outpatient oxygen therapy intervention were compared. The number of hospital visits for acute exacerbation of chronic respiratory insufficiency and the medical costs incurred within 6 months before and after the outpatient oxygen therapy intervention were also compared. RESULTS: After 6 months of outpatient oxygen therapy intervention, the compliance with oxygen therapy was significantly improved, the average daily oxygen therapy duration was significantly prolonged, the oxygen saturation (SaO2) and partial pressure of oxygen (PaO2) values were significantly increased, and the mMRC score was significantly decreased (P<0.05), while the differences in the ADL scores were not statistically significant (P>0.05). The number of hospital visits and the medical expenses due to acute exacerbation of chronic respiratory insufficiency within 6 months after the outpatient oxygen therapy intervention were significantly lower than those in the 6 months before the intervention (P<0.05). CONCLUSIONS: As a relatively new clinical service in China, outpatient oxygen therapy can improve the efficacy of home oxygen therapy for patients with chronic respiratory insufficiency through patient assessment, personalized selection of oxygen therapy equipment, and standardization of the implementation of home oxygen therapy. It provides an economically valuable treatment.

Analysis of Cardiac Ultrasound Images of Critically Ill Patients Using Deep Learning.

Cardiovascular disease remains a substantial cause of morbidity and mortality in the developed world and is becoming an increasingly important cause of death in developing countries too. While current cardiovascular treatments can assist to reduce the risk of this disease, a large number of patients still retain a high risk of experiencing a life-threatening cardiovascular event. Thus, the advent of new treatments methods capable of reducing this residual risk remains an important healthcare objective. This paper proposes a deep learning-based method for section recognition of cardiac ultrasound images of critically ill cardiac patients. A convolution neural network (CNN) is used to classify the standard ultrasound video data. The ultrasound video data is parsed into a static image, and InceptionV3 and ResNet50 networks are used to classify eight ultrasound static sections, and the ResNet50 with better classification accuracy is selected as the standard network for classification. The correlation between the ultrasound video data frames is used to construct the ResNet50 + LSTM model. Next, the time-series features of the two-dimensional image sequence are extracted and the classification of the ultrasound section video data is realized. Experimental results show that the proposed cardiac ultrasound image recognition model has good performance and can meet the requirements of clinical section classification accuracy.

The efficacy and safety of high-flow nasal cannula therapy in patients with COPD and type II respiratory failure: a meta-analysis and systematic review.

BACKGROUND: High-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) have been used for the treatment of COPD and respiratory failure in clinical settings. We aimed to evaluate the efficacy and safety of HFNC therapy in patients with COPD and type II respiratory failure, to provide evidence to the clinical COPD management. METHODS: We searched Cochrane et al. databases up to Dec 31, 2020 for randomized controlled trials (RCTs) on the use of HFNC therapy in patients with COPD and type II respiratory failure. Two researchers independently screened the literature according to the inclusion and exclusion criteria, and evaluated the quality of the literature and extracted data. We used Revman5.3 software for statistical analysis of collected data. RESULTS: A total of 6 RCTs involving 525 COPD and type II respiratory failure patients. Meta-analyses indicated that compared with NIV, HFNC could significantly reduce PaCO2 level (MD = - 2.64, 95% CI (- 3.12 to - 2.15)), length of hospital stay ((MD = - 1.19, 95 CI (- 2.23 to - 0.05)), the incidence of nasal facial skin breakdown ((OR = 0.11, 95% CI (0.03-0.41)). And there were no significant differences between the two groups in PaO2 ((MD = 2.92, 95% CI (- 0.05 to 5.90)), incidence of tracheal intubation ((OR = 0.74, 95% CI (0.34-1.59)) and mortality (OR = 0.77, 95% CI (0.28-2.11)). CONCLUSIONS: HFNC is more advantageous over NIV in the treatment of COPD and type II respiratory failure. Future studies with larger sample size and strict design are needed to further elucidate the role of HFNC in COPD and respiratory failure.

Identification of a novel PAK1 inhibitor to treat pancreatic cancer.

Pancreatic cancer is one of the most aggressive cancers with poor prognosis and a low 5-year survival rate. The family of P21-activated kinases (PAKs) appears to modulate many signaling pathways that contribute to pancreatic carcinogenesis. In this work, we demonstrated that PAK1 is a critical regulator in pancreatic cancer cell growth. PAK1-targeted inhibition is therefore a new potential therapeutic strategy for pancreatic cancer. Our small molecule screening identified a relatively specific PAK1-targeted inhibitor, CP734. Pharmacological and biochemical studies indicated that CP734 targets residue V342 of PAK1 to inhibit its ATPase activity. Further in vitro and in vivo studies elucidated that CP734 suppresses pancreatic tumor growth through depleting PAK1 kinase activity and its downstream signaling pathways. Little toxicity of CP734 was observed in murine models. Combined with gemcitabine or 5-fluorouracil, CP734 also showed synergistic effects on the anti-proliferation of pancreatic cancer cells. All these favorable results indicated that CP734 is a new potential therapeutic candidate for pancreatic cancer.

Changes in different organic matter fractions during conventional treatment and advanced treatment.

XAD-8 resin isolation of organic matter in water was used to divide organic matter into the hydrophobic and hydrophilic fractions. A pilot plant was used to investigate the change in both fractions during conventional and advanced treatment processes. The treatment of hydrophobic organics (HPO), rather than hydrophilic organicas (HPI), should carry greater emphasis due to HPO's higher trihalomethane formation potential (THMFP) and haloacetic acid formation potential (HAAFP). The removal of hydrophobic matter and its transmission into hydrophilic matter reduced ultimate DBP yield during the disinfection process. The results showed that sand filtration, ozonation, and biological activated carbon (BAC) filtration had distinct influences on the removal of both organic fractions. Additionally, the combination of processes changed the organic fraction proportions present during treatment. The use of ozonation and BAC maximized organic matter removal efficiency, especially for the hydrophobic fraction. In sum, the combination of pre-ozonation, conventional treatment, and O3-BAC removed 48% of dissolved organic carbon (DOC), 60% of HPO, 30% of HPI, 63% of THMFP, and 85% of HAAFP. The use of conventional treatment and O3-BAC without pre-ozonation had a comparable performance, removing 51% of DOC, 56% of HPO, 45% of HPI, 61% of THMFP, and 72% of HAAFP. The effectiveness of this analysis method indicated that resin isolation and fractionation should be standardized as an applicable test to help assess water treatment process efficiency.

Disinfection by-products and their precursors in a water treatment plant in North China: Seasonal changes and fraction analysis.

A one-year-long monitoring project was conducted to assay the concentrations of THMs, HAAs and their formation potential along the conventional process in a water treatment plant in North China. Subsequent investigations of organic matter fractionation and the contribution of the algae to the precursor were also conducted to trace the source of the DBPs. The results showed that the concentration of DBPs and their formation potential varied with the seasons. The highest concentrations of THMs and the highest HAAs formation potential, each almost 500 microg/L, were detected in autumn and the lowest were in spring, no more than 100 microg/L. Both organic matter and algae were found to be important DBP precursors. The hydrophobic acid fraction in dissolved organic matter has the highest formation potential for both THM and HAA. Algae contribute about 20% to 50% of the total formation potential during an algal bloom. The efficiency of each unit process for DBPs and precursors was also assayed. Unfortunately, the conventional drinking water treatment process is limited in its efficiency for precursor removal. The pre-chlorination and filtration process had a negative effect on DBP or precursor removal.

Waste water disinfection during SARS epidemic for microbiological and toxicological control.

OBJECTIVE: To evaluate the disinfection of wastewater in China. METHODS: During the SARS epidemic occurred in Beijing, a study of different disinfection methods used in the main local wastewater plants including means of chlorine, chlorine dioxide, ozone, and ultraviolet was carried out in our laboratory. The residual coliform, bacteria and trihalomethanes, haloacetic acids were determined after disinfection. RESULTS: Chlorine had fairly better efficiency on microorganism inactivation than chlorine dioxide with the same dosage. Formation of THMs and HAAs does not exceed the drinking water standard. UV irradiation had good efficiency on microorganism inactivation and good future of application in China. Organic material and ammonia nitrogen was found to be significant on inactivation and DBPs formation. CONCLUSION: Chlorine disinfection seems to be the best available technology for coliform and bacteria inactivation. And it is of fairly low toxicological hazard due to the transformation of monochloramine.

[Optimal process combination for control of disinfection by-products and precursors].

It is compared that the efficiency of control disinfection by-products and their precursors by sequential-chlorination disinfection and traditional free chlorination disinfection following different processes combination. Compared with traditional chlorination, sequeutial chlorination, i. e. short-term free chlorine plus chloramine disinfection can lower 35.8% - 77.0% of trihalomethane formation and 36.6% - 54.8% of haloacetic acids formation. Moreover, the poorer the influent quality is, the more advantages sequential chlorination disinfection have over free chlorination disinfection. The formation of trihalomethane and haloacetic acids by sequential chlorination following the simplest traditional process is even less than their formation by free chlorination following the most complex process, pre-ozonization plus traditional one and ozonization-active carbon process. The results show that ozonization-active carbon process and pre-ozonization have better efficiency on control of disinfection by-products and their precursors. We recommend that water plants apply the sequential chlorination disinfection and ozonization-active carbon process.