Objective To investigate the effect of lovaslatin on proliferation of cultured rat mesangial cells. Methods Cultured rat mesangial cells were stimulated by 10% fetal calf serum (FCS) or platelet-derived growth factor (PDGF) in the absence or the presence of lovastain and mevalonate metabolites. 5-Bromo-2-deoxyuridine incorporation was used to assess DNA synthesis. Results FCS or PDGF caused a marked stimulation of DNA synthesis in the mesangial cells. Lovastatin inhibited FCS or PDGF-stimulated BrdU incorporation and cell proliferation. Mevalonic acid, farnesyl pyrophosphate and geranylgeranyl pyrophosphate significantly prevented inhibitory effect of lovastatin on mesangial proliferation induced by FCS. Mevalonic acid and geranylgeranyl pyrophosphate also significantly reversed inhibitory effect of lovastatin on mesangial proliferation induced by PDGF. But farnesyl pyrophosphate only partly reversed inhibitory effect of lovastatin. Conclusions Lovastatin, by inhibiting the synthesis of isoprenoid metabolites of mevalonate, can suppress mesangial cell proliferation. It is possible to provide a new approach for treatment of proliferative glomerular diseases.

Objective To study the value of laparoscopic operation in the management of ectopic pregnancy. Methods The management of 509 cases of ectopic pregnancy reviewed retrospectively in our hospital from January 1999 to December 2001.Selected 60 cases treated by laparoscopy in 2001 were compared with 58 cases treated by laparotomy without hypovolemia shock.Operating time, postoperative hospital stay, time returning to normal temperature,total cost were compared. Results Laparoscopic surgery was performed in three cases in 1999,twenty three cases in 2000 and sixty cases in 2001. Comparison between laparoscopic and laparotomy group showed the operating time (66.3?25.3) min vs (75.9?22.0)min( t =-2.02, P =0.03);postoperative hospital stay (3.3?1.9)days vs (5.1?1.7)days( t =-5.42, P =0.00); total cost (7318.4?1440.1) RMB vs (5567.8?1567.8) RMB ( t =6.32, P =0.00). Conclutions Laparoscopic surgery is superior to laparotomy in the management of ectopic pregnancy.

Objective To evaluate clinical effectiveness of transcatheter closure of atrial septal defects ( ASD) with severe pulmonary arterial hyperyension ( sPAH) by fenestrated Amplatzer septal occluders ( ASO) . Methods From September 2002 to April 2013, 17 patients of ASD with sPAH received transcatheter ASD closure using fenestrated occluders. Aged from 18 - 72 years, the diameters of ASDs were 18 - 33 mm. The systolic pulmonary arterial hypertension measured by transthoracic echocardiogram were 80 - 112 (96. 9 ± 8. 9) mmHg. The follow-up study included electrocardiography, chest radiography and echocardiography. All the patients were followed up for 1. 5 - 12 ( mean 6. 4 ± 0. 7) years. Results Systolic pulmonary arterial pressure (sPAP) of 60 - 108 (88. 7 ± 11. 7) mmHg and mean pulmonary artery pressure ( mPAP) of 29. 3 - 60 (51. 0 ± 8. 1) mmHg were measured by cardiac catheterization before ASD closure. Qp/ Qs was 1. 50 - 2. 44 (1. 8 ± 0. 31) and the pulmonary vascular resistance was 3. 1 - 9. 7 (5. 6 ± 1. 5) wood units (wu) . Immediately after the implantation of fenestrated occluders, sPAP decreased to 56 - 99 (70 ± 11. 5) mmHg and mPAP to 27 - 51. 7 (41. 1 ± 7. 1) mmHg. On the 3 d, 3 m and 6 m follow-up exam, RVEDd decreased ( P ﹤ 0. 05), while LVEDd, LVEDV and LVEF increased significantly (P ﹤ 0. 05) . sPAP decreased significantly after transcatheter closure at 3 m and 6 m as compared to pre-closure levels (both P ﹤ 0. 05) . The mean sPAP in long term follow up was (60. 2 ± 13. 3) mmHg which had significant decrease compared to pre-closure level ( P ﹤ 0. 01), but no significant difference found when compared to 6 m follow up (P ﹥ 0. 05). Conclusions ASD closure with fenestrated ASO is a satisfactory approach for ASD with severe PAH.

OBJECTIVETo evaluate the accuracy of sentinel lymph node biopsy (SLNB) to predict the axillary lymph node status in breast cancer patients and its clinical significance.

METHODSSeventy patients with clinical TNM status T(1 - 2)N(0)M(0) underwent sentinel lymph node biopsy using Tc-99m sulfur colloid radiotracer and gamma probe, which was followed by standard axillary dissection. SLNB was compared with standard axillary dissection for its ability to reflect the final pathological status of the axillary nodes. The SLNs that were tumor negative in conventional HE staining were further evaluated using immunohistochemical stains for CK8, CK19 and KP-1 antibodies.

RESULTSThe sentinel lymph node (SLN) was successfully identified in 67 (95.7%) out of 70 patients. The number of sentinel nodes harvested ranged from 1 to 5 (average 1.6). The nonsentinel nodes ranged from 5 to 20 (average 12.3). Of the 67 patients, 29 (43.3%) had histologically positive axillary lymph nodes. SLN was positive in 24 patients with metastasis (35.8%), and in 7 patients without metastasis (10.4%). In 5 patients, SLN was negative for tumor with positive nodes. The accuracy of sentinel lymph node biopsy to predict the axillary lymph node status was 92.5% and the false negative rate was 7.5%. For tumors with diameter less than or equal to 2 cm, the accuracy was 100%. 65 SLNs that were negative for HE stain were also non-reactive to immunostain for CK8 and CK19 antibody.

CONCLUSIONSSLNB can accurately predict the axillary lymph node status in most of breast cancer patients. The accuracy is about 100% in patients with T(1) lesions. Immunohistochemical staining at the same level of HE stain can not increase the detection of lymph node micrometastasis.

Adult ; Aged ; Aged, 80 and over ; Axilla ; Breast Neoplasms ; pathology ; Female ; Humans ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Middle Aged ; Sentinel Lymph Node Biopsy

Objective To explore the safety and mid-term efficacy of autologous hamstring tendon implantation in the treatment of severe anterior vaginal wall prolapse.Methods We performed a prospective single arm clinical study.From May 2021,pelvic organ prolapse(POP)patients with severe anterior vaginal wall prolapse as the main cause who had symptoms and required surgical treatment were included.The patient was fully informed and voluntarily selected autologous hamstring tendon implantation and high sacral ligament suspension.Postoperative follow-ups were carried out on the Pelvic Organ Prolapse Quantification(POP-Q),Pelvic Floor Distress Inventory-Short Form 20(PFDI-20),postoperative satisfaction score,and Patient Global Impression of Improvement(PGI-I).Function of the lower limb on the tendon removal side,as well as postoperative complications and re-operations were recorded.Results The operation time of tendon removal was(19.7±8.3)min,the operation time of pelvic floor was(122.1±37.8)min,the median intraoperative bleeding volume was 70 ml(range,50-400 ml),and there was no intraoperative co-morbidity or postoperative fever.A total of 12 cases were followed up for(26.4±2.5)months.The measured values of Aa,Ba,and C were 3(-1-3),5(2-10),and 4(-1-10)before operation and-3(-3-3),-3(-3-3),and-6(-6-3)at 24 months after operation,respectively,with significant difference(P＜0.05).The PFDI-20 scores of the 12 patients before surgery and at 24 months after surgery were 88.0 points(range,16.7-204.2 points)and 8.3 points(range,0-32.3 points),respectively,with significant difference(Z=-2.803,P=0.005).The PGI-I questionnaire showed 11 patients with significant improvement in postoperative symptoms and 1 patient with improvement.The satisfaction scores at 6 and 24 months after surgery were(4.8±0.4)points and(4.6±0.7)points,respectively.One patient experienced vaginal prolapse at 12 months after surgery,with a Ⅲ degree prolapse of the anterior wall and vaginal vault,the recurrence rate being 8.3％(1/12).Two patients had pulmonary embolism at 9 d and 2 weeks after surgery,with Clavien-Dindo Ⅱ and Ⅲ grades,and recovered after outpatient and hospitalization treatment.One patient was found fascia exposure at the vagina,and had improvement with medication treatment.All the patients had good wound healing at the tendon removal site,with normal muscle strength and lower limb activity.No re-operation was required due to recurrence or complications of tendon surgery.Conclusions Autologous hamstring tendon implantation is safe in the treatment of severe anterior vaginal wall prolapse with satisfactory mid-term efficacy.Before surgery,it is necessary to educate patients on lower limb exercise to prevent complications of venous thrombosis.

Objective:This study aims to evaluate the prognostic effect of peripheral blood cells in multiple myeloma (MM) patients treated with bortezomib.Methods:The clinical data of 155 newly diagnosed MM patients in two blood disease treatment centers from January 2014 to December 2016 were retrospectively studied. All patients received bortezomib as the first-line treatment. The results of the peripheral blood cell counts, including absolute neutrophil count, absolute monocyte count (AMC) , hemoglobin level, mean corpuscular volume (MCV) , and platelet count, and other clinical features were analyzed.Results:AMC (>0.6×10 9/L) , MCV (>99.1 fl) , and platelet count (<150×10 9/L) significantly affected patients’ PFS and OS. The above three factors were assigned 1 point, respectively, to form the blood cell score. The analysis showed that 64 cases (41.3% ) had a score of 0, 57 cases (36.8% ) had 1, 32 cases (20.6% ) had 2, and 2 cases (1.3% ) had 3. The median PFS of the four groups were 42.8 m, 26.5 m, 15.8 m, and 6.4 m, respectively ( P<0.001) . The median OS were NR, 48.2 m, 31.1 m, and 31.4 m, respectively ( P=0.001) . Multivariate analysis suggested that the blood cell score (2-3 vs 0-1) and the proportion of marrow plasma cells (>30% ) were independent prognostic factors for PFS ( HR=1.95 and 1.76, respectively) , while age (>65y vs ≤65y) , R-ISS stage (3 vs 1-2) , and blood cell score (2-3 vs 0-1) were independent prognostic factors for OS ( HR=2.08, 2.13 and 2.12, respectively) . Conclusion:As an easy-to-access biomarker, the blood cell score can be used to evaluate the prognosis of newly diagnosed MM patients in the era of new drugs, but it is still necessary to expand the cases and make further confirmation in the prospective study.

Multiple myeloma (MM) is a common malignant hematological tumor in adults, which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins (M protein), leading to bone destruction, hypercalcemia, anemia, and renal insufficiency (Alexandrakis et al., 2015; Yang et al., 2018). Since a large number of new drugs, represented by proteasome inhibitors and immunomodulators, have been successfully used to treat MM, treatment efficacy and survival of patients have been significantly improved. However, due to the high heterogeneity of this disease, patients have responded differently to treatments with these new drugs (Palumbo and Anderson, 2011; Wang et al., 2016; Huang et al., 2020). Growth and survival of MM cells depend on the bone marrow microenvironment, especially numerous inflammatory cytokines secreted by myeloma cells and bone marrow stromal cells, such as vascular endothelial growth factor (VEGF), interleukin (IL)‍-6, transforming growth factor-‍β (TGF‍‍-‍‍β), and IL-10. These cytokines can promote the growth of myeloma cells, induce angiogenesis, and inhibit antitumor immunity, and are often linked to patient prognosis (Kumar et al., 2017). In this era of new drugs, the prognostic values of the serum levels of these cytokines in MM need further evaluation.
Adult ; Humans ; Cytokines ; Disease Progression ; Interleukin-10 ; Interleukin-6/metabolism* ; Multiple Myeloma/drug therapy* ; Tumor Microenvironment ; Vascular Endothelial Growth Factor A

Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor-kappaB (NF-κB) p65, pp65, pIKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, pIKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF-κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Bortezomib ; pharmacology ; therapeutic use ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; drug effects ; Drug Screening Assays, Antitumor ; Humans ; Multiple Myeloma ; drug therapy ; metabolism ; pathology ; NF-kappa B ; metabolism ; Signal Transduction ; drug effects ; Structure-Activity Relationship ; Ubiquitin-Protein Ligases ; genetics ; metabolism

ObjectiveTaking the rat model of spleen-stomach damp-heat syndrome（SSDHS） as the research object， this study aimed to investigate the potential biomarkers of SSDHS and the related metabolic pathways based on urine metabolomics， and tried to reveal the essence of SSDHS at the level of endogenous small molecular metabolites. MethodSixteen SD rats were randomly divided into normal and model groups. The normal group was fed normal chow and the model group was fed with 200 g·L^-1 honey water daily， and lard and Chinese Baijiu alternately on alternate days for 17 days. The SSDHS model rats were exposed to external dampness-heat environment with temperature at 30-34 ℃， relative humidity of 95% for 2 h at the same time every day from the 10^th day for 7 d. Then， the model was evaluated by observing the general conditions of the rats， measuring the contents of motilin（MTL） and gastrin（GT） in plasma by enzyme-linked immunosorbent assay（ELISA）， and examining the histopathology of gastronitestinal tissues. In additon， the urine metabolomics analysis was performed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS）， and the detection conditions was as follows：ACQUITY™ UPLC BEH C₁₈ column（2.1 mm×100 mm， 1.7 μm）， mobile phase of 0.1% formic acid aqueous solution（A）-0.1% formic acid acetonitrile solution（B） for gradient elution （0-3 min， 1%-18%B； 3-8 min， 18%-40%B； 8-10 min， 40%-100%B）， the flow rate of 0.4 mL·min^-1， electrospray ionization（ESI） in positive and negative ion modes， scanning range of m/z 50-1 000. The univariate and multivariate statistical analysis were constructed for screening inter-group differential ions， the element composition was calculated according to the precise relative molecular weight， and ion information was matched with databases such as Human Metabolome Database（HMDB） to identify biomarkers. Kyoto Encyclopedia of Genes and Genomes（KEGG） database was used to obtain the biological information of metabolites， and their associated metabolic pathways were analyzed by MetaboAnalyst 5.0. ResultCompared with the normal group， the rectal temperature of the model group increased significantly（P<0.01）， the levels of plasma MTL and GT decreased significantly（P<0.05， P<0.01）， and pathological changes such as bleeding， congestion and inflammatory infiltration in the gastric and colonic tissues. A total of 25 differential metabolites such as L-histidine， citric acid and isocitric acid were found to be the potential biomarker of SSDHS by urine metabolomics， 13 of which were phase Ⅱ metabolites of endogenous substances（glucuronic acid conjugates， sulfuric acid conjugates and acetyl conjugates）， involving the metabolic pathways of histidine metabolism， tricarboxylic acid cycle， glyoxylate and dicarboxylate metabolism. ConclusionSSDHS primarily causes disorders of histidine metabolism， tricarboxylic acid cycle， glyoxylate and dicarboxylate metabolism， as well as the imbalance of the activation/inactivation of endogenous metabolites， which may involve the immune response， material and energy metabolism， inflammatory response and intestinal flora， and may provide a basis for the establishment and application of SSDHS model.