ABSTRACT
Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.
Subject(s)
Male , Humans , Prostate-Specific Antigen , Treatment Outcome , Prostatic Neoplasms, Castration-Resistant/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Retrospective StudiesABSTRACT
A 70-year-old male with chronic lymphocytic leukemia (CLL) 9 years ago initially presenting elevation of prostate specific antigen (PSA) was diagnosed with high-risk prostate cancer in March, 2018. He received 18F-FDG positron emission tomography/computed tomography (PET/CT), which showed mild FDG-avidity in swollen lymph nodes across the entire body, considering CLL. Then he underwent neoadjuvant androgen deprivation therapy for 1 month and then robot-assisted radical prostatectomy and biopsy of the right iliac vascular obturator lymph nodes. The prostate pathology was prostate cancer, and the pathology of lymph nodes was CLL. His serum PSA levels 1 month and 3 months after operation both reached the level of cure. For the patients with concomitant high-risk prostate cancer and CLL, PET/CT may be valuable in distinguishing whether the swollen lymph nodes were infiltrated by prostate cancer and guiding the lymphadenectomy.
ABSTRACT
The objectives of this study were to investigate the effects of the CRISPR/Cas9 system mediated by the HPV pseudotype virus on SiHa cytobiology behavior by cutting the HPV16 E6 gene selectively and to explore the role of this system in the treatment of cervical cancer.After designing specific gRNA sequences targeting HPV 16 E6,generating hCas9-EGFP and E6-gRNA-RFP plasmids,and preparing the pseudovirus of HPV16 carrying E6-gRNA and Cas9 plasmids,we determined the titer of the pseudotype virus using the TCID50 method.We obtained the pseudotype virus of HPV16 carrying E6-gRNA and Cas9 plasmids to transfect cervical cancer SiHa cells.Experimental subjects were divided into control group,empty virus group,E6-gRNA transfected group,Cas9 transfected group and Cas9+E6-gRNA transfected group.The molecular size of the cutting sequence was detected using the T7E1 enzyme digestion method and agarose gel electrophoresis,and the cleavage function of CRISPR/Cas9 on the E6 gene was determined at the same time.RT-PCR and Western blotting were performed to detect the mRNA and protein expression levels of E6 in all the groups;the Transwell cell migration assay was performed to detect the cell migration ability and metastasis in all groups.Heterotopic transplantation tumors were incorporated into mice and were used to investigate the effects of the CRISPR/Cas9 system mediated by the HPV pseudovirus on the tumorigenic ability of SiHa cells by selectively cutting HPV16 E6.The HPV16 pseudotype virus carrying E6-gRNA and Cas9 plasmids could successfully infect SiHa cells,and there were two cutting zones in the Cas9+E6-gRNA transfected group.However,the empty virus group,E6-gRNA transfected group and Cas9 transfected group had no corresponding zone.Compared with those in the control group,the empty virus group,E6-gRNA transfected group and Cas9 transfected group,the mRNA and protein expression levels of E6 in SiHa cells were downregulated in the Cas9+E6-gRNA transfected group (P＜0.01).In addition,the proliferation and migration abilities of SiHa cells were significantly inhibited (P＜0.01).There were no significant differences among the other groups.In contrast to the control group,the HPV pseudotype virus carrying E6-gRNA and Cas9 plasmids could significantly delay the growth of tumor cells of the ectopic tumor transplantation model (P＜0.01).The CRISPR/Cas9 system mediated by the HPV pseudotype virus to knockout E6 gene expression exhibited a clear inhibitory effect on the biological function of SiHa cells,which indicated that knocking out the E6 gene using the CRISPR/Cas9 system mediated by the HPV pseudotype virus had a potential effect of eliminating HPV infection and inhibiting the growth of HPV-related tumors.Taken together,these findings provide insight into a new treatment strategy for the prevention and treatment of hr-HPV infected disease,particularly in HPV-related tumors.
ABSTRACT
The objectives of this study were to investigate the effects of the CRISPR/Cas9 system mediated by the HPV pseudotype virus on SiHa cytobiology behavior by cutting the HPV16 E6 gene selectively and to explore the role of this system in the treatment of cervical cancer.After designing specific gRNA sequences targeting HPV 16 E6,generating hCas9-EGFP and E6-gRNA-RFP plasmids,and preparing the pseudovirus of HPV16 carrying E6-gRNA and Cas9 plasmids,we determined the titer of the pseudotype virus using the TCID50 method.We obtained the pseudotype virus of HPV16 carrying E6-gRNA and Cas9 plasmids to transfect cervical cancer SiHa cells.Experimental subjects were divided into control group,empty virus group,E6-gRNA transfected group,Cas9 transfected group and Cas9+E6-gRNA transfected group.The molecular size of the cutting sequence was detected using the T7E1 enzyme digestion method and agarose gel electrophoresis,and the cleavage function of CRISPR/Cas9 on the E6 gene was determined at the same time.RT-PCR and Western blotting were performed to detect the mRNA and protein expression levels of E6 in all the groups;the Transwell cell migration assay was performed to detect the cell migration ability and metastasis in all groups.Heterotopic transplantation tumors were incorporated into mice and were used to investigate the effects of the CRISPR/Cas9 system mediated by the HPV pseudovirus on the tumorigenic ability of SiHa cells by selectively cutting HPV16 E6.The HPV16 pseudotype virus carrying E6-gRNA and Cas9 plasmids could successfully infect SiHa cells,and there were two cutting zones in the Cas9+E6-gRNA transfected group.However,the empty virus group,E6-gRNA transfected group and Cas9 transfected group had no corresponding zone.Compared with those in the control group,the empty virus group,E6-gRNA transfected group and Cas9 transfected group,the mRNA and protein expression levels of E6 in SiHa cells were downregulated in the Cas9+E6-gRNA transfected group (P＜0.01).In addition,the proliferation and migration abilities of SiHa cells were significantly inhibited (P＜0.01).There were no significant differences among the other groups.In contrast to the control group,the HPV pseudotype virus carrying E6-gRNA and Cas9 plasmids could significantly delay the growth of tumor cells of the ectopic tumor transplantation model (P＜0.01).The CRISPR/Cas9 system mediated by the HPV pseudotype virus to knockout E6 gene expression exhibited a clear inhibitory effect on the biological function of SiHa cells,which indicated that knocking out the E6 gene using the CRISPR/Cas9 system mediated by the HPV pseudotype virus had a potential effect of eliminating HPV infection and inhibiting the growth of HPV-related tumors.Taken together,these findings provide insight into a new treatment strategy for the prevention and treatment of hr-HPV infected disease,particularly in HPV-related tumors.
ABSTRACT
Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a high-fat diet, we found that: (1) the acute thermal pain sensory threshold did not change in obese mice; (2) the model obese mice had fewer nociceptive responses in formalin-induced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation; (3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice, indicating the dysmodulation of topical leptin-leptin receptor signaling in these mice; and (4) leptin-leptin receptor signaling-deficient mice (ob/ob and db/db) or leptin-leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wild-type mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin-leptin receptor pathway could be a peripheral target against acute inflammatory pain.
Subject(s)
Animals , Male , Mice , Diet, High-Fat , Inflammation , Metabolism , Leptin , Metabolism , Pharmacology , Mice, Inbred C57BL , Nociception , Physiology , Nociceptive Pain , Metabolism , Obesity , Metabolism , Pain Measurement , Pain Threshold , Physiology , Receptors, Leptin , Metabolism , Signal Transduction , PhysiologyABSTRACT
Increasing evidence indicates that inflammation may play important roles in tumorigenesis and progression, and an elevated peripheral monocyte count predicts a poor prognosis in various types of malignancies. Here, we evaluate the roles of peripheral monocyte count in the diagnosis and prognosis for prostate cancer in Chinese patients. A total of 1107 consecutive patients who had undergone prostate biopsy and 290 prostate cancer patients receiving androgen deprivation therapy as first-line therapy were retrospectively analyzed. The parameters were measured at the time of diagnosis. Univariate and multivariate logistic regression analyses were performed to identify the independent predictors of a positive biopsy. Patients were categorized in two groups using a cutoff point of 0.425 × 109 l-1 as calculated by the receiver-operating curve analysis for prognosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of monocyte count with progression-free survival, cancer-specific survival, and overall survival. Multivariate logistic regression analyses showed that monocyte count, age, prostate-specific antigen (PSA), free/total PSA, and prostate volume were independent predictors for prostate cancer. Multivariate Cox regression analyses identified an elevated monocyte count as an independent prognostic factor for worse cancer-specific survival (hazard ratio = 2.244, P < 0.05) and overall survival (hazard ratio = 1.995, P < 0.05), but not progression-free survival (P = 0.117). Our results indicated that an elevated monocyte count was an independent diagnostic biomarker for prostate cancer, and pretreatment peripheral monocyte count might play a significant role in the prognosis of prostate cancer patients treated with androgen deprivation therapy.
ABSTRACT
OBJECTIVE@#To explore the safety and efficacy of eye drops without benzalkonium chloride (BAK) in treating glaucoma and ocular hypertension.@*METHODS@#The clinical case-control literatures about eye drops without BAK treating glaucoma and ocular hypertension were retrieved in PubMed, EMBASE, Cochrane and Chinese Biological and Medical database. Meta 5.0 software was used to analyze the literatures.@*RESULTS@#Five clinical control studies were included. The results indicated both eye drops could lower the intraocular pressure, and the intraocular pressure-lowering difference between two eye drops was 0.07 mmHg (95% CI: 0.04, 0.19) (P>0.05). Two adverse reactions occurred more were conjunctival injection (10.78%) and allergic conjunctivitis (4.78%). The odd ratio of two eye drops occurring conjunctival injection and allergic conjunctivitis was 0.67 (95% CI, 0.25, 1.10) and 0.82 (95% CI, 0.09, 1.54), respectively (P<0.05) in fixed effect model.@*CONCLUSIONS@#There is no difference between the eye drops with or without BAK in lowering intraocular pressure, but the latter is of higher safety. In consideration of the relatively small sample size of this research, more high-quality clinical research contrasts are needed as evidence.
Subject(s)
Humans , Benzalkonium Compounds , Intraocular Pressure , Ocular Hypertension , Drug Therapy , Ophthalmic Solutions , Chemistry , Pharmacology , Therapeutic Uses , Preservatives, PharmaceuticalABSTRACT
Objective To investigate the epidemiological features of patients with nosoeomial invasive fungal infection. Methods Fungi in blood were identified by BaeT ALERT 3D, other clinical samples were cultured by Sabouraud' s dextrose agar (SDA) medium. Candidas were isolated and identified by CHRO Magar candida color medium. Fungus-cultured positive cases from Jan. 2004 to Nov. 2007 were analyzed on items as patients' age, underlying disease, sample, strain, and species distribution. All statistical analyses were carried out by SPSS 13.0. Results The overall incidence rate of invasive fungal infections was 4.12%. The average age of patients was 7-96 with most patients were male, with geriatric problems and different kinds of underlying diseases. Lower respiratory tract infection was the most frequent infection site, followed by urinary tract, gastrointestinal tract. The main pathogens of invasive fungal infections were Candidas (93.80%). Strains of Candida albicans were the most frequent organisms which accounted for 67.29% of all the isolates. Mould fungus infections accounted for only 6.20%. During the 4 years of observation, the detection rate of fungi, specimen sources and the distribution of species and compartment were different with significant differences (P<0.0083). Conduslon The epidemiological properties such as the source of specimen, the distribution of species and composition sections of invasive fungal infections were changing. Candida slaP. were still the main pathogens of invasive fungal infections but the sections of fungi changed. The incidence of Aspergillus infections had been increasing recently.
ABSTRACT
A digital tongue image analysis instrument (TIAI) based on computer for Traditional Chinese Medicine is introduced. Some of the key techniques, including the image acquiring condition and method, the evaluation of tongue characters, and the management of tongue image data, are discussed as well. TIAI can provide a non-invasive, quantitative, and objective analysis approach and enhance the theory level and practical ability of the Traditional Chinese tongue diagnosis.