Long-term complete remission and peripheral biomarkers in Hodgkin lymphoma patients after decitabine-plus-camrelizumab epi-immunotherapy and treatment cessation.

Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.

Progress: Targeted Therapy, Immunotherapy, and New Chemotherapy Strategies in Advanced Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, accounting for approximately 15% of cases, and is defined by the lack of expression of hormone receptors (estrogen and progesterone receptors) and lack of amplification or overexpression of human epidermal growth receptor 2 (HER2). Due to the lack of targets of hormone receptors and HER2, treatment of TNBC or advanced TNBC relies on conventional chemotherapeutic agents, but their efficacy and prognosis are poor. In patients with advanced TNBC, poorer outcomes are observed. Recently, with the launch of clinical trials and advancements in molecular studies, targeted therapy for signaling transduction pathways, immunotherapy for immune checkpoints, and new chemotherapy strategies have provided feasible or potential therapeutic options for advanced TNBC. This review aimed to summarize recent progress in targeted therapy, immunotherapy, and chemotherapy for advanced TNBC.

Brain lipid binding protein mediates the proliferation of human glioblastoma cells by regulating ERK1/2 signaling pathway in vitro.

Brain lipid binding protein (BLBP) is highly expressed in the radial glial cells (RGCs) of the central nervous system (CNS), in glioblastomas, and, in vitro, in U251 cells. In this report, we have demonstrated that increased BLBP expression in glioblastoma is associated with poor survival and used a double-vector CRISPR/Cas9 lentiviral system to deplete endogenous BLBP from U251 cells, we found that loss of BLBP induced cell growth inhibition and S-phase arrest. Moreover, an increase in P53 and a decrease in p-ERK1/2 were observed after BLBP depletion, suggesting a potential mechanism by which loss of BLBP results in growth inhibition.

Overexpression of Lhx8 inhibits cell proliferation and induces cell cycle arrest in PC12 cell line.

LIM-homeobox genes play a pivotal function in tissue patterning and differentiation, Lhx8 is a member of LIM-homeobox gene family, and it is selectively expressed in embryonic basal forebrain and is a key factor for the determination of cholinergic cells fate. However, besides cholinergic differentiation, little is known about the potential role of Lhx8 in cell biology. In this study, we transfected Lhx8 complementary DNA (cDNA) into PC12 cell line using lentiviral vectors to acquire the cells which stably expressed high level of Lhx8, and we provide the experimental evidence that overexpression of Lhx8 inhibits cell proliferation and induces cell cycle arrest but not apoptosis in vitro. In conclusion, besides cholinergic differentiation, our results suggest that Lhx8 also plays as a suppressor gene of proliferation in cell biology.

Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy.

The therapeutic potential of umbilical cord blood mesenchymal stem cells has been studied in several diseases. However, the possibility that human umbilical cord Wharton's jelly-derived mesenchymal stem cells (hUCMSCs) can be used to treat neonatal hypoxic-ischemic encephalopathy (HIE) has not yet been investigated. This study focuses on the potential therapeutic effect of hUCMSC transplantation in a rat model of HIE. Dermal fibroblasts served as cell controls. HIE was induced in neonatal rats aged 7 days. hUCMSCs labeled with Dil were then transplanted into the models 24 hr or 72 hr post-HIE through the peritoneal cavity or the jugular vein. Behavioral testing revealed that hUCMSC transplantation but not the dermal fibroblast improved significantly the locomotor function vs. vehicle controls. Animals receiving cell grafts 24 hr after surgery showed a more significant improvement than at 72 hr. More hUCMSCs homed to the ischemic frontal cortex following intravenous administration than after intraperitoneal injection. Differentiation of engrafted cells into neurons was observed in and around the infarct region. Gliosis in ischemic regions was significantly reduced after hUCMSC transplantation. Administration of ganglioside (GM1) enhanced the behavioral recovery on the base of hUCMSC treatment. These results demonstrate that intravenous transplantation of hUCMSCs at an early stage after HIE can improve the behavior of hypoxic-ischemic rats and decrease gliosis. Ganglioside treatment further enhanced the recovery of neurological function following hUCMSC transplantation.

Upregulation of Lhx8 increase VAChT expression and ACh release in neuronal cell line SHSY5Y.

Lhx8 is a transcription factor for cholinergic differentiation. Our previous experiments found upregulation of Lhx8 promoted cholinergic neuronal differentiation of hippocampal neural stem/progenitor cells or hippocampal newborn neurons in vitro. However, the role of Lhx8 in VAChT expression and ACh release is still less understood. In this report, we transfected Lhx8 cDNA into neuronal cell line SHSY5Y by lentiviral vectors to acquire the cells which stably expressed high level of Lhx8. Using this cell model, we provided experimental evidence that increasing Lhx8 upregulated the expression of ChAT and VAChT, and also increased the ACh release in culture medium. We suggested that Lhx8 overexpression is a useful strategy to increase the release of ACh and maybe of therapeutic value to neurodegenerative diseases.

Unifying protein inference and peptide identification with feedback to update consistency between peptides.

We first propose a new method to process peptide identification reports from databases search engines. Then via it we develop a method for unifying protein inference and peptide identification by adding a feedback from protein inference to peptide identification. The feedback information is a list of high-confidence proteins, which is used to update an adjacency matrix between peptides. The adjacency matrix is used in the regularization of peptide scores. Logistic regression (LR) is used to compute the probability of peptide identification with the regularized scores. Protein scores are then calculated with the LR probability of peptides. Instead of selecting the best peptide match for each MS/MS, we select multiple peptides. By testing on two datasets, the results have shown that the proposed method can robustly assign accurate probabilities to peptides, and have a higher discrimination power than PeptideProphet to distinguish correct and incorrect identified peptides. Additionally, not only can our method infer more true positive proteins but also infer less false positive proteins than ProteinProphet at the same false positive rate. The coverage of inferred proteins is also significantly increased due to the selection of multiple peptides for each MS/MS and the improvement of their scores by the feedback from the inferred proteins.

Ectopic neurogenesis in the forebrain cholinergic system-related areas of a rat dementia model.

Lesions to the fimbria fornix (FiFx) plus cingulate bundle (CB), the principal routes of communication of forebrain cholinergic regions, produce lasting impairment of spatial learning and memory in mice. We report that extensive neurogenesis takes place in the FiFx, CB, and basalis magnocellularis following FiFx plus CB transection. Immunofluorescence revealed that nestin-expressing cells were present in all 3 areas following lesion; the majority of nestin-positive cells were also positive for 5-bromo-2-deoxy-uridine, a marker of DNA synthesis. Nestin-positive proliferative cells were almost entirely absent from unlesioned tissue. Neurospheres cultured in vitro from lesioned FiFx displayed the characteristics of neural stem cells--proliferation, expression of embryonic markers, and multipotential differentiation into neurons, astrocytes, and oligodendrocytes. At early stages after transection, a small number of immature and migrating doublecortin-immunopositive neurons were detected in lesioned FiFx, where neuronal cell bodies are normally absent. At later stages, postlesion immature neurons developed into ß-tubulin III-positive mature neurons. Lentivirus labeling assay implied that the injury-induced neurogenesis in FiFx may be from local neurogenic astrocytes but not from dentate gyrus. These results demonstrate that insult to cholinergic tracts can stimulate neural stem cell proliferation and neuronal regeneration not only in innervated regions but also in the projection pathways themselves. Ectopic neurogenesis in cholinergic system-related areas provides an additional mechanism for repair of cholinergic innervation following damage.

Assigning probabilities to Mascot peptide identification using logistic regression.

We propose a method to assign probabilities to Mascot peptide identification by using logistic regression. Three key scores, Mascot ions score (MIS), identity threshold, and homology threshold, are integrated into the logistic regression model. Two features in the model are constructed as the differences between MIS and the two thresholds, respectively. Newton-Raphson method is then adopted to solve the model and the weight vector is estimated by maximizing the likelihood of training data. By applying the method to two datasets with known validity, the results demonstrate that the proposed method can assign accurate probabilities to Mascot peptide identifications and have a high discrimination power to separate correct and incorrect peptide identifications.

Charge state determination of peptide tandem mass spectra using support vector machine (SVM).

A single mass spectrometry experiment could produce hundreds of thousands of tandem mass spectra. Several search engines have been developed to interpret tandem mass spectra. All search engines need to determine the masses of peptide ions from their mass/charge ratios. Unfortunately, mass spectrometers do not detect the charges of ions. A current strategy is to search candidate peptides multiple times, once for each possible charge state (typically +2 or +3 ). However, this strategy not only wastes the search time, but also increases the risk of false positive peptide identification. This paper aims at discriminating doubly charged spectra from triply charged ones. Twenty-eight features are introduced to describe the discriminant characteristics of doubly charged and triply charged spectra. The support vector machine (SVM) technique is used to train the classifier on these 28 features. To verify the proposed method, computational experiments are conducted on two types of datasets: ISB dataset generated from the low-resolution ion-trap instrument and TOV dataset generated from the high-resolution quadrupole-time-of-flight instrument. For each type of dataset, the SVM-based classifiers are trained and tested on 20 randomly sampled subdatasets. The results show that the proposed method reaches average correct rates of 95% and 93% to discriminate doubly charged spectra from triply charged ones for the low-resolution ISB dataset and the high-resolution TOV dataset, respectively.