Mechanism of acupuncture and moxibustion in ameliorating liver injury induced by cisplatin by regulating IRE-1 signaling pathway. / "扶正益肝"é’ˆç¸ç©´æ–¹åŸºäºŽè‚Œé†‡éœ€æ±‚é ¶1ä¿¡å·é€šè·¯æ”¹å–„é¡ºé“‚è‡´å°é¼ è‚æŸä¼¤çš„æœºåˆ¶.

OBJECTIVES: To investigate the mechanism of the effect of acupuncture and moxibustion on improving liver injury in cisplatin (DDP) induced liver injury model mice by observing the changes of inositol-requiring enzyme (IRE) -1 signaling pathway. METHODS: Forty KM mice were randomly divided into control, model, acupuncture and moxibustion groups, with 10 mice in each group. The liver injury model was replicated by intraperitoneal injection of DDP (10 mg/kg). In the acupuncture group and the moxibustion group, acupuncture and moxibustion were performed at "Dazhui"(GV14), and bilateral "Ganshu"(BL18), "Shenshu" (BL23), and "Zusanli"(ST36), respectively for 6 min, once per day for 7 d. The apoptosis of hepatocytes was detected by TUNEL staining. The expression of phosphorylation(p)-IRE-1α, glucose-regulated protein (Grp) 78 and cysteine aspartic protease (Caspase) -12 in liver tissue were detected by immunohistochemistry and Western blot, respectively. The expression levels of Grp78 and Caspase-12 mRNA in liver tissue were detected by quantitative real-time PCR. RESULTS: Compared with the control group, the apoptosis rate of hepatocytes was increased (P<0.05), the positive expression and protein expression of p-IRE-1α, Grp78, and Caspase-12 were increased (P<0.05), the expression levels of Grp78 and Caspase-12 mRNA were increased (P<0.05) in the model group. Compared with the model group, all these indicators showed opposite trends (P<0.05) in the acupuncture and moxibustion groups. CONCLUSIONS: Acupuncture and moxibustion can reduce liver injury due to DDP chemotherapy by modulating IRE-1 signaling pathway, inhibiting the excessive activation of endoplasmic reticulum stress, and reducing liver cell apoptosis.

FAM53B promotes pancreatic ductal adenocarcinoma metastasis by regulating macrophage M2 polarization.

BACKGROUND: Our study investigated the role of FAM53B in regulating macrophage M2 polarization and its potential mechanisms in promoting pancreatic ductal adenocarcinoma (PDAC) metastasis. AIM: To further investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism in promoting PDAC metastasis. Our goal is to determine how FAM53B affects macrophage M2 polarization and to define its underlying mechanism in PDAC metastasis. METHODS: Cell culture and various experiments, including protein analysis, immunohistochemistry, and animal model experiments, were conducted. We compared FAM53B expression between PDAC tissues and healthy tissues and assessed the correlation of FAM53B expression with clinical features. Our study analyzed the role of FAM53B in macrophage M2 polarization in vitro by examining the expression of relevant markers. Finally, we used a murine model to study the role of FAM53B in PDAC metastasis and analyzed the potential underlying mechanisms. RESULTS: Our research showed that there was a significant increase in FAM53B levels in PDAC tissues, which was linked to adverse tumor features. Experimental findings indicated that FAM53B can enhance macrophage M2 polarization, leading to increased anti-inflammatory factor release. The results from the mouse model further supported the role of FAM53B in PDAC metastasis, as blocking FAM53B prevented tumor cell invasion and metastasis. CONCLUSION: FAM53B promotes PDAC metastasis by regulating macrophage M2 polarization. This discovery could lead to the development of new strategies for treating PDAC. For example, interfering with the FAM53B signaling pathway may prevent cancer spread. Our research findings also provide important information for expanding our understanding of PDAC pathogenesis.

[Effect of Recombinant Human Thrombopoietin on Platelet Reconstitution after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma].

OBJECTIVE: To analyze the effect of recombinant human thrombopoietin (rhTPO) on platelet (PLT) reconstitution after autologous peripheral blood stem cell transplantation (APBSCT) in patients with multiple myeloma (MM). METHODS: The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed. According to whether rhTPO was used during APBSCT, the patients were divided into rhTPO group (80 cases) and control group (67 cases). The time of PLT engraftment, blood product infusion requirements, the proportion of patients with PLT recovery to≥50×109/L and≥100×109/L at +14 days and +100 days after transplantation, and adverse reactions including the incidence of bleeding were compared between the two groups. RESULTS: There were no significant differences between the two groups in sex, age, M protein type, PLT count at the initial diagnosis, median duration of induction therapy before APBSCT, and number of CD34+ cells reinfused (all P >0.05). The median time of PLT engraftment in the rhTPO group was 10 (6-14) days, which was shorter than 11 (8-23) days in the control group (P < 0.001). The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U, which was less than 20 (0-80)U in the control group (P =0.001). At +14 days after transplantation, the proportions of patients with PLT≥50×109/L in the rhTPO group and the control group were 66.3% and 52.2%, while the proportions of patients with PLT≥100×109/L were 23.8% and 11.9%, respectively, with no significant differences (all P >0.05). At +100 days after transplantation, the proportion of patients with PLT≥50×109/L in rhTPO group and control group was 96.3% and 89.6%, respectively (P >0.05), but the proportion of patients with PLT≥100×109/L in rhTPO group was higher than that in control group (75.0% vs 55.2%, P =0.012). There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups. In rhTPO group, the rhTPO administration was well tolerated, and the incidences of abnormal liver and kidney function and infection were similar to those in the control group. CONCLUSION: When MM patients undergo first-line APBSCT, subcutaneous injection of rhTPO can shorten the time of platelet engraftment, reduce the transfusion volume of blood products, and be well tolerated, moreover, more patients have achieve a high level of PLT recovery after transplantation, which is very important for ensuring the safety of APBSCT and maintenance therapy.

Activation of RIG-I signaling in the early stage of Paragonimus proliferus infection causes lung injury via type I immune response in rat.

Paragonimiasis is a common zoonotic parasitic disease. The retinoic acid-inducible gene I (RIG-I) signaling is very important for the host to recognize invading pathogens (especially viruses and bacteria). However, the role of RIG-I signaling in the early stages of P. proliferus infection remains unclear. Therefore, in this study, Sprague-Dawley (SD) rat models with lung damage caused by P. proliferus were established. Experimental methods including Enzyme-linked Immuno Sorbent Assay (ELISA), real-time fluorescent quantitative polymerase chain reaction (PCR), western blotting, and hematoxylin and eosin (HE) staining were used to explore the mechanisms of lung injury caused by P. proliferus. As a result, the expression of the mRNA and proteins of RIG-I signal-related key target molecules, including RIG-I, tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), interferon regulatory Factor 7 (IRF7), IPS-1, and downstream C-X-C chemokine ligand 10 (CXCL10), were significantly up-regulated immediately after infection, peaked at 3 or 7 days, and showed a downward trend on after 14 days. The levels of pro-inflammatory cytokines interleukin-1 (IL-1), interferon (IFN)-α, -ß, and -γ, which represent type 1 immune response, gradually increased and reached a peak by 14 days, which was consistent with the changes in the degree of inflammatory damage observed under HE staining of lung tissues. In conclusion, RIG-I signaling is activated in the early stage (before 14 days) of P. proliferus infection, it is inferred that the lung injury of the host may be related to the activation of RIG-I like signaling to induce type I immune response.

Application of computer-aided diagnosis to predict malignancy in BI-RADS 3 breast lesions.

Purpose: To evaluate the ability of computer-aided diagnosis (CAD) system (S-Detect) to identify malignancy in ultrasound (US) -detected BI-RADS 3 breast lesions. Materials and methods: 148 patients with 148 breast lesions categorized as BI-RADS 3 were included in the study between January 2021 and September 2022. The malignancy rate, accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) were calculated. Results: In this study, 143 breast lesions were found to be benign, and 5 breast lesions were malignant (malignancy rate, 3.4 %, 95 % confidence interval (CI): 0.5-6.3). The malignancy rate rose significantly to 18.2 % (4/22, 95 % CI: 2.1-34.3) in the high-risk group with a "possibly malignant" CAD result (p = 0.017). With a "possibly benign" CAD result, the malignancy rate decreased to 0.8 % (1/126, 95 % CI: 0-2.2) in the low-risk group (p = 0.297). The AUC, sensitivity, specificity, accuracy, PPV, and NPV of the CAD system in BI-RADS 3 breast lesions were 0.837 (95 % CI: 77.7-89.6), 80.0 % (95 % CI: 73.6-86.4), 87.4 % (95 % CI: 82.0-92.7), 87.2 % (95 % CI: 81.8-92.6), 18.2 % (95 % CI: 2.1-34.3) and 99.2 % (95 % CI: 97.8-100.0), respectively. Conclusions: CAD system (S-Detect) enables radiologists to distinguish a high-risk group and a low-risk group among US-detected BI-RADS 3 breast lesions, so that patients in the low-risk group can receive follow-up without anxiety, while those in the high-risk group with a significantly increased malignancy rate should actively receive biopsy to avoid delayed diagnosis of breast cancer.

Intratumoral injection of norcantharidin liposome emulsion hybrid delivery system amplifies the cancer-fighting effects of oral sorafenib against hepatocellular carcinoma.

Interventional therapies are increasingly used in clinical trials for hepatocellular carcinoma (HCC). Sorafenib is the front-line remedy for HCC, however, chemoresistance occurs immutably and affects the effectiveness of treatment. In a previous study, a norcantharidin liposome emulsion hybrid (NLEH) delivery system for HCC was developed. This study aims to examine the therapeutic effects of the combination of intratumoral injection of NLEH and sorafenib in treating HCC. Sorafenib combined with NLEH activated the apoptosis pathway by synergistically upregulating caspase-9, promoting cytotoxicity, apoptosis (64.57%), and G2/M cell cycle arrest (48.96%). Norcantharidin could alleviate sorafenib resistance by counteracting sorafenib-induced phosphorylation of Akt. Additionally, intratumoral injection of NLEH exhibited a sustained accumulation in the tumor within 24 h and didn't distribute to other major organs. Intratumoral injection of NLEH in combination with oral sorafenib displayed the most potent tumor growth inhibitory effect (77.91%) in vivo. H&E staining results and the indicators of the renal and liver function tests demonstrated the safety of this combination therapy. Overall, these results showed that intratumoral injection of NLEH in combination with oral sorafenib treatment represented a rational potential therapeutic option for HCC.

Clinical Application of Computer-Aided Diagnosis System in Breast Ultrasound: A Prospective Multicenter Study.

OBJECTIVES: Ultrasound tends to present very high sensitivity but relatively low specificity and positive predictive value (PPV), which would result in unnecessary breast biopsies. The purpose of this study is to analyze the diagnostic performance of computer-aided diagnosis (CAD) (S-Detect) system in differentiating breast lesions and reducing unnecessary biopsies in non-university hospitals in less-developed regions of China. METHODS: The study was a prospective multicenter study from 8 hospitals. The ultrasound images, and cine, CAD analysis, and BI-RADS were recorded. The accuracy, sensitivity, specificity, PPV, negative predictive value (NPV), and area under the curve (AUC) were analyzed and compared between CAD and radiologists. The Youden Index (YI) was used to determine optimal cut-off for the number of planes to downgrade. RESULTS: A total of 491 breast lesions were included in the study. Less-experienced radiologists combined CAD was superior to less-experienced radiologists alone in AUC (0.878 vs 0.712, p < 0.001), and specificity (81.3% vs 44.6%, p < 0.001). There was no statistical difference in AUC (0.891 vs 0.878, p = 0.346), and specificity (82.3% vs 81.3%, p = 0.791) between experienced radiologists and less-experienced radiologists combined CAD. With CAD assistance, the biopsy rate of less-experienced radiologists was significantly decreased (100.0% vs 25.6%, p < 0.001), and malignant rate of biopsy was significantly increased (15.0% vs 43.9%, p < 0.001). CONCLUSIONS: CAD system can be an effective auxiliary tool in differentiating breast lesions and reducing unnecessary biopsies for radiologists from non-university hospitals in less-developed regions of China.

Barley HOMOCYSTEINE METHYLTRANSFERASE 2 confers drought tolerance by improving polyamine metabolism.

Drought stress poses a serious threat to crop production worldwide. Genes encoding homocysteine methyltransferase (HMT) have been identified in some plant species in response to abiotic stress, but its molecular mechanism in plant drought tolerance remains unclear. Here, transcriptional profiling, evolutionary bioinformatics, and population genetics were conducted to obtain insight into the involvement of HvHMT2 from Tibetan wild barley (Hordeum vulgare ssp. agriocrithon) in drought tolerance. We then performed genetic transformation coupled with physio-biochemical dissection and comparative multiomics approaches to determine the function of this protein and the underlying mechanism of HvHMT2-mediated drought tolerance. HvHMT2 expression was strongly induced by drought stress in tolerant genotypes in a natural Tibetan wild barley population and contributed to drought tolerance through S-adenosylmethionine (SAM) metabolism. Overexpression of HvHMT2 promoted HMT synthesis and efficiency of the SAM cycle, leading to enhanced drought tolerance in barley through increased endogenous spermine and less oxidative damage and growth inhibition, thus improving water status and final yield. Disruption of HvHMT2 expression led to hypersensitivity under drought treatment. Application of exogenous spermine reduced accumulation of reactive oxygen species (ROS), which was increased by exogenous mitoguazone (inhibitor of spermine biosynthesis), consistent with the association of HvHMT2-mediated spermine metabolism and ROS scavenging in drought adaptation. Our findings reveal the positive role and key molecular mechanism of HvHMT2 in drought tolerance in plants, providing a valuable gene not only for breeding drought-tolerant barley cultivars but also for facilitating breeding schemes in other crops in a changing global climate.

Soluble CD4 effectively prevents excessive TLR activation of resident macrophages in the onset of sepsis.

T lymphopenia, occurring in the early phase of sepsis in response to systemic inflammation, is commonly associated with morbidity and mortality of septic infections. We have previously shown that a sufficient number of T cells is required to constrain Toll-like receptors (TLRs) mediated hyperinflammation. However, the underlying mechanisms remains unsolved. Herein, we unveil that CD4+ T cells engage with MHC II of macrophages to downregulate TLR pro-inflammatory signaling. We show further that the direct contact between CD4 molecule of CD4+ T cells or the ectodomain of CD4 (soluble CD4, sCD4), and MHC II of resident macrophages is necessary and sufficient to prevent TLR4 overactivation in LPS and cecal ligation puncture (CLP) sepsis. sCD4 serum concentrations increase after the onset of LPS sepsis, suggesting its compensatory inhibitive effects on hyperinflammation. sCD4 engagement enables the cytoplasmic domain of MHC II to recruit and activate STING and SHP2, which inhibits IRAK1/Erk and TRAF6/NF-κB activation required for TLR4 inflammation. Furthermore, sCD4 subverts pro-inflammatory plasma membrane anchorage of TLR4 by disruption of MHC II-TLR4 raft domains that promotes MHC II endocytosis. Finally, sCD4/MHCII reversal signaling specifically interferes with TLR4 but not TNFR hyperinflammation, and independent of the inhibitive signaling of CD40 ligand of CD4+ cells on macrophages. Therefore, a sufficient amount of soluble CD4 protein can prevent excessive inflammatory activation of macrophages via alternation of MHC II-TLR signaling complex, that might benefit for a new paradigm of preventive treatment of sepsis.

Deep Learning-Based Computer-Aided Diagnosis for Breast Lesion Classification on Ultrasound: A Prospective Multicenter Study of Radiologists Without Breast Ultrasound Expertise.

BACKGROUND. Computer-aided diagnosis (CAD) systems for breast ultrasound interpretation have been primarily evaluated at tertiary and/or urban medical centers by radiologists with breast ultrasound expertise. OBJECTIVE. The purpose of this study was to evaluate the usefulness of deep learning-based CAD software on the diagnostic performance of radiologists without breast ultrasound expertise at secondary or rural hospitals in the differentiation of benign and malignant breast lesions measuring up to 2.0 cm on ultrasound. METHODS. This prospective study included patients scheduled to undergo biopsy or surgical resection at any of eight participating secondary or rural hospitals in China of a breast lesion classified as BI-RADS category 3-5 on prior breast ultrasound from November 2021 to September 2022. Patients underwent an additional investigational breast ultrasound, performed and interpreted by a radiologist without breast ultrasound expertise (hybrid body/breast radiologists, either who lacked breast imaging subspecialty training or for whom the number of breast ultrasounds performed annually accounted for less than 10% of all ultrasounds performed annually by the radiologist), who assigned a BI-RADS category. CAD results were used to upgrade reader-assigned BI-RADS category 3 lesions to category 4A and to downgrade reader-assigned BI-RADS category 4A lesions to category 3. Histologic results of biopsy or resection served as the reference standard. RESULTS. The study included 313 patients (mean age, 47.0 ± 14.0 years) with 313 breast lesions (102 malignant, 211 benign). Of BI-RADS category 3 lesions, 6.0% (6/100) were upgraded by CAD to category 4A, of which 16.7% (1/6) were malignant. Of category 4A lesions, 79.1% (87/110) were downgraded by CAD to category 3, of which 4.6% (4/87) were malignant. Diagnostic performance was significantly better after application of CAD, in comparison with before application of CAD, in terms of accuracy (86.6% vs 62.6%, p < .001), specificity (82.9% vs 46.0%, p < .001), and PPV (72.7% vs 46.5%, p < .001) but not significantly different in terms of sensitivity (94.1% vs 97.1%, p = .38) or NPV (96.7% vs 97.0%, p > .99). CONCLUSION. CAD significantly improved radiologists' diagnostic performance, showing particular potential to reduce the frequency of benign breast biopsies. CLINICAL IMPACT. The findings indicate the ability of CAD to improve patient care in settings with incomplete access to breast imaging expertise.

Clinical application status and prospect of the combined anti-tumor strategy of ablation and immunotherapy.

Image-guided tumor ablation eliminates tumor cells by physical or chemical stimulation, which shows less invasive and more precise in local tumor treatment. Tumor ablation provides a treatment option for medically inoperable patients. Currently, clinical ablation techniques are widely used in clinical practice, including cryoablation, radiofrequency ablation (RFA), and microwave ablation (MWA). Previous clinical studies indicated that ablation treatment activated immune responses besides killing tumor cells directly, such as short-term anti-tumor response, immunosuppression reduction, specific and non-specific immune enhancement, and the reduction or disappearance of distant tumor foci. However, tumor ablation transiently induced immune response. The combination of ablation and immunotherapy is expected to achieve better therapeutic results in clinical application. In this paper, we provided a summary of the principle, clinical application status, and immune effects of tumor ablation technologies for tumor treatment. Moreover, we discussed the clinical application of different combination of ablation techniques with immunotherapy and proposed possible solutions for the challenges encountered by combined therapy. It is hoped to provide a new idea and reference for the clinical application of combinate treatment of tumor ablation and immunotherapy.

Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies.

Unprecedented advances have been achieved in hepatobiliary cancer treatment with immune checkpoint blockade (ICB). However, the efficacy of ICB in patients with hepatobiliary malignancies is still limited. Resistance to immunotherapies is often orchestrated by complicated tumor-host-microenvironment interactions but could also occur after initial efficacy, mostly when only partial responses are obtained. Clarification of cancer-resistance mechanisms will be beneficial to provide the rationale for the administration of personalized drugs. Here, we review the factors related to resistance to immune-targeted therapies in hepatobiliary malignancies and discuss the potential strategies for overcoming resistance and future directions of immunotherapy development.

[A Propensity Score Matching Study of Autologous Hematopoietic Stem Cell Transplantation and New Drug Chemotherapy for Newly Diagnosed Multiple Myeloma].

OBJECTIVE: To compare the clinical efficacy, survival, and prognosis of autologous hematopoietic stem cell transplantation (ASCT) with new drug chemotherapy in the treatment of newly diagnosed multiple myeloma (NDMM) in the new drug era. METHODS: The clinical data of 149 patients with NDMM treated with new drug induction regimen in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2012 to December 2019 were retrospectively analyzed. Twenty-four patients who received ASCT were in ASCT group, and 125 patients who did not receive ASCT were in non-ASCT group. The median follow-up time was 43 (1-90) months. The propensity score matching (PSM) method was used to balance confounding factors, then depth of response, overall survival (OS), and progression-free survival (PFS) between the two groups were compared and subgroup analysis was performed. RESULTS: After matching, the covariates were balanced between the two groups. Fifty-one patients (15 cases in ASCT group and 36 cases in non-ASCT group) were included. ASCT patients had a better complete response (CR) rate than non-ASCT patients receiving maintenance therapy (93.3% vs 42.3%, P=0.004), while there were no statistical differences in deep response rate and overall response rate (ORR) between the two groups (93.3% vs 65.4%, P=0.103; 93.3% vs 96.2%, P=1.000). Before matching, the 3 and 5-year PFS rate and median PFS (mPFS) in ASCT group and non-ASCT group were [89.6% vs 66.5%, P=0.024; 69.8% vs 42.7%; non-response (NR) vs 51.0 months], and the 3 and 5-year OS rate and median OS (mOS) were (100% vs 70.6%, P=0.002; 92.3% vs 49.6%; NR vs 54.0 months). After matching, the 3 and 5-year PFS rate and mPFS in ASCT group and non-ASCT group were (83.6% vs 61.7%, P=0.182; 62.7% vs 45.7%; NR vs 51.0 months), the 3 and 5-year OS rate and mOS were (100% vs 65.6%, P=0.018; 88.9% vs 46.9%; NR vs 51.0 months). Subgroup analysis showed that patients with mSMART 3.0 high risk stratification, the 3-year PFS rate and mPFS in ASCT group and non-ASCT group were (83.3% vs 41.5%, P=0.091; NR vs 34.0 months), and the 3-year OS rate and mOS were (100% vs 41.5%, P=0.034; NR vs 34.0 months). Patients with mSMART 3.0 standard risk stratification, the 3-year PFS rate and OS rate in ASCT group and non-ASCT group were (83.3% vs 76.8%, P=0.672; 100% vs 87.2%, P=0.155). The 3-year PFS and OS rate in MM patients who achieved deep response within 3 months after transplantation compared with non-ASCT patients who achieved deep response after receiving maintenance therapy were (83.1% vs 56.7%, P=0.323; 100% vs 60.5%, P=0.042), and the 3-year PFS and OS rate in patients who achieved overall response in both groups were (83.1% vs 62.5%, P=0.433; 100% vs 68.1%, P=0.082). After matching, Cox multivariate regression analysis showed that mSMART 3.0 risk stratification and ASCT were independent prognostic factors for OS. CONCLUSION: In the new drug era, ASCT can increase CR rate and prolong OS of NDMM patients. ASCT patients who are mSMART 3.0 high risk stratification or achieved deep response within 3 months after transplantation have better OS than non-ASCT patients receiving new drug chemotherapy. ASCT and mSMART 3.0 risk stratification are independent prognostic factors for OS in NDMM patients.

Treatment for CD57-negative γδ T-cell large granular lymphocytic leukemia with pure red cell aplasia: A case report.

BACKGROUND: T-cell large granular lymphocytic leukemia (T-LGLL) is a rare type of aplastic anemia with diverse clinical manifestations. Concomitant diseases are often present at the first manifestation. We describe the treatment of a patient with CD57-negative γδT-LGLL with pure red cell aplasia (PRCA). CASE SUMMARY: A 34-year-old woman with a 20-year history of anemia visited our hospital owing to severe dizziness and was admitted. Her condition was diagnosed as CD57-negative γδT-LGLL with PRCA through bone marrow cytology, bone marrow pathology, bone marrow flow cytometry, bone marrow multiplex polymerase chain reaction combined with fluorescent fragment analysis, and other tests. Treatment with prednisone, methotrexate, and subcutaneous erythropoietin did not significantly change her hemoglobin level. After treatment with oral cyclophosphamide for 3 mo, her hemoglobin level increased to approximately 100 g/L. After 5 mo of treatment, the patient could perform activities of daily living independently. CONCLUSION: The treatment of CD57-negative γδT-LGLL with PRCA with cyclophosphamide helps to improve prognosis.

Elevated LOXL2 expression by LINC01347/miR-328-5p axis contributes to 5-FU chemotherapy resistance of colorectal cancer.

Chemotherapy resistance after curative surgery is a major contributor to the mortality of colorectal cancer (CRC). Detailed mechanism studies of specific molecular alterations are critical to improving the available therapies for long-term disease administration. We explored the functional role of LINC01347 in chemotherapy resistance of CRC. Elevated LINC01347 expression was correlated with CRC disease progression during chemotherapy treatment. However, the functional role of LINC01347 and mechanism remained undefined. In this study, we demonstrated that elevated LINC01347 expression was correlated with late clinical stage and poor prognosis in CRC tumor tissues with TCGA data. Exogenous LINC01347 expression promoted cell proliferation and 5-FU resistance of CRC cells, while LINC01347 knockdown attenuated cell growth and 5-FU resistance in vitro and in vivo. Molecular analysis indicated that LINC01347 participated in the transcriptional regulation of LOXL2 by sponging miR-328-5p. LOXL2 knockdown impaired the LINC01347 overexpression induced 5-FU resistance in CRC cells. The clinical analysis supported miR-328-5p/LOXL2 as a candidate biomarker for chemotherapy resistance of CRC patients. Our study provided a molecular basis for the development of 5-FU based chemotherapy resistance in CRC by LINC01347/miR-328/LOXL2 axis. We identified LINC01347 as a prognostic biomarker and potential therapeutic target against 5-FU based chemotherapy resistance of CRC.

LncRNA POU3F3 Contributes to Dacarbazine Resistance of Human Melanoma Through the MiR-650/MGMT Axis.

Background: Alkylating agents are critical therapeutic options for melanoma, while dacarbazine (DTIC)-based chemotherapy showed poor sensitivity in clinical trials. Long non-coding RNAs (lncRNAs) were highlighted in the progression of malignant tumors in recent years, whereas little was known about their involvement in melanoma. Methods: The functional role and molecular mechanism of lncRNA POU3F3 were evaluated on DTIC-resistant melanoma cells. Further studies analyzed its clinical role in the disease progression of melanoma. Results: We observed elevated the expression of lncRNA POU3F3 in the DTIC-resistant melanoma cells. Gain-of-function assays showed that the overexpression of lncRNA POU3F3 maintained cell survival with DTIC treatment, while the knockdown of lncRNA POU3F3 restored cell sensitivity to DTIC. A positive correlation of the expression O6-methylguanine-DNA-methyltransferase (MGMT) was observed with lncRNA POU3F3 in vitro and in vivo. Bioinformatic analyses predicted that miR-650 was involved in the lncRNA POU3F3-regulated MGMT expression. Molecular analysis indicated that lncRNA POU3F3 worked as a competitive endogenous RNA to regulate the levels of miR-650, and the lncRNA POU3F3/miR-650 axis determined the transcription of MGMT in melanoma cells to a greater extent. Further clinical studies supported that lncRNA POU3F3 was a risk factor for the disease progression of melanoma. Conclusion: LncRNA POU3F3 upregulated the expression of MGMT by sponging miR-650, which is a crucial way for DTIC resistance in melanoma. Our results indicated that lncRNA POU3F3 was a valuable biomarker for the disease progression of melanoma.

Novel Fluorinated 7-Hydroxycoumarin Derivatives Containing an Oxime Ether Moiety: Design, Synthesis, Crystal Structure and Biological Evaluation.

A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety have been designed, synthesized and evaluated for their antifungal activity. All the target compounds were determined by 1H-NMR, 13C-NMR, FTIR and HR-MS spectra. The single-crystal structures of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal activities against Botrytis cinerea (B. cinerea), Alternariasolani (A. solani), Gibberella zeae (G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata) were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds displayed the promising antifungal activities against the above tested fungi. Strikingly, the target compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 µg/mL, with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising fungicide candidate against B. cinerea with the EC50 values of 5.75 µg/mL, which was obviously better than Osthole (33.20 µg/mL) and Azoxystrobin (64.95 µg/mL). Meanwhile, the compound 5f showed remarkable antifungal activities against R. solani with the EC50 values of 28.96 µg/mL, which was better than Osthole (67.18 µg/mL) and equivalent to Azoxystrobin (21.34 µg/mL). The results provide a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good antifungal activity.

Expression and clinical significance of PTPN12 in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a common urological disease. Expression of the protein tyrosine phosphatase 12 gene (PTPN12) is decreased in many cancers; however, the relationship between PTPN12 gene function and renal cancer remains unclear. METHODS: We detected PTPN12 protein expression in ccRCC and corresponding normal tissues from 64 patients with ccRCC by immunohistochemistry, and relative PTPN12 mRNA levels by real-time quantitative polymerase chain reaction. The relationships between the relative expression levels of PTPN12 mRNA and the patients' clinical data were analyzed. RESULTS: PTPN12 protein and mRNA expression levels were significantly lower in ccRCC compared with the corresponding normal tissues. The mRNA expression levels in the ccRCC and corresponding normal tissues from the 64 patients with ccRCC were 0.459±0.445 and 1.001±0.128, respectively, compared with the control (glyceraldehyde 3-phosphate dehydrogenase). There was a significant correlation between relative expression of PTPN12 mRNA in ccRCC tissues and tumor diameter and clinical stage. CONCLUSION: The expression levels of PTPN12 protein and mRNA were significantly lower in ccRCC tissues compared with normal tissues. The role of PTPN12 may provide new insights and evidence to aid the diagnosis and targeted therapy of ccRCC.

Synthesis of gem-difluoroalkenes via nickel-catalyzed allylic defluorinative reductive cross-coupling of trifluoromethyl alkenes with epoxides.

A nickel-catalyzed defluorinative reductive cross-coupling of trifluoromethyl alkenes with epoxides has been developed. Various substituted trifluoromethyl alkenes and epoxides were found to be suitable reaction substrates. This reaction enabled C(sp3)-C(sp3) bond construction through allylic defluorinative cross-coupling of trifluoromethyl alkenes under mild reaction conditions. This methodology was highly compatible with various sensitive functional groups, providing access to a diverse array of functionalized gem-difluoroalkene-containing alcohol compounds.