Opportunities and Challenges in the Development of Antibody-Drug Conjugate for Triple-Negative Breast Cancer: The Diverse Choices and Changing Needs.

Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancer subtype, which is also characterized by the aggressive phenotype, high recurrence rate, and poor prognosis. Antibody-drug conjugate (ADC) is a monoclonal antibody with a cytotoxic payload connected by a linker. ADC is gaining more and more attention as a targeted anti-cancer agent. Clinical studies of emerging ADC drugs such as sacituzumab govitecan and trastuzumab deruxtecan in patients with metastatic breast cancer (including TNBC) are progressing rapidly. In view of its excellent clinical efficacy and good tolerability, Sacituzumab govitecan gained accelerated approval by the FDA for the treatment of advanced metastatic TNBC in 2020. This review discusses the treatment status and challenges in TNBC, with an emphasis on the current status of ADC development and clinical trials in TNBC and metastatic breast cancer. We also summarize the clinical experience and future exploration directions of ADC development for TNBC patients.

Enhanced antitumor effects of radiotherapy combined local nimustine delivery rendezvousing with oral temozolomide chemotherapy in glioblastoma patients.

BACKGROUND: Glioblastoma (GBM) is one of the worst cancers with bad prognosis despite systemic chemotherapy and radiotherapy after surgery. METHODS: In this study, 71 patients with GBM were enrolled and randomly assigned to two groups: Receiving radiotherapy with concomitant and adjuvant temozolomide (TMZ) (TMZ, standard therapy) after surgery, or receiving radiotherapy with concomitant and adjuvant local delivery of nimustine (ACNU) rendezvousing with oral TMZ (rendezvous therapy). In the follow-up of all patients and the progression-free survival (PFS), overall survival (OS), Karnofsky performance score (KPS) and toxicities were recorded. RESULTS: For the whole cohort, the median OS was 18.0 months, and the median PFS was 7.8 months. A significantly longer OS was observed in patients received rendezvous therapy than those who receiving standard therapy (18.5 months vs. 16.0 months; P = 0.014), as well as PFS (8.8 months vs. 7.0 months; P = 0.008). The KPS ≥70 rates were 81.8%, 40.9%, 20.5% in 1, 2, and 3 years for the rendezvous therapy group, significantly superior to standard therapy group. The most common toxicities were tolerable gastrointestinal reaction, liver dysfunction, and hematological toxicities, which were relieved with symptomatic treatment. Grade 3 or 4 toxicity was documented in 8 (18.3%) patients in rendezvous therapy group, while it was observed in 6 (22.2%) patients in standard therapy group during whole treatment process. CONCLUSIONS: Compared to standard therapy, the antitumor effects of rendezvous therapy were more effective in GBM patients without increasing the toxicities.

Combination of endogenous neural stem cell mobilization and lithium chloride treatment for hydrocephalus following intraventricular hemorrhage.

As there are multiple factors causing hydrocephalus subsequent to intraventricular hemorrhage (IVH), it is difficult to achieve the best treatment effect using a single drug alone. In the present study, the protective effect of combination treatment with granulocyte-colony stimulating factor (G-CSF) and lithium chloride against hydrocephalus after IVH was investigated. A total of 130 adult male Sprague-Dawley rats were divided into five groups, including the IVH control, G-CSF treatment, lithium chloride treatment, combination treatment and sham surgery groups. An IVH rat model was established in order to examine the effect of combination treatment on hydrocephalus incidence. A TUNEL assay was performed to detect neuronal apoptosis in the five groups. In addition, the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blot analysis. The differentiation of nerve cells in the brain tissue obtained from the five rat groups was also determined with double immunofluorescence staining. The results demonstrated that administration of G-CSF or lithium chloride alone was able to only partly relieve the incidence of hydrocephalus after IVH. By contrast, combination treatment with G-CSF and lithium chloride significantly attenuated the development of hydrocephalus following IVH. TUNEL assay showed that neuronal apoptosis was significantly reduced by the combination treatment with G-CSF and lithium chloride. Furthermore, the expression of Bcl-2 was upregulated, whereas Bax expression was downregulated in the combination treatment group. The results also detected the highest expression of BrdU/GFAP, BrdU/NeuN and BrdU/PSA-NCAM in the combination treatment group. In conclusion, the combination of endogenous neural stem cell mobilization (using G-CSF) and lithium chloride treatment resulted in highly reduced incidence of hydrocephalus after IVH by inhibiting neuronal apoptosis.

Identification of candidate target genes of pituitary adenomas based on the DNA microarray.

The present study aimed to explore molecular mechanisms involved in pituitary adenomas (PAs) and to discover target genes for their treatment. The gene expression profile GSE4488 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the Limma package and analyzed by two­dimensional hierarchical clustering. Gene ontology (GO) and pathway enrichment analyses were performed in order to investigate the functions of DEGs. Subsequently, the protein­protein interaction (PPI) network was constructed using Cytoscape software. DEGs were then mapped to the connectivity map database to identify molecular agents associated with the underlying mechanisms of PAs. A total of 340 upregulated and 49 downregulated DEGs in PA samples compared with those in normal controls were identified. Hierarchical clustering analysis showed that DEGs were highly differentially expressed, indicating their aptness for distinguishing PA samples from normal controls. Significant gene ontology terms were positive regulation of immune system-associated processes for downregulated DEGs and skeletal system development for upregulated DEGs. Pathways significantly enriched by DEGs included extracellular matrix (ECM)­receptor interaction, the Hedgehog (Hh) signaling pathway and neuroactive ligand­receptor interaction. The PPI network was constructed with 117 nodes, 123 edges and CD44 and Gli2 as hub nodes. Furthermore, depudecin, a small molecule drug, was identified to be mechanistically associated with PA. The genes CD44 and Gli2 have important roles in the progression of PAs via ECM­receptor interaction and the Hh signaling pathway and are therefore potential target genes of PA. In addition, depudecin may be a candidate drug for the treatment of PAs.

Toll-like receptor 4/nuclear factor-kappa B signaling detected in brain after early subarachnoid hemorrhage.

BACKGROUND: Inflammation and immunity play a vital role in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). Nuclear factor-kappa B (NF-kappaB) regulates many genes essential for inflammation and immunity and is activated by toll-like receptor (TLR). This study aimed to detect the expression of the toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kappaB) signaling in the rat brain after early SAH. METHODS: The rats were decapitated and their brains were removed at 0, 2, 4, 6, 12, 24 and 48 hours after a single injection of blood into the prechiasmatic cistern. mRNA expression of TLR4 was measured by Taqman real-time RT-PCR, and protein expression by immunohistochemistry and Western blotting. NF-kappaB activity and concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: TaqMan real-time RT-PCR and Western blotting identified a biphasic change in TLR4 expression in both mRNA and protein: an initial peak (2 - 6 hours) and a sustained elevation (12 - 48 hours). Immunohistochemical staining showed the inducible expression of TLR4-like immunoreactions predominantly in glial cells and vascular endothelium. A similar biphasic change in the activation of NF-kappaB subunit p65 as well as the production of NF-kappaB-regulated proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) were detected by ELISA. CONCLUSIONS: These data suggest that experimental SAH induces significant up-regulation of TLR4 expression and the NF-kappaB signaling in early brain injury. Activation of the TLR4/NF-kappaB signaling may regulate the inflammatory responses after SAH.

WITHDRAWN: Activation of TLR4/NF-kappaB signaling pathway in early brain injury after subarachnoid hemorrhage.

Ahead of Print article withdrawn by publisher.

[Micro-neurosurgical treatment of cranionasal tumors in combination with transnasal endoscopy].

OBJECTIVE: To explore an effective microsurgical approach to the treatment of cranionasal tumors. METHODS: A retrospective review of 18 micro-neurosurgical patients with cranionasal tumors (June 2005 to June 2007) was undertaken. RESULTS: All of the 18 patients were treated with subfrontal approaches in combination with transnasal endoscopy. Tumors were resected in the stage-one operations (14 were totally resected and 4 were subtotally resected). The anterior skull bases were reconstructed. Transient CSF rhinorrhea was found in two cases. All of the patients experienced good recoveries, with no operative death. The follow up after 5 to 29 months revealed that only four patients had tumor recurrence. Three patients lost in the follow up. CONCLUSION: Subfrontal microsurgical operation combined with transnasal endoscopy is an effective approach to the treatment of cranionasal tumors. It enables high total resection rate and has low complications.

[Cloning and expression of a new glucoamylase gene].

According to the reported gene sequence of Rhizopus oryzae glucoamylases, the glucoamylase gene containing four introns was cloned from the total DNA of the natural Rhizopus arrhizu. Specific primers were designed to delete introns by overlapping PCR and a new cDNA sequence of Rhizopus arrhizu glucoamylase was obtained. The accession number in gene bank is DQ903853. This gene is successfully expressed in the Picha pastoris, producing a new protein with a high activity of glucoamylase.

[Detection of methylation of hMSH2 gene promoter region of esophageal cancer].

OBJECTIVE: To detect methylation in promoter region of hMSH2 gene in esophageal cancer. METHODS: Specimens of cancer and normal tissues freshly removed from 32 cases of esophageal cancer patients without previous radiotherapy, chemotherapy or other treatment were preserved at -80 degrees C within 30 min. Methylation specific PCR (MSP) was used to detect methylation of mismatch repair gene (MMR) hMSH2 in promoter region in esophageal cancer and normal esophageal tissues. RESULTS: The frequencies of methylation of hMSH2 gene in promoter region of cancer and normal esophageal tissues were 32.4% (11/32) and 0/30 (0%), respectively, and significant difference was found between the two groups (P < 0.01). The frequency of methylation in elder patients (> or = 70 years old) was significantly higher than that in younger patients (< 70 years old) (P < 0.05). Methylation was less frequently found in grade I-II (18.2%) than in grade III-IV (70.0%) (P < 0.05). CONCLUSION: Methylation of hMSH2 gene in promoter region is related to patients' age and histopathological grade of the esophageal cancer.

[Expression of hMSH2 gene in esophageal cancer].

OBJECTIVE: To observe the expression of DNA mismatch repair gene hMSH2 mRNA in esophageal cancer tissues. METHODS: This study included 32 esophageal cancer patients who received no previous radiotherapy, chemotherapy or other treatments. Within 30 min following surgical removal of the tumor tissues, specimens of the tumor, the tissue adjacent to the tumor and normal tissue at the esophageal stump (1 cmx1 cmx1 cm in size for each specimen) were obtained for examining hMSH2 expression with hMSH2 ISH detection kit. RESULTS: The positivity rate of hMSH2 was 46.88% in the esophageal cancer tissues, 53.12% in the adjacent tissues, and 84.38% in normal tissues at the esophageal stump, showing significant difference of the former two tissues from the normal tissue (P<0.05). No significant correlation was noted between the positivity rate of hMSH2 and such factors as the patients' age, sex, tumor size, tumor location, pathological type, histological grade, lymphatic metastasis or degree of tumor invasion (P>0.05). CONCLUSION: The deletion of hMSH2 is an early event in the development of esophageal cancer.