Enhancing the Repair of Substantial Volumetric Muscle Loss by Creating Different Levels of Blood Vessel Networks Using Pre-Vascularized Nerve Hydrogel Implants.

Volumetric muscle loss (VML), a severe muscle tissue loss from trauma or surgery, results in scarring, limited regeneration, and significant fibrosis, leading to lasting reductions in muscle mass and function. A promising approach for VML recovery involves restoring vascular and neural networks at the injury site, a process not extensively studied yet. Collagen hydrogels have been investigated as scaffolds for blood vessel formation due to their biocompatibility, but reconstructing blood vessels and guiding innervation at the injury site is still difficult. In this study, collagen hydrogels with varied densities of vessel-forming cells are implanted subcutaneously in mice, generating pre-vascularized hydrogels with diverse vessel densities (0-145 numbers/mm2) within a week. These hydrogels, after being transplanted into muscle injury sites, are assessed for muscle repair capabilities. Results showed that hydrogels with high microvessel densities, filling the wound area, effectively reconnected with host vasculature and neural networks, promoting neovascularization and muscle integration, and addressing about 63% of the VML.

Engineering large and geometrically controlled vascularized nerve tissue in collagen hydrogels to restore large-sized volumetric muscle loss.

Developing scalable vascularized and innervated tissue is a critical challenge for the successful clinical application of tissue-engineered constructs. Collagen hydrogels are extensively utilized in cell-mediated vascular network formation because of their naturally excellent biological properties. However, the substantial increase in hydrogel contraction induced by populated cells limits their long-term use. Previous studies attempted to mitigate this issue by concentrating collagen pre-polymer solutions or synthesizing covalently crosslinked collagen hydrogels. However, these methods only partially reduce hydrogel contraction while hindering blood vessel formation within the hydrogels. To address this challenge, we introduced additional support in the form of a supportive spacer to counteract the contraction forces of populated cells and prevent hydrogel contraction. This approach was found to promote cell spreading, resist hydrogel contraction, control hydrogel/tissue geometry, and even facilitate the engineering of functional blood vessels and host nerve growth in just one week. Subsequently, implanting these engineered tissues into muscle defect sites resulted in timely anastomosis with the host vasculature, leading to enhanced myogenesis, increased muscle innervation, and the restoration of injured muscle functionality. Overall, this innovative strategy expands the applicability of collagen hydrogels in fabricating large vascularized nerve tissue constructs for repairing volumetric muscle loss (∼63 %) and restoring muscle function.

Reconstructing vascular networks promotes the repair of skeletal muscle following volumetric muscle loss by pre-vascularized tissue constructs.

Current treatment for complex and large-scale volumetric muscle loss (VML) injuries remains a limited success and have substantial disadvantages, due to the irreversible loss of muscle mass, slow muscle regeneration, and rapid formation of non-functional fibrosis scars. These VML injuries are accompanied by denervation and the destruction of native vasculature which increases difficulties in the functional restoration of muscle. Here, reconstruction of the vascular network at the injury site was offered as a possible solution for improving the repair of muscle defects through the timely supply of nutrients and oxygen to surrounding cells. A hydrogel-based tissue construct containing various densities of the vascular network was successfully created in the subcutaneous space of mice by manipulating hydrogel properties, and then implanted into the VML injury site. One month after implantation, the mouse treated with the highly vascularized tissue had extensive muscle repair at the injury site and only spent a shorter time completing the inclined plane tests. These findings suggest that the reconstruction of the functional vascular network at the VML injury site accelerated muscle fiber repair through a timely supply of sufficient blood and avoided invasion by host fibroblasts.

SOX1 Functions as a Tumor Suppressor by Repressing HES1 in Lung Cancer.

The development of lung cancer is a complex process that involves many genetic and epigenetic changes. Sex-determining region Y (SRY)-box (SOX) genes encode a family of proteins that are involved in the regulation of embryonic development and cell fate determination. SOX1 is hypermethylated in human cancers. However, the role of SOX1 in the development of lung cancer is unclear. We used quantitative methylation-specific polymerase chain reaction (MSP), quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, and web tools to confirm the frequent epigenetic silencing of SOX1 in lung cancer. Stable overexpression of SOX1 repressed cell proliferation, anchorage-independent growth, and invasion in vitro as well as cancer growth and metastasis in a xenograft mouse model. Knockdown of SOX1 by the withdrawal of doxycycline partly restored the malignant phenotype of inducible SOX1-expressing NSCLC cells. Next, we discovered the potential downstream pathways of SOX1 using RNA-seq analysis and identified HES1 as a direct target of SOX1 using chromatin immunoprecipitation (ChIP)-PCR. Furthermore, we performed phenotypic rescue experiments to prove that overexpression of HES1-FLAG in SOX1-expressing H1299 cells partly reversed the tumor-suppressive effect. Taken together, these data demonstrated that SOX1 acts as a tumor suppressor by directly inhibiting HES1 during the development of NSCLC.

Use artificial neural network to recommend the lumbar spinal endoscopic surgical corridor.

Objectives: The transforaminal and interlaminar approaches are the two main surgical corridors of full endoscopic lumbar surgery. However, there are no quantifying methods for assessing the best surgical approach for each patient. This study aimed to establish an artificial intelligence (AI) model using an artificial neural network (ANN). Materials and Methods: Patients who underwent full endoscopic lumbar spinal surgery were enrolled in this research. Fourteen pre-operative factors were fed into the ANN. A three-layer deep neural network was constructed. Patient data were divided into the training, validation, and testing datasets. Results: There were 899 patients enrolled. The accuracy of the training, validation, and test datasets were 87.3%, 85.5%, and 85.0%, respectively. The positive predictive values for the transforaminal and interlaminar approaches were 85.1% and 89.1%, respectively. The area under the curve of the receiver operating characteristic was 0.91. The SHapley Additive exPlanations algorithm was utilized to explain the relative importance of each factor. The surgical lumbar level was the most important factor, followed by herniated disc localization and migrating disc zone level. Conclusion: ANN can effectively learn from the choice of an experienced spinal endoscopic surgeon and can accurately predict the appropriate surgical approach.

Dynamic patterns of microRNA expression during acute myeloid leukemia state-transition.

MicroRNAs (miRNAs) have been shown to hold prognostic value in acute myeloid leukemia (AML); however, the temporal dynamics of miRNA expression in AML are poorly understood. Using serial samples from a mouse model of AML to generate time-series miRNA sequencing data, we are the first to show that the miRNA transcriptome undergoes state-transition during AML initiation and progression. We modeled AML state-transition as a particle undergoing Brownian motion in a quasi-potential and validated the AML state-space and state-transition model to accurately predict time to AML in an independent cohort of mice. The critical points of the model provided a framework to align samples from mice that developed AML at different rates. Our mathematical approach allowed discovery of dynamic processes involved during AML development and, if translated to humans, has the potential to predict an individual's disease trajectory.

Strategy for improving cell-mediated vascularized soft tissue formation in a hydrogen peroxide-triggered chemically-crosslinked hydrogel.

The physically-crosslinked collagen hydrogels can provide suitable microenvironments for cell-based functional vascular network formation due to their biodegradability, biocompatibility, and good diffusion properties. However, encapsulation of cells into collagen hydrogels results in extensive contraction and rapid degradation of hydrogels, an effect known from their utilization as a pre-vascularized graft in vivo. Various types of chemically-crosslinked collagen-based hydrogels have been successfully synthesized to decrease volume contraction, retard the degradation rate, and increase mechanical tunability. However, these hydrogels failed to form vascularized tissues with uniformly distributed microvessels in vivo. Here, the enzymatically chemically-crosslinked collagen-Phenolic hydrogel was used as a model to determine and overcome the difficulties in engineering vascular networks. Results showed that a longer duration of inflammation and excessive levels of hydrogen peroxide limited the capability for blood vessel forming cells-mediated vasculature formation in vivo. Lowering the unreacted amount of crosslinkers reduced the densities of infiltrating host myeloid cells by half on days 2-4 after implantation, but blood vessels remained at low density and were mainly located on the edge of the implanted constructs. Co-implantation of a designed spacer with cell-laden hydrogel maintained the structural integrity of the hydrogel and increased the degree of hypoxia in embedded cells. These effects resulted in a two-fold increase in the density of perfused blood vessels in the hydrogel. Results agreed with computer-based simulations. Collectively, our findings suggest that simultaneous reduction of the crosslinker-induced host immune response and increase in hypoxia in hydrogen peroxide-triggered chemically-crosslinked hydrogels can effectively improve the formation of cell-mediated functional vascular networks.

Viscous Fingering as a Rapid 3D Pattering Technique for Engineering Cell-Laden Vascular-Like Constructs.

Tissues are much larger than the diffusion limit distance, so rapidly providing blood vessels to supply embedded cells inside tissues with sufficient nutrients and oxygen is regarded as a major strategy for the success of bioengineered large and thick tissue constructs. Here, a patterning technique, viscous fingering, is developed to bioengineer vascularized-like tissues within a few minutes. By controlling viscosity, flow rate, and the volume of photo-cross-linkable prepolymer, macro- and microscale vascular network structures can be precisely engineered using the Hele-Shaw cell that is designed in this study. After cross-linking, a vascular-like gel with fingering structures is formed between the bottom and top base gels, creating a sandwich-like structure. Cells can be incorporated into the fingers, bases, or both gels. The spreading and growth direction of the embedded cells are successfully controlled and guided by manipulating the physical properties of the fingering and base gels individually. Moreover, fingering is generated, connected, and surrounded prepared cell-laden microgels in base prepolymers to form prevascularized tissue-like constructs. Taken together, the 3D cell patterning technique extends the potential for modeling and fabricating large and stackable vascularized tissue-like constructs for both ex vivo and in vivo applications.

A strategy to engineer vascularized tissue constructs by optimizing and maintaining the geometry.

The success of engineered tissues is limited by the need for rapid perfusion of a functional vascular network that can control tissue engraftment and promote survival after implantation. Diabetic conditions pose an additional challenge, because high glucose and lipid concentrations cause an aggressive oxidative environment that impairs vessel remodeling and stabilization and impedes integration of engineered constructs into surrounding tissues. Thus, to achieve rapid vasculogenesis, angiogenesis, and anastomosis, hydrogels incorporating cells in their structure have been developed to facilitate formation of functional vascular networks within implants. However, their transport diffusivity decreases with increasing thickness, preventing the formation of a thick vascularized tissue. To address this, we used diffusion-based computational simulations to optimize the geometry of hydrogel structures. The results show that the micro-patterned constructs improved diffusion, thus supporting cell viability, and spreading while retaining their mechanical properties. Thick cell-laden bulk, linear, or hexagonal infill patterned hydrogels were implanted; and structural stability due to skin mobility was improved by the protective spacer. Larger and thicker perfused vascular networks formed in the hexagonal structures (∼17 mm diameter, ∼1.5 mm thickness) in both normal and diabetic mice on day 3, and they became functional and uniformly distributed on day 7. Moreover, transplanted islets were rapidly integrated subcutaneously in this engineered functional vascular bed, which significantly enhanced islet viability and insulin secretion. In summary, we developed a promising strategy for generating large, thick vascularized tissue constructs, which may support transplanted islet cells. These constructs showed potential for engineering other vascularized tissues in regenerative therapy. STATEMENT OF SIGNIFICANCE: Diffusion-based computational simulations were used to optimize the geometry of hydrogel structures, i.e., hexagonal cell-laden hydrogels. To maintain the hydrogel's structural integrity, a spacer was designed and co-implanted subcutaneously to increase the permeability of explants. The spacer provides the structural integrity to improve the permeability of the implanted hydrogel. Otherwise, the implanted hydrogel may be easily squeezed and deformed by compression from the skin mobility of mice. Here, we successfully developed a cell-based strategy for rapidly generating large, functional vasculature (diameter ∼17 mm and thickness ∼1.5 mm) in both normal and diabetic mice and demonstrated its advantages over currently available methods in a clinically-relevant animal model. This concept could serve as a basis for engineering and repairing other tissues in animals.

Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance.

Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML.

Sonographic septation: a useful diagnostic predictor of complicated parapneumonic effusion.

Sonographic septation is associated with prolonged hospitalization and increased mortality in patients diagnosed with empyema. However, it is unknown whether sonographic septation is associated with complicated parapneumonic effusion (CPPE) or the need for invasive procedures among patients with pneumonia. In this retrospective study, we included 180 patients with non-purulent neutrophilic exudative pleural effusion secondary to pulmonary infections such as pneumonia and lung abscess. We performed univariate and multivariate logistic regression analyses, including baseline clinical characteristics, values from blood samples, and sonographic echogenicity, to identify variables correlated with CPPE and the need for invasive procedures. Seventy of the 180 included patients (38.89%) displayed sonographic septation. Multivariate logistic regression analysis identified that sonographic septation (adjusted OR (AOR)=3.38 (95% CI 1.64 to 6.98), p=0.001) and younger age (AOR=2.63 (95% CI 1.24 to 5.58), p=0.012) were independently associated with CPPE. With regard to treatment strategy, sonographic septation (AOR 9.06 (95% CI 3.71 to 22.11), p<0.001) and total serum protein level (AOR=1.80 (95% CI 1.13 to 2.86), p=0.013) were independently associated with the need for subsequent invasive procedures in patients with CPPE using multivariate logistic regression analysis. Sonographic septation is a useful predictor of CPPE and may imply the need for early invasive procedures.

Dynamically and Spatially Controllable Albumin-Based Hydrogels for the Prevention of Postoperative Adhesion.

Since the degree of severity and the geometry of wounds vary, it is necessary to prepare an antiadhesive hydrogel that possesses dynamically controllable material properties, exhibits biodegradability, and possesses drug-releasing properties. Injectable, oxygen peroxide-sensitive, and photo-cross-linkable hydrogels that permit in situ dynamic and spatial control of their physicochemical properties were synthesized for the prevention of postoperative adhesion. Albumin is the most abundant protein in blood serum and serves as a carrier for several molecules that exhibit poor water solubility. It is therefore a suitable biomaterial for the fabrication of hydrogels since it presents a low risk of life-threatening complications and does not require immunosuppressive therapy for preventing graft rejection. The physicochemical properties of this hydrogel can then be spatially postadjusted via transdermal exposure to light to release drugs, depending on what is required for the injury. A significant reduction in postoperative peritoneal adhesion was observed in an animal model involving severe sidewall and bowel abrasions. This study demonstrated that the fabricated dually cross-linked, albumin-based hydrogels have great potential in such applications because they showed a low immune response, easy handling, full wound coverage, and tunable biodegradability. Precise spatial and controllable drug-release profiles may also be achieved via in situ transdermal post-tuning of the biomaterials, depending on the injury.

Comprehensive Comparisons among Inotropic Agents on Mortality and Risk of Renal Dysfunction in Patients Who Underwent Cardiac Surgery: A Network Meta-Analysis of Randomized Controlled Trials.

Several kinds of inotropes have been used in critically ill patients to improve hemodynamics and renal dysfunction after cardiac surgery; however, the treatment strategies for reducing mortality and increasing renal protection in patients who underwent cardiac surgery remain controversial. Therefore, we performed a comprehensive network meta-analysis to overcome the lack of head-to-head comparisons. A systematic database was searched up to 31 December 2020, for randomized controlled trials that compared different inotropes on mortality outcomes and renal protective effects after cardiac surgery. A total of 29 trials were included and a frequentist network meta-analysis was performed. Inconsistency analyses, publication bias, and subgroup analyses were also conducted. Compared with placebo, use of levosimendan significantly decreased the risks of mortality (odds ratio (OR): 0.74; 95% confidence interval (CI): 0.56-0.97) and risk of acute renal injury (OR: 0.61; 95% CI: 0.45-0.82), especially in low systolic function patients. Use of levosimendan also ranked the best treatment based on the P-score (90.1%), followed by placebo (64.5%), milrinone (49.6%), dopamine (49.5%), dobutamine (29.1%), and fenoldopam (17.0%). Taking all the available data into consideration, levosimendan was a safe renal-protective choice for the treatment of patients undergoing cardiac surgery, especially for those with low systolic function.

A Crucial Role of Mitochondrial Dynamics in Dehydration Resistance in Saccharomyces cerevisiae.

Mitochondria are dynamic organelles as they continuously undergo fission and fusion. These dynamic processes conduct not only mitochondrial network morphology but also activity regulation and quality control. Saccharomyces cerevisiae has a remarkable capacity to resist stress from dehydration/rehydration. Although mitochondria are noted for their role in desiccation tolerance, the mechanisms underlying these processes remains obscure. Here, we report that yeast cells that went through stationary growth phase have a better survival rate after dehydration/rehydration. Dynamic defective yeast cells with reduced mitochondrial genome cannot maintain the mitochondrial activity and survival rate of wild type cells. Our results demonstrate that yeast cells balance mitochondrial fusion and fission according to growth conditions, and the ability to adjust dynamic behavior aids the dehydration resistance by preserving mitochondria.

CDC25B induces cellular senescence and correlates with tumor suppression in a p53-dependent manner.

The phosphatase cell division cycle 25B (Cdc25B) regulates cell cycle progression. Increased Cdc25B levels are often detected in cancer cell lines and human cancers and have been implicated in contributing to tumor growth, potentially by providing cancer cells with the ability to bypass checkpoint controls. However, the specific mechanism by which increased Cdc25B impacts tumor progression is not clear. Here we analyzed The Cancer Genome Atlas (TCGA) database and found that patients with high CDC25B expression had the expected poor survival. However, we also found that high CDC25B expression had a p53-dependent tumor suppressive effect in lung cancer and possibly several other cancer types. Looking in more detail at the tumor suppressive function of Cdc25B, we found that increased Cdc25B expression caused inhibition of cell growth in human normal fibroblasts. This effect was not due to alteration of specific cell cycle stage or inhibition of apoptosis, nor by induction of the DNA damage response. Instead, increased CDC25B expression led cells into senescence. We also found that p53 was required to induce senescence, which might explain the p53-dependent tumor suppressive function of Cdc25B. Mechanistically, we found that the Cdc25B phosphatase activity was required to induce senescence. Further analysis also found that Cdc25B stabilized p53 through binding and dephosphorylating p53. Together, this study identified a tumor-suppressive function of Cdc25B that is mediated through a p53-dependent senescence pathway.

Surgical outcomes of full endoscopic spinal surgery for lumbar disc herniation over a 10-year period: A retrospective study.

OBJECTIVE: Full endoscopic lumbar discectomy (FELD) for lumbar disc herniation (LDH) has become popular in recent years. Previous studies have proven the efficacy, but few have discussed the possible risk factors of poor outcome. In this study, we reviewed patients who underwent FELD at Changhua Christian Hospital in the past 10 years and sought to identify factors associated with poor surgical outcomes and re-operations. METHODS: We retrospectively reviewed records from mid-2009 to mid-2018. Patients had undergone FELD and follow-up for ≥1 year were included. Factors included in the outcome evaluations were age, sex, surgical time, body mass index, surgical methods, disc herniation type, extension of herniation, degree of canal compromised, disc degenerative grade, smoking and alcohol use, surgical lumbar level, symptom duration, Oswestry low back disability index, and visual analog scale score. We had evolved from inside-out methods to outside-in methods after 2016, thus, we included this factor in the analysis. The primary outcomes of interest were poor/fair MacNab score and re-operation. RESULTS: From mid-2009 to mid-2018, 521 patients met our criteria and were analyzed. The median follow-up was 1685 days (range, 523-3923 days). Thirty-one (6.0%) patients had poor surgical outcomes (fair/poor MacNab score) and 45 (8.6%) patients required re-operation. Prolapsed herniated disc (P < 0.001), higher disc degenerative grade (P = 0.047), higher lumbar level (P = 0.026), longer preoperative symptoms (P < 0.001), and surgery before 2017 (outside-in technique, P = 0.020) were significant factors associated with poor outcomes in univariate analyses. In multivariate analyses, prolapsed herniated disc (P < 0.001), higher disc degenerative grade (P = 0.030), and higher lumbar level (P = 0.046) were statistically significant. The most common adverse symptom was numbness. Factors possibly associated with higher re-operation rate were older age (P = 0.045), alcohol use (P = 0.073) and higher lumbar level (P = 0.069). Only alcohol use showed statistically significant re-operation rates in multivariate analyses (P = 0.035). CONCLUSIONS: For treating LDH by FELD, we concluded that prolapsed disc, higher disc degenerative grade, higher lumbar level, and longer preoperative symptom duration were possibly associated with unsatisfactory surgical outcomes (poor/fair MacNab score). The outside-in technique might be superior to the inside-out technique. Older age and alcohol use might be associated with a higher re-operation rate.

Impact of meteorological conditions and air pollution on COVID-19 pandemic transmission in Italy.

Italy was the first, among all the European countries, to be strongly hit by the COVID-19 pandemic outbreak caused by the severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2). The virus, proven to be very contagious, infected more than 9 million people worldwide (in June 2020). Nevertheless, it is not clear the role of air pollution and meteorological conditions on virus transmission. In this study, we quantitatively assessed how the meteorological and air quality parameters are correlated to the COVID-19 transmission in two large metropolitan areas in Northern Italy as Milan and Florence and in the autonomous province of Trento. Milan, capital of Lombardy region, it is considered the epicenter of the virus outbreak in Italy. Our main findings highlight that temperature and humidity related variables are negatively correlated to the virus transmission, whereas air pollution (PM2.5) shows a positive correlation (at lesser degree). In other words, COVID-19 pandemic transmission prefers dry and cool environmental conditions, as well as polluted air. For those reasons, the virus might easier spread in unfiltered air-conditioned indoor environments. Those results will be supporting decision makers to contain new possible outbreaks.

Suprapedicular Retrocorporeal Technique of Transforaminal Full-Endoscopic Lumbar Discectomy for Highly Downward-Migrated Disc Herniation.

OBJECTIVE: Anatomical barriers (e.g., pedicles, narrow foramina) can hinder direct access to, and removal of, disc fragments that have migrated far downward. Using transforaminal full-endoscopic lumbar discectomy (FELD), we devised a modified technique, the suprapedicular retrocorporeal approach, for herniations in which the disc has migrated to the axilla of the traversing nerve roots. In the present report, we have described our preliminary results. METHODS: Soft, highly downward-migrated disc herniation was treated with transforaminal FELD through the suprapedicular retrocorporeal approach in 22 patients from June 2017 to May 2019. The clinical outcomes were evaluated, including the preoperative and postoperative visual analog scale scores for the back and leg, Oswestry disability index, and MacNab criteria for surgical success. RESULTS: The affected discs were at L4-L5 in 14 patients, L3-L4 in 6 patients, and L5-S1 in 2 patients. In each case, the affected disc was successfully removed using the suprapedicular retrocorporeal approach. The mean follow-up was 18.1 ± 5.7 months. The mean visual analog scale scores for back and leg pain improved significantly (P < 0.05 for both). The mean Oswestry disability index had decreased from 62.5 ± 14.2 preoperatively to 10.5 ± 5.9 postoperatively (P < 0.05). Using the MacNab criteria, 13 patients reported excellent outcomes and 9, good outcomes. No complications or recurrence developed during follow-up. CONCLUSIONS: The suprapedicular retrocorporeal technique is a feasible and effective surgical option in transforaminal FELD for the treatment of herniation in which the disc has migrated to the axilla of the traversing nerve roots.

Long-range air pollution transport in East Asia during the first week of the COVID-19 lockdown in China.

Long-range transport (LRT) of air pollutants from East Asia during the northeast monsoon season impacts several downwind locations. In 2020, the initial COVID-19 lockdowns in China overlapped with Week 3 of the Chinese New Year (CNY) holiday, and an Asian outflow event. Thus, movement of the Chinese populace from city to city was already greatly reduced by the time of the LRT episode, although the reductions in industrial output are less clear. We found NO2 column concentrations were reduced by 24% during the CNY Week 3 this year compared to previous years. The attenuated transport event arrived to northern Taiwan with a PM2.5 concentration <45 µg m-3 and most often <35 µg m-3, which is 2-3 times lower than LRT episodes of similar back-trajectory and synoptic patterns. The whole episode persisted for about 60 h, longer than most LRT episodes from China to Taiwan. CMAQ v5.2.1 modeling of the LRT event with 100% emission and reduced emission scenarios, revealed emissions in China were approximately 50% less than normal periods. Due to the length of the episode and the significant reduction in emissions, Taiwan avoided a PM2.5 surplus of 19.2 µg m-3 on average during the episode, equivalent to a 0.5 µg m-3 reduction for the whole 3-month winter season. Employing the 100% emission model scenario and scaling up to the average episode hours each winter, the PM2.5 surplus delivered via plumes on the northeast monsoon is equivalent to a 0.5 µg m-3 surplus for the whole year.

Synthesis and biological evaluation of thiophenylbenzofuran derivatives as potential P-glycoprotein inhibitors.

P-Glycoprotein (P-gp) overexpression is a major mechanism by which cancer cells acquire the multidrug resistance (MDR) phenotype, and is associated with poor clinical outcome in patients. In an effort to develop MDR-reversal agents, we synthesized and evaluated a series of thiophenylbenzofuran derivatives (4-31) as P-gp inhibitors, among which compounds 4, 10, and 14 represented the optimal agent in reversing the MDR phenotype. These P-gp inhibitors were dramatically effective than verapamil in sensitizing the human ABCB1-overexpressing ABCB1/Flp-In™-293 cells and MDR KBvin cells to a series of chemotherapeutic agents, including vincristine and paclitaxel, as manifested by multi-fold decreases in the respective IC50 values to therapeutically attainable levels.