S309-CAR-NK cells bind the Omicron variants in vitro and reduce SARS-CoV-2 viral loads in humanized ACE2-NSG mice.

Recent progress on chimeric antigen receptor (CAR)-NK cells has shown promising results in treating CD19-positive lymphoid tumors with minimal toxicities [including graft versus host disease (GvHD) and cytokine release syndrome (CRS) in clinical trials. Nevertheless, the use of CAR-NK cells in combating viral infections has not yet been fully explored. Previous studies have shown that CAR-NK cells expressing S309 single-chain fragment variable (scFv), hereinafter S309-CAR-NK cells, can bind to SARS-CoV-2 wildtype pseudotyped virus (PV) and effectively kill cells expressing wild-type spike protein in vitro. In this study, we further demonstrate that the S309-CAR-NK cells can bind to different SARS-CoV-2 variants, including the B.1.617.2 (Delta), B.1.621 (Mu), and B.1.1.529 (Omicron) variants in vitro. We also show that S309-CAR-NK cells reduce virus loads in the NOD/SCID gamma (NSG) mice expressing the human angiotensin-converting enzyme 2 (hACE2) receptor challenged with SARS-CoV-2 wild-type (strain USA/WA1/2020). Our study demonstrates the potential use of S309-CAR-NK cells for inhibiting infection by SARS-CoV-2 and for the potential treatment of COVID-19 patients unresponsive to otherwise currently available therapeutics. IMPORTANCE: Chimeric antigen receptor (CAR)-NK cells can be "off-the-shelf" products that treat various diseases, including cancer, infections, and autoimmune diseases. In this study, we engineered natural killer (NK) cells to express S309 single-chain fragment variable (scFv), to target the Spike protein of SARS-CoV-2, hereinafter S309-CAR-NK cells. Our study shows that S309-CAR-NK cells are effective against different SARS-CoV-2 variants, including the B.1.617.2 (Delta), B.1.621 (Mu), and B.1.1.529 (Omicron) variants. The S309-CAR-NK cells can (i) directly bind to SARS-CoV-2 pseudotyped virus (PV), (ii) competitively bind to SARS-CoV-2 PV with 293T cells expressing the human angiotensin-converting enzyme 2 (hACE2) receptor (293T-hACE2 cells), (iii) specifically target and lyse A549 cells expressing the spike protein, and (iv) significantly reduce the viral loads of SARS-CoV-2 wild-type (strain USA/WA1/2020) in the lungs of NOD/SCID gamma (NSG) mice expressing hACE2 (hACE2-NSG mice). Altogether, the current study demonstrates the potential use of S309-CAR-NK immunotherapy as an alternative treatment for COVID-19 patients.

Structure Evolution of Iron (Hydr)oxides under Nanoconfinement and Its Implication for Water Treatment.

In the development of nanoenabled technologies for large-scale water treatment, immobilizing nanosized functional materials into the confined space of suitable substrates is one of the most effective strategies. However, the intrinsic effects of nanoconfinement on the decontamination performance of nanomaterials, particularly in terms of structural modulation, are rarely unveiled. Herein, we investigate the structure evolution and decontamination performance of iron (hydr)oxide nanoparticles, a widely used material for water treatment, when confined in track-etched (TE) membranes with channel sizes varying from 200 to 20 nm. Nanoconfinement drives phase transformation from ferrihydrite to goethite, rather than to hematite occurring in bulk systems, and the increase in the nanoconfinement degree from 200 to 20 nm leads to a significant drop in the fraction of the goethite phase within the aged products (from 41% to 0%). The nanoconfinement configuration is believed to greatly slow down the phase transformation kinetics, thereby preserving the specific adsorption of ferrihydrite toward As(V) even after 20-day aging at 343 K. This study unravels the structure evolution of confined iron hydroxide nanoparticles and provides new insights into the temporospatial effects of nanoconfinement on improving the water decontamination performance.

Bilateral Pectoralis Major Muscle Flaps in Treating Deep Sternal Wound Infection following CABG in Diabetic Patients: Two Case Reports.

Deep sternal wound infection (DSWI) is a life-threatening complication after cardiac operations, especially after coronary artery bypass grafting (CABG) in diabetic patients. Bilateral pectoralis major muscle flaps have been performed to treat DSWI. Two diabetic patients suffering from DSWI after CABG were treated by bilateral pectoralis major muscle flaps in our hospital. Both patients were discharged with full recovery. Satisfactory results can be obtained with bilateral pectoralis major muscle flaps following tissue debridement and drainage. This procedure should be performed when DSWI occurs in diabetic patients after CABG.

MALT1 Positively Relates to T Helper 1 and T Helper 17 cells, and Serves as a Potential Biomarker for Predicting 30-Day Mortality in Stanford Type A Aortic Dissection Patients.

Mucosa-associated lymphoid tissue 1 (MALT1) regulates inflammation and T helper (Th) cell differentiation, which may participate in the progression of Stanford type A aortic dissection (TAAD). This study intended to assess the association of MALT1 expression with prognosis in TAAD patients. In this prospective study, MALT1 expression was measured by reverse transcription-quantitative polymerase chain reaction assay from peripheral blood samples in 100 TAAD patients and 100 non-AD controls (non-AD patients with chest pain) before treatment. Besides, Th1, Th2, and Th17 cells of TAAD patients before treatment were measured by flow cytometry assay, and their 30-day mortality was recorded. MALT1 expression was ascended in TAAD patients vs. non-AD controls (P < 0.001). In TAAD patients, elevated MALT1 expression was linked with hypertension complication (P = 0.009), increased systolic blood pressure (r = 0.291, P = 0.003), C-reactive protein (CRP) (r = 0.286, P = 0.004), and D-dimer (r = 0.359, P < 0.001). Additionally, MALT1 expression was positively correlated with Th1 cells (r = 0.312, P = 0.002) and Th17 cells (r = 0.397, P < 0.001), but not linked with Th2 cells (r = -0.166, P = 0.098). Notably, the 30-day mortality of TAAD patients was 28.0%. MALT1 expression [odds ratio (OR) = 1.936, P = 0.004], CRP (OR = 1.108, P = 0.002), D-dimer (OR = 1.094, P = 0.003), and surgery timing (emergency vs. selective) (OR = 8.721, P = 0.024) independently predicted increased risk of death within 30 days in TAAD patients. Furthermore, the combination of the above-mentioned independent factors had an excellent ability in predicting 30-day mortality with the area under curve of 0.949 (95% confidence interval: 0.909-0.989). MALT1 expression relates to increased Th1 cells, Th17 cells, and 30-day mortality risk in TAAD patients.

[ST266 inhibits neointimal hyperplasia after arterial balloon injury in rats].

Objective    To examine the effect of Human Amnion-Derived Multipotent Progenitor (AMP) cells and their novel ST266 secretome on neointimal hyperplasia after arterial balloon injury in rats.Material and Methods    Sprague-Dawley male rats were randomly divided into four groups (n=7): Control (PBS) group, systemic ST266 group, systemic AMP group and local AMP implant group. Neointimal hyperplasia was induced in the iliac using a 2F Fogarty embolectomy catheter. After surgery, the rats in the ST266 group were treated with 0.1, 0.5, or 1ml ST266 iv daily. In the systemic AMP groups, a single dose (SD) of 0.5 ×106 or 1×106 AMP cells was injected via the inferior vena cava after arterial balloon injury. In local AMP implant groups, 1×106, 5×106, or 20×106 AMP cells were implanted in 300 µl Matrigel (Mtgl) around the iliac artery after balloon injury. The iliac arteries were removed for histologic analysis at 28 days after the surgery. Re-endothelialization index was measured at 10 days after balloon injury.Results    ST266 (1 ml) group had a lower level of the Neointima / Neointima+Media ratio (N / N+M) 0.3±0.1 vs 0.5±0.1, p=0.004) and luminal stenosis (LS) percentage (18.2±1.9 % vs 39.2±5.8 %, p=0.008) compared with the control group. Single-dose AMP (1×106) decreased LS compared to the control group (19.5±5.4 % vs 39.2±5.8 %, p=0.033). Significant reduction in N / N+M were found between implanted AMPs (20×106) and the control group (0.4±0.1 vs 0.5±0.1, p=0.003) and the Mtgl-only group (0.5±0.1, p=0.007). Implanted AMPs (20×106) decreased the LS compared with both the control (39.2±5.8 %, p=0.001) and Mtgl-only group (37.5±8.6 %, p=0.016). ST266 (1 ml) significantly increased the re-endothelialization index compared to the control (0.4±0.1 vs 0.1±0.1, p=0.002).Conclusion    ST266 and AMP cells reduce neointimal formation and increase the re-endothelialization index after arterial balloon injury. ST266 is potentially a novel, therapeutic agent to prevent vascular restenosis in human.

Identification of sitagliptin binding proteins by affinity purification mass spectrometry.

Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with increasing incidence. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin has been used for the treatment of T2DM worldwide. Although sitagliptin has excellent therapeutic outcome, adverse effects are observed. In addition, previous studies have suggested that sitagliptin may have pleiotropic effects other than treating T2DM. These pieces of evidence point to the importance of further investigation of the molecular mechanisms of sitagliptin, starting from the identification of sitagliptin-binding proteins. In this study, by combining affinity purification mass spectrometry (AP-MS) and stable isotope labeling by amino acids in cell culture (SILAC), we discover seven high-confidence targets that can interact with sitagliptin. Surface plasmon resonance (SPR) assay confirms the binding of sitagliptin to three proteins, i. e., LYPLAL1, TCP1, and CCAR2, with binding affinities (K D) ranging from 50.1 µM to 1490 µM. Molecular docking followed by molecular dynamic (MD) simulation reveals hydrogen binding between sitagliptin and the catalytic triad of LYPLAL1, and also between sitagliptin and the P-loop of ATP-binding pocket of TCP1. Molecular mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis indicates that sitagliptin can stably bind to LYPLAL1 and TCP1 in active sites, which may have an impact on the functions of these proteins. SPR analysis validates the binding affinity of sitagliptin to TCP1 mutant D88A is ~10 times lower than that to the wild-type TCP1. Our findings provide insights into the sitagliptin-targets interplay and demonstrate the potential of sitagliptin in regulating gluconeogenesis and in anti-tumor drug development.

Total Arch Replacement Combined with Stented Elephant Trunk Implantation for Acute Type A Aortic Dissection in an Octogenarian Patient.

BACKGROUND: The indications and outcome of surgery for Acute type A aortic dissection (ATAAD) in elderly patients are still debated, especially when they were above 80 years old.  Case presentation: This report describes the case of an octogenarian patient with ATAAD who underwent total arch replacement (TAR) combined with stented elephant trunk (SET) implantation. CONCLUSION: Emergent surgery should be performed on the ATAAD octogenarians without serious preoperative complications. Acceptable outcomes could be received by total arch replacement combined with SET implantation.

A group of CLE peptides regulates de novo shoot regeneration in Arabidopsis thaliana.

Known for their regulatory roles in stem cell homeostasis, CLAVATA3/ESR-RELATED (CLE) peptides also function as mediators of external stimuli such as hormones. De novo shoot regeneration, representing the remarkable plant cellular plasticity, involves reconstitution of stem cells under control of stem-cell regulators. Yet whether and how stem cell-regulating CLE peptides are implicated in plant regeneration remains unknown. By CRISPR/Cas9-induced loss-of-function studies, peptide application, precursor overexpression, and expression analyses, the role of CLE1-CLE7 peptides and their receptors in de novo shoot regeneration was studied in Arabidopsis thaliana. CLE1-CLE7 are induced by callus-induction medium and dynamically expressed in pluripotent callus. Exogenously-applied CLE1-CLE7 peptides or precursor overexpression effectively leads to shoot regeneration suppression, whereas their simultaneous mutation results in enhanced regenerative capacity, demonstrating that CLE1-CLE7 peptides redundantly function as negative regulators of de novo shoot regeneration. CLE1-CLE7-mediated shoot regeneration suppression is impaired in loss-of-function mutants of callus-expressed CLAVATA1 (CLV1) and BARELY ANY MERISTEM1 (BAM1) genes, indicating that CLV1/BAM1 are required for CLE1-CLE7-mediated shoot regeneration signaling. CLE1-CLE7 signaling resulted in transcriptional repression of WUSCHEL (WUS), a stem cell-promoting transcription factor known as a principal regulator of plant regeneration. Our results indicate that functionally-redundant CLE1-CLE7 peptides genetically act through CLV1/BAM1 receptors and repress WUS expression to modulate shoot-regeneration capacity, establishing the mechanistic basis for CLE1-CLE7-mediated shoot regeneration and a novel role for CLE peptides in hormone-dependent developmental plasticity.

SARS-CoV-2-specific antibody response characteristics in COVID-19 patients of different ages.

Age has been found to be one of the main risk factors for the severity and outcome of COVID-19. However, differences in SARS-CoV-2 specific antibody responses among COVID-19 patients of different age groups remain largely unknown. In this study, we analyzed the IgG/IgM responses to 21 SARS-CoV-2 proteins and 197 peptides that fully cover the spike protein against 731 sera collected from 731 COVID-19 patients aged from 1 to We show that there is no overall difference in SARS-CoV-2 antibody responses in COVID-19 patients in the 4 age groups. By antibody response landscape maps, we find that the IgG response profiles of SARS-CoV-2 proteins are positively correlated with age. The S protein linear epitope map shows that the immunogenicity of the S-protein peptides is related to peptide sequence, disease severity and age of the COVID-19 patients. Furthermore, the enrichment analysis indicates that low S1 IgG responses are enriched in patients aged <50 and high S1 IgG responses are enriched in mild COVID-19 patients aged >60. In addition, high responses of non-structural/accessory proteins are enriched in severe COVID-19 patients aged >70. These results suggest the distinct immune response of IgG/IgM to each SARS-CoV-2 protein in patients of different age, which may facilitate a deeper understanding of the immune responses in COVID-19 patients.

Signaling peptides direct the art of rebirth.

Signaling peptide-mediated cell-cell communication is crucial for plant growth, development, and adaptive responses to environmental stimuli. Given the prominent roles signaling peptides play in stem cell homeostasis, we propose investigating their impact on plant regeneration, which requires cellular reprogramming of differentiated cells to stem cells and establishment of nascent meristems.

Reactive Oxygen Species and Oxidative Stress in Vascular-Related Diseases.

Oxidative stress (OS) refers to the enhancement of oxidation and the decreased of related antioxidant enzymes activity under pathological conditions, resulting in relatively excess reactive oxygen species (ROS), causing cytotoxicity, which leads to tissue damage and is linked to neurodegenerative diseases, cardiovascular diseases, diabetes, cancers, and many other pathologies. As an important intracellular signaling molecule, ROS can regulate numerous physiological actions, such as vascular reactivity and neuronal function. According to several studies, the uncontrolled production of ROS is related to vascular injury. The growing evidence revealing how traditional risk factors translate into ROS and lead to vasculitis and other vascular diseases. In this review, we sought to mainly discuss the role of ROS and antioxidant mechanisms in vascular-related diseases, especially cardiovascular and common macrovascular diseases.

Metabolic reprogramming in the arsenic carcinogenesis.

Chronic exposure to arsenic has been associated with a variety of cancers with the mechanisms undefined. Arsenic exposure causes alterations in metabolites in bio-samples. Recent research progress on cancer biology suggests that metabolic reprogramming contributes to tumorigenesis. Therefore, metabolic reprogramming provides a new clue for the mechanisms of arsenic carcinogenesis. In the present manuscript, we review the latest findings in reprogramming of glucose, lipids, and amino acids in response to arsenic exposure. Most studies focused on glucose reprogramming and found that arsenic exposure enhanced glycolysis. However, in vivo studies observed "reverse Warburg effect" in some cases due to the complexity of the disease evolution and microenvironment. Arsenic exposure has been reported to disturb lipid deposition by inhibiting lipolysis, and induce serine-glycine one-carbon pathway. As a dominant mechanism for arsenic toxicity, oxidative stress is considered to link with metabolism reprogramming. Few studies analyzed the causal relationship between metabolic reprogramming and arsenic-induced cancers. Metabolic alterations may vary with exposure doses and periods. Identifying metabolic alterations common among humans and experiment models with human-relevant exposure characteristics may guide future investigations.

Application of the Type, Entry Site, and Malperfusion Classification in Treatment of Aortic Dissection.

BACKGROUND: Our goal is to investigate a new practical dissection classification system, including type of dissection, location of the tear of the primary entry, and malperfusion. METHODS: The outcome of 151 patients with aortic dissection between January 2019 and May 2020 retrospectively were analyzed. All cases were classified with the Stanford dissection classification (A and B) by adding type non-A non-B. They were then further classified by the new classification system, including location of the primary Entry (E) and Malperfusion (M). All cases were followed up for six months. RESULTS: The distribution of 151 patients was 53.0%, 27.8%, and 19.2%, respectively, in type A, B, and non-A non-B. The in-hospital mortality rate was 8.8%, 2.4%, and 3.4% in type A, B, and non-A non-B (P < 0.05) and postoperative neurological complications occurred in 33.8%, 7.1%, and 13.8% in type A, B, and non-A non-B (P < 0.05). Total arch replacement was performed in 53.8%, 4.8%, and 13.8% in type A, B, and non-A non-B. The in-hospital mortality rate was 12.0%, 10.4%, and 8.5% in type E1, E2 and E3, while it was 20.0%, 10.4%, and 8.5% in type M1, M2 and M3 (P < 0.05). CONCLUSIONS: The new practical dissection classification system is useful as a supplement to the Stanford dissection classification by regarding the extent of the disease process, aiding in decision-making about the operative indication and plan, and helping in anticipating prognosis.

[Enzymatic synthesis of acylated quercetin 3-O-glycosides: a review].

Quercetin 3-O-glycosides (Q3Gs) are important members of quercetin glycosides with excellent pharmacological activities such as anti-oxidation, anti-inflammation, anti-cancer and anti-virus. Two representatives of Q3Gs, rutin and troxerutin, have been developed into clinical drugs, demonstrating Q3Gs have become one of the important sources of innovative drugs. However, the applications of Q3Gs in food and pharmaceutical industries are hampered by its poor bioavailability. Of the known means, selective acylation modification of Q3Gs through enzymatic catalysis to obtain Q3G esters is one of the effective ways to improve its bioavailability. Herein, the enzyme-mediated acylation of Q3Gs were reviewed in details, focusing on the four tool enzymes (acyltransferases, lipases, proteases and esterases) and the whole-cell mediated biotransformation, as well as the effect of acylations on the biological activities of Q3Gs. Furthermore, the highly efficient synthesis and diversification of acylated site for Q3G esters were also discussed. Taken together, this review provides a new perspective for further structural modifications of Q3Gs towards drug development.

Early and late outcomes of non-total aortic arch replacement for repair of acute Stanford Type A aortic dissection.

OBJECTIVE: This study evaluated the early and late outcomes of non-total aortic arch replacement for acute Stanford A aortic dissection. METHODS: 131 cases of acute Stanford Type A aortic dissection with no rupture admitted to our hospital from January 2016 to December 2019 were selected for non-total aortic arch replacement. According to different surgical methods, 51 patients with tear-oriented ascending/hemiarch replacement were included in Group A, and 80 patients who underwent total arch replacement surgery were enrolled in Group B. The perioperative indicators, 30-day mortality rate, and the incidence of postoperative complications were compared between the two groups, and the survival rate of patients were compared by follow-up after discharge. RESULTS: The cardiopulmonary bypass time, cardiac perfusion time, invasive ventilation and ICU hospitalization in Group A were critically shorter than those in Group B (P<0.05). The incidence of transient cerebral dysfunction in Group A was substantially lower than that in Group B (P<0.05). The difference of comparison in perioperative mortality, incidence of permanent neurological dysfunction, and incidence of acute kidney and liver damage between the two groups was statistically insignificant (P>0.05). In addition, the two groups had statistically insignificant difference in survival during postoperative follow-up (P>0.05). CONCLUSION: For acute Stanford type A aortic dissection without rupture in aortic arch, the non-total aortic arch replacement has simple surgical method with high perioperative safety and long-term efficacy that similar to total arch replacement.

Human Immunodeficiency Viruses Pseudotyped with SARS-CoV-2 Spike Proteins Infect a Broad Spectrum of Human Cell Lines through Multiple Entry Mechanisms.

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19), enters cells through attachment to the human angiotensin converting enzyme 2 (hACE2) via the receptor-binding domain (RBD) in the surface/spike (S) protein. Several pseudotyped viruses expressing SARS-CoV-2 S proteins are available, but many of these can only infect hACE2-overexpressing cell lines. Here, we report the use of a simple, two-plasmid, pseudotyped virus system comprising a SARS-CoV-2 spike-expressing plasmid and an HIV vector with or without vpr to investigate the SARS-CoV-2 entry event in various cell lines. When an HIV vector without vpr was used, pseudotyped SARS-CoV-2 viruses produced in the presence of fetal bovine serum (FBS) were able to infect only engineered hACE2-overexpressing cell lines, whereas viruses produced under serum-free conditions were able to infect a broader range of cells, including cells without hACE2 overexpression. When an HIV vector containing vpr was used, pseudotyped viruses were able to infect a broad spectrum of cell types regardless of whether viruses were produced in the presence or absence of FBS. Infection sensitivities of various cell types did not correlate with mRNA abundance of hACE2, TMPRSS2, or TMPRSS4. Pseudotyped SARS-CoV-2 viruses and replication-competent SARS-CoV-2 virus were equally sensitive to neutralization by an anti-spike RBD antibody in cells with high abundance of hACE2. However, the anti-spike RBD antibody did not block pseudotyped viral entry into cell lines with low abundance of hACE2. We further found that CD147 was involved in viral entry in A549 cells with low abundance of hACE2. Thus, our assay is useful for drug and antibody screening as well as for investigating cellular receptors, including hACE2, CD147, and tyrosine-protein kinase receptor UFO (AXL), for the SARS-CoV-2 entry event in various cell lines.

Systematic evaluation of IgG responses to SARS-CoV-2 spike protein-derived peptides for monitoring COVID-19 patients.

Serological tests play an essential role in monitoring and combating the COVID-19 pandemic. Recombinant spike protein (S protein), especially the S1 protein, is one of the major reagents used for serological tests. However, the high cost of S protein production and possible cross-reactivity with other human coronaviruses pose unavoidable challenges. By taking advantage of a peptide microarray with full spike protein coverage, we analyzed 2,434 sera from 858 COVID-19 patients, 63 asymptomatic patients and 610 controls collected from multiple clinical centers. Based on the results, we identified several S protein-derived 12-mer peptides that have high diagnostic performance. In particular, for monitoring the IgG response, one peptide (aa 1148-1159 or S2-78) exhibited a sensitivity (95.5%, 95% CI 93.7-96.9%) and specificity (96.7%, 95% CI 94.8-98.0%) comparable to those of the S1 protein for the detection of both symptomatic and asymptomatic COVID-19 cases. Furthermore, the diagnostic performance of the S2-78 (aa 1148-1159) IgG was successfully validated by ELISA in an independent sample cohort. A panel of four peptides, S1-93 (aa 553-564), S1-97 (aa 577-588), S1-101 (aa 601-612) and S1-105 (aa 625-636), that likely will avoid potential cross-reactivity with sera from patients infected by other coronaviruses was constructed. The peptides identified in this study may be applied independently or in combination with the S1 protein for accurate, affordable, and accessible COVID-19 diagnosis.

Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) has increasing worldwide incidence but when unresectable lacks curative options. Treatment with a kinase inhibitor Sorafenib (Sf), while initially effective, results in only short increases in patient survival, thus there is a need for improved treatment regimens. Numerous treatment regimens have been explored wherein Sf is combined with other agents, such as non-toxic botanicals like Curcumin or Silibinin. Recently, we have shown that carnosic acid (CA), a component of the food preservative Rosemary Extract, can markedly enhance the cytotoxic actions of Sf in several cell lines derived from HCC, but not in the cell line Hu1545 derived from normal hepatocytes. CA has been shown to enhance Sf-induced cell death in the neoplastic cell lines, principally due to the composite of increased apoptosis and cytotoxic autophagy. In the present study we focused on the mechanisms that underlie the reduced proliferation and survival of HCC cells when CA is added to Sf and how this relates to the increase in Sf-induced DNA damage as well as to the elevation of cytoplasmic levels of reactive oxygen species (ROS). Importantly, the elevation of ROS levels induced by Sf was increased by adding CA. We found that CA enhanced Sf-induced prolongation of cell cycle, and the overall decrease in cell growth was associated with reduced activation of both STAT3 transcription factor (TF) and extracellular signal-regulated protein kinase (Erk)1/2. Our data suggest that a regimen incorporating CA, an inexpensive and non-toxic food additive, in the treatment of advanced HCC merits clinical evaluation.

TWEAK Promotes the Proliferation of Squamous Cell Carcinoma Cells Through Activating cIAP1 Signals.

Recent studies showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) induces the proliferation of squamous cell carcinoma (SCC) cells. However, the precise mechanism underlying such effect of TWEAK remains unclear. This study was designed to elucidate the role of cellular inhibitor of apoptosis 1 (cIAP1) in TWEAK-induced proliferation of SCC cells. Human SCC cells (SCC-13, A431, and SCC-9) were cultured in vitro, receiving the stimulation of TWEAK or TNF-related apoptosis-inducing ligand (TRAIL). We found that TWEAK induced cytoplasmic cIAP1 importation and RIP1 ubiquitination in cells, followed by the activation of canonical nuclear factor kappa B signals. MV1, a cIAP1 inhibitor, abrogated TWEAK-induced proliferation of these cells. Moreover, the interaction between TWEAK and its receptor, fibroblast growth factor-inducible 14 (Fn14), enhanced the expression of TRAIL receptor types 3 and 4 (TRAIL-R3/4). Furthermore, the transfection of TRAIL-R3/4 siRNA abrogated the promotion effect of TWEAK on SCC-13 cell proliferation and cIAP1 expression. Therefore, TWEAK/Fn14 interaction promotes the proliferation of SCC cells through activating cIAP1 signals. Targeting the downstream cIAP1 signals might attenuate the effect of TWEAK on SCC cells.

Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation.

Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC-induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA. Using thiol antioxidants, such as N-acetyl cysteine (NAC), we found a significant inhibition of ECD, yet this occurred in the absence of any detectable change in cellular ROS levels. In contrast, NAC reduced the vitamin D receptor (VDR) abundance and its signaling of ECD. Importantly, VDR knockdown and NAC similarly inhibited ECD without producing an additive effect. Thus, the proposed post-AraC therapy may be compromised by agents that reduce VDR levels in AML blasts.