Novel Triazolopyridine-Based BRD4 Inhibitors as Potent HIV-1 Latency Reversing Agents.

Bromodomain-containing protein 4 (BRD4) inhibitors have been proven to be a promising option for anti-HIV-1 latency therapeutics. We herein describe the design, synthesis, and anti-HIV-1 latency bioevaluation of triazolopyridine derivatives as BRD4 inhibitors. Among them, compound 13d displayed favorable HIV-1 reactivation and prominent safety profile without triggering abnormal immune activation. It exerted strong synergism when combined with the PKC activator prostratin and has the same BRD4-targeting latency mechanism as observed with JQ1, by stimulating Tat-dependent HIV-1 elongation. Besides, it neither affected the antiviral efficacies of antiviral drugs nor caused secondary infections to uninfected cells and the latency reversing potency of 13d, in turn, was not affected by different classes of antiviral drugs.

Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation.

The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called 'shock-and-kill' regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection.

CT-guided percutaneous cryoablation combined with systemic chemotherapy for liver metastases from esophageal carcinoma: Initial experience.

OBJECTIVE: To explore the feasibility, safety and effectiveness of percutaneous cryoablation combined with systemic chemotherapy in the treatment of liver metastases from esophageal carcinoma (ECLM). MATERIALS AND METHODS: We retrospectively collected data of 16 patients who received CT-guided percutaneous cryoablation concurrent systemic chemotherapy for liver metastases after primary esophageal carcinoma resection. Functional Assessment of Cancer Therapy-General (FACT-G) was used for the assessment of quality of life (QOL), and overall survival (OS), progression-free survival (PFS) and complications were also evaluated. RESULTS: The technical success rate was 96%, and no major complications related to cryoablation procedure were detected. Median OS and PFS after cryoablation were 14.5 months (range, 4-51 months) and 7.5 months (range, 1-31 months), respectively. The 1-year, 2-year, and 3-year survival rates were 56.3%, 31.3%, and 18.8%, respectively. The PFS rate at 6-month, 1-year, and 2-year after procedure were 68.8%, 31.3% and 18.8%, respectively. Furthermore, the QOL of patients was improved after cryoablation therapy compared with preoperative scores (P < 0.05). CONCLUSIONS: Percutaneous cryoablation combined with systemic chemotherapy is a safe, feasible and effective method to treat liver metastases from esophageal carcinoma. And to a certain extent, this approach is very efficacious in improving the QOL of patients with ECLM.

CT-guided percutaneous cryoablation for palliative therapy of gastric cancer liver metastases.

OBJECTIVE: Liver metastases occur in approximately 4%-14% of gastric cancer patients and are associated with high mortality. However, no standardized treatment approach is available for these patients. We aimed to assess the clinical outcomes of patients with gastric cancer liver metastases (GCLM) who underwent percutaneous cryoablation. METHODS: We retrospectively enrolled 19 patients with 27 metastatic hepatic tumors who underwent cryoablation for liver metastases after gastrectomy for primary gastric cancer. Complications, overall survival (OS), local tumor progression-free survival (PFS), recurrence rates, and quality of life were assessed. RESULTS: After cryoablation therapy, the median OS for all 19 patients was 16.0 months (range, 5-50 months), and the 1-, 2-, and 3-year OS rates were 78.9%, 43.4%, and 21.7%, respectively. The median local tumor PFS was 8.0 months (range, 3-24 months), and the local tumor PFS rates at 6 and 12 months were 59.2% and 23.2%, respectively. Overall, patients' quality of life improved after cryoablation therapy (P < 0.05). Complications in this study were mild; no severe complications caused by technique were detected. CONCLUSIONS: Cryoablation provided good local control, improved patients' quality of life and had a low complication rate. Our research showed that cryoablation may be an effective palliative treatment for GCLM.

Diagnostic value evaluation of trefoil factors family 3 for the early detection of colorectal cancer.

AIM: The purpose of this study was to evaluate the diagnostic value of trefoil factor family 3 (TFF3) for the early detection of colorectal cancer (CC). METHODS: Serum TFF3 and carcino-embryonic antigen (CEA) were detected in 527 individuals, including 115 healthy control (HC), 198 colorectal adenoma (CA), and 214 CC individuals in the training group. RESULTS: Serum TFF3 showed no significant correlation with age, gender, or tumor location but showed significant correlation with the tumor stage. Serum TFF3 in the CC group was significantly higher than in the HC or CA group. The AUC values of TFF3 for discriminating between HC and CC and between CA and CC were 0.930 (0.903, 0.958) and 0.834 (0.796, 0.873). A multivariate model combining TFF3 and CEA was built. Compared to TFF3 or CEA alone, the multivariate model showed significant improvement (P < 0.001). For discriminating between HC and CC, HC and early stage CC, HC and advanced stage CC, CA and CC, CA and early stage CC, and CA and advanced stage CC in the training group, the sensitivities were 92.99%, 91.46%, 93.18%, 73.83%, 76.83%, and 81.82%, and the specificities were 91.30%, 91.30%, 93.91%, 88.38%, 77.27%, and 88.38%, respectively. After validation, the sensitivities were 89.39%, 85.71%, 90.79%, 72.73%, 71.43%, and 78.95%, and the specificities were 87.85%, 87.85%, 2.52%, 87.85%, 80.77%, and 87.50%, respectively. CONCLUSION: The multivariate diagnostic model that included TFF3 and CEA showed significant improvement over the conventional biomarker CEA and might provide a potential method for the early detection of CC.

CCL15 overexpression predicts poor prognosis for hepatocellular carcinoma.

OBJECTIVES: The purpose of this study was to study the expression of CCL15 in hepatocellular carcinoma (HCC) and explore its clinicopathological significance, and study relationships between expressions of CCL15 and malignant behaviors of HCC. METHODS: The SP immunohistochemical method was used to detect expression of CCL15 in routinely paraffin-embedded sections from 80 cases of HCC, 80 of adjacent cancerous specimens and 50 of normal liver tissue. In these patients with HCC, Kaplan-Meier was used to assess survival outcomes. RESULTS: The positive rates and scores of CCL15 were significantly higher in HCC than adjacent cancerous specimens and normal liver tissue (p < 0.05), but not significantly higher between adjacent cancerous specimens and normal liver tissue (p > 0.05). The expression of CCL15 was significantly correlated to tumor size, tumor thrombi in portal vein of HCC, capsule and TNM stage (p < 0.05), but not to sex, age, liver cirrhosis and the level of AFP so on (p > 0.05). Survival time of the patients with positive CCL15 expression was significantly decreased, and multivariate analysis indicated CCL15 expression was one of the independent predictors of survival (p = 0.042). CONCLUSION: The expression of CCL15 was significantly correlated with malignant behaviors of HCC, and CCL15 might be important biological markers for reflecting the carcinogenesis, progression, biological behaviors and prognosis of HCC.

Expression of prostate-specific membrane antigen in lung cancer cells and tumor neovasculature endothelial cells and its clinical significance.

BACKGROUND: Prostate-specific membrane antigen (PSMA) has been found in tumor neovasculature endothelial cells (NECs) of non-prostate cancers and may become the most promising target for anti-tumor therapy. To study the value of PSMA as a potential new target for lung cancer treatment, PSMA expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) tissues and its relationship with clinicopathology were investigated in the current study. METHODS: Immunohistochemistry was used to detect PSMA expression in a total of 150 lung specimens of patients with lung cancer. The data were analyzed using univariate and multivariate statistical analyses. RESULTS: The percentages of NSCLC patients who had PSMA (+) tumor cells and PSMA (+) NECs were 54.02% and 85.06%, respectively. The percentage of patients younger than 60 years old who had PSMA (+) tumor cells was 69.05%, which was significantly greater than the percentage of patients aged 60 years or older (40.00%, p<0.05). A significant difference was observed in the percentage of NSCLC patients with PMSA (+) NECs and stage I or II cancer (92.98%) and those patients with stage III or IV cancer (76.77%). In the SCLC tissues, NEC PSMA expression (70.00%) did not differ significantly from NSCLC. SCLC tumor cells and normal lung tissues cells were all negative. There was no significant correlation between the presence of PSMA (+) NECs in SCLC patients and the observed clinicopathological parameters. CONCLUSIONS: PSMA is expressed not only in NECs of NSCLC and SCLC but also in tumor cells of most NSCLC patients. The presence of PSMA (+) tumor cells and PSMA (+) NECs in NSCLC was negatively correlated with age and the clinicopathological stage of the patients, respectively.

Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes.

Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of immunomodulatory and supporting hematopoiesis. Nevertheless, it is unclear whether the characteristics of MSCs are altered in diseased states. In this study, we obtained and expanded MSCs from bone marrow of patients with myelodysplastic syndromes (MDS). Our results showed that MSCs derived from MDS (MDS-MSCs) were similar to normal adult bone marrow derived MSCs in morphology, growth property, surface epitopes, and differentiation ability in vitro. In addition, MDS-MSCs had normal karyotype and ultrastructure. However, MDS-MSCs appeared to be impaired in immunomodulatory and supporting hematopoiesis function. Although, MDS-MSCs could express hematopoietic cytokines and support hematopoiesis in long term culture, Real time quantitative polymerase chain reaction showed that the expression of hematopoietic cytokines in MDS-MSCs was much lower than that of normal adult derived MSCs. Moreover, MDS-MSCs showed reduced hematopoiesis support function, as compared to their normal counterparts. Lastly, the capacity of MDS-MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. These results indicate that MDS-MSCs have impaired immunomodulatory and hematopoiesis support functions, suggesting their critical role in the pathogenesis of MDS.

[Expression and significance of macrophage migration inhibitory factor in gastric adenocarcinoma].

OBJECTIVE: To investigate the expression of MIF on the gastric adenocarcinoma, evaluate the relation between the MIF expression and tumor differentiation, lymph node metastasis and other clinical patho-features. METHODS: 120 gastric adenocarcinoma cancer tissues, 40 tissues besides cancer and 40 common mucosa tissues specimens are collected. Detect the expression of MIF with immunohistochemistry method (Streptavidin-Peroxidase). RESULTS: Positive rate of MIF expression in gastric cancer is 80.8% (97/120). Those in poorly differentiated, moderately differentiated and well-differentiated gastric adenocarcinoma are 97.5% (39/40), 82.5% (33/40), 62.5% (25/40), analytical factor of Spearman rank correlation r(s) is 0.458 (χ(2) = 27.046, P < 0.001). Positive rate of MIF expression in tissues besides cancer is 40% (16/40) and that in normal gastric mucosa is 7.5% (3/40). Positive rate of MIF expression in gastric adenocarcinoma without lymph node metastasis is 40% (22/55) and the rate with lymph node metastasis is 67% (44/65). CONCLUSIONS: There is overexpression of MIF in the gastric adenocarcinoma. Expression of MIF in different differentiated cancer is different. Expression in poorly differentiated is higher than that in moderately differentiated and well-differentiated cancer. The level of expression of MIF malignancy has positive correlation with malignancy degree of gastric adenocarcinoma. MIF expression has nothing to do with age, gender, tumor sizes or location.

[A preliminary clinical study of targeted cryoablation of prostate in the treatment of T3N0M0 prostate cancer].

OBJECTIVE: To evaluate the clinical efficacy, safety and application value of rectal ultrasound-guided targeted cryoablation of prostate (TCAP) in the treatment of T3N0M0 prostate cancer. METHODS: Transrectal ultrasound (TRUS)-guided TCAPs were performed. And prostate-specific antigen (PSA), TRUS-measured prostate volume, endorectal magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) at before, 12, 24, 36 months after TCAP were recorded and evaluated. The biochemical relapse free survival (bRFS) and clinical progression (local recurrence and distant metastasis) at 1, 2 and 3 years post-cryoablation were also recorded. The post-TCAP quality of life was also observed by the EORTC questionnaire QLQ-PR25. RESULTS: The suess rate of this technique was 100%. The follow-up period had a range of 10 to 45 months. The PSA level decreased dramatically (P < 0.01). The TRUS-measured prostate volumes significantly decreased (P < 0.01) versus those at pre-cryoablation. The bRFS at 1, 2 and 3 years post-TCAP was 92.5% (37/40), 87.1% (27/31) and 73.3% (11/15) respectively. The result of quality of life showed that the sexuality scores decreased at 6 months post-TCAP, but there was no statistical significance (P = 0.06) and recovered to baseline level at 12 months. Urinary symptoms improved significantly (P < 0.01). The clinical progression rate in this study at 3 years was 24.4% (11/45). To be specific, local recurrence rate was 54.5% (6/11) and distant metastasis rate 45.5% (5/11). Repeated cryoablation was performed for the patients with local recurrence and satisfactory results were achieved during a follow-up of 10 - 15 months. Endocrine treatment was adopted for the patients with distant metastasis and appeared to have biochemical progression free survival during a follow-up of 6 - 13 months. The therapy was safe. Most of side effects were mild and there was no occurrence of severe complications such as urethral fistulas, etc. CONCLUSION: Treating T3N0M0 prostate cancer with TCAP as a monotherapy can obtain a satisfactory outcome during a follow-up of 3 years. But its clinical application value deserves further studies.

[Percutaneous verterbreplasty combined with radiotherapy treating malignant vertebrate metastasis].

OBJECTIVE: To evaluate retrospectively the treatment effects and side effects of malignant vertebrate metastasis who had received radiotherapy or percutaneous verterbreplasty (PVP) or PVP combined with radiotherapy. METHODS: Two hundred and sixty-three patients who had been diagnosed as malignant tumor with vertebrate metastasis received PVP (87 patients) or radiotherapy (111 patients) or PVP combined with radiotherapy (65 patients). Radiotherapy was done one week after PVP procedure in PVP combined with radiotherapy group. All patients received regular follow-up. The changes of pain scale were analyzed by NRS. The improvement of quality of life was evaluated by inquiry questionnaire of EORTC QLQ-C30. The side effects were also observed. RESULTS: All defects in vertebrate metastasis in PVP treating were fully filled by polymethylmethacrylate (PMMA) under CT examination. The NRS number decreased significantly after 6 hours after treating in PVP Group and PVP combined with radiotherapy Group (P < 0.01), which shows basement of pain was rapid. The NRS number decreased significantly after one month after treating in radiotherapy Group (P < 0.01), which shows basement of pain was slow. The score of EORTC QLQ-C30 inquiry questionnaire in three Groups reduced, which indicated that the quality of life had been improved. In PVP Group and PVP combined with radiotherapy Group, the score of EORTC QLQ-C30 changed most significantly (P < 0.01). There were no severe clinical complications. CONCLUSIONS: It is safe and effective to treat malignant tumor patients with vertebrate metastasis by PVP combined with radiotherapy and quality of life had been improved significantly with long catabasis.

[Expression of hepatitis B surface antigen gene in ginseng cell].

The recombinant plasmid pBIBSa containing the HBsAg DNA fragment was transferred into Agrobacterium tumefaciens strain LBA4404 directly. Ginseng cells were co-cultivated with Agrobacterium tumefaciens carrying pBIBSa. The ginseng cell lines carrying HBsAg-S gene were obtained. Transgenic cells were checked for the presence of target gene using PCR and RT-PCR. Samples containing the target gene showed a clear band at the site of 700 bp by agarose electrophoresis analysis (Figs. 2, 3). Expression levels determined by ELISA showed maximum expression levels of 184 ng HBsAg/g FW and 0.009% of the total soluble protein. HBsAg in ginseng cells were located both on the membrane and in the nuclei (Fig. 4).