Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

Liquid biopsy: Precise diagnosis and therapy for cholangiocarcinoma.

The following letter to the editor highlights the review titled "Liquid biopsy in cholangiocarcinoma: Current status and future perspective" in World J Gastrointest Oncol 2021; 13: 332-350. It is necessary to realize individualized therapy to improve the clinical prognosis of patients with cholangiocarcinoma.

Photodynamic therapy: A next alternative treatment strategy for hepatocellular carcinoma?

Liver cancer is one of the most common cancers in the world. Of all types of liver cancer, hepatocellular carcinoma (HCC) is known to be the most frequent primary liver malignancy and has seriously compromised the health status of the general population. Locoregional thermal ablation techniques such as radiofrequency and microwave ablation, have attracted attention in clinical practice as an alternative strategy for HCC treatment. However, their aggressive thermal effect may cause undesirable complications such as hepatic decompensation, hemorrhage, bile duct injury, extrahepatic organ injuries, and skin burn. In recent years, photodynamic therapy (PDT), a gentle locoregional treatment, has attracted attention in ablation therapy for patients with superficial or luminal tumors as an alternative treatment strategy. However, some inherent defects and extrinsic factors of PDT have limited its use in clinical practice for deep-seated HCC. In this contribution, the aim is to summarize the current status and challenges of PDT in HCC treatment and provide potential strategies to overcome these deficiencies in further clinical translational practice.

Ab initio study of the moisture stability of lead iodine perovskites.

The stability of hybrid lead iodine perovskite in a humid environment has been a major obstacle to developing long-term photovoltaic devices. However, understanding the detailed degradation mechanism of lead iodine perovskite in moisture is still challenging. Herein, using first-principles calculations, we show that embedded water molecules will facilitate the decomposition of lead iodine perovskite. Alloying FAPbI3 and CsPbI3 to form mixed-cation lead iodine perovskites not only can optimize the tolerance factor to obtain better phase stability, but also can improve the moisture stability of them. With the accumulation of water molecules in the perovskite lattice, the optical absorption spectra show a blue-shift and decreased intensity, and the moisture stabilities of lead iodine perovskites are further lowered. The iodine vacancy in lead iodine perovskites can facilitate the water molecule migration and thus is a disadvantage in improving the moisture stability of them, which should be minimized during perovskite growth. These findings provide new insight in understanding the poor moisture stability of lead iodine perovskites, which should be helpful for the future design and optimization of stable perovskite solar cells.

Preliminary molecular epidemiology of the Staphylococcus aureus in lower respiratory tract infections: a multicenter study in China.

BACKGROUND: Staphylococcus aureus (S. aureus) remains as an important microbial pathogen resulting in community and nosocomial acquired infections with significant morbidity and mortality. Few reports for S. aureus in lower respiratory tract infections (LRTIs) have been documented. The aim of this study was to explore the molecular epidemiology of S. aureus in LRTIs in China. METHODS: A multicenter study of the molecular epidemiology of S. aureus in LRTIs was conducted in 21 hospitals in Beijing, Shanghai and twelve other provinces from November 2007 to February 2009. All the collected S. aureus strains were classified as minimum inhibitory concentration (MIC), mecA gene, virulence genes Panton-Valentine Leukocidin (PVL) and γ-hemolysin (hlg), staphylococcal cassette chromosome mec (SCCmec) type, agr type, and Multilocus Sequence Typing (MLST). RESULTS: Totally, nine methicillin-sensitive S. aureus (MSSA) and 29 methicillin-resistant S. aureus (MRSA) strains were isolated after culture from a total of 2829 sputums or bronchoalveolar lavages. The majority of MRSA strains (22/29) had a MIC value of ≥ 512 µg/ml for cefoxitin. The mecA gene acting as the conservative gene was carried by all MRSA strains. PVL genes were detected in only one S. aureus strain (2.63%, 1/38). The hlg gene was detected in almost the all S. aureus (100% in MSSA and 96.56% in MRSA strains). About 75.86% of MRSA strains carried SCCmec III. Agr type 1 was predominant (78.95%) among the identified three agr types (agr types 1, 2, and 3). Totally, ten sequence type (ST) of S. aureus strains were detected. A new sequence type (ST1445) was found besides confirming ST239 as the major sequence type (60.53%). A dendrogram generated from our own MLST database showed all the bootstrap values ≤ 50%. CONCLUSION: Our preliminary epidemiology data show SCCmec III, ST239 and agr type 1 of S. aureus as the predominant strains in LRTIs in Mainland of China.

Drug-resistant genes carried by Acinetobacter baumanii isolated from patients with lower respiratory tract infection.

BACKGROUND: Acinetobacter baumanii (A. baumanii ) remains an important microbial pathogen resulting in nosocomial acquired infections with significant morbidity and mortality. The mechanism by which nosocomial bacteria, like A. baumanii, attain multidrug resistance to antibiotics is of considerable interest. The aim in this study was to investigate the spread status of antibiotic resistance genes, such as multiple ß-lactamase genes and aminoglycoside-modifying enzyme genes, from A. baumanii strains isolated from patients with lower respiratory tract infections (LRTIs). METHODS: Two thousand six hundred and ninety-eight sputum or the bronchoalveolar lavage samples from inpatients with LRTIs were collected in 21 hospitals in the mainland of China from November 2007 to February 2009. All samples were routinely inoculated. The isolated bacterial strains and their susceptibility were analyzed via VITEK-2 expert system. Several kinds of antibiotic resistant genes were further differentiated via polymerase chain reaction and sequencing methods. RESULTS: Totally, 39 A. baumanii strains were isolated from 2698 sputum or bronchoalveolar lavage samples. There was not only a high resistant rate of the isolated A. baumanii strains to ampicillin and first- and second-generation cephalosporins (94.87%, 100% and 97.44%, respectively), but also to the third-generation cephalosporins (ceftriaxone at 92.31%, ceftazidine at 51.28%) and imipenem (43.59%) as well. The lowest antibiotic resistance rate of 20.51% was found to amikacin. The OXA-23 gene was identified in 17 strains of A. baumanii, and the AmpC gene in 23 strains. The TEM-1 gene was carried in 15 strains. PER-1 and SHV-2 genes were detected in two different strains. Aminoglycoside-modifying enzyme gene aac-3-Ia was found in 23 strains, and the aac-6'-Ib gene in 19 strains. aac-3-Ia and aac-6'-Ib genes hibernated in three A. baumanii strains that showed no drug-resistant phenotype. CONCLUSIONS: A. baumanii can carry multiple drug-resistant genes at the same time and result in multi-drug resistance. Aminoglycoside-modifying enzyme genes could be hibernating in aminoglycoside sensitive strains without expressing their phenotype.

[Familial idiopathic pulmonary fibrosis: case report and review of literature].

OBJECTIVE: To investigate the clinical features of familial idiopathic pulmonary fibrosis (FIPF) and therefore to improve the recognition of the disease. METHODS: Clinical data of 5 patients with idiopathic pulmonary fibrosis belonging to 2 families were analyzed retrospectively. RESULTS: There were 3 patients in one family and 2 in another family. The average age at first diagnosis of the 5 patients with FIPF were (55 +/- 12) years. The most common initial symptoms were cough and progressive dyspnea, bibasilar end-inspiratory Velcro and clubbed fingers. HRCT revealed reticular opacities and diffuse honeycombing. Pulmonary ventilatory function was normal, but the diffusing capacity for carbon monoxide was reduced. One case was confirmed to have usual interstitial pneumonia by surgical lung biopsy. CONCLUSIONS: The clinical features of FIPF are similar to those of nonfamilial IPF. Asymptomatic FIPF can be identified early by lung HRCT.

[Cell apoptosis and the associated signal expression in epithelial cells from patients with idiopathic pulmonary fibrosis].

OBJECTIVE: To investigate the changes and significance of cell apoptosis, Fas/FasL and P53 protein in epithelial cells from patients with idiopathic pulmonary fibrosis (IPF). METHODS: Cell apoptosis and the expressions of Fas/FasL and P53 protein in lung tissues from 12 patients with IPF (IPF group) and 10 normal controls (control group) were detected by terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) and immunohistochemistry. RESULTS: Compared with the control group (0/10), the percentage of apoptosis in alveolar epithelial cells and bronchial cells of the IPF group (12/12) was higher. The percentage of Fas, FasL and P53 protein expressions (12/12, 12/12, 11/12) in alveolar epithelial cells of the IPF group were higher than those of the control group (5/10, 2/10, 0/10); and the percentage of Fas, FasL and P53 protein expressions (12/12, 12/12, 11/12) in bronchial cells of the IPF group were also higher than those of the control group (6/10, 3/10, 0/10). There was a significant correlation between the percentage of apoptosis and Fas/FasL and P53 protein expression (r=0.625-0.839, all P<0.01). The correlation of the Fas/FasL and P53 protein expression was also significant (r=0.571-0.760, all P<0.01). CONCLUSION: The apoptosis percentage of epithelial cells and the expression of Fas/FasL and P53 protein are up-regulated in lung tissues of IPF, which may play an important role in the development of the disease.